Chapter 35. Endocrine Disorders
KEY POINTS
20891 Hyperandrogenism (HA) most often presents as hirsutism, which usually arises as a
result of androgen excess related to abnormalities of function in the ovary or adrenal
glands. By contrast, virilization is rare and indicates marked elevation in androgen
levels.
2 The most common cause of HA and hirsutism is polycystic ovarian syndrome
(PCOS). The diagnostic schema for PCOS requires two of three criteria (HA
[clinical or biochemical], ovarian dysfunction, and or PCO morphology) and
identifies four phenotypes: (1) HA (clinical or biochemical) with ovarian
dysfunction and PCO morphology, (2) HA (clinical or biochemical) with ovarian
dysfunction, (3) HA (clinical or biochemical) with PCO morphology, (4) ovarian
dysfunction and PCO morphology. Caution is recommended in affixing the PCOS
diagnosis in adolescence. Patients with PCOS frequently exhibit insulin resistance
and hyperinsulinemia.
3 Combination oral contraceptives (OCs) decrease adrenal and ovarian androgen
production and reduce hair growth in nearly two-thirds of hirsute patients.
4 Because hyperinsulinemia appears to play a role in PCOS-associated anovulation,
treatment with insulin sensitizers may shift the endocrine balance toward ovulation
and pregnancy, either alone or in combination with other treatment modalities.
5 Excluding cases that are of iatrogenic or factitious etiology, adrenocorticotropic
hormone–independent forms of Cushing syndrome are adrenal in origin. Adrenal
cancers are usually very large by the time Cushing syndrome is manifest.
6 Congenital adrenal hyperplasia is an autosomal recessive disorder. Deficiency of 21-
hydroxylase is responsible for more than 90% of cases of adrenal hyperplasia
resulting from an adrenal enzyme deficiency.
7 Patients with severe hirsutism, virilization, or recent and rapidly progressing signs of
androgen excess require careful investigation for the presence of an androgensecreting neoplasm. Ovarian neoplasms are the most frequent androgen-producing
tumors.
8 Elevations in prolactin may cause amenorrhea, galactorrhea, both, or neither.
Amenorrhea without galactorrhea is associated with hyperprolactinemia in
approximately 15% of women. Normal prolactin levels are found in 50% of women
with isolated galactorrhea. Two thirds of women with both galactorrhea and
amenorrhea have hyperprolactinemia and one-third will have a pituitary
microadenoma.
9 Because levels of thyroid-stimulating hormone (TSH) are sensitive to excessive or
deficient levels of circulating thyroid hormone, and because most disorders of
hyperthyroidism and hypothyroidism are related to dysfunction of the thyroid gland,
TSH levels are used to screen for these disorders. Autoimmune thyroid disorders are
the most common thyroid abnormalities in women and represent the combined
effects of the multiple antibodies produced. Severe primary hypothyroidism is
associated with amenorrhea or anovulation. The classic triad of exophthalmos,
goiter, and hyperthyroidism are diagnostic for Graves disease.
2090The endocrine disorders encountered most frequently in gynecologic patients
are those related to disturbances in the regular occurrence of ovulation and
accompanying menstruation. The most prevalent of these disorders,
polycystic ovary syndrome, is characterized by androgen excess and is often
accompanied by insulin resistance. Less common conditions associated with
hyperandrogenism, hirsutism and ovulatory dysfunction are also reviewed.
Common disorders of the pituitary and thyroid are reviewed in this chapter.
HYPERANDROGENISM
[1] Hyperandrogenism (HA) most often presents as hirsutism. Hirsutism
arises as a result of androgen excess related to abnormalities of function in the
ovary or adrenal glands, the constitutive increase in expression of androgen
effects at the level of the pilosebaceous unit, or both. By contrast, virilization is
rare and indicates marked elevations in androgen levels. Virilization
commonly is caused by an ovarian or adrenal neoplasm that may be benign or
malignant.
Hirsutism
Hirsutism, the most frequent manifestation of androgen excess in women, is
defined as excessive growth of terminal hair in a male distribution pattern.
This refers particularly to midline hair, side burns, moustache, beard, chest or
intermammary hair, and inner thigh and midline lower back hair entering the
intergluteal area. The response of the pilosebaceous unit to androgens in these
androgen-responsive areas transforms vellus hair (fine, nonpigmented, and short)
that is normally present into terminal hair (coarse, stiff, pigmented, and long).
Androgen effects on hair vary in relation to specific body surface regions.
Hair that shows no androgen dependence includes lanugo, eyebrows, and
eyelashes. The hair of the limbs and portions of the trunk exhibits minimal
sensitivity to androgens. Pilosebaceous units of the axilla and pubic region are
sensitive to low levels of androgens, such that the modest androgenic effects of
adult levels of adrenal androgens are sufficient to result in the substantial
expression of terminal hair in these areas. Follicles in the distribution associated
with male patterns of facial and body hair (midline, facial, inframammary) require
higher levels of androgens, as seen with normal testicular function or abnormal
ovarian or adrenal androgen production. Scalp hair is inhibited by gonadal
androgens, in varying degrees, as determined by age and genetic determination of
follicular responsiveness, resulting in the common frontal–parietal balding seen in
some males and in virilized females. Hirsutism results from increased
androgen production and skin sensitivity to androgens. Skin sensitivity
2091depends on the genetically determined local activity of 5α-reductase, the
enzyme that converts testosterone to dihydrotestosterone (DHT), the
bioactive androgen in hair follicles.
Hair follicles demonstrate cyclic activity between growth (anagen),
involution (catagen), and resting (telogen) phases. The durations of the
growth and resting phases vary according to region of the body, genetic
factors, age, and hormonal effects. The cycles of growth, rest, and shedding are
normally dyssynchronous, but when synchronous, entry into telogen phase in
follicles is triggered by major metabolic or endocrine events, such as pregnancy
and delivery, or severe illness, and dramatic (although transient) hair loss may
occur in the following months (telogen effluvium).
Hirsutism is a relative, rather than absolute, designation. What is normal in
one setting may be considered abnormal in others; social and clinical reactions to
hirsutism can vary significantly, reflecting ethnic variation in skin sensitivity to
androgens and cultural ideals. Androgen-dependent hair (excluding pubic and
axillary hair) occurs in only 5% of premenopausal white women and is considered
abnormal by white women of North America. In contrast, considerable facial and
male pattern hair in other areas may be more common and more often considered
acceptable and normal among groups such as the Inuit and women of
Mediterranean background.
Hypertrichosis and Virilization
Two conditions should be distinguished from hirsutism. Hypertrichosis is the
term reserved for androgen-independent terminal hair in nonsexual areas,
such as the trunk and extremities. This may be the result of an autosomaldominant congenital disorder, a metabolic disorder (such as anorexia nervosa,
hyperthyroidism, porphyria cutanea tarda), or medications (e.g., acetazolamide,
anabolic steroids, androgenic progestins, androgens, cyclosporine, diazoxide,
dehydroepiandrosterone [DHEA], heavy metals, interferon, methyldopa,
minoxidil, penicillamine, phenothiazines, phenytoin, streptomycin, reserpine,
valproic acid). Virilization is a marked and global masculine transformation
that includes coarsening of the voice, increase in muscle mass, clitoromegaly
(normal clitoral dimensions é standard deviation [SD] are 3.4 + 1 mm width
by 5.1 + 1.4 mm length) and features of defeminization (loss of breast volume
and body fat contributing to feminine body contour) (1). Although hirsutism
accompanies virilization, the presence of virilization indicates a high
likelihood of more serious conditions that are more common than with
hirsutism alone and should prompt evaluation to exclude ovarian or adrenal
neoplasm. Although rare, these diagnoses become likely when onset of androgen
effects is rapid and/or sufficiently pronounced to produce the picture of
2092virilization.
The history should focus on the age of onset and rate of progression of
hirsutism or virilization. A rapid rate of progression or virilization is
associated with a more severe degree of HA and should raise suspicion of
ovarian and adrenal neoplasms or Cushing syndrome. This is true whether
rapid progression or virilization occurs before, during, or after puberty.
Anovulation, manifesting as amenorrhea or oligomenorrhea, increases the
probability that there is underlying HA. Hirsutism occurring with regular cycles is
more commonly associated with normal androgen levels and thus is attributed to
increased genetic sensitivity of the pilosebaceous unit and is termed idiopathic
hirsutism. When virilization is present, anovulation virtually always occurs.
In determining the extent of hirsutism, a sensitive and tactful approach by
the physician is mandatory and should include questions regarding the use
and frequency of shaving and/or chemical or mechanical depilatories.
Typically, clinical evaluation of the degree of hirsutism is subjective. Most
physicians arbitrarily classify the degree of hirsutism as mild, moderate, or
severe. Objective assessment is helpful, however, especially in establishing a
baseline from which therapy can be evaluated. The Ferriman–Gallwey Scoring
System for Hirsutism quantitates the extent of hair growth in the most androgensensitive sites. It is a scoring scale of androgen-sensitive hair in nine body areas
rated on a scale of 0 to 4 (2). A total score higher than 8 is defined as hirsutism
(Fig. 35-1) (3). Although widely used, this scoring system has its limitations, one
of which is the fact that the scale does not include the sideburn, buttocks, and
perineal areas. Substantial hirsutism may be confined to one or two areas without
exceeding the cutoff value in total hirsutism score. This score does not reflect the
extent to which hirsutism affects a woman’s well-being (3,4).
2093FIGURE 35-1 Ferriman–Gallwey hirsutism scoring system. Each of the nine body areas
most sensitive to androgen is assigned a score from 0 (no hair) to 4 (frankly virile), and
these separate scores are summed to provide a hormonal hirsutism score. (Reproduced
from Hatch R, Rosefield RL, Kim MH, et al. Hirsutism: implications, etiology, and
management. Am J Obstet Gynecol 1981;140:815–830. © Elsevier.)
A family history should be obtained to disclose evidence of idiopathic
hirsutism, PCOS, congenital or adult-onset adrenal hyperplasia (CAH or
AOAH), diabetes mellitus, and cardiovascular disease. A history of drug use
should be obtained. In addition to drugs that commonly cause hypertrichosis,
anabolic steroids and testosterone derivatives may cause hirsutism and even
virilization. During the physical examination, attention should be directed to the
presence of obesity, hypertension, galactorrhea, male-pattern baldness, acne (face
and back), and hyperpigmentation. With virilization, the presence of an androgenproducing ovarian neoplasm or Cushing syndrome must be considered. In many
cases of Cushing syndrome, the patient’s presenting symptom is hirsutism which
in early stages may masquerade as disorders such as PCOS or AOAH. When
considering the possibility of Cushing syndrome, the physician should search for
the physical signs of the syndrome. A moon-shaped face, upper body obesity,
proximal muscle weakness (difficulty arising from a squatting position), and the
development of a pad of fat between the shoulder blades are particularly notable
to patients and diagnosticians considering the diagnosis of Cushing syndrome.
Role of Androgens
2094Androgens and their precursors are produced by the adrenal glands and the
ovaries in response to their respective trophic hormones, adrenocorticotropic
hormone (ACTH), and luteinizing hormone (LH) (Fig. 35-2). Biosynthesis
begins with the rate-limiting conversion of cholesterol to pregnenolone by sidechain cleavage enzyme. Thereafter, pregnenolone undergoes a two-step
conversion to the 17-ketosteroid DHEA along the Δ-5 steroid pathway. This
conversion is accomplished by CYP17, an enzyme with 17α-hydroxylase and
17,20-lyase activities. In a parallel fashion, progesterone undergoes
transformation to androstenedione in the Δ-4 steroid pathway. The metabolism of
Δ-5 to Δ-4 intermediates is accomplished via a Δ-5-isomerase, 3β-hydroxysteroid
dehydrogenase (3β-HSD).
Adrenal 17-Ketosteroids
Secretion of adrenal 17-ketosteroids increases prepubertally and
independently of pubertal maturation of the hypothalamic–pituitary–ovarian
axis. This alteration in adrenal steroid secretion is termed adrenarche and is
characterized by a dramatic change in the response of the adrenal cortex to ACTH
and with preferential secretion of Δ-5 steroids, including 17-
hydroxypregnenolone, DHEA, and dehydroepiandrosterone sulfate (DHEAS).
The basis for this action is related to the increase in the zona reticularis and in the
increased activity of the 17-hydroxylase and the 17,20-lyase enzymes.
Independent of the increase in ovarian androgen secretion accompanying puberty,
the increase in adrenal androgens owing to adrenarche can account for significant
increases in pubic and axillary hair and sweat production by the axillary
pilosebaceous units.
2095FIGURE 35-2 Major steroid biosynthesis pathway.
Testosterone
Approximately half of a woman’s serum testosterone is derived from
peripheral conversion of secreted androstenedione and the other half is
derived from direct glandular (ovarian and adrenal) secretion. The ovaries
and adrenal glands contribute about equally to testosterone production in
women. The contribution of the adrenals is achieved primarily through
secretion of androstenedione.
Approximately 66% to 78% of circulatory testosterone is bound to sex
2096hormone–binding globulin (SHBG) and is considered biologically inactive. Most
of the proportion of serum testosterone that is not bound to SHBG is weakly
associated with albumin (20% to 32%). A small percentage (1% to 2%) of
testosterone is entirely unbound or free. The fraction of circulating testosterone
that is unbound by SHBG has an inverse relationship with the SHBG
concentration. Increased SHBG levels are noted in conditions associated with
high estrogen levels. Pregnancy, the luteal phase, use of estrogen (including oral
contraceptives [OCs]), and conditions causing elevated thyroid hormone levels
and cirrhosis are associated with reduced fractions of free testosterone as a result
of elevated SHBG levels. Conversely, levels of SHBG decrease and result in
elevated free testosterone fractions in response to androgens, androgenic disorders
(PCOS, adrenal hyperplasia or neoplasm, Cushing syndrome), androgenic
medications (i.e., progestational agents with androgenic biologic activities, such
as danazol, glucocorticoids, and growth hormones), hyperinsulinemia, obesity,
and prolactin.
Laboratory Assessment of Hyperandrogenemia
In hyperandrogenic states, increases in testosterone production are not
proportionately reflected in increased total testosterone levels because of the
depression of SHBG levels that occurs concomitant with increasing androgen
effects on the liver. Therefore, when moderate HA, characteristic of many
functional hyperandrogenic states, occurs, elevations in total testosterone levels
may remain within the normal range, and only free testosterone levels will reveal
the HA. Severe HA, as occurs in virilization and that results from neoplastic
production of testosterone, is reliably detected by measures of total
testosterone. Therefore, in practical clinical evaluation of the hyperandrogenic
patient, determination of the total testosterone level in concert with clinical
assessment is frequently sufficient for diagnosis and management. When more
precise delineation of the degree of HA is desired, measurement or estimation of
free testosterone levels can be undertaken and will more reliably reflect increases
in testosterone production. These measurements are not necessary in evaluating
the majority of patients, but they are common in clinical research studies and may
be useful in some clinical settings. Because many practitioners measure some
form of testosterone level, they should understand the methods used and their
accuracy. Although equilibrium dialysis is the gold standard for measuring free
testosterone, it is expensive, complex, and usually limited to research settings. In
a clinical setting, free testosterone levels can be estimated by assessment of
testosterone binding to albumin and SHBG.
Testosterone that is nonspecifically bound to albumin (AT) is linearly related to
free testosterone (FT) by the equation:
2097where AT is the albumin-bound testosterone, Ka is the association constant of
albumin for testosterone, and [A] is the albumin concentration.
In many cases of hirsutism, albumin levels are within a narrow physiologic
range and thus do not significantly affect the free testosterone concentration.
When physiologic albumin levels are present, the free testosterone level can be
estimated by measuring the total testosterone and SHBG. In individuals with
normal albumin levels, this method has reliable results compared with those of
equilibrium dialysis. It provides a rapid, simple, and accurate determination of the
total and calculated free testosterone levels as well as the concentration of SHBG.
The bioavailable testosterone level is based on the relationship of albumin and
free testosterone and incorporates the actual albumin level with the total
testosterone and SHBG. This combination of total testosterone, SHBG, and
albumin level measurements—bioavailable testosterone level—can be applied to
derive a more accurate estimate of available bioactive testosterone and thus the
androgen effect derived from testosterone. Bioactive testosterone determined in
this manner provides a superior estimate of the effective androgen effect derived
from testosterone (5).
Pregnancy can alter the accuracy of measurements of bioavailable
testosterone. During pregnancy, high circulating estradiol levels occupy a large
proportion of SHBG binding sites, so that measurement of SHBG levels can
overestimate the binding capacity of SHBG for testosterone. Derived estimates of
free testosterone, as opposed to direct measure by equilibrium dialysis, are
therefore inaccurate during pregnancy. Testosterone measurements in pregnancy
are primarily of interest when autonomous secretion by tumor or luteoma is in
question, and for these, total testosterone determinations provide sufficient
information for diagnosis.
For testosterone to exert its biologic effects on target tissues, it must be
converted into its active metabolite, DHT, by 5α-reductase (a cytosolic
enzyme that reduces testosterone and androstenedione). Two isozymes of 5α-
reductase exist: type 1, which predominates in the skin, and type 2, or acidic 5α-
reductase, which is found in the liver, prostate, seminal vesicles, and genital skin.
The type 2 isozyme has a 20-fold higher affinity for testosterone than type 1. Both
type 1 and 2 deficiencies in males result in ambiguous genitalia, and both
isozymes may play a role in androgen effects on hair growth. Dihydrotestosterone
is more potent than testosterone, primarily because of its higher affinity and
slower dissociation from the androgen receptor. Although DHT is the key
intracellular mediator of most androgen effects, measurements of circulating
levels are not clinically useful. The relative androgenicity of androgens is as
2098follows: DHT = 300, Testosterone = 100, Androstenedione = 10, DHEAS = 5.
Until adrenarche, androgen levels remain low. Around 8 years of age,
adrenarche is heralded by a marked increase in DHEA and DHEAS. The half-life
of free DHEA is extremely short (about 30 minutes) but extends to several hours,
if DHEA is sulfated. Although no clear role is identified for DHEAS, it is
associated with stress, and levels decline steadily throughout adult life. After
menopause, ovarian estrogen secretion ceases, and DHEAS levels continue to
decline, whereas testosterone levels are maintained or may even increase.
Although postmenopausal ovarian steroidogenesis contributes to testosterone
production, testosterone levels retain diurnal variation, reflecting an ongoing and
important adrenal contribution. Peripheral aromatization of androgens to
estrogens increases with age, but because small fractions (2% to 10%) of
androgens are metabolized in this fashion, such conversion is rarely of clinical
significance.
Laboratory Evaluation
The 2008 Endocrine Society Clinical Practice Guidelines suggested testing
for elevated androgen levels in women with moderate (Ferriman–Gallwey
hirsutism score 9 or greater) or severe hirsutism or hirsutism of any degree
when it is sudden in onset, rapidly progressive, or associated with significant
acne, obesity, or clitoromegaly. These guidelines suggested against testing for
elevated androgen levels in women with isolated mild hirsutism, such as is
associated with PCOS, because the likelihood of identifying a medical
disorder that would change management or outcome is extremely low (Fig.
35-3) (4).
When laboratory testing for the assessment of hirsutism is indicated, either a
bioavailable testosterone level (includes a total testosterone, SHBG, and albumin
level) or a calculated free testosterone level (if albumin levels are assumed to be
normal) provides the most accurate assessment of the effective androgen effect
derived from testosterone. In clinical situations requiring a testosterone
evaluation, the addition of 17-hydroxyprogesterone (17-OHP) will screen for
adult-onset adrenal hyperplasia, when indicated (Table 35-1). When hirsutism is
accompanied by absent or abnormal menstrual periods, assessment of prolactin
and thyroid-stimulating hormone (TSH) values is required to diagnose an
ovulatory disorder. Hypothyroidism and hyperprolactinemia may result in
reduced levels of SHBG and may increase the fraction of unbound testosterone
levels, occasionally resulting in hirsutism. In cases of suspected Cushing
syndrome, patients should undergo screening with a 24-hour urinary cortisol
(most sensitive and specific) assessment or an overnight dexamethasone
suppression test. For this test, the patient takes 1 mg of dexamethasone at 11 pm,
2099and a blood cortisol assessment is performed at 8 am the next day. Cortisol levels
of 2 μg/dL or higher after overnight dexamethasone suppression require a further
workup for evaluation of Cushing syndrome. Elevated 17-OHP levels identify
patients who may have AOAH, found in 1% to 5% of hirsute women. The 17-
OHP levels can vary significantly within the menstrual cycle, increasing in the
periovulatory period and luteal phase, and may be modestly elevated in PCOS.
Standardized testing requires early morning testing during the follicular phase.
2100FIGURE 35-3 Evaluation of hirsute women for hyperandrogenism. Evaluation includes
2101more than the assessment of the degree of hirsutism. When hirsutism is moderate (>9) or
severe or if mild hirsutism is accompanied by features that suggest an underlying disorder,
elevated androgen levels should be ruled out. Disorders to be considered include
endocrinopathies, of which PCOS is the most common, and neoplasms. Plasma
testosterone is best assessed in the early morning on days 4 to 10 in regularly cycling
women. A 17-hydroxyprogesterone is also indicated when symptoms warrant a
bioavailable testosterone measurement. *3β-hydroxysteroid dehydrogenase deficiency in
severe forms presents with mineralocorticoid and cortisol deficiency. Mild forms are
diagnosed with a mean post-ACTH(1-24) stimulation: 17-hydroxypregnenolone/17-
hydroxyprogesterone ratio of 11 compared with 3.4 in normals. 11β-hydroxylase
deficiency presents with hypertension in the first years of life in two-thirds of patients. The
mild form presents with vitalization or precocious puberty without hypertension.
Undiagnosed adults demonstrate hirsutism, acne, and amenorrhea. Diagnosis is confirmed
with an 11-desoxycortisol level >25 ng/mL 60 minutes after ACTH(1-24) stimulation.
ACTH, adrenocorticotropic hormone; AOAH, adult-onset adrenal hyperplasia; DHEAS,
dehydroepiandrosterone sulfate; HAIR-AN, hyperandrogenemia, insulin resistanceacanthosis nigricans (see references (2–11,15)).
Table 35-1 Normal Values for Serum Androgensa
Testosterone (total) 20–80 ng/dL
Free testosterone (calculated) 0.6–6.8 pg/mL
Percentage free testosterone 0.4–2.4%
Bioavailable testosterone 1.6–19.1 ng/dL
SHBG 18–114 nmol/L
Albumin 3,300–4,800 mg/dL
Androstenedione 20–250 ng/dL
Dehydroepiandrosterone sulfate 100–350 μg/dL
17-Hydroxyprogesterone (follicular phase) 30–200 ng/dL
aNormal values may vary among different laboratories. Free testosterone is calculated
using measurements for total testosterone and sex hormone–binding globulin, whereas
bioavailable testosterone is calculated using measured total testosterone, sex hormone–
binding globulin, and albumin. Calculated values for free and bioavailable testosterone
compare well with equilibrium dialysis methods of measuring unbound testosterone when
albumin levels are normal. Bioavailable testosterone includes free plus very weakly bound
(non-SHBG, nonalbumin) testosterone. Bioavailable testosterone is the most accurate
2102assessment of bioactive testosterone in the serum without performing equilibrium dialysis.
According to the Endocrine Society clinical guidelines, patients with morning
follicular phase 17-OHP levels of less than 300 ng/dL (10 nmol/L) are likely
unaffected. When levels are greater than 300 ng/dL but less than 10,000 ng/dL
(300 nmol/L), ACTH testing should be performed to distinguish between PCOS
and AOAH. Levels greater than 10,000 ng/dL (300 nmol/L) are virtually
diagnostic of congenital adrenal hyperplasia.
Precocious puberty (PP) precedes the diagnosis of adult-onset congenital
adrenal hyperplasia in 5–20% of cases. Measurement of 17-OHP should be
performed in patients presenting with PP and a subsequent ACTH stimulation test
is recommended if basal 17-OHP is greater than 200 ng/dL. A study using a 200
ng/dL threshold for basal 17-OHP plasma levels to prompt ACTH stimulation
testing offered 100% (95% confidence interval [CI], 69 to 100) sensitivity and
99% (95% CI, 96 to 100) specificity for the diagnosis of adult-onset congenital
adrenal hyperplasia within the cohort with PP (6).
Because increased testosterone production is not reliably reflected by total
testosterone levels, the clinician may choose to rely on typical male pattern
hirsutism as confirmation of its presence, or may elect measures that reflect levels
of free or unbound testosterone (bioavailable or calculated free testosterone
levels). Total testosterone does, however, serve as a reliable marker for
testosterone-producing neoplasms. Total testosterone levels greater than 200
ng/dL should prompt a workup for ovarian or adrenal tumors.
Although the ovary is the principal source of androgen excess in most of PCOS
patients, between 20% and 30% of patients with PCOS will demonstrate elevated
levels of DHEAS, particularly when overweight. Measuring circulating levels of
DHEAS has very limited diagnostic value, and overinterpretation of DHEAS
levels should be avoided (7).
Previously, testing for androgen conjugates (e.g., 3α-androstenediol G [3α-diol
G] and androsterone G [AOG] as markers for 5α-reductase activity in the skin)
was advocated. Routine determination of androgen conjugates to assess hirsute
patients is not recommended, because hirsutism itself is an excellent bioassay of
free testosterone action on the hair follicle and because these androgen conjugates
arise from adrenal precursors and are likely markers of adrenal and not ovarian
steroid production (8).
In the zona reticularis layer of the adrenal cortex, DHEAS is generated by
SULT2A1 (9). This layer of the adrenal cortex is thought to be the primary source
of serum DHEAS. DHEAS levels decline as a person ages and the reticularis
layer diminishes in size. In most laboratories, the upper limit of a DHEAS level is
350 μg/dL (9.5 nmol/L). A random sample is sufficient because the level of
2103variation is minimized as a result of the long half-life characteristic of sulfated
steroids. DHEAS is used as a screen for androgen-secreting adrenocortical tumors
(ACT-AS); however, moderate elevations are a common finding in the presence
of PCOS, obesity, and stress, which reduces its specificity in testing for ACT-AS
(10).
A study of women with ACT-AS (N = 44), compared to women with nontumor
androgen excess (NTAE) (N = 102), sheds additional light on the choice of
hormones used to screen for an adrenocortical tumor. In the study, the
demographics and prevalence of hirsutism, acne, and oligo/amenorrhea were not
different. Free testosterone (free T) was the most commonly elevated androgen in
ACT-AS (94%), followed by androstenedione (A) (90%), DHEAS (82%), and
total testosterone (total T) (76%), and all three androgens were simultaneously
elevated in 56% of the cases. Serum androgen levels became subnormal in all
ACT-AS patients after the tumor was removed. In NTAE alone, the most
commonly elevated androgen was androstenedione (93%), while all three
androgens (T, A, and DHEAS) were elevated in only 22% of the cases. Free
testosterone values above 6.85 pg/mL (23.6 pmol/L) had the best diagnostic value
for ACT-AS (sensitivity 82%, 95% CI 57% to 96%; specificity 97%, 95% CI
91% to 100%; Table 35-2). The large overlap of androstenedione, testosterone,
and DHEAS levels between ACT-AS and androgen excess groups suggests that
thoughtful consideration should be employed when choosing hormone studies for
this evaluation (11).
The heterogeneity of hormone secretion patterns in the adrenocortical tumor
group reveals the complexities of hormone-level screening for adrenocortical
tumors: 7 of 44 patients (15.9%) had tumors secreting androgens alone, 2 of 44
(4.5%) had tumors secreting androgens and estrogens, and 28 of 44 (63.6%) had
tumors secreting both androgens and cortisol, and 7 of 44 (15.9%) had tumors
secreting androgens, cortisol, and estrogens. Compound S or 11-desoxycortisol
was increased (≥10 ng/mL or 28.9 nmol/L) in 23 of 27 ACT-AS patients (85%),
20 of 21 patients with malignant tumors, and 3 of 6 patients with apparently
benign tumors, although 11-desoxycortisol was normal and inferior to 6 ng/mL
(17.3 nmol/L) in 35 of 35 NTAE patients (100%). Youden’s index displayed that
11-desoxycortisol level above 7 ng/mL (20.2 nmol/L) has a sensitivity of 89%
(95% CI 71% to 98%) and a specificity of 100% (95% CI 90% to 100%) for the
detection of ACT-AS (11,12).
Thus, when signs of androgen excess reach the point of virilization or the
free testosterone level is above 6.85 pg/mL (23.6 pmol/L), follow-up testing
with an 11-desoxycortisol >7 ng/mL, DHEAS >3.6 lg/mL, and 24-hour
urinary cortisol >45 lg per day are the most sensitive and specific for the
detection of an ACT-AS. Careful consideration of the sensitivity and
2104specificity, diurnal variation, and age-related variation of potentially
measureable androgens will aid in choosing the most useful measurements
(Table 35-2). Clinically, assessment of androgens is uncommon in routine
practice and is performed when hirsutism is sudden in onset, rapidly
progressive, or associated with significant acne, obesity, or clitoromegaly.
Mild hirsutism associated with clinical findings of PCOS very rarely yields
actionable results.
Table 35-2 Sensitivity and Specificity of Basal Hormone Levels in the Evaluation of
Female Patients With Androgen-Secreting Adrenocortical Tumors (ACTAS) and Nontumor Causes of Androgen Excess (NTAE)
Polycystic Ovary Syndrome
PCOS is one of the most common endocrine disorders in women of
reproductive age, affecting 5% to 10% of women worldwide. This familial
disorder appears to be inherited as a complex genetic trait (13). It is characterized
by a combination of HA (either clinical or biochemical), chronic anovulation, and
polycystic ovaries. It is frequently associated with insulin resistance (IR) and
obesity (14). PCOS receives considerable attention because of its high prevalence
and possible reproductive, metabolic, and cardiovascular consequences. It is the
most common cause of HA, hirsutism, and anovulatory infertility in
developed countries (15,16). The association of amenorrhea with bilateral
polycystic ovaries and obesity was first described in 1935 by Stein and Leventhal
(17). Its genetic origins are likely polygenic and/or multifactorial (18).
Diagnostic Criteria
In an international conference on PCOS organized by the National Institutes of
2105Health (NIH) in 1990, diagnostic criteria for PCOS were based on consensus
rather than clinical trial evidence. Their diagnostic criteria recommended clinical
and/or biochemical evidence of HA, chronic anovulation, and exclusion of other
known disorders. These criteria were an important initial step in standardizing
diagnosis and led to a number of landmark randomized clinical trials in PCOS
(19).
Since the 1990 NIH-sponsored PCOS conference, evolving perception is that
the syndrome may constitute a broader spectrum of signs and symptoms of
ovarian dysfunction than those set forth in the original NIH diagnostic criteria.
The 2003 Rotterdam Consensus Workshop concluded that PCOS is a syndrome
of ovarian dysfunction along with the cardinal features HA and polycystic ovary
(PCO) morphology (Table 35-3).
It is recognized that women with regular cycles, HA, and PCO
morphology may be part of the syndrome. It is also recognized that some
women with the syndrome will have PCO morphology without clinical evidence
of androgen excess, but will display evidence of ovarian dysfunction with
irregular cycles. In this new schema, PCOS remains a diagnosis of exclusion with
the need to rule out other disorders that mimic the PCOS phenotype (19).
Applying the recommended Rotterdam PCOS Diagnostic Criteria, the
presence of two of the three criteria is sufficient to diagnosis PCOS:
menstrual cycle anomalies (amenorrhea, oligomenorrhea), clinical and/or
biochemical HA, and/or the ultrasound appearance of polycystic ovaries
after all other diagnoses are ruled out. [2] This approach results in four
phenotypes: (1) HA (clinical or biochemical) with ovarian dysfunction and
PCO morphology, (2) HA (clinical or biochemical) with ovarian dysfunction,
(3) HA (clinical or biochemical) with PCO morphology, (4) ovarian
dysfunction and PCO morphology. This diagnostic approach for PCOS has
been ratified by the Endocrine Society (2013) for adult women, but in
adolescents the diagnosis should be based on persistent anovulation and
clinical or biochemical HA. Other pathologies that can result in a PCOS
phenotype include AOAH, adrenal or ovarian neoplasm, Cushing syndrome,
hypo- or hypergonadotropic disorders, hyperprolactinemia, and thyroid
disease (Fig. 35-4).
All other frequently encountered manifestations offer less consistent findings
and therefore qualify only as minor diagnostic criteria for PCOS. They include
elevated LH-to-FSH (follicle-stimulating hormone) ratio, IR, perimenarchal onset
of hirsutism, and obesity.
Table 35-3 Revised Diagnostic Criteria of Polycystic Ovary Syndrome
21061990 Criteria (both 1 and 2)
1. Chronic anovulation
2. Clinical and/or biochemical signs of hyperandrogenism and exclusion of other
etiologies
Revised 2003 criteria (2 out of 3)
1. Oligoovulation or anovulation
2. Clinical and/or biochemical signs of hyperandrogenism
3. Polycystic ovaries and exclusion of other etiologies (congenital adrenal
hyperplasia, androgen-secreting tumors, Cushing syndrome)
With permission from Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop
Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to
polycystic ovary syndrome. Fertil Steril 2004;81:19–25.
Clinical HA includes hirsutism, male pattern alopecia, and acne (19).
Hirsutism occurs in approximately 70% of patients with PCOS in the United
States and in only 10% to 20% of patients with PCOS in Japan (20,21). A likely
explanation for this discrepancy is the genetically determined differences in skin
5α-reductase activity (22,23).
Nonclassic adrenal hyperplasia and PCOS may present with similar clinical
features. It is important to measure the basal follicular phase 17-OHP level in all
women presenting with hirsutism to exclude the presence of nonclassic congenital
adrenal hyperplasia, regardless of the presence of polycystic ovaries or metabolic
dysfunction (24).
The menstrual dysfunction in PCOS arises from anovulation or oligo-ovulation
and ranges from amenorrhea to oligomenorrhea. Regular menses in the presence
of anovulation in PCOS is uncommon, though one report found that among
hyperandrogenic women with regular menstrual cycles, the rate of anovulation is
21% (25). Classically, PCOS is lifelong and characterized by abnormal
menses from puberty with acne and hirsutism arising in the teens. It may,
however, arise in adulthood, concomitant with the emergence of obesity,
presumably because this is accompanied by increasing hyperinsulinemia
(26).
2107FIGURE 35-4 Diagnostic algorithm for polycystic ovary syndrome. (Modified with
permission from Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med
2005;353:2578–2588.)
The sonographic criteria for PCOS morphology requires the presence of
20 or more follicles in either ovary measuring 2 to 9 mm in diameter and/or
increased ovarian volume (>10 mL). A single ovary meeting these criteria is
sufficient to affix the PCO morphology (27). The appearance of PCO on
ultrasound scanning is common. Only a fraction of those with PCO appearance,
however, have the clinical and/or endocrine features of PCOS. A PCO appearance
is found in about 23% of women of reproductive age, while estimates of the
incidence of PCOS vary between 5% and 10% (28). Polycystic appearing ovaries
in women with PCOS were not associated with increased cardiovascular disease
risk, and were independent of body mass index (BMI), age, and insulin levels
(29). An English study demonstrated that without symptoms of PCOS, a PCO
appearance alone is not associated with impaired fecundity or fertility (30). Other
studies indicate that anti-mullerian hormone (AMH) is a reliable predictor of the
small (2 to 9 mm) antral follicle count independent of PCOS or ovarian
morphology (31).
Obesity occurs in more than 50% of patients with PCOS. The body fat is
usually deposited centrally (android obesity), and a higher waist-to-hip ratio is
2108associated with IR indicating an increased risk of diabetes mellitus and
cardiovascular disease (32). Among women with PCOS, there is widespread
variability in the degree of adiposity by geographic location and ethnicity. In
studies in Spain, China, Italy, and the United States, the percentage of obese
women with PCOS were 20%, 43%, 38%, and 69%, respectively (33).
Because increased adiposity, particularly abdominal, is associated with
hyperandrogenemia and increased metabolic risk, it is recommended that
PCOS patients have a BMI calculation and measurement of waist circumference.
Insulin resistance resulting in hyperinsulinemia is commonly exhibited in
PCOS. Insulin resistance may eventually lead to the development of
hyperglycemia and type 2 diabetes mellitus (34). About one-third of obese PCOS
patients have impaired glucose tolerance (IGT), and 7.5% to 10% have type 2
diabetes mellitus (35). These rates are mildly increased even in nonobese women
who have PCOS (10% IGT and 1.5% diabetes), compared with the general
population of the United States (7.8% IGT and 1% diabetes) (36,37). Because of
the high risk of IGT and type 2 diabetes mellitus in PCOS, periodic screening
of patients to detect early abnormalities in glucose tolerance is recommended
(fasting and a 2-hour glucose level using a 75-g oral glucose load).
Abnormal lipoproteins are common in PCOS and include elevated total
cholesterol, triglycerides, and low-density lipoproteins (LDL) and low levels of
high-density lipoproteins (HDL) and apoprotein A-I (32,38). According to one
report, the most characteristic lipid alteration is decreased levels of HDL2α (39).
Other observations in women with PCOS include impaired fibrinolysis, as
shown by elevated circulating levels of plasminogen activator inhibitor (40), an
increased incidence of hypertension over the years (which reaches 40% by
perimenopause), a greater prevalence of atherosclerosis and cardiovascular
disease, and an estimated 7-fold increased risk for myocardial infarction (38,40–
43). It is recommended that adolescents and women with PCOS be screened for
the following cardiovascular disease risk factors: family history of early
cardiovascular disease, cigarette smoking, IGT/T2DM, hypertension,
dyslipidemia, obstructive sleep apnea, and obesity (especially increased
abdominal adiposity) and manage these when present (Fig. 35-4).
Pathology
Macroscopically, ovaries in women with PCOS are two to five times the
normal size. A cross section of the surface of the ovary discloses a white,
thickened cortex with multiple cysts that are typically less than a centimeter in
diameter. Microscopically, the superficial cortex is fibrotic and hypocellular and
may contain prominent blood vessels. In addition to smaller atretic follicles, there
is an increase in the number of follicles with luteinized theca interna. The stroma
2109may contain luteinized stromal cells (44).
Pathophysiology and Laboratory Findings
The HA and anovulation that accompany PCOS may be caused by abnormalities
in four endocrinologically active compartments: (i) the ovaries, (ii) the adrenal
glands, (iii) the periphery (fat), and (iv) the hypothalamus–pituitary compartment
(Fig. 35-5).
In patients with PCOS, the ovarian compartment is the most consistent
contributor of androgens. Dysregulation of CYP17, the androgen-forming
enzyme in both the adrenals and the ovaries, may be one of the pathogenetic
mechanisms underlying HA in PCOS (45). The ovarian stroma, theca, and
granulosa contribute to ovarian HA and are stimulated by LH (46). This hormone
relates to ovarian androgenic activity in PCOS in a number of ways.
1. Total and free testosterone levels correlate directly with LH levels (47).
2. The ovaries are more sensitive to gonadotropic stimulation, possibly as a result
of CYP17 dysregulation (45).
3. Treatment with a gonadotropin-releasing hormone (GnRH) agonist effectively
suppresses serum testosterone and androstenedione levels (48).
4. Larger doses of a GnRH agonist are required for androgen suppression than
for endogenous gonadotropin-induced estrogen suppression (49).
The increased testosterone levels in patients with PCOS are considered
ovarian in origin. The serum total testosterone levels are usually no more
than twice the upper normal range (20 to 80 ng/dL). However, in ovarian
hyperthecosis, values may reach 200 ng/dL or more (50). The adrenal
compartment plays a role in the development of PCOS. Although the
hyperfunctioning CYP17 androgen-forming enzyme coexists in the ovaries and
the adrenal glands, DHEAS is increased in only about 50% of patients with PCOS
(51,52). The hyperresponsiveness of DHEAS to stimulation with ACTH, the
onset of symptoms around puberty, and the observation of 17,20-lyase activation
(one of the two CYP17 enzymes) are key events in adrenarche that led to the
hypothesis that PCOS arises as an exaggeration of adrenarche (50).
2110FIGURE 35-5 Pathophysiologic characteristics of the polycystic ovary syndrome (PCOS).
2111Insulin resistance results in a compensatory hyperinsulinemia, which stimulates ovarian
androgen production in an ovary genetically predisposed to PCOS. Arrest of follicular
development (red “X”) and anovulation could be caused by the abnormal secretion of
gonadotropins such as follicle-stimulating hormone (FSH) or luteinizing hormone (LH)
(perhaps induced by hyperinsulinemia), intraovarian androgen excess, direct effects of
insulin, or a combination of these factors. Insulin resistance, in concert with genetic
factors, may also lead to hyperglycemia and an adverse profile of cardiovascular risk
factors. (Modified with permission from Rosenfield RL. Clinical practice. Hirsutism. N
Engl J Med 2005;353:2578–2588.)
The peripheral compartment, defined as the skin and the adipose tissue,
manifests its contribution to the development of PCOS in several ways.
1. The presence and activity of 5α-reductase in the skin largely determines the
presence or absence of hirsutism (23,24).
2. Aromatase and 17β-hydroxysteroid dehydrogenase activities are increased in
fat cells and peripheral aromatization is increased with increased body weight
(53,54).
3. With obesity, the metabolism of estrogens, by way of reduced 2-hydroxylation
and 17α-oxidation, is decreased and metabolism via estrogen active 16-
hydroxyestrogens (estriol) is increased (55).
4. While E2 (estradiol) is at a follicular phase level in patients with PCOS, E1
(estrone) levels are increased as a result of peripheral aromatization of
androstenedione (56).
5. A chronic hyperestrogenic state, with reversal of the E1-to-E2 ratio, results
and is unopposed by progesterone.
The hypothalamic–pituitary compartment also participates in aspects
critical to the development of PCOS.
1. An increase in LH pulse frequency relative to those in the normal follicular
phase is the result of increased GnRH pulse frequency (57).
2. This increase in LH pulse frequency explains the frequent observation of an
elevated LH and LH-to-FSH ratio.
3. FSH is not increased with LH, likely because of the combination of increased
gonadotropin pulse frequency and the synergistic negative feedback of
chronically elevated estrogen levels and normal follicular inhibin.
4. About 25% of patients with PCOS exhibit mildly elevated prolactin levels,
which may result from abnormal estrogen feedback to the pituitary gland. In
some patients with PCOS, bromocriptine has reduced LH levels and restored
ovulatory function (58).
2112PCOS is a complex multigenetic disorder that results from the interaction
between multiple genetic and environmental factors. Genetic studies of PCOS
reported allele sharing in large PCOS patient populations. Linkage studies
focused on candidate genes, most likely to be involved in the pathogenesis of
PCOS, reveal genes grouped into four categories: (i) IR-related genes, (ii)
genes that interfere with the biosynthesis and the action of androgens, (iii)
genes that encode inflammatory cytokines, and (iv) other candidate genes
(59).
In PCOS genome-wide association studies (GWAS), there is evidence for
candidate genes related to insulin signaling, FSH receptor, insulin receptor, sexual
hormone function, type 2 diabetes (T2D), calcium signaling, interleukin-6,
teleomerase activity, gamma-aminobutyric acid (GABA) A receptors, and
endocytosis (1q22, 2p16.3, 2p21, 3q26.33, 4p12, 4q35.2, 8q24.2, 9q21.32,
9q33.3, 9q22.32, 11p13, 11q22.1, 12q13.2, 12q14.3, 16p13.3, 16q12.1, 19p13.3,
20q13.2) (60). GWAS in a European PCOS cohort has identified six
susceptibility loci mapping to 11q22.1 (YAP1), 2p21 (THADA), 11p14.1 (FSHB),
2q34 (ERBB4), 12q21.2 (KRR1), and 5q31.1 (RAD50). The first four have been
confirmed in Han Chinese (61).
Other linkage studies have identified the follistatin, CYP11A, Calpain 10, IRS-
1 and IRS-2 regions and loci near the insulin receptor (19p13.3), SHBG, TCF7L2,
and the insulin genes, as likely PCOS candidate genes (62–68). A polymorphic
variant, D19S884, in FBN3 was found to be associated with risk of PCOS (69).
Using theca cells derived from women with PCOS elevated mRNA levels was
noted for CYP11A, 3BHSD2, and CYP17 genes with corresponding
overproduction of testosterone, 17-α-hydroxyprogesterone, and progesterone.
Despite the characteristically heightened steroidogenesis in POCS, the STARB
gene was not overexpressed (62). Microarray data using theca cells from PCOS
women did not identify any genes near the 19p13.3 locus that were differentially
expressed; however, the mRNAs of several genes that map to 19p13.3, including
the insulin receptor, p114-Rho-GEF, and several expressed sequence tags, were
detected in both PCOS and normal theca cells. Those studies identified new
factors that might impact theca cell steroidogenesis and function, including
cAMP-GEFII, genes involved in all-transretinoic acid (atRA) synthesis signaling,
genes that participate in the Wnt signal transduction pathway, and transcription
factor GATA6. These findings suggest that a 19p13.3 locus or some other
candidate gene may be a signal transduction gene that results in overexpression of
a suite of genes downstream that may affect steroidogenic activity (70).
Polymorphisms in major folliculogenesis genes, GDF9, BMP15, AMH, and
AMHR2, are not associated with PCOS susceptibility (71).
2113Insulin Resistance
Patients with PCOS frequently exhibit IR and hyperinsulinemia. Insulin
resistance and hyperinsulinemia participate in the ovarian steroidogenic
dysfunction of PCOS. Insulin alters ovarian steroidogenesis independent of
gonadotropin secretion in PCOS. Insulin and insulin-like growth factor I (IGF-I)
receptors are present in the ovarian stromal cells. A specific defect in the early
steps of insulin receptor–mediated signaling (diminished autophosphorylation)
was identified in 50% of women with PCOS (72).
Insulin has both direct and indirect roles in the pathogenesis of HA in PCOS.
Insulin in collaboration with LH enhances the androgen production of theca cells.
Insulin also inhibits the hepatic synthesis of SHBG, the main circulating protein
that binds to testosterone, and thus increases the proportion of unbound or
bioavailable testosterone (13).
The most common cause of IR and compensatory hyperinsulinemia is
obesity, but despite its frequent occurrence in PCOS, obesity alone does not
explain this important association (58). The IR associated with PCOS is not
solely the result of HA based on the following:
1. Hyperinsulinemia is not a characteristic of HA in general but is uniquely
associated with PCOS (73).
2. In obese women with PCOS, 30% to 45% have glucose intolerance or frank
diabetes mellitus, whereas ovulatory hyperandrogenic women have normal
insulin levels and glucose tolerance (73). It seems that the associations
between PCOS and obesity on the action of insulin are synergistic.
3. Suppression of ovarian steroidogenesis in women with PCOS with long-acting
GnRH analogs does not change insulin levels or IR (74).
4. Oophorectomy in patients with hyperthecosis accompanied by
hyperinsulinemia and hyperandrogenemia does not change IR, despite a
decrease in androgen levels (74,75).
Acanthosis nigricans is a reliable marker of IR in hirsute women. This
thickened, pigmented, velvety skin lesion is most often found in the vulva and
may be present on the axilla, over the nape of the neck, below the breast, and
on the inner thigh (76). The HAIR-AN syndrome consists of HA, IR, and
acanthosis nigricans (AN) (72,77). These patients often have high testosterone
levels (>150 ng/dL), fasting insulin levels of greater than 25 µIU/mL (normal <20
to 24 µIU/mL), and maximal serum insulin responses to glucose load (75 g)
exceeding 300 µIU/mL (normal is <160 µIU/m: at 2 hours postglucose load).
Screening Strategies for Diabetes, Insulin Resistance and Metabolic Syndrome
2114Professional societies collectively recommend that obese women with PCOS
and nonobese PCOS patients with risk factors for IR, such as a family
history of diabetes, should be screened for metabolic syndrome, including
glucose intolerance with an Hgb A1c or oral glucose tolerance test (OGTT)
(19). The standard 2-hour OGTT (75 g) provides an assessment of the
degrees of hyperinsulinemia and glucose tolerance and yields the highest
amount of information for a reasonable cost and risk (7). While an HbA1c
test alone provides a diagnosis in the setting of uncontrolled chronic
hyperglycemia, utilizing an OGTT allows early detection and intervention to
prevent complications.
Multiple other testing or screening schemas were proposed to assess the
presence of hyperinsulinemia and IR. In one, the fasting glucose-to-insulin
ratio is determined, and values less than 4.5 indicate IR. Using the 2-hour
GTT with insulin levels, 10% of nonobese and 40% to 50% of obese PCOS
women have IGT (2-hour glucose level ê140 but Ä199 mg/dL) or overt type 2
diabetes mellitus (any glucose level >200 mg/dL). Some research studies have
utilized a peak insulin level of over 150 lIU/mL or a mean level of over 84
lIU/mL over the three blood draws of a 2-hour GTT as a criterion to
diagnose hyperinsulinemia.
The documentation of hyperinsulinemia using either the glucose-to-insulin
ratio or the 2-hour GTT with insulin is problematic. When compared with the
gold standard measure for IR, the hyperinsulemic–euglycemic clamp, it shows
that the glucose-to-insulin ratio does not always accurately portray IR. When
hyperglycemia is present, a relative insulin secretion deficit is present. This
deficient insulin secretion exacerbates the effects of IR and renders inaccurate the
use of hyperinsulinemia as an index of IR. Thus, routine measurements of insulin
levels may not be particularly useful.
Although detection of IR, per se, is not of practical importance to the diagnosis
or management of PCOS, testing women with PCOS for glucose intolerance is of
value because their risk of cardiovascular disease may correlate with this finding.
An appropriate frequency for such screening depends on age, BMI, and waist
circumference, all of which increase risk.
Interventions
Two-Hour Glucose Tolerance Test Normal Glucose Ranges (World Health Organization
criteria, after 75-g glucose load)
Fasting: 64 to 128 mg/dL
One hour: 120 to 170 mg/dL
Two hours: 70 to 140 mg/dL
2115Two-Hour Glucose Values for Impaired Glucose Tolerance and Type 2 Diabetes (World
Health Organization criteria, after 75-g glucose load)
Normal (2-hour) <140 mg/dL
Impaired (2-hour) = 140 to 199 mg/dL
Type 2 diabetes mellitus (2-hour) = 200 mg/dL
Abnormal glucose metabolism may be significantly improved with weight
reduction, which may also reduce HA and restore ovulatory function (78). In
obese, insulin-resistant women, caloric restriction that results in weight
reduction will reduce the severity of IR (a 40% decrease in insulin level with
a 10-kg weight loss) (79). This decrease in insulin levels should result in a
marked decrease in androgen production (a 35% decrease in testosterone levels
with a 10-kg weight loss) (80). Exercise also reduces IR, independent from any
associated weight loss, but data on the impact of exercise on the principal
manifestations of PCOS are lacking.
In addition to addressing of the increased risk for diabetes, the clinician
should recognize IR or hyperinsulinemia as a cluster syndrome called
metabolic syndrome or dysmetabolic syndrome X. Recognition of the
importance of IR or hyperinsulinemia as a risk factor for cardiovascular
disease has led to diagnostic criteria for the metabolic syndrome. The more
metabolic syndrome criteria present, the higher the level of IR and its
downstream consequences. The presence of three of the following five
criteria confirms the diagnosis, and an insulin-lowering agent and/or other
interventions may be warranted (19).
METABOLIC SYNDROME DIAGNOSTIC CRITERIA
Female waist >35 in (88 cm)
Triglycerides >150 mg/dL
HDL <50 mg/dL
Blood pressure >130/85 mm Hg
Fasting glucose: 110 to 126 mg/dL
Two-hour glucose from 75-g OGTT: 140 to 199 mg/dL
Risk factors for metabolic syndrome include nonwhite race, sedentary
lifestyle, BMI greater than 25, age over 40 years, cardiovascular disease,
hypertension, PCOS, hyperandrogenemia, IR, HAIR-AN syndrome,
nonalcoholic steatohepatitis (NASH), and a family history of type 2 diabetes
mellitus, gestational diabetes, or IGT.
2116Long-Term Risks and Interventions
Comprehensive treatment of PCOS addresses reproductive, metabolic, and
psychological features.
Metabolic Syndrome
A recent report by the Androgen Excess and PCOS Society concluded that
lifestyle management, either alone or combined with antiobesity
pharmacologic and/or surgical treatments, should be used as the primary
therapy in overweight and obese women with PCOS (33). Lifestyle
management of obesity in PCOS is multifactorial. Dietary management of obesity
should focus on reducing body weight, maintaining a lower long-term body
weight, and preventing weight gain. An initial weight loss of greater than or equal
to 5% to 10% is recommended. In obese and overweight women with PCOS,
dietary interventions with a resultant weight reduction of more than 5% to less
than 15% over the starting body weight is associated with a reduction in either
total or free testosterone, adrenal androgens, and improvement in SHBG levels.
Metabolic improvements in fasting insulin, glucose, glucose tolerance, total
cholesterol, triglycerides, plasminogen activator inhibitor-1, and free fatty acids
are reported. Clinically, hirsutism, menstrual function, and ovulation are all
improved (33).
Structured exercise improves IR and offers significant benefits in PCOS. The
incorporation of structured exercise, behavior modification, and stress
management strategies as fundamental components of lifestyle management
increases the success of the weight loss strategy (Table 35-4).
Even though lifestyle management strategies should be used as the primary
therapy in obese and overweight women with PCOS, they are difficult to maintain
long term. Alternative approaches to the treatment of obesity include the use of
pharmacologic agents, such as orlistat, sibutramine, and rimonabant, or bariatric
surgery (33). The NIH clinical recommendations advise bariatric surgery when
BMI is greater than 40 kg/m2 or greater than 35 kg/m2 in patients with a highrisk, obesity-related condition after failure of other treatments for weight control
(33,81).
Table 35-4 Lifestyle Modification Principles Suggested for Obesity Management in
Polycystic Ovary Syndrome (PCOS)
Guidelines for Dietary and Lifestyle Intervention in PCOS
1. Lifestyle modification is the first form of therapy, combining behavioral (reduction
of psychosocial stressors), dietary, and exercise management
21172. Reduced-energy diets (500–1,000 kcal/day reduction) are effective options for
weight loss and can reduce body weight by 7–10% over a period of 6–12 months
3. Dietary plans should be nutritionally complete and appropriate for life stage and
should aim for <30% of calories from fat, <10% of calories from saturated fat, with
increased consumption of fiber, whole-grain breads and cereals, and fruit and
vegetables
4. Alternative dietary options (increasing dietary protein, reducing glycemic index,
reducing carbohydrate) may be successful for achieving and sustaining a reduced
weight but more research is needed in PCOS specifically
5. The structure and support within a weight-management program is crucial and may
be more important than the dietary composition. Individualization of the program,
intensive follow-up and monitoring by a physician, and support from the physician,
family, spouse, and peers will improve retention
6. Structured exercise is an important component of a weight-loss regime; aim for >30
min/day
Reprinted with permission from Moran LJ, Pasquali R, Teede HJ, et al. Treatment of
obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and
Polycystic Ovary Syndrome Society. Fertil Steril 2009;92:1966–1982.
Dyslipidemia is one of the most common metabolic disorders seen in PCOS
patients (up to 70% prevalence in a US PCOS population) (82). It is
associated with IR and HA in combination with environmental (diet, physical,
exercise) and genetic factors. Various abnormal patterns include decreased levels
of HDL, elevated levels of triglycerides, decreased total and LDL levels, and
altered LDL quality (83,84).
To assess cardiovascular risks and potentially prevent disease in patients with
PCOS, multiple professional societies have recommended the following (84):
1. Waist circumference and BMI measurement at every visit, using the National
Health and Nutrition Examination Survey method.
2. A complete lipid profile based on the American Heart Association guidelines
(Fig. 35-6). If the fasting serum lipid profile is normal, it should be reassessed
every 2 years or sooner if weight gain occurs.
3. A 2-hour post-75-g oral glucose challenge measurement in PCOS women with
a BMI greater than 30 kg/m2, or alternatively in lean PCOS women with
advanced age (40 years), personal history of gestational diabetes, or family
history of type 2 diabetes. An HgbA1c test only provides information on
impaired fasting blood glucose levels in the setting of uncontrolled chronic
2118hyperglycemia.
4. Blood pressure measurement at each visit. The ideal blood pressure is 120/80
or lower. Prehypertension should be treated because blood pressure control has
the largest benefit in reducing cardiovascular diseases.
5. Regular assessment for depression, anxiety, and quality of life.
FIGURE 35-6 Lipid guidelines in PCOS to prevent cardiovascular disease risk (values in
mg/dL). (Non-HDL = Total cholesterol − HDL, if TG < 400 mg/dL.) (Data for figure
derived from Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of
cardiovascular risk and prevention of cardiovascular disease in women with the polycystic
ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary
Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 2010;95(5): 2038–2049.)
A significant proportion of the population and particularly the obese population
have been noted to have inadequate vitamin D levels. Because vitamin D plays a
role in many metabolic activities, assessment and supplementation when indicated
can be considered.
25-HYDROXY VITAMIN D LEVELS
Deficient: 8 ng/mL or less (≤20 nmol/L);
2119Insufficient: 8 to 20 ng/mL (20 to 50 nmol/L);
Optimal: 20 to 60 ng/mL (50 to 150 nmol/L; 40 to 50 ng/mL is treatment
goal);
High: 60 to 90 ng/mL (150 to 225 nmol/L);
Toxic: >90 ng/mL or greater (≥225 nmol/L).
SUPPLEMENTATION FACTS
1. The body uses 3,000 to 5,000 IU D3 per day.
2. In the absence of the sun, 600 IU of D3 are required to maintain vitamin D
levels.
3. D2 is more rapidly metabolized and is less potent than D3.
4. Patients receiving 50,000 IU of vitamin D2 once a week for 8 weeks will
usually correct a vitamin D deficiency, and this can be followed by giving
50,000 U of vitamin D2 once every other week to maintain vitamin D
sufficiency.
5. D3 is more potent and appropriate dosing to correct levels is still under
investigation but 600 IU/day is considered a safe intake for adults.
Cancer
In chronic anovulatory patients with PCOS, persistently elevated estrogen
levels, which are uninterrupted by progesterone, increase the risk of
endometrial carcinoma (85,86). These endometrial cancers are usually well
differentiated, stage I lesions with a cure rate of more than 90% (see Chapter
37). Endometrial biopsy should be considered in PCOS patients, because they
may occasionally harbor these cancers as early as the second decade of life.
Abnormal bleeding, increasing weight, and age are factors that should lower the
threshold for endometrial sampling. Prevention of endometrial cancer is a core
management goal for patients with PCOS. If other dimensions of management
do not induce regular ovulation (e.g., clomiphene, letrazole, or gonadotropins) or
impose continuous progestation influence (e.g., OCs, pregnancy), regular
secretory transformation and menstruation should be induced with periodic
administration of a progestational agent. Even though the hyperestrogenic state is
associated with an increased risk of breast cancer, studies examining the
relationship between PCOS and breast cancer have not always identified a
significantly increased risk (86–90). The risk of ovarian cancer is increased 2-
fold to 3-fold in women with PCOS (86,91).
Depression and Mood Disorders
2120The clinical features of PCOS, such as infertility, acne, hirsutism, and obesity,
promote psychological morbidity. Women with PCOS face challenges to their
feminine identity that can lead to loss of self-esteem, anxiety, poor body image,
and depression (92).
A study examining the prevalence of depression and other mood disorders in
women with PCOS reported a significantly increased prevalence of depression
(35% to 40%) when compared with controls (10.7%), after adjusting for BMI,
and a family history of depression and/or infertility. Other mood disorders such as
anxiety and eating disorders were common in women with PCOS (93). The high
prevalence of depression and other mental health disorders in women with
PCOS suggests that assessment and treatment of mental health disorders
should be included in the evaluation and management plan (93). Lifestyle
management improves quality of life and depression in obese and overweight and
women with PCOS (92). A simple two-item questionnaire can initiate the
conversation (PHQ-2: Little interest or pleasure in doing things 0–3, Feeling
down, depressed, or hopeless 0–3).
Treatment of Hyperandrogenism and PCOS
Treatment depends on a patient’s goals. Some patients require hormonal
contraception, whereas others desire ovulation induction. In all cases where
there is significant ovulatory dysfunction, progestational interruption of the
unopposed estrogen effects on the endometrium is necessary. This may be
accomplished by periodic luteal function resulting from ovulation induction,
progestational suppression via contraceptive formulations, or intermittent
administration of progestational agents for endometrial or menstrual regulation.
Interruption of the steady state of HA and control of hirsutism usually can
be accomplished simultaneously. Patients desiring pregnancy are an
exception, and for them effective control of hirsutism may not be possible.
Treatment regimens for hirsutism are listed in Table 35-5. The induction of
ovulation and treatment of infertility are discussed in Chapter 36.
Table 35-5 Medical Treatment of Hirsutism
Treatment Category Specific Regimens
Weight loss
Hormonal suppression Oral contraceptives
Medroxyprogesterone
2121Gonadotropin-releasing hormone analogues
Glucocorticoids
Steroidogenic enzyme inhibitors Ketoconazole
5α-Reductase inhibitors Finasteride
Antiandrogens Spironolactone
Cyproterone acetate
Flutamide
Insulin sensitizer Metformin
Mechanical Temporary
Permanent
Electrolysis
Laser hair removal
Weight Reduction
Weight reduction is the initial recommendation for patients with
accompanying obesity because it promotes health, reduces insulin, SHBG,
and androgen levels, and may restore ovulation either alone or combined
with ovulation-induction agents (79). Weight loss of as little as 5% to 7%
over a 6-month period can reduce the bioavailable or calculated free
testosterone level significantly and restore ovulation and fertility in more
than 75% of women (94). Exercise involving large muscle groups (i.e., thigh)
reduces IR and can be an important component of nonpharmacologic, lifestylemodifying management.
Oral Contraceptives
[3] Combination OCs decrease adrenal and ovarian androgen production
and reduce hair growth in nearly two-thirds of hirsute patients (95–98).
Treatment with OCs offers the following benefits:
1. The progestin component suppresses LH, resulting in diminished ovarian
androgen production.
2. The estrogen component increases hepatic production of SHBG, resulting
in decreased free testosterone concentration (99,100).
21223. Circulating androgen levels are reduced, including those of DHEAS, which
to some extent is independent of the effects of both LH and SHBG (32,101).
4. Estrogens decrease conversion of testosterone to DHT in the skin by
inhibition of 5α-reductase.
When an OC is used to treat hirsutism, a balance must be maintained
between the decrease in free testosterone levels and the intrinsic
androgenicity of the progestin. Three progestin compounds that are present in
OCs (norgestrel, norethindrone, and norethindrone acetate) are believed to be
androgen dominant. The androgenic bioactivity of these steroids may be a factor
of their shared structural similarity with 19-nortestosterone steroids (102). OCs
containing the so-called new progestins (desogestrel, gestodene, norgestimate,
and drospirenone) have minimized androgenic activity. However, there is limited
evidence of clinically measurable differences in outcome resulting from the
disparity of in vitro estimates of androgenic potency.
The use of OCs alone may be relatively ineffective (<10% success rate) in the
treatment of hirsutism in women with PCOS, and the OCs may exacerbate IR
in these patients (103,104). Therefore, effective protocols for pharmacologic
management of significant hirsutism with OCs usually include coadministration
of agents that impede androgen action.
Medroxyprogesterone Acetate
Oral or intramuscular administration of medroxyprogesterone acetate (MPA)
successfully treats hirsutism (105). It directly affects the hypothalamic–pituitary
axis by decreasing GnRH production and the release of gonadotropins, thereby
reducing testosterone and estrogen production by the ovary. Despite a decrease in
SHBG, total and free androgen levels are decreased significantly (106). The
recommended oral dose for GnRH suppression is 20 to 40 mg daily in
divided dosages or 150 mg given intramuscularly every 6 weeks to 3 months
in the depot form. Hair growth is reduced in up to 95% of patients (107). Side
effects of the treatment include amenorrhea, bone mineral density loss,
depression, fluid retention, headaches, hepatic dysfunction, and weight gain.
MPA is not commonly used for hirsutism.
Gonadotropin-Releasing Hormone Agonists
Administration of GnRH agonists may allow the differentiation of androgen
produced by adrenal sources from that of ovarian sources (49). GnRH
agonists have been shown to suppress ovarian steroids to castrate levels in
patients with PCOS (108). Treatment with leuprolide acetate given
intramuscularly every 28 days decreases hirsutism and hair diameter in idiopathic
2123hirsutism and hirsutism secondary to PCOS (109). Ovarian androgen levels are
significantly and selectively suppressed. The addition of OC or estrogen
replacement therapy to GnRH agonist treatment (add-back therapy) prevents bone
loss and other side effects of menopause, such as hot flushes and genital atrophy.
The hirsutism-reducing effect is retained (106,110). Suppression of hirsutism is
not potentiated by the addition of estrogen replacement therapy to GnRH agonist
treatment (111).
Glucocorticoids
Dexamethasone may be used to treat patients with PCOS who have either adrenal
or mixed adrenal and ovarian HA. Doses of dexamethasone as low as 0.25 mg
nightly or every other night are used initially to suppress DHEAS concentrations
to less than 400 μg/dL. Because dexamethasone has 40 times the glucocorticoid
effect of cortisol, daily doses greater than 0.5 mg every evening should be
avoided to prevent the risk of adrenal suppression and severe side effects
that resemble Cushing syndrome. To avoid oversuppression of the pituitary–
adrenal axis, morning serum cortisol levels should be monitored intermittently
(maintain at >2 μg/dL). Reduction in hair growth rate was reported, and
significant improvement in acne associated with adrenal HA (112).
Ketoconazole
Ketoconazole inhibits the key steroidogenic cytochromes. Administered at a low
dose (200 mg per day), it can significantly reduce the levels of androstenedione,
testosterone, and calculated free testosterone (113). It is rarely used for the
chronic inhibition of androgen production in women with HA because of the
serious risk of adrenocortical suppression and development of adrenal crisis (15).
Spironolactone
Spironolactone is a specific antagonist of aldosterone, which competitively binds
to the aldosterone receptors in the distal tubular region of the kidney. It is an
effective potassium-sparing diuretic that originally was used to treat hypertension.
The effectiveness of spironolactone in the treatment of hirsutism is based on the
following mechanisms:
1. Competitive inhibition of DHT at the intracellular receptor level (22).
2. Suppression of testosterone biosynthesis by a decrease in the CYP enzymes
(114).
3. Increase in androgen catabolism (with increased peripheral conversion of
testosterone to estrone).
4. Inhibition of skin 5α-reductase activity (22).
2124Although total and free testosterone levels are reduced significantly in patients
with both PCOS and idiopathic hirsutism (HA with regular menses) after
treatment with spironolactone, total and free testosterone levels in patients with
PCOS remain higher than those with idiopathic hirsutism (HA with regular
menses) (115). In both groups, SHBG levels are unaltered. The reduction in
circulating androgen levels observed within a few days of spironolactone
treatment partially accounts for the progressive regression of hirsutism.
At least a modest improvement in hirsutism can be anticipated in 70% to 80%
of women using at least 100 mg of spironolactone per day for 6 months (116).
Spironolactone reduces the daily linear growth rate of sexual hair, hair shaft
diameters, and daily hair volume production (117). Combination therapy with
spironolactone and OCs seems effective via their differing but synergistic
activities (15,118).
The most common dose is 50 to 100 mg twice daily. Women treated with
200 mg per day show a greater reduction in hair shaft diameter than women
receiving 100 mg per day (119). Maximal inhibition of hirsutism is noted
between 3 and 6 months but continues for 12 months. Electrolysis can be
recommended 9 to 12 months after the initiation of spironolactone for permanent
hair removal.
The most common side effect of spironolactone is menstrual irregularity
(usually metrorrhagia), which may occur in over 50% of patients with a
dosage of 200 mg per day (119). Normal menses may resume with reduction of
the dosage. Infrequently, other side effects such as mastodynia, urticaria, or scalp
hair loss may occur. Nausea and fatigue can occur with high doses (116). Because
spironolactone can increase serum potassium levels, its use is not recommended
in patients with renal insufficiency or hyperkalemia. Periodic monitoring of
potassium and creatinine levels is suggested.
Return of normal menses in amenorrheic patients is reported in up to 60% of
cases (115). Patients must be counseled to use contraception while taking
spironolactone because it theoretically can feminize a male fetus.
Cyproterone Acetate
Cyproterone acetate is a synthetic progestin derived from 17-OHP, which has
potent antiandrogenic properties. The primary mechanism of cyproterone
acetate is competitive inhibition of testosterone and DHT at the level of the
androgen receptor (120). This agent induces hepatic enzymes and may increase
the metabolic clearance rate of plasma androgens (121).
A European formulation of ethinyl estradiol with cyproterone acetate
significantly reduces plasma testosterone and androstenedione levels, suppresses
gonadotropins, and increases SHBG levels (122). Cyproterone acetate shows
2125mild glucocorticoid activity (and may reduce DHEAS levels) (120,123).
Administered in a reverse sequential regimen (cyproterone acetate 100 mg per
day on days 5 to 15, and ethinyl estradiol 30 to 50 mg per day on cycle days 5 to
26), this cyclic schedule allows regular menstrual bleeding, provides excellent
contraception, and is effective in the treatment of even severe hirsutism and acne
(124).
Side effects of cyproterone acetate include fatigue, weight gain, decreased
libido, irregular bleeding, nausea, and headaches. These symptoms occur less
often when ethinyl estradiol is added. Cyproterone acetate administration is
associated with liver tumors in beagles and is not approved by the U.S. Food and
Drug Administration (FDA) for use in the United States.
Flutamide
Flutamide, a pure nonsteroidal antiandrogen, is approved for treatment of
advanced prostate cancer. Its mechanism of action is inhibition of nuclear binding
of androgens in target tissues. Although it has a weaker affinity to the androgen
receptor than spironolactone or cyproterone acetate, larger doses (250 mg given
two or three times daily) may compensate for the reduced potency. Flutamide is a
weak inhibitor of testosterone biosynthesis.
In a single, 3-month study of flutamide alone, most patients demonstrated
significant improvement in hirsutism with no change in androgen levels (125).
Significant improvement in hirsutism with a significant drop in androstenedione,
DHT, LH, and FSH levels was observed in an 8-month follow-up of flutamide
and low-dose OCs in women who did not respond to OCs alone (126). The side
effects of flutamide treatment combined with a low-dose OC included dry skin,
hot flashes, increased appetite, headaches, fatigue, nausea, dizziness, decreased
libido, liver toxicity, and breast tenderness (127).
In hyperinsulinemic, hyperandrogenemic, nonobese PCOS adolescents on a
combination of metformin (850 mg per day) and flutamide (62.5 mg per day), and
the low-dose OC containing drospirenone, resulted in a more effective and more
efficient reduction in total and abdominal fat excess than was demonstrated by
those utilizing an OC with gestodene as the progestin (128). The combination of
ethinyl-drospirenone, metformin, and flutamide is effective in reducing excess
total fat, abdominal fat, and attenuating dysadipocytokinemia in young women
with hyperinsulinemic PCOS. The use of the antiandrogen flutamide appeared to
emphasize effects (129). Many patients taking flutamide (50% to 75%) report dry
skin, blue-green discoloration of urine, and liver enzyme elevation. Liver toxicity
or failure and death are rare but severe side effects of flutamide appear to be doserelated (130). The 2008 Endocrine Society clinical practice guidelines do not
recommend using flutamide as first-line therapy for treating hirsutism. If it is
2126used, the lowest effective dose should be given, and the patient’s liver function
should be monitored closely (4). Flutamide should not be used in women desiring
pregnancy.
Finasteride
Finasteride is a specific inhibitor of type 2 5α-reductase enzyme activity,
approved in the United States at a 5-mg dose for the treatment of benign prostatic
hyperplasia, and at a 1-mg dose to treat male-pattern baldness. In a study in which
finasteride (5 mg daily) was compared with spironolactone (100 mg daily), both
drugs resulted in similar significant improvement in hirsutism, despite differing
effects on androgen levels (131). Most of the improvement in hirsutism with
finasteride occurred after 6 months of therapy with 7.5 mg of finasteride daily
(132). The improvement in hirsutism in the presence of rising testosterone levels
is convincing evidence that it is the binding of DHT, and not testosterone, to the
androgen receptor that is responsible for hair growth. Finasteride does not
prevent ovulation or cause menstrual irregularity. The increase in SHBG caused
by OCs further decreases free testosterone levels; OCs in combination with
finasteride are more effective in reducing hirsutism than finasteride alone. As
with spironolactone and flutamide, finasteride could theoretically feminize a male
fetus; therefore, these agents are used only with additional contraception.
Ovarian Wedge Resection
Bilateral ovarian wedge resection is associated with only a transient
reduction in androstenedione levels and a prolonged minimal decrease in
plasma testosterone (133,134). In patients with hirsutism and PCOS who had
wedge resection, hair growth was reduced by approximately 16% (17,135).
Although Stein and Leventhal’s original report cited a pregnancy rate of 85%
following wedge resection and maintenance of ovulatory cycles, subsequent
reports show lower pregnancy rates and a concerning incidence of periovarian
adhesions (17,136). Instances of premature ovarian failure and infertility were
reported (137).
Laparoscopic Electrocautery
Laparoscopic ovarian electrocautery is used as an alternative to wedge resection
in patients with severe PCOS whose condition is resistant to clomiphene citrate.
In one series, ovarian drilling was achieved laparoscopically with an insulated
electrocautery needle, using 100-W cutting current to assist entry and 40-W
coagulating current to treat each microcyst over 2 seconds (8-mm needle in
ovary) (138). In each ovary, 10 to 15 punctures were created. This led to
spontaneous ovulation in 73% of patients, with 72% conceiving within 2 years.
2127Of those who had undergone a follow-up laparoscopy, 11 of 15 were adhesion
free. To reduce adhesion formation, a technique that cauterized the ovary in only
four points led to a similar pregnancy rate, with a miscarriage rate of 14% (139).
Other laparoscopic techniques using laser instead of electrocautery for
laparoscopic ovarian drilling were described (140). Most series report a decrease
in androgen and LH concentrations and an increase in FSH concentrations
(141,142). The beneficial endocrinologic effects of laparoscopic ovarian drilling
and the improvement in hirsutism were sustained for up to 9 years in patients with
PCOS (143). Unilateral diathermy results in bilateral ovarian activity (144).
Further studies are anticipated to define candidates who may benefit most from
such a procedure. The risk of adhesion formation, reduction in AMH and
alternative therapies should be discussed during informed consent (145).
Physical Methods of Hair Removal
Depilatory creams remove hair only temporarily. They break down and dissolve
hair by hydrolyzing disulfide bonds. Although depilatories can have a dramatic
effect, many women cannot tolerate these irritative chemicals. The topical use of
corticosteroid cream may prevent contact dermatitis. Eflornithine hydrochloride
cream, also known as difluoromethylornithine (DMFO), irreversibly blocks
ornithine decarboxylase (ODC), the enzyme in hair follicles that is important in
regulating hair growth. It is effective in the treatment of unwanted facial hair
(146). Noticeable results take about 6 to 8 weeks of therapy. Treatment must be
continued while inhibition of hair growth is desired, and when the cream is
discontinued, hair returns to pretreatment levels after about 8 weeks (4).
Shaving is effective and, contrary to common belief, it does not change the
quality, quantity, or texture of hair. However, plucking, if done unevenly and
repeatedly, may cause inflammation and damage to hair follicles and render them
less amenable to electrolysis. Waxing is a grouped method of plucking in which
hairs are plucked out from under the skin surface. The results of waxing last
longer (up to 6 weeks) than shaving or depilatory creams (147).
Bleaching removes the hair pigment through the use of hydrogen peroxide
(usually 6% strength), which is sometimes combined with ammonia. Although
hair lightens and softens during oxidation, this method is frequently associated
with hair discoloration or skin irritation and is not always effective (146).
Electrolysis and laser hair removal are the only permanent means
recommended for hair removal. Under magnification, a trained technician
destroys each hair follicle individually. When a needle is inserted into a hair
follicle, galvanic current, electrocautery, or both used in combination (blend)
destroy the hair follicle. After the needle is removed, a forceps is used to remove
the hair. Hair regrowth ranges from 15% to 50%. Problems with electrolysis
2128include pain, scarring, and pigmentation. Cost can also be an obstacle (148).
Laser hair removal destroys the hair follicle through photoablation. These
methods are most effective after medical therapy has arrested further growth.
Insulin Sensitizers
[4] Because hyperinsulinemia appears to play a role in PCOS-associated
anovulation, treatment with insulin sensitizers may shift the endocrine
balance toward ovulation and pregnancy, either alone or in combination
with other treatment modalities.
Metformin (Glucophage) is an oral biguanide antihyperglycemic drug used
extensively for non–insulin-dependent diabetes. Metformin is pregnancy category
B drug with no known human teratogenic effect. It lowers blood glucose mainly
by inhibiting hepatic glucose production and by enhancing peripheral glucose
uptake. Metformin enhances insulin sensitivity at the postreceptor level and
stimulates insulin-mediated glucose disposal (149).
Metformin has been used extensively to treat oligo-ovulatory infertility, IR, and
HA in PCOS patients. Metformin has been used to treat PCOS oligo-ovulatory
infertility either alone or in combination with dietary restriction, clomiphene,
letrozole, or gonadotropins. In randomized control studies, metformin has been
found to improve the odds of ovulation in women with PCOS when compared
with placebo (150,151). A large multicenter, randomized control trial in
women with PCOS concluded that clomiphene is superior to metformin in
achieving live births in infertile women with PCOS. When ovulation was used
as the outcome, the combination of metformin and clomiphene was superior to
either clomiphene alone or metformin alone (152). Metformin alone compared
with placebo increases the ovulation rate in women with PCOS. However,
ovulation induction agents such as clomiphene or letrozole alone are much more
effective in increasing ovulation, pregnancy, and live birth rates in women with
PCOS than metformin alone. There is fair evidence that metformin alone does not
increase rates of miscarriage when stopped at the initiation of pregnancy and
insufficient evidence that metformin in combination with other agents used to
induce ovulation increases live birth rates but may improve ovulation rates in
clomiphene- or letrazole-resistant cases (153). The combination of metformin and
letrazole has been shown to be comparable to gonadotropins in pregnancy and
live birth rates in clomiphene-resistant PCOS patients and superior to other
interventions (154). Ovulation induction with clomiphene has been associated
with a thinner endometrial lining compared with other agents like letrozole (155).
A recent meta-analysis provided weak evidence that letrozole appears to improve
live birth and pregnancy rates in subfertile women with anovulatory PCOS,
compared with clomiphene (156). In women with PCOS, baseline serum AMH
2129levels were higher in those who did not respond to ovulation induction and
conversely lower among women who ovulated. Women with higher baseline
AMH levels required higher doses of clomiphene or letrozole to achieve
ovulation, suggesting that AMH levels may be a marker of ovarian resistance to
ovulation induction (157).
The most common side effects are gastrointestinal, including nausea, vomiting,
diarrhea, bloating, and flatulence. Because the drug caused fatal lactic acidosis in
men with diabetes and renal insufficiency, baseline renal function testing is
suggested (158). The drug should not be given to women with elevated serum
creatinine levels (149).
Concepts regarding the role of obesity and IR or hyperinsulinemia in
PCOS suggest that the primary intervention should be recommending and
assisting with weight loss (5% to 10% of body weight). A percentage of
PCOS patients will respond to weight loss alone with spontaneous ovulation.
Metformin and lifestyle interventions has been associated with a lower BMI
and improved menstruation in women with PCOS compared to lifestyle
interventions and placebo over 6 months (159). In those who do not respond
to weight loss alone or who are unable to lose weight, the addition of an
insulin sensitizer, after failing the ovulation induction agent alone, may
promote ovulation without resorting to injectable gonadotropins.
A prevailing concern over the increased incidence of spontaneous abortions in
women with PCOS and the potential reduction afforded by insulin sensitizers
suggests that insulin sensitizers may be beneficial in combination with
gonadotropin therapy for ovulation induction or in vitro fertilization (160).
Women with early pregnancy loss have a low level of IGF-binding protein-1
(IGFBP-1), and of circulating glycodelin, which has immunomodulatory effects
protecting the developing fetus. Use of metformin increased levels of both factors,
which might explain early findings suggesting that metformin use may reduce the
high spontaneous abortion rates seen among women with PCOS (161).
A number of observational studies suggested that metformin reduces the risk of
pregnancy loss (162,163). However, there are no adequately designed and
sufficiently powered randomized control trials to address this issue. In the
prospective randomized PPCOS (Pregnancy and PCOS) trial, there was a
concerning nonsignificant trend toward a greater rate of miscarriages in the
metformin only group (162). This trend was not noted in other trials.
There are no conclusive data to support a beneficial effect of metformin on
pregnancy loss, and the trend toward a higher miscarriage rate in the PPCOS trial,
which used extended-release metformin, is of some concern (150,152).
The incidence of ovarian hyperstimulation syndrome is reduced with adjuvant
metformin in PCOS patients at risk for severe ovarian hyperstimulation syndrome
2130(164).
Cushing Syndrome
The adrenal cortex produces three classes of steroid hormones: glucocorticoids,
mineralocorticoids, and sex steroids (androgen and estrogen precursors).
Hyperfunction of the adrenal gland can produce clinical signs of increased
activity of any or all of these hormones. Increased glucocorticoid action results in
nitrogen wasting and a catabolic state. This causes muscle weakness,
osteoporosis, atrophy of the skin with striae, nonhealing ulcerations and
ecchymoses, reduced immune resistance that increases the risk of bacterial and
fungal infections, and glucose intolerance resulting from enhanced
gluconeogenesis and antagonism to insulin action.
Although most patients with Cushing syndrome gain weight, some lose it.
Obesity is typically central, with characteristic redistribution of fat over the
clavicles around the neck and on the trunk, abdomen, and cheeks. Cortisol excess
may lead to insomnia, mood disturbances, depression, and even overt psychosis.
With overproduction of sex steroid precursors, women may exhibit HA
(hirsutism, acne, oligomenorrhea or amenorrhea, thinning of scalp hair).
Masculinization is rare, and its presence suggests an autonomous adrenal origin,
most often an adrenal malignancy. With overproduction of mineralocorticoids,
patients may manifest arterial hypertension and hypokalemic alkalosis. The
associated fluid retention may cause pedal edema (Table 35-6) (165).
Characteristic clinical laboratory findings associated with hypercortisolism are
confined mainly to a complete blood count showing evidence of granulocytosis
and reduced levels of lymphocytes and eosinophils. Increased urinary calcium
secretion may be present.
Causes
The six recognized noniatrogenic causes of Cushing syndrome can be divided
between those that are ACTH dependent and those that are ACTH
independent (Table 35-7). The ACTH-dependent causes can result from
ACTH secreted by pituitary adenomas or from an ectopic source. The
hallmark of ACTH-dependent forms of Cushing syndrome is the presence of
normal or high plasma ACTH concentrations with increased cortisol levels.
The adrenal glands are hyperplastic bilaterally. Pituitary ACTH-secreting
adenoma, or Cushing disease, is the most common cause of endogenous
Cushing syndrome (165). These pituitary adenomas are usually microadenomas
(<10 mm in diameter) that may be as small as 1 mm. They behave as though they
are resistant, to a variable degree, to the feedback effect of cortisol. Like the
2131normal gland, these tumors secrete ACTH in a pulsatile fashion; unlike the
normal gland, the diurnal pattern of cortisol secretion is lost. Ectopic ACTH
syndrome most often is caused by malignant tumors (166). About one-half of
these tumors are small-cell carcinomas of the lung (167). Other tumors include
bronchial and thymic carcinomas, carcinoid tumors of the pancreas, and
medullary carcinoma of the thyroid.
Ectopic corticotropin-releasing hormone (CRH) tumors are rare and include
tumors such as bronchial carcinoids, medullary thyroid carcinoma, and metastatic
prostatic carcinoma (167). The presence of an ectopic CRH-secreting tumor
should be suspected in patients whose dynamic testing suggests pituitary ACTHdependent disease but who have rapid disease progression and very high plasma
ACTH levels.
The most common cause of ACTH-independent Cushing syndrome is
exogenous or iatrogenic (i.e., supraphysiologic therapy with corticosteroids)
or factitious (self-induced). Corticosteroids are used in pharmacologic quantities
to treat a variety of diseases with an inflammatory component. Over time, such
therapy will result in Cushing syndrome. When corticosteroids are taken by the
patient but not prescribed by a physician, the diagnosis may be especially
challenging. The diagnostic workup for Cushing syndrome focuses on the ability
to suppress autonomous cortisol secretion and whether ACTH is elevated or
suppressed. According to the Endocrine Society’s clinical practice guidelines for
the diagnosis of Cushing syndrome, the initial use of one test with high diagnostic
accuracy (24-hour urinary free cortisol [UFC], late night salivary cortisol, 1 mg
overnight or 2 mg 48-hour dexamethasone suppression test) is recommended. The
24-hour UFC should be used to diagnose Cushing syndrome in pregnant women
and in patients with epilepsy, whereas the 1-mg overnight dexamethasone
suppression test, rather than UFC, should be used for initial testing for Cushing
syndrome in patients with severe renal failure and adrenal incidentaloma. The 2-
mg 48-hour dexamethasone suppression test is the optimal test in conditions that
are associated with overactivation of the hypothalamic–pituitary–adrenal (HPA)
axis: depression, morbid obesity, alcoholism, and diabetes mellitus.
Table 35-6 Overlapping Conditions and Clinical Features of Cushing Syndrome
Symptoms Signs Overlapping
Conditions
Features that best discriminate Cushing syndrome; most do not have a high sensitivity
Easy bruising
2132Facial plethora
Proximal myopathy (or proximal
muscle weakness)
Striae (especially if reddish purple and
>1 cm wide)
In children, weight gain with
decreasing growth velocity
Cushing syndrome features in the general population that are common and/or less
discriminatory
Depression Dorsocervical fat pad (“buffalo
hump”)
Hypertensiona
Fatigue Facial fullness Incidental adrenal
mass
Weight gain Obesity Vertebral
osteoporosisa
Back pain Supraclavicular fullness Polycystic ovary
syndrome
Changes in appetite Thin skina Type 2 diabetesa
Decreased concentration Peripheral edema Hypokalemia
Decreased libido Acne Kidney stones
Impaired memory
(especially short term)
Hirsutism or female balding Unusual
infections
Insomnia Poor skin healing
Irritability
Menstrual abnormalities
In children, slow growth In children, abnormal genital
virilization
In children, short stature
In children, pseudoprecocious puberty
2133or delayed puberty
Features are listed in random order.
aCushing syndrome is more likely if onset of the feature is at a younger age.
Table 35-7 Causes of Cushing Syndrome
Category Cause Relative Incidence
ACTH-dependent Cushing Disease 60%
Ectopic ACTH-secreting tumors 15%
Ectopic CRH-secreting tumors Rare
ACTH-independent Adrenal cancer 15%
Adrenal adenoma 10%
Micronodular adrenal hyperplasia Rare
Iatrogenic/factitious Common
ACTH-dependent Cushing syndrome may be caused by pituitary adenoma, basophil
hyperplasia, nodular adrenal hyperplasia, or cyclic Cushing syndrome.
ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.
2134FIGURE 35-7 Algorithm for testing patients suspected of having Cushing syndrome (CS).
Diagnostic criteria that suggest Cushing syndrome are a urinary free cortisol (UFC) greater
than the normal range for the assay, serum cortisol greater than 1.8 μg/dL (50 nmol/L) after
1 mg dexamethasone (1 mg DST), and a late-night salivary cortisol greater than 145 ng/dL
(4 nmol/L). (Based on recommendations from Nieman LK, Biller BM, Findling JW, et
al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab 2008;93:1526–1540.)
Patients with an abnormal result should see an endocrinologist and undergo a
second test, either one of the above or, in some cases, a serum midnight cortisol
or dexamethasone CRH test. These guidelines are summarized in Figure 35-7
(165).
Treatment of ACTH-Independent Forms of Cushing Syndrome
[5] Excluding cases that are of iatrogenic or factitious etiology, ACTHindependent forms of Cushing syndrome are adrenal in origin. Adrenal
cancers are usually very large by the time Cushing syndrome is manifest.
This is because the tumors are relatively inefficient synthesizers of steroid
hormones. Tumors are larger than 6 cm in diameter and are easily detectable by
computed tomography (CT) scanning or magnetic resonance imaging (MRI).
Adrenal cancers often produce steroids other than cortisol. Thus, when Cushing
syndrome is accompanied by hirsutism or virilization in women or feminization
2135in men, adrenal cancer should be suspected.
An adrenal tumor that appears large and irregular on radiologic imaging is
suggestive of carcinoma. In these cases, a unilateral adrenalectomy through an
abdominal exploratory approach is preferable. In most malignant tumors,
complete resection is virtually impossible. However, a partial response to
postoperative chemotherapy or radiation may be achieved. Most patients with
malignancy die within 1 year. When administered immediately after surgery,
mitotane (O,P-DDD, an adrenocorticolytic drug) may be of benefit in preventing
or delaying recurrent disease (168). Manifestations of Cushing syndrome in these
patients are controlled by adrenal enzyme inhibitors.
Adrenal adenomas are smaller than carcinomas and on average 3 cm in
diameter. These tumors are usually unilateral and infrequently associated with
other steroid-mediated syndromes. Micronodular adrenal disease is a disorder of
children, adolescents, and young adults. The adrenal glands contain numerous
small (>3 mm) nodules, which often are pigmented and secrete sufficient cortisol
to suppress pituitary ACTH. This condition can be sporadic or familial.
Surgical removal of a neoplasm is the treatment of choice (169,170). If a
unilateral, well-circumscribed adenoma is identified by MRI or CT scanning, the
flank approach may be the most convenient. The cure rate following surgical
removal of adrenal adenomas approaches 100%. Because normal function of the
HPA axis is suppressed by autonomous cortisol production, cortisol replacement
follows surgery and is titrated downward over several months, during which
recovery of normal adrenal function is monitored.
Treatment of Cushing Disease
The main goals of treatment in ACTH-dependent Cushing syndrome are reversal
of clinical features, normalization of biochemical changes with minimal
morbidity, and long-term control without recurrence (166).
The treatment of choice for Cushing disease is transsphenoidal resection.
The remission rate is approximately 70% to 90% and the recurrence rate is 5% to
10% at 5 years and 10% to 20% at 10 years in patients with microadenomas who
undergo surgery by an experienced surgeon (171–175). Patients with
macroadenoma have lower remission rates (<60%) and higher recurrence rates
(12% to 45%) (176–178). Following surgery, transient diabetes insipidus and
enduring compromise of anterior pituitary secretion of growth hormone,
gonadotropins, and TSH are common (178,179).
Radiation Therapy
Fractionated external beam radiotherapy or stereotactic radiosurgery is used to
treat patients with Cushing disease in whom transsphenoidal microsurgery was
2136not successful or in patients who are poor surgical candidates. This therapy can
achieve control of hypercortisolemia in approximately 50% to 60% of patients
within 3 to 5 years (166,180,181). Hypopituitarism is the most common side
effect of pituitary irradiation, and long-term follow-up is essential to detect
relapse, which can occur after an initial response to radiotherapy.
High-voltage external pituitary radiation (4,200 to 4,500 cGy) is given at a rate
not exceeding 200 cGy per day. Only 15% to 25% of adults show total
improvement, but approximately 80% of children respond (179,182).
Medical Therapy
Mitotane can be used to induce medical adrenalectomy during or after pituitary
radiation (168). The role of medical therapy is to prepare the severely ill patient
for surgery and to maintain normal cortisol levels while a patient awaits the full
effect of radiation. Occasionally, medical therapy is used for patients who respond
to therapy with only partial remission. Adrenal enzyme inhibitors include
aminoglutethimide, metyrapone, trilostane, and etomidate.
A combination of aminoglutethimide and metyrapone may cause a total adrenal
enzyme block, requiring corticosteroid-replacement therapy. Ketoconazole, an
FDA-approved antifungal agent, inhibits adrenal steroid biosynthesis at the side
arm cleavage and 11β-hydroxylation steps. The dose of ketoconazole for adrenal
suppression is 600 to 800 mg per day for 3 months to 1 year (183). Ketoconazole
is effective for long-term control of hypercortisolism of either pituitary or adrenal
origin.
Nelson syndrome results from adenomatous progression of ACTH-secreting
cells in patients with Cushing syndrome treated with bilateral adrenalectomy. The
macroadenoma that causes this syndrome produces sellar pressure symptoms of
headaches, visual field disturbances, and ophthalmoplegia. Extremely high ACTH
levels in Nelson syndrome are associated with severe hyperpigmentation
(melanocyte-stimulating hormone activity). The treatment is surgical removal or
radiation. The offending adenomatous tissue is often resistant to complete surgical
removal (184). This syndrome reportedly complicates 10% to 50% of bilateral
adrenalectomy cases. Measuring pituitary MRI and ACTH plasma levels at
regular intervals after bilateral adrenalectomy will allow detection of the early
progression of corticotroph tumors and the possibility of cure by surgery,
particularly with microadenomas (166). Nelson syndrome is less common today
because bilateral adrenalectomy is less frequently used as initial treatment.
Congenital Adrenal Hyperplasia
[6] CAH is transmitted as an autosomal recessive disorder. Several
adrenocortical enzymes necessary for cortisol biosynthesis may be affected.
2137Failure to synthesize the fully functional enzyme has the following effects:
1. A relative decrease in cortisol production
2. A compensatory increase in ACTH levels
3. Hyperplasia of the zona reticularis of the adrenal cortex
4. An accumulation of the precursors of the affected enzyme in the bloodstream
21-Hydroxylase Deficiency
Deficiency of 21-hydroxylase is responsible for over 90% of all cases of adrenal
hyperplasia as a result of adrenal synthetic enzyme deficiency. The disorder
produces a spectrum of conditions; CAH, with or without salt wasting, and milder
forms that are expressed as HA of pubertal onset (adult-onset adrenal hyperplasia,
AOAH). Salt-wasting CAH, the most severe form, affects 75% of patients with
congenital manifestations during the first 2 weeks of life and results in a lifethreatening hypovolemic salt-wasting crisis, accompanied by hyponatremia,
hyperkalemia, and acidosis. The salt-wasting form results from a severity of
enzyme deficiency sufficient to result in ineffective aldosterone synthesis. With or
without salt-wasting and newborn adrenal crisis, the condition is usually
diagnosed earlier in affected female newborns than in males as genital virilization
(e.g., clitoromegaly, labioscrotal fusion, and abnormal urethral course) is apparent
at birth.
In simple virilizing CAH, affected patients are diagnosed as virilized newborn
females or as rapidly growing masculinized boys at 3 to 7 years of age. Diagnosis
is based on basal levels of the substrate for 21-hydroxylase, 17-OHP; in cases of
congenital adrenal hyperplasia as a result of 21-hydroxylase deficiency and in
milder forms of the disorder with manifestations later in life (acquired, late-onset,
or adult-onset adrenal hyperplasia), diagnosis depends on basal and ACTHstimulated levels of 17-OHP.
Patients with morning follicular phase 17-OHP levels of less than 300 ng/dL
(10 nmol/L) are likely unaffected. When levels are greater than 300 ng/dL, but
less than 10,000 ng/dL (300 nmol/L), ACTH testing should be performed to
distinguish between 21-hydroxylase deficiency and other enzyme defects or to
make the diagnosis in borderline cases. Levels greater than 10,000 ng/dL (300
nmol/L) are virtually diagnostic of congenital adrenal hyperplasia.
Nonclassic Adult-Onset Congenital Adrenal Hyperplasia
The nonclassic type of 21-hydroxylase deficiency represents partial deficiency in
21-hydroxylation, which produces a late-onset, milder hyperandrogenemia. Its
occurrence depends on some degree of functional deficit resulting from mutations
affecting both alleles for the 21-hydroxylase enzyme. Heterozygote carriers for
2138mutations in the 21-hydroxylase enzyme will demonstrate normal basal and
modestly elevated stimulated levels of 17-OHP, but no abnormalities in
circulating androgens. Some women with mild gene defects in both alleles
demonstrate modest elevations in circulating 17-OHP concentrations, but no
clinical symptoms or signs.
The hyperandrogenic symptoms of AOAH are mild and typically present at or
after puberty. The three phenotypic varieties are as follows (185):
1. Those with ovulatory abnormalities and features consistent with PCOS (39%)
2. Those with hirsutism alone without oligomenorrhea (39%)
3. Those with elevated circulating androgens but without symptoms (cryptic)
(22%)
Precocious puberty (PP) reveals late-onset congenital adrenal hyperplasia in
5% to 20% of cases that mainly are caused by nonclassic 21-hydroxylase
deficiency.
Measurement of 17-OHP should be performed in patients presenting with PP,
and a subsequent ACTH stimulation test is recommended if basal 17-OHP is
greater than 200 ng/dL.
The need for screening patients with hirsutism for adult-onset adrenal
hyperplasia depends on the patient population. The frequency of some form of the
disorder varies by ethnicity and is estimated at 0.1% of the general population,
1% to 2% of Hispanics and Yugoslavs, and 3% to 4% of Ashkenazi Jews (186).
Genetics of 21-Hydroxylase Deficiency
1. The 21-hydroxylase gene is at 6p21.3 amid HLA B and HLA DR genes of the
human leukocyte antigen (HLA).
2. The 21-hydroxylase gene is now termed CYP21. Its homolog is the
pseudogene CYP21P (187).
3. Because CYP21P is a pseudogene, the lack of transcription renders it
nonfunctional. The CYP21 is the active gene.
4. The CYP21 gene and the CYP21P pseudogene alternate with two genes called
C4B and C4A, both of which encode for the fourth component (C4) of serum
complement (187).
5. The close linkage between the 21-hydroxylase genes and HLA alleles has
allowed the study of 21-hydroxylase inheritance patterns in families through
blood HLA typing (e.g., linkage of HLA-B14 was found in Ashkenazi Jews,
Hispanics, and Italians) (188).
Prenatal Diagnosis and Treatment
2139Women with congenital and adult-onset forms of the disorder are at a significant
risk for having affected infants, owing to the high frequency of 21-hydroxylase
mutations in the general population. This presents an important rationale for
screening hyperandrogenic women for this disorder when they anticipate
childbearing. In families at risk for CAH and in instances where one partner
expresses the congenital or adult-onset form of the disease, first-trimester prenatal
screening using chorionic villus sampling is advocated (187). The fetal DNA is
used for specific amplification of the CYP21 gene using polymerase chain
reaction (PCR) amplification (189). When the fetus is at risk for CAH, maternal
dexamethasone treatment can suppress the fetal HPA axis and prevent genital
virilization in affected females (190). The dose is 20 μg/kg in three divided doses
administered as soon as pregnancy is recognized and no later than 9 weeks of
gestation. This is done prior to performing chorionic villus sampling or
amniocentesis in the second trimester. Dexamethasone crosses the placenta and
suppresses ACTH in the fetus. If the fetus is determined to be an unaffected
female or a male, treatment is discontinued. If the fetus is an affected female,
dexamethasone therapy is continued.
The practice of prenatal dexamethasone treatment for women whose fetuses are
at risk for CAH is controversial; seven of eight pregnancies will be treated with
dexamethasone unnecessarily, albeit briefly, to prevent one case of ambiguous
genitalia. The efficacy and safety of prenatal dexamethasone treatment is not
established, and long-term follow-up data on the offspring of treated pregnancies
are lacking (191).
Numerous studies in experimental animal models showed that prenatal
dexamethasone exposure could impair somatic growth, brain development, and
blood pressure regulation. A human study of 40 fetuses at risk for CAH who were
treated prenatally with dexamethasone to prevent virilization of affected females
reported long-term effects on neuropsychological functions and scholastic
performance (190,192).
The 2010 Endocrine Society guidelines conclude that prenatal dexamethasone
therapy should be pursued only through institutional review boards’ approved
protocols at centers capable of collecting sufficient outcome data (193).
11β-Hydroxylase Deficiency
In a small percentage of patients with CAH, hypertension, rather than
mineralocorticoid deficiency, develops. The hypertension responds to
corticosteroid replacement (194–197). Many of these patients have a deficiency in
11β-hydroxylase (195,196). In most populations, 11β-hydroxylase deficiency
accounts for 5% to 8% of the cases of CAH, or 1 in 100,000 births (197). A much
higher incidence, 1 in 5,000 to 7,000, was described in Moroccan Jewish
2140immigrants (197).
Two 11β-hydroxylase isoenzymes are responsible for cortisol and aldosterone
synthesis, respectively, CYP11-B1 and CYP11-B2. They are encoded by two
genes on the middle of the long arm of chromosome 8 (198–200).
Inability to synthesize a fully functional 11β-hydroxylase enzyme causes a
decrease in cortisol production, a compensatory increase in ACTH secretion, and
increased production of androstenedione, 11-deoxycortisol, 11-
deoxycorticosterone, and DHEA. The diagnosis of 11β-hydroxylase-deficient
late-onset adrenal hyperplasia is determined when 11-deoxycortisol levels are
higher than 25 ng/mL 60 minutes after ACTH(1-24) stimulation (201).
Patients with 11β-hydroxylase deficiency may present with either a classic
pattern of the disorder or symptoms of a mild deficiency. The severe classic form
is found in about two-thirds of the patients with mild-to-moderate hypertension
during the first years of life. In about one-third of the patients, it is associated with
left ventricular hypertrophy, with or without retinopathy, and occasionally death
is reported from cerebrovascular accident (194). Signs of androgen excess are
common in the severe form and are similar to those seen in the 21-hydroxylase
deficiency.
In the mild, nonclassic form, children have virilization or PP but not
hypertension. Adult women seek treatment for postpubertal onset of hirsutism,
acne, and amenorrhea.
3aβ-Hydroxysteroid Dehydrogenase Deficiency
Deficiency of 3β-HSD occurs with varying frequency in hirsute patients
(202,203). The enzyme is found in the adrenal glands and ovaries (unlike 21- and
11-hydroxylase) and is responsible for transforming Δ-5 steroids into the
corresponding Δ-4 compounds, a step integral to the synthesis of glucocorticoids,
mineralocorticoids, testosterone, and estradiol. In severe forms, cortisol and
mineralocorticoids are deficient. The clinical spectrum of 3β-HSD deficiency
ranges from the classic salt wasting, hypogonadism, and ambiguous genitalia in
males and females, to nonclassic hyperandrogenic symptoms in children and
young women (204). In mild forms, elevated ACTH levels overcome these
critical deficiencies, and the diagnosis of this disorder relies on the relationship of
Δ-5 and Δ-4 steroids. A marked elevation of DHEA and DHEAS in the presence
of normal, or mildly elevated, testosterone or androstenedione can suggest the
initiation of a screening protocol for 3β-HSD deficiency using exogenous ACTH
stimulation (202). Following intravenous administration of a 0.25-mg ACTH(1-
24) bolus, within 60 minutes, 17-hydroxypregnenolone levels rise significantly in
women with 3β-HSD deficiency, compared with normal women (2,276 ng/dL
compared with normal of 1,050 ng/dL). The mean poststimulation ratio between
214117-hydroxypregnenolone and 17-OHP is markedly elevated (mean ratio of 11
compared with 3.4 in normal controls and 0.4 in 21-hydroxylase deficiency). The
rarity of this disorder indicates that routine screening of hyperandrogenic patients
is not justified (202,203).
Treatment of Adult-Onset Congenital Adrenal Hyperplasia
Many patients with congenital AOAH do not need treatment. Glucocorticoid
treatment should be avoided in asymptomatic patients with AOAH because the
potential adverse effects of glucocorticoids probably outweigh any benefits
(191,193).
Glucocorticoid therapy is recommended only to reduce HA for those with
significant symptoms. Dexamethasone and antiandrogen drugs (both cross the
placenta) should be used with caution and in conjunction with OCs in adolescent
girls and young women with signs of virilization or irregular menses. When
fertility is desired, ovulation induction might be necessary, and a glucocorticoid
that does not cross the placenta (e.g., prednisolone or prednisone) should be used
(190).
Many patients, those who are undiagnosed but actually have AOAH, are
treated with therapies for ovarian HA and/or PCOS, with progestins for
endometrial regulation, clomiphene, letrozole, or gonadotropins for ovulation
induction, or progestins and antiandrogens for control of hirsutism. These
therapies may be appropriate, as an alternative to glucocorticoid therapy, even
when AOAH is recognized as the cause for the patient’s symptoms.
Androgen-Secreting Ovarian and Adrenal Tumors
[7] Patients with severe hirsutism, virilization, or recent and rapidly
progressing signs of androgen excess require careful investigation for the
presence of an androgen-secreting neoplasm. The two most common sources
of androgen-secreting tumors are the adrenal glands and the ovaries. To
assess the symptoms, serum and urine tests for androgens and their metabolites
should be obtained along with modern abdominal imaging techniques such as CT,
MRI, and ultrasound scans (205). In prepubertal girls, virilizing tumors may cause
signs of heterosexual PP in addition to hirsutism, acne, and virilization. In
patients suspected of harboring an adrenal or ovarian tumor because of rapidly
progressing or severe HA, the bioavailable testosterone level (free testosterone
level above 6.85 pg/mL; 23.6 pmol/L), followed by an 11-desoxycortisol (above 7
ng/mL; 20.2 nmol/L), DHEAS (>3.6 μg/mL), and a 24-hour urinary cortisol (>45
μg per day) are the most sensitive and specific for the detection of an ACT-AS
(Table 35-2). A markedly elevated free testosterone level (2.5 times the upper
2142normal range) is considered typical of an adrenal androgen-secreting tumor, while
moderately elevated free testosterone levels are often ovarian in origin. A
DHEAS level greater than 800 μg/dL is typical of an adrenal tumor. An adrenal
tumor is unlikely when serum DHEAS and urinary 17-ketosteroid excretion
measurements are in the normal basal range and the serum cortisol concentration
is less than 3.3 μg/dL after dexamethasone administration (206). The results of
other dynamic tests, especially testosterone suppression and stimulation, are
unreliable (207).
A vaginal and abdominal ultrasonographic examination is the first step in the
evaluation of findings suggesting an ovarian neoplasm. Duplex Doppler scanning
may increase the accuracy of tumor diagnosis and localization (208).
CT scanning can reveal tumors larger than 10 mm (1 cm) in the adrenal gland
but may not help to distinguish among different types of solid tumors or benign
incidental nodules (209). In the ovaries, CT scanning cannot help differentiate
hormonally active from functional tumors (208,209).
MRI is comparable, if not superior, to CT scanning in detecting ovarian
neoplasms, but is neither more sensitive than high-quality ultrasound nor more
useful in clinical decision-making when ultrasound identifies a likely neoplasm.
Nuclear medicine imaging of the abdomen and pelvis after injection with NP-59
((131-iodine) 6-beta-iodomethyl-19-norcholesterol), preceded by adrenal and
thyroid suppression, may facilitate tumor localization. In the rare circumstances
when imaging fails to provide clear evidence for a neoplastic source of excess
androgens, selective venous catheterization with measurement of site-specific
androgen levels to identify an occult source of for androgen excess may be
utilized (210). If all four vessels are catheterized transfemorally, selective venous
catheterization allows direct localization of the tumor. Samples are obtained for
hormonal analysis, with positive localization defined as a 5:1 testosterone
gradient compared with lower vena cava values (211). Under such circumstances,
specificity approaches 80%, but this rate should be weighed against the 5% rate of
significant complications, such as adrenal hemorrhage and infarction, venous
thrombosis, hematoma, and radiation exposure (212).
Androgen-Producing Ovarian Neoplasms
Ovarian neoplasms are the most frequent androgen-producing tumors. Granulosa
cell tumors constitute 1% to 2% of all ovarian tumors and occur mostly in adult
women (more frequently in postmenopausal than in premenopausal women; see
Chapter 39). Usually associated with estrogen production, they are the most
common functioning tumors in children and can lead to isosexual PP (213).
Patients can present with vaginal bleeding caused by endometrial hyperplasia or
endometrial cancer resulting from prolonged exposure to tumor-derived estrogen
2143(214). Total abdominal hysterectomy and bilateral salpingo-oophorectomy are the
treatments of choice. If fertility is desired, a more conservative approach
involving unilateral salpingo-oophorectomy with careful staging can be
performed in women with stage IA (the cancer does not extend outside the
involved ovary and a concomitant uterine cancer is excluded) (214). The
malignant potential of these lesions is variable. The 10-year survival rates vary
from 60% to 90%, depending on the stage, tumor size, and histologic atypia
(213).
Thecomas are rare and occur in older patients. In one study, only 11% were
androgenic, even in the presence of steroid-type cells (luteinized thecomas) (213).
They are unilateral in more than 90% of the cases and rarely malignant. A
unilateral salpingo-oophorectomy is adequate treatment (215).
Sclerosing stromal tumors are benign neoplasms that usually occur in patients
younger than 30 years (213). A few cases with estrogenic or androgenic
manifestations were reported.
Sertoli–Leydig cell tumors, previously classified as androblastoma or
arrhenoblastoma, account for 11% of solid ovarian tumors. They contain various
proportions of Sertoli cells, Leydig cells, and fibroblasts (213). Sertoli–Leydig
cell tumors are the most common virilizing tumors in women of reproductive age;
however, masculinization occurs in only one-third of patients. The tumor is
bilateral in 1.5%. In 80% of cases, it is diagnosed at stage IA (213). Sertoli–
Leydig cell tumors are frequently low-grade malignancies, and their prognosis is
related to their degree of differentiation and stage of disease (216). Treatment
with unilateral salpingo-oophorectomy is justified in patients with stage IA
disease who desire fertility. Total abdominal hysterectomy, bilateral salpingooophorectomy, and adjuvant therapy are recommended for postmenopausal
women who have advanced-stage disease.
Pure Sertoli cell tumors are usually unilateral. For a premenopausal woman
with stage I disease, a unilateral salpingo-oophorectomy is the treatment of
choice. Malignant tumors are rapidly fatal (217).
Gynandroblastomas are benign tumors with well-differentiated ovarian and
testicular elements. A unilateral oophorectomy or salpingo-oophorectomy is
sufficient treatment.
Sex cord tumors with annular tubules (SCTAT) are frequently associated with
Peutz–Jeghers syndrome (gastrointestinal polyposis and mucocutaneous melanin
pigmentation) (218). Their morphologic features range between those of the
granulosa cell and Sertoli cell tumors.
While SCTAT with Peutz–Jeghers syndrome tends to be bilateral and benign,
SCTAT without Peutz–Jeghers syndrome is almost always unilateral and
malignant in one-fifth of cases (213).
2144Steroid Cell Tumors
According to Young and Scully, steroid cell tumors are composed entirely of
steroid-secreting cells subclassified into stromal luteoma, Leydig cell tumors
(hilar and nonhilar), and steroid cell tumors that are not otherwise specific (213).
Virilization or hirsutism is encountered with three-fourths of Leydig cell tumors,
with one-half of steroid cell tumors not otherwise specific, and with 12% of
stromal luteomas.
Nonfunctioning Ovarian Tumors
Ovarian neoplasms that do not directly secrete androgens are occasionally
associated with androgen excess, resulting from excess secretion by adjacent
ovarian stroma, and include serous and mucinous cystadenomas, Brenner tumors,
Krukenberg tumors, benign cystic teratomas, and dysgerminomas (219).
Gonadoblastomas arising in the dysgenetic gonads of patients with a Y
chromosome are rarely associated with androgen and estrogen secretion
(220,221).
Stromal Hyperplasia and Stromal Hyperthecosis
Stromal hyperplasia is a nonneoplastic proliferation of ovarian stromal cells.
Stromal hyperthecosis is defined as the presence of luteinized stromal cells at a
distance from the follicles (222). Stromal hyperplasia, which is typically seen in
patients between 60 and 80 years of age, may be associated with HA, endometrial
carcinoma, obesity, hypertension, and glucose intolerance (222,223).
Hyperthecosis is also seen in a mild form in older patients. In patients of
reproductive age, hyperthecosis may demonstrate severe clinical manifestations of
virilization, obesity, and hypertension (224). Hyperinsulinemia and glucose
intolerance may occur in up to 90% of patients with hyperthecosis and may play a
role in the etiology of stromal luteinization and HA (76). Hyperthecosis is found
in many patients with HAIR-AN syndrome.
In patients with hyperthecosis, levels of ovarian androgens, including
testosterone, DHT, and androstenedione, are increased, usually in the male range.
The predominant estrogen, as in PCOS, is estrone, which is derived from
peripheral aromatization. The E1-to-E2 ratio is increased. Unlike in PCOS,
gonadotropin levels are normal (225). Ovaries with stromal hyperthecosis have
variable sonographic appearances (226).
Wedge resection for the treatment of mild hyperthecosis was successful and
resulted in resumption of ovulation and a pregnancy (227). In cases of more
severe hyperthecosis and high total testosterone levels, the ovulatory response to
wedge resection is transient (225). In a study in which bilateral oophorectomy
2145was used to control severe virilization, hypertension and glucose intolerance
sometimes disappeared (228). When a GnRH agonist was used to treat patients
with severe hyperthecosis, ovarian androgen production was dramatically
suppressed (229).
Virilization During Pregnancy
Luteomas of pregnancy are frequently associated with maternal and fetal
masculinization. This is not a true neoplasm but rather a reversible hyperplasia,
which usually regresses postpartum. A review of the literature reveals a 30%
incidence of maternal virilization and a 65% incidence of virilized female
newborns in the presence of a pregnancy luteoma and maternal masculinization
(230–232).
Other tumors causing virilization in pregnancy include (in descending order of
frequency) Krukenberg tumors, mucinous cystic tumors, Brenner tumors, serous
cystadenomas, endodermal sinus tumors, and dermoid cysts (213).
Virilizing Adrenal Neoplasms
The most common virilizing adrenal neoplasms are adrenal carcinomas.
Adrenocortical carcinomas are rare aggressive tumors that have a bimodal age
incidence, with most cases presenting at ages 40 to 50 years (233). Virilization
was reported in 20% to 30% of adults with functional adrenocortical carcinoma
(234).
When these malignancies virilize, frequently they are associated with
elevations in 11-deoxycortisol, cortisol, and DHEAS. These tumors are
commonly large and often detectable on abdominal examination. Adrenal tumors
that secrete androgens exclusively, whether benign or malignant, are
extraordinarily rare (205,235). Modern imaging techniques, such as CT,
ultrasonography, MRI, or venous sampling, are extremely useful for
distinguishing between an ovarian and an adrenal tumor as a cause of virilization
(233).
PROLACTIN DISORDERS
Prolactin was first identified as a product of the anterior pituitary, in 1933
(236). It is found in nearly every vertebrate species. Its presence in humans was
long inferred by the association of the syndrome of amenorrhea and galactorrhea
in the presence of pituitary macroadenomas, though it was not definitively
identified as a human hormone until 1971. The specific activities of human
prolactin (hPRL) were defined by the separation of its activity from growth
2146hormone and subsequently by the development of radioimmunoassays (237–239).
Although the initiation and maintenance of lactation is the primary function
of prolactin, many studies document roles for prolactin activity within and
beyond the reproductive system.
Prolactin Secretion
There are 199 amino acids within hPRL, with a molecular weight (MW) of
23,000 D (Fig. 35-8). Although human growth hormone and placental lactogen
have significant lactogenic activity, they have only a 16% and 13% amino acid
sequence homology with prolactin, respectively. In the human genome, a single
gene on chromosome 6 encodes prolactin. The prolactin gene (10 kb) has five
exons and four introns, and its transcription is regulated in the pituitary by a
proximal promotor region and in extrapituitary locations by a more upstream
promotor (240).
FIGURE 35-8 Amino acid sequence of prolactin. Three cysteine disulfide bands are
located within the molecule. (With permission from Bondy PK. Rosenberg Leukocyte
Esterase: Metabolic Control and Disease. 8th ed. Philadelphia, PA: WB Saunders; 1980.)
In the basal state, three forms are released: a monomer, a dimer, and a
2147multimeric species, called little, big, and big-big prolactin, respectively (241–
243). The two larger species can be degraded to the monomeric form by reducing
disulfide bonds (244). The proportions of each of these prolactin species vary
with physiologic, pathologic, and hormonal stimulation (244–247). The
heterogeneity of secreted forms remains an active area of research. Studies
indicate that little prolactin (MW 23,000 D) constitutes more than 50% of all
combined prolactin production and is most responsive to extrapituitary
stimulation or suppression (244,246,247). Clinical assays for prolactin measure
the little prolactin, and in all but extremely rare circumstances, these
measures are sufficient to assess diseases of abnormal pituitary production of
the hormone. Prolactin, and its relatives, growth hormone and placental lactogen,
do not require glycosylation for most of their primary activities, as is the case for
the gonadotropins and TSH. Glycosylated forms are secreted, and glycosylation
does affect the bioactivity and immunoreactivity of little prolactin (248–251). It
appears that the glycosylated form is the predominant species secreted, but the
most potent biologic form appears to be the 23,000-D nonglycosylated form of
prolactin (250). Prolactin has over 300 known biologic activities. Prolactin’s most
recognized activities include those associated with reproduction (lactation, luteal
function, reproductive behavior) and homeostasis (immune responsivity,
osmoregulation, and angiogenesis) (252). Despite these many activities, the only
recognized disorder associated with deficiency of prolactin secretion is the
inability to lactate.
To some degree, the physical heterogeneity of prolactin may explain the
biologic heterogeneity of this hormone, and although this complicates the
physiologic evaluation of prolactin’s myriad effects, it is of little importance in
the diagnosis and management of hyperprolactinemic states.
In contrast to other anterior pituitary hormones, which are controlled by
hypothalamic-releasing factors, prolactin secretion is primarily under inhibitory
control mediated by dopamine. Multiple lines of evidence suggest that
dopamine, which is secreted by the tuberoinfundibular dopaminergic
neurons into the portal hypophyseal vessels, is the primary prolactininhibiting factor. Dopamine receptors were found on pituitary lactotrophs, and
treatment with dopamine or dopamine agonists suppresses prolactin secretion
(253–259). The dopamine antagonist metoclopramide abolishes the pulsatility of
prolactin release and increases serum prolactin levels (255,256,260). Interference
with dopamine transit from the hypothalamus to the pituitary by mass
lesions, or blockade of the dopamine receptor as that occurs with
antipsychotic and other medications, increases serum prolactin levels.
Thyrotropin-releasing hormone (TRH) causes prolactin release when present at
supraphysiologic levels (as in primary hypothyroidism), but does not appear to
2148play an important modulatory role in the normal physiologic regulation of
prolactin secretion. GABA and other neurohormones and neurotransmitters also
may function as prolactin-inhibiting factors (261–264). Several hypothalamic
polypeptides that modulate prolactin-releasing activity are listed in Table 35-8. It
appears that dopamine and TRH act as primary controlling neurohormones, while
others (i.e., neuropeptide Y, galanin, and enkephalin) act as modulators. It is
likely that under differing physiologic conditions (i.e., pregnancy, lactation,
stress, aging), a modulator may become a principal regulator of hormone
secretion.
The prolactin receptor is a member of the class 1 cytokine receptor superfamily
and is encoded by a gene on chromosome 5 (265). Transcriptional regulation of
the prolactin receptor is accomplished through three tissue-specific promoter
regions: promoter I for the gonads, promoter II for the liver, and promoter III, a
generic promoter that includes the mammary gland (266).
Hyperprolactinemia
Physiologic disturbances, pharmacologic agents, or markedly compromised
renal function may cause elevations in prolactin levels, and transient
elevations occur with acute stress or painful stimuli. The most common cause
of elevated prolactin levels is likely pharmacologic; most patients using
antipsychotic medications and many other patients using agents with
antidopaminergic properties will exhibit moderately elevated prolactin
levels. Drug-related and physiologic conditions resulting in hyperprolactinemia
do not always require direct intervention to normalize prolactin levels.
Table 35-8 Chemical Factors Modulating Prolactin Release and Conditions That
Result in Hyperprolactinemia
Inhibitory factors
Dopamine
γ-Aminobutyric acid
Histidyl-proline diketopiperazine
Pyroglutamic acid
Somatostatin
Stimulatory factors
2149b-Endorphin
17b-Estradiol
Enkephalins
Gonadotropin-releasing hormone
Histamine
Serotonin
Substance P
Thyrotropin-releasing hormone
Vasoactive intestinal peptide
Physiologic conditions
Anesthesia
Empty sella syndrome
Idiopathic
Intercourse
Major surgery and disorders of chest wall (burns, herpes, chest percussion)
Newborns
Nipple stimulation
Pregnancy
Postpartum (nonnursing: days 1–7; nursing: with suckling)
Sleep
Stress
Postpartum
Hypothalamic conditions
Arachnoid cyst
2150Craniopharyngioma
Cystic glioma
Cysticercosis
Dermoid cyst
Epidermoid cyst
Histiocytosis
Neurotuberculosis
Pineal tumors
Pseudotumor cerebri
Sarcoidosis
Suprasellar cysts
Tuberculosis
Pituitary conditions
Acromegaly
Addison disease
Craniopharyngioma
Cushing syndrome
Hypothyroidism
Histiocytosis
Lymphoid hypophysitis
Metastatic tumors (especially of the lungs and breasts)
Multiple endocrine neoplasia
Nelson syndrome
Pituitary adenoma (microadenoma or macroadenoma)
2151Post-oral contraception
Sarcoidosis
Thyrotropin-releasing hormone administration
Trauma to stalk
Tuberculosis
Metabolic dysfunction
Ectopic production (hypernephroma, bronchogenic sarcoma)
Hepatic cirrhosis
Renal failure
Starvation refeeding
Drug conditions
α-Methyldopa
Antidepressants (amoxapine, imipramine, amitriptyline)
Cimetidine
Dopamine antagonists (phenothiazines, thioxanthenes, butyrophenone,
diphenylbutylpiperidine, dibenzoxazepine, dihydroindolone, procainamide,
metoclopramide)
Estrogen therapy
Opiates
Reserpine
Sulpiride
Verapamil
Evaluation
Plasma levels of immunoreactive prolactin are 5 to 27 ng/mL throughout the
normal menstrual cycle. Samples should not be drawn soon after the patient
awakes or after procedures. Prolactin is secreted in a pulsatile fashion with a
2152pulse frequency ranging from about 14 pulses per 24 hours in the late
follicular phase to about 9 pulses per 24 hours in the late luteal phase. There
is also a diurnal variation, with the lowest levels occurring in midmorning.
Levels rise 1 hour after the onset of sleep and continue to rise until peak values
are reached between 5 and 7 am (267,268). The pulse amplitude of prolactin
appears to increase from early to late follicular and luteal phases (269–271).
Because of the variability of secretion and inherent limitations of
radioimmunoassay, an elevated level should always be rechecked. This sample
preferably is drawn midmorning and not after stress, previous venipuncture,
breast stimulation, or physical examination, all of which transiently increase
prolactin levels.
When prolactin levels are found to be elevated, hypothyroidism and
medications should first be ruled out as a cause. Prolactin and TSH
determinations are basic evaluations in anovulatory infertile women. Infertile
men with hypogonadism also should be tested. Likewise, prolactin levels should
be measured in the evaluation of amenorrhea, galactorrhea, hirsutism with
amenorrhea, anovulatory bleeding, and delayed puberty (Fig. 35-9).
In cases of asymptomatic, incidental hyperprolactinemia, the finding of a
macroprolactin elevation will preclude further diagnostic workup and expense as
big and big-big prolactin elevations are not associated with adenomas or
recognized symptomatology (272).
Physical Signs of Hyperprolactinemia
[8] Elevations in prolactin may cause amenorrhea, galactorrhea, both, or
neither. Amenorrhea without galactorrhea is associated with
hyperprolactinemia in approximately 15% of women (273–275). The
cessation of normal ovulatory processes resulting from elevated prolactin levels is
primarily caused by the suppressive effects of prolactin, via hypothalamic
mediation, on GnRH pulsatile release (254,273,274,276–284). In addition to
causing a hypogonadotropic state, prolactin elevations may secondarily impair the
mechanisms of ovulation by causing a reduction in granulosa cell number and
FSH binding, inhibition of granulosa cell 17β-estradiol production by interfering
with FSH action, and by causing inadequate luteinization and reduced luteal
secretion of progesterone (285–290). Other etiologies for amenorrhea are detailed
in Chapter 34.
Although isolated galactorrhea is considered indicative of
hyperprolactinemia, prolactin levels are within the normal range in nearly
50% of such patients (291–293) (Fig. 35-9). In these cases, whether caused by a
prior transient episode of hyperprolactinemia or other unknown factors, the
sensitivity of the breast to the lactotrophic stimulus engendered by normal
2153prolactin levels is sufficient to result in galactorrhea. This situation is very similar
to that observed in nursing mothers in whom milk secretion, once established,
continues and even increases despite progressive normalization of prolactin
levels. Repeat testing is occasionally helpful in detecting hyperprolactinemia.
Approximately one-third of women with galactorrhea have normal menses.
Conversely, hyperprolactinemia commonly occurs in the absence of
galactorrhea (66%), which may result from inadequate estrogenic or
progestational priming of the breast.
[8] In patients with both galactorrhea and amenorrhea, approximately twothirds will have hyperprolactinemia; in that group, approximately one-third
will have a pituitary adenoma (294). In anovulatory women, 3% to 10% of
women diagnosed with PCO disease have coexistent and usually modest
hyperprolactinemia (295,296) (Fig. 35-10).
Prolactin and TSH levels should be measured in all patients with delayed
puberty. Pituitary abnormalities, including craniopharyngiomas and adenomas,
should be considered in all cases of delayed puberty accompanied by low levels
of gonadotropins, regardless of whether prolactin levels are elevated. When
prolactin-secreting pituitary adenomas are present, the condition of multiple
endocrine neoplasia type 1 (MEN-1) syndrome (gastrinomas, insulinoma,
parathyroid hyperplasia, and pituitary neoplasia) should be considered, although
symptoms of pituitary adenoma are rarely the presenting symptom. Patients who
have a pituitary adenoma and a family history of multiple adenomas warrant
special attention (297). Prolactinomas are noted in approximately 20% of patients
with MEN-1. The MEN-1 gene is localized to chromosome 11q13 and appears to
act as a constitutive tumor suppressor gene. An inactivating mutation results in
development of the tumor. It is thought that prolactin-secreting pituitary
adenomas that occur in patients with MEN-1 may be more aggressive than
sporadic cases (298).
When an elevated prolactin level is documented and medications or
hypothyroidism as the underlying cause is excluded, knowledge of neuroanatomy,
imaging techniques, and their interpretation is essential to further evaluation (see
Chapter 7). Pituitary hyperprolactinemia is most often caused by a
microadenoma or associated with normal imaging findings. These patients
can be reassured that the probable course of their condition is benign.
Macroadenomas or juxtasellar lesions are less common and require more
complex evaluation and treatment, including surgery, radiation, or both.
Levels of TSH should be measured in all patients with hyperprolactinemia (Fig.
35-9).
Imaging Techniques
2154In patients with larger microadenomas and macroadenomas, prolactin levels
usually are higher than 100 ng/mL. However, levels lower than 100 ng/mL
may be associated with smaller microadenomas, macroadenomas that
produce a “stalk section” effect, and suprasellar tumors that may be missed
on a “coned-down” view of the sella turcica. Modest elevations of prolactin can
be associated with microadenomas or macroadenomas, nonlactotroph pituitary
tumors, and other central nervous system abnormalities. Imaging of the pituitary
gland must be considered when otherwise unexplained and persistent prolactin
elevation is present. In patients with a clearly identifiable drug-induced or
physiologic hyperprolactinemia, imaging is not necessary unless
accompanied by symptoms suggesting a mass lesion (headache, visual field
deficits). MRI with gadolinium enhancement of the sella and pituitary gland
appears to provide the best anatomic detail (299). The cumulative radiation dose
from multiple CT scans may cause cataracts, and the “coned-down” views or
tomograms of the sella are very insensitive and expose the patient to radiation.
For patients with hyperprolactinemia who desire future fertility, MRI is indicated
to differentiate a pituitary microadenoma from a macroadenoma and to identify
other potential sellar-suprasellar masses. Although rare, when pregnancy-related
complications of a pituitary adenoma occur, they occur more frequently in the
presence of macroadenomas.
21552156FIGURE 35-9 Workup for hyperprolactinemia. TSH, thyroid-stimulating hormone; MRI,
magnetic resonance imaging; CT, computed tomography; HRT, hormone replacement
therapy; OCPs, oral contraceptive pills; CNS, central nervous system.
FIGURE 35-10 Prolactin levels in 235 patients with galactorrhea. Among patients with a
tumor, open triangles denote associated acromegaly, and solid circles and solid triangles
2157denote previous radiotherapy or surgical resection, respectively. (With permission from
Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48
with pituitary tumors. N Engl J Med 1977;296: 589–600.)
In over 90% of untreated women, microadenomas do not enlarge over a 4-
to 6-year period. The argument that medical therapy will prevent a
microadenoma from growing is false. While prolactin levels correlate with tumor
size, both elevations and reductions in prolactin levels may occur without any
change in tumor size. If during follow-up, the prolactin level rises significantly or
central nervous system symptoms (headache, visual changes) are noted, repeat
imaging may be indicated.
Hypothalamic Disorders
Dopamine was the first of many substances whose production was demonstrated
in the arcuate nucleus. Dopamine-releasing neurons innervate the external zone of
the median eminence. When released into the hypophyseal portal system,
dopamine inhibits prolactin release in the anterior pituitary. Lesions that disrupt
dopamine release can result in hyperprolactinemia. Such lesions may arise
from the suprasellar area, pituitary gland, and infundibular stalk, as well as from
adjacent bone, brain, cranial nerves, dura, leptomeninges, nasopharynx, and
vessels. Numerous pathologic entities and physiologic conditions in the
hypothalamic–pituitary region can disrupt dopamine release and cause
hyperprolactinemia.
Pituitary Disorders
Microadenoma
In more than one-third of women with hyperprolactinemia, a radiologic
abnormality consistent with a microadenoma (<1 cm) is found. Release of
pituitary stem cell growth inhibition via activation or loss-of-function
mutations results in cell cycle dysregulation and is critical to the development
of pituitary microadenomas and macroadenomas. Microadenomas are
monoclonal in origin. Genetic mutations are thought to release stem cell
growth inhibition and result in autonomous anterior pituitary hormone
production, secretion, and cell proliferation. Additional anatomic factors
that may contribute to adenoma formation include reduced dopamine
concentrations in the hypophyseal portal system and vascular isolation of the
tumor, or both. Recently, the heparin-binding secretory-transforming (HST)
gene has been noted in a variety of cancers and in prolactinomas (300).
Patients with microadenomas can be reassured of a probable benign course,
and many of these lesions exhibit gradual spontaneous regression (301,302).
2158Both microadenomas and macroadenomas are monoclonal in origin.
Lactotoph adenomas are histologically granulated either sparsely or densely. The
sparsely granulated lactotrope adenomas have trabecular, papillary, or solid
patterns. Calcification of these tumors may take the form of a psammoma body or
a pituitary stone. Densely granulated lactotrope adenomas are strongly acidophilic
tumors and appear to be more aggressive than sparsely granulated lactotrope
adenomas. Unusual acidophil stem cell adenomas can be associated with
hyperprolactinemia, with some clinical or biochemical evidence of growth
hormone excess.
Microadenomas rarely progress to macroadenomas. Six large series of
patients with microadenomas reveal that, with no treatment, the risk for
progression of microadenoma to a macroadenoma is only 7% (303). Treatments
include expectant, medical, or, rarely, surgical therapy. All affected women
should be advised to notify their physicians of chronic headaches, visual
disturbances (particularly tunnel vision consistent with bitemporal hemianopsia),
and extraocular muscle palsies. Formal visual field testing is rarely helpful, unless
imaging suggests compression of the optic nerves.
Autopsy and radiographic series reveal that 14.4% to 22.5% of the US
population harbor microadenomas, and approximately 25% to 40% stain
positively for prolactin (304). Clinically significant pituitary tumors requiring
some type of intervention affect only 14 per 100,000 individuals (304).
Expectant Management
In women who do not desire fertility, expectant management can be used for
microadenomas and hyperprolactinemia without an adenoma while
menstrual function remains intact. Hyperprolactinemia-induced estrogen
deficiency, rather than prolactin itself, is the major factor in the development of
osteopenia (305). Therefore, estrogen replacement with typical hormone
replacement regimens or hormonal contraceptives is indicated for patients
with amenorrhea or irregular menses. Patients with drug-induced
hyperprolactinemia can be managed expectantly with attention to the risks
of osteoporosis. In the absence of symptoms of pituitary enlargement,
imaging may be repeated in 12 months, and if prolactin levels remain stable,
less frequently thereafter, to assess further growth of the microadenoma.
Medical Treatment
Ergot alkaloids are the mainstay of therapy. In 1985, bromocriptine was
approved for use in the United States to treat hyperprolactinemia caused by a
pituitary adenoma. These agents act as strong dopamine agonists, thus decreasing
prolactin levels. Effects on prolactin levels occur within hours, and lesion size
2159may decrease within 1 or 2 weeks. Bromocriptine decreases prolactin synthesis,
DNA synthesis, cell multiplication, and overall size of prolactinomas.
Bromocriptine treatment results in normal prolactin blood levels or return of
ovulatory menses in 80% to 90% of patients.
Because ergot alkaloids, like bromocriptine, are excreted via the biliary tree,
caution is required when using it in the presence of liver disease. The major
adverse effects include nausea, headaches, hypotension, dizziness, fatigue and
drowsiness, vomiting, headaches, nasal congestion, and constipation. Many
patients tolerate bromocriptine when the dose is increased gradually, by 1.25
mg (one-half tablet) daily each week until prolactin levels are normal or a
dose of 2.5 mg twice daily is reached. A proposed regimen is as follows: onehalf tablet every evening (1.25 mg) for 1 week, one-half tablet morning and
evening (1.25 mg) during the second week, one-half tablet in the morning
(1.25 mg) and a full tablet every evening (2.5 mg) during the third week, and
one tablet every morning and every evening during the fourth week and
thereafter (2.5 mg twice a day). The lowest dose that maintains the prolactin
level in the normal range is continued (1.25 mg twice daily often is sufficient to
normalize prolactin levels in individuals with levels less than 100 ng/mL).
Pharmacokinetic studies show peak serum levels occur 3 hours after an oral dose,
with a nadir at 7 hours. Because little detectable bromocriptine is in the serum by
11 to 14 hours, twice-a-day administration is required. Prolactin levels can be
checked soon (6 to 24 hours) after the last dose.
One rare adverse effect of bromocriptine is a psychotic reaction. Symptoms
include auditory hallucinations, delusional ideas, and changes in mood that
quickly resolve after discontinuation of the drug (306).
Many investigators report no difference in fibrosis, calcification, prolactin
immunoreactivity, or the surgical success in patients pretreated with
bromocriptine compared with those not receiving bromocriptine (303).
An alternative to oral administration is the vaginal administration of
bromocriptine tablets, which is well tolerated, and actually results in increased
pharmacokinetic measures (307). Cabergoline, another ergot alkaloid, has a very
long half-life and can be given orally twice per week. Its long duration of action is
attributable to slow elimination by pituitary tumor tissue, high-affinity binding to
pituitary dopamine receptors, and extensive enterohepatic recirculation.
Cabergoline, which appears to be as effective as bromocriptine in lowering
prolactin levels and in reducing tumor size, has substantially fewer adverse effects
than bromocriptine. Very rarely, patients experience nausea and vomiting or
dizziness with cabergoline; they may be treated with intravaginal cabergoline as
with bromocriptine. A gradually increasing dosage helps avoid the side effects of
nausea, vomiting, and dizziness. Cabergoline at 0.25 mg twice per week is
2160usually adequate for hyperprolactinemia with values less than 100 ng/mL. If
required to normalize prolactin levels, the dosage can be increased by 0.25 mg per
dose on a weekly basis to a maximum of 1 mg twice weekly.
Recent studies reveal an increased risk of cardiac valve regurgitation in patients
with Parkinson disease who were treated with high doses of cabergoline or
pergolide but not with bromocriptine (308,309). Higher doses and a longer
duration of therapy were associated with a higher risk of valvulopathy. It is
postulated that 5HT2b-receptor stimulation leads to fibromyoblast proliferation
(310). A recent cross-sectional study showed a higher rate of asymptomatic
tricuspid regurgitation among cabergoline-treated patients compared with
untreated patients with newly diagnosed prolactinomas and normal controls
(311,312).
The demonstrated relative safety of bromocriptine in reproductive-aged
women and during more than 2,500 pregnancies suggests bromocriptine is the
first choice for hyperprolactinemia and micro- and macroadenomas (313).
When bromocriptine or cabergoline cannot be used, other medications such as
pergolide or metergoline may be used. In patients with a microadenoma who are
receiving bromocriptine therapy, a repeat MRI scan may be performed 6 to 12
months after prolactin levels are normal, if indicated. Normal prolactin levels and
resumption of menses should not be considered absolute proof of tumor response
to treatment. Further MRI scans should be performed if new symptoms appear.
Discontinuation of bromocriptine therapy after 2 to 3 years may be attempted
in a select group of patients who have maintained normoprolactinemia while on
therapy (314,315). In a retrospective series of 131 patients treated with
bromocriptine for a median of 47 months, normoprolactinemia was sustained in
21% at a median follow-up of 44 months after treatment discontinuation (315).
Discontinuation of cabergoline therapy was successful in patients treated for 3 to
4 years who maintained normoprolactinemia (316). In cabergoline discontinuers
who met stringent inclusion criteria, a recurrence rate of 64% was noted (317). A
meta-analysis involving 743 patients noted sustained normoprolactinemia in only
a minority of patients (21%) after discontinuation. Patients with 2 years or more
of therapy before discontinuation and no demonstrable tumor visible on MRI had
the highest chance of persistent normoprolactinemia (318). Recurrence rates are
higher for macroadenomas (as compared to microadenomas or
hyperprolactinemia without adenoma) after cessation of either bromocriptine or
cabergoline, warranting a close follow-up with serum prolactin and MRI after
cessation of therapy. In patients with macroadenomas, withdrawal of therapy
should proceed with caution, as rapid tumor re-expansion may occur.
Macroadenomas
2161Macroadenomas are pituitary tumors that are larger than 1 cm in size.
Bromocriptine is the best initial and potentially long-term treatment option, but
transsphenoidal surgery may be required. High-dose cabergoline therapy was
used in bromocriptine-resistant or -intolerant macroadenoma patients
successfully; however, cautions remain regarding the development of cardiac
valve abnormalities (319).
Evaluation for pituitary hormone deficiencies may be indicated. Symptoms of
macroadenoma enlargement include severe headaches, visual field changes, and,
rarely, diabetes insipidus and blindness. After prolactin has reached normal levels
following ergot alkaloid treatment, a repeat MRI is indicated within 6 months to
document shrinkage or stabilization of the size of the macroadenoma. This
examination may be performed earlier if new symptoms develop or if there is no
improvement in previously noted symptoms. Normalized prolactin levels or
resumption of menses should not be taken as absolute proof of tumor response to
treatment, particularly with a macroadenoma.
Medical Treatment
Treatment with bromocriptine decreases prolactin levels and the size of
macroadenomas; nearly one-half show a 50% reduction in size, and another onefourth show a 33% reduction after 6 months of therapy. Because tumor regrowth
occurs in more than 60% of cases after discontinuation of bromocriptine therapy,
long-term therapy is usually required.
After stabilization of tumor size is documented, the MRI scan is repeated 6–12
months later and, if stable, yearly for several years. This examination may be
performed earlier if new symptoms develop or if there is no improvement in
symptoms. Serum prolactin levels are measured every 6 months. Because tumors
may enlarge despite normalized prolactin values, a reevaluation of symptoms at
regular intervals (6 months) is prudent. Normalized prolactin levels or resumption
of menses should not be taken as absolute proof of tumor response to treatment
(318,320).
Surgical Intervention
Tumors that are unresponsive to bromocriptine or that cause persistent visual
field loss require surgical intervention. Some neurosurgeons have noted that a
short (2- to 6-week) preoperative course of bromocriptine increases the efficacy
of surgery in patients with larger adenomas (303). Despite surgical resection,
recurrence of hyperprolactinemia and tumor growth is common. Complications of
surgery include cerebral carotid artery injury, diabetes insipidus, meningitis, nasal
septal perforation, partial or panhypopituitarism, spinal fluid rhinorrhea, and third
nerve palsy. Periodic MRI scanning after surgery is indicated, particularly in
2162patients with recurrent hyperprolactinemia.
Metabolic Dysfunction and Hyperprolactinemia
Occasionally, patients with hypothyroidism exhibit hyperprolactinemia with
remarkable pituitary enlargement caused by thyrotroph hyperplasia. These
patients respond to thyroid replacement therapy with reduction in pituitary
enlargement and normalization of prolactin levels (321).
Hyperprolactinemia occurs in 20% to 75% of women with chronic renal
failure. Prolactin levels are not normalized through hemodialysis but are
normalized after transplantation (322–324). Occasionally, women with
hyperandrogenemia also have hyperprolactinemia. Elevated prolactin levels may
alter adrenal function by enhancing the release of adrenal androgens such as
DHEAS (325).
Drug-Induced Hyperprolactinemia
Numerous drugs interfere with dopamine secretion and can be responsible
for hyperprolactinemia and its attendant symptoms (Table 35-8). If
medication can be discontinued, resolution of hyperprolactinemia is
uniformly prompt. If not, endocrine management should be directed at
estrogen replacement and normalization of menses for those with disturbed
or absent ovulation. Treatment with dopamine agonists may be utilized if
ovulation is desired and the drug-inducing hyperprolactinemia cannot be
discontinued.
Use of Estrogen in Hyperprolactinemia
In rodents, pituitary prolactin-secreting adenomas occur with high-dose estrogen
administration (326). Elevated levels of estrogen, as found in pregnancy, are
responsible for hypertrophy and hyperplasia of lactotrophic cells and account for
the progressive increase in prolactin levels in normal pregnancy. The increase in
prolactin during pregnancy is physiologic and reversible; adenomas are not
fostered by the hyperestrogemia of pregnancy. Pregnancy may have a favorable
influence on preexisting prolactinomas (327,328). Estrogen administration is not
associated with clinical, biochemical, or radiologic evidence of growth of
pituitary microadenomas or the progression of idiopathic hyperprolactinemia to
an adenoma status (329–332). For these reasons, estrogen replacement or OC
use is appropriate for hypoestrogenic patients with hyperprolactinemia
secondary to microadenoma or hyperplasia.
Monitoring Pituitary Adenomas During Pregnancy
Prolactin-secreting microadenomas rarely create complications during pregnancy.
2163Monitoring of patients with serial gross visual field examinations and funduscopic
examination is recommended. If persistent headaches, visual field deficits, or
visual or funduscopic changes occur, MRI scanning is advisable. Because serum
prolactin levels progressively rise throughout pregnancy, prolactin
measurements are rarely of value.
For those women who become pregnant while taking bromocriptine to
treat a return of spontaneous ovulations, discontinuation of bromocriptine is
recommended. This does not preclude subsequent use of bromocriptine during
the pregnancy to treat symptoms (visual field defects, headaches) that arise from
further enlargement of the microadenoma (313,333–335). Bromocriptine did not
exhibit teratogenicity in animals, and observational data do not suggest harm to
pregnancy or fetus in humans.
Pregnant women with previous transsphenoidal surgery for microadenomas or
macroadenomas may be monitored with monthly Goldman perimetry visual field
testing. Periodic MRI scanning may be necessary in women with symptoms or
visual changes. Breastfeeding is not contraindicated in the presence of
microadenomas or macroadenomas (313,333–335). The use of bromocriptine
and presumably other dopaminergic agents that may cause blood pressure
elevation during the postpartum period is contraindicated (336–340).
2164THYROID DISORDERS
Thyroid disorders are 10 times more common in women than men.
Approximately 1% of the female population of the United States will develop
overt hypothyroidism (341). Even prior to the discovery of the long-acting thyroid
stimulator (LATS) in women with Graves disease in 1956, numerous
investigations demonstrated a link between these autoimmune thyroid disorders
and reproductive physiology and pathology (342).
Thyroid Hormones
Iodide is a critical component of the class of hormones known as thyronines,
among which the most important are triiodothyronine (T3) and thyroxine (T4).
Iodide obtained from dietary sources is actively transported into the thyroid
follicular cell for the synthesis of these hormones. The sodium–iodide symporter
(NIS) is a key molecule in thyroid function. It allows the accumulation of iodide
from the circulation into the thyrocyte against an electrochemical gradient. The
NIS requires energy that is supplied by Na-K ATPase, and iodine uptake is
stimulated by TSH or thyrotropin. The enzyme thyroid peroxidase (TPO) then
oxidizes iodide near the cell-colloid surface and incorporates it into tyrosyl
residues within the thyroglobulin molecule, which results in the formation of
monoiodotyrosine (MIT) and diiodotyrosine (DIT). T3 and T4, formed by
secondary coupling of MIT and DIT, are catalyzed by TPO. The membranebound, heme-containing oligomer, TPO, is localized in the rough endoplasmic
reticulum, Golgi vesicles, lateral and apical vesicles, and on the follicular cell
surface. Thyroglobulin, the major protein formed in the thyroid gland, has an
iodine content of 0.1% to 1.1% by weight. About 33% of the iodine is present in
thyroglobulin in the form of T3 and T4, and the remainder is present in MIT and
DIT or found as unbound iodine. Thyroglobulin provides a storage capacity
capable of maintaining a euthyroid state for nearly 2 months without the
formation of new thyroid hormones. The thyroid antimicrosomal antibodies found
in patients with autoimmune thyroid disease (ATD) are directed against the TPO
enzyme (343,344).
TSH regulates thyroidal iodine metabolism by activation of adenylate cyclase.
This facilitates endocytosis as a component of iodide uptake, digestion of
thyroglobulin-containing colloid, and the release of thyroid hormones T4, T3, and
reverse T3. T4 is released from the thyroid at 40 to 100 times the concentration of
T3. The concentration of reverse T3, which has no intrinsic thyroid activity, is
216530% to 50% of T3 and 1% of T4 concentration. Of thyroid hormones released,
70% are bound by circulating thyroid-binding globulin (TBG). T4 is present in
higher concentrations in the circulating storage pool and has a slower turnover
rate than T3. Approximately 30% of T4 is converted to T3 in the periphery.
Reverse T3 participates in regulation of the conversion of T4 to T3. T3 is the
primary physiologically functional thyroid hormone at the cellular level. T3 binds
the nuclear receptor with 10 times the affinity of T4. Thyroid hormone effects on
cells include increased oxygen consumption, heat production, and metabolism of
fats, proteins, and carbohydrates. Systemically, thyroid hormone activity is
responsible for the basal metabolic rate. It balances fuel efficiency with
performance. Hyperthyroid states result in excessive fuel consumption with
marginal performance, while hypothyroidism reduces both fuel consumption and
performance.
Iodide Metabolism
Normal function of the thyroid gland is dependent on iodine. The World Health
Organization recommends 150 μg of iodine per day in women of reproductive age
and 250 μg per day is recommended during pregnancy and nursing. Adequate
iodination of household salt is defined as salt containing 15 to 40 mg of iodine per
kilogram of salt (345).
Optimal iodine intake to prevent disease lies within a relatively narrow range
around the recommended daily consumption. Extreme iodine deficiency states are
associated with cretinism, goiter, and hypothyroidism, while iodine sufficiency is
associated with ATD and reduced remission rates in Graves disease (346).
Risk Factors for Autoimmune Thyroid Disorders
Environmental factors associated with the occurrence of ATDs include pollutants
(plasticizers, polychlorinated biphenyls) and exposure to infections such as
Yersinia enterocolitica, coxsackie B, Helicobacter pylori, and hepatitis C
(347,348). For reasons not entirely known, women experience a 5- to 10-fold
increased incidence of ATD (349). This difference is postulated to be the result of
differences in sex steroid hormone levels, differences in environmental exposures,
innate differences in female and male immune systems, and inherent
chromosomal differences in the sexes (350,351). The immunoglobulins produced
against the thyroid are polyclonal, and the multiple combinations of various
antibodies consolidate to create the clinical spectrum of ATDs that may affect
health and reproductive function.
2166Evaluation
Thyroid Function
Measurements of free serum T4 and T3 are complicated by the low levels of free
hormone in systemic circulation, with only 0.02% to 0.03% of T4 and 0.2% to
0.3% of T3 circulating in the unbound state (351). Of the T4 and T3 in circulation,
approximately 70% to 75% is bound to TBG, 10% to 15% attached to
prealbumin, 10% to 15% bound to albumin, and a minor fraction (<5%) is bound
to lipoprotein (352,353). Total thyroid measurements are dependent on levels of
TBG, which are variable and affected by many conditions such as pregnancy, OC
pill use, estrogen therapy, hepatitis, and genetic abnormalities of TBG. Thus,
assays for the measurement of free T4 and T3 are more clinically relevant
than measuring total thyroid hormone levels.
There are many different laboratory techniques to measure estimated free
serum T4 and T3. These methods invariably measure a portion of free hormone
that is dissociated from the in vivo protein-bound moiety. This is of little clinical
significance assuming the same proportions are measured for all assays and
considered in the calibration of the assay (354). The T3 resin uptake (T3 RU) test
is an example of one laboratory method used to estimate free T4 in the serum. The
T3 RU determines the fractional binding of radiolabeled T3, which is added to a
serum sample in the presence of a resin that competes with TBG for T3 binding.
The binding capacity of TBG in the sample is inversely proportional to the
amount of labeled T3 bound to the artificial resin. Therefore, a low T3 RU
indicates high TBG T3 receptor site availability and implies high circulating TBG
levels.
The free T4 index (FTI) is obtained by multiplying the serum T4 concentration
by the T3 RU percentage, yielding an indirect estimate of the levels of free T4:
T3 RU% × T4 total = free T4 index.
A high T3 RU percentage indicates reduced TBG receptor site availability and
high FTI and thus hyperthyroidism, whereas a low T3 RU percentage is a result of
increased TBG receptor site binding and thus hypothyroidism. Equilibrium
dialysis and ultrafiltration techniques may be used to determine the free T4
directly. Free T4 and T3 may also be determined by radioimmunoassay. Most
available laboratory methods used for determining estimations of free T4 are able
to correct for moderate variations in serum TBG but are prone to error in the
2167setting of large variations of serum TBG, when endogenous T4 antibodies are
present, and in the setting of inherent albumin abnormalities (352).
[9] Because most disorders of hyperthyroidism and hypothyroidism are related
to dysfunction of the thyroid gland and TSH levels are sensitive to excessive or
deficient levels of circulating thyroid hormone, TSH levels are used to screen for
these disorders. Thyrotropin or TSH sandwich immunoassays are extremely
sensitive and capable of differentiating low-normal from pathologic or
iatrogenically subnormal values and elevations. TSH measurements provide the
best way to screen for thyroid dysfunction and accurately predict thyroid hormone
dysfunction in about 80% of cases (355). Reference values for TSH are
traditionally based on the central 95% of values for healthy individuals, and some
controversy exists regarding the upper limit of normal. Values in the upper limit
of normal may predict future thyroid disease (354,356). In a longitudinal study,
women with positive thyroid antibodies (TPOAbs or TgAbs), the prevalence of
hypothyroidism at follow-up was 12.0% (3.0% to 21.0%; 95% CI) when baseline
TSH was 2.5 mU/L or less, 55.2% (37.1% to 73.3%) for TSH between 2.5 and 4.0
mU/L, and 85.7% (74.1% to 97.3%) for TSH above 4.0 mU/L (357). Physicians
ordering thyrotropin values should be aware of their limitations in the setting of
acute illness, central hypothyroidism, and the presence of heterophile antibodies
and TSH autoantibodies. In the setting of heterophile antibodies or TSH
autoantibodies, TSH values will be falsely elevated (354). In cases of central
hypothyroidism, decreased sialylation of TSH results in a longer half-life and a
reduction in bioactivity (358,359). TSH levels may be elevated or normal when
the patient remains clinically hypothyroid in states of central hypothyroidism, and
successful treatment is often associated with low or undetectable TSH levels.
Immunologic Abnormalities
Many antigen–antibody reactions affecting the thyroid gland can be detected.
Antibodies to TgAb, the TSH receptor (TSHRAb), TPOAb, the NIS (NISAb),
and to thyroid hormone were identified and implicated in ATD states (360). A
number of recognized thyroid autoantigens are listed in Table 35-9. Antibody
production to thyroglobulin depends on a breach in normal immune surveillance
(361,362). The prevalence of thyroid autoantibodies in various autoimmune
thyroid disorders is shown in Table 35-10.
Table 35-9 Thyroid Autoantigens
Antigen Location Function
Thyroglobulin (Tg) Thyroid Thyroid hormone
2168storage
Thyroid peroxidase
(TPO) (microsomal
antigen)
Thyroid Transduction of
signal from TSH
TSH receptor (TSHR) Thyroid, lymphocytes, fibroblasts,
adipocytes (including retro-orbital), and
cancers
Transduction of
signal from TSH
Na+/I− symporter
(NIS)
Thyroid, breast, salivary or lacrimal
gland, gastric or colonic mucosa, thymus,
pancreas
ATP-driven
uptake of I− along
with Na+
TSH, thyroid-stimulating hormone; ATP, adenosine triphosphate.
Table 35-10 Prevalence of Thyroid Autoantibodies in Autoimmune Thyroid
Disorders
Hypothyroid
Antibody General
Population
Autoimmune
Thyroiditis
Graves
Disease
Antithyroglobulin (TgAb) 3% 35–60% 12–30%
Antimicrosomal thyroid
peroxidase (TPOAb)
10–15% 80–99% 45–80%
Anti-TSH receptor (TSHRAb) 1–2% 6–60% 70–100%
Anti-Na/I symporter (NISAb) 0% 25% 20%
TSH, thyroid-stimulating hormone.
Antithyroglobulin antibodies are predominantly in the noncomplement fixing,
polyclonal, immunoglobulin-G (IgG) class. Antithyroglobulin antibodies are
found in 35% to 60% of patients with hypothyroid autoimmune thyroiditis, 12%
to 30% of patients with Graves disease, and 3% of the general population (363–
365). Antithyroglobulin antibodies are associated with acute thyroiditis, nontoxic
goiter, and thyroid cancer (360).
Previously referred to as antimicrosomal antibodies, TPO antibodies are
directed against TPO and are found in Hashimoto thyroiditis, Graves disease, and
postpartum thyroiditis. The antibodies produced are characteristically cytotoxic,
2169complement-fixing IgG antibodies. In patients with thyroid autoantibodies, 99%
will have positive anti-TPO antibodies, whereas only 36% will have positive
antithyroglobulin antibodies, making anti-TPO a more sensitive test for ATD
(365). Anti-TPO antibodies are present in 80% to 99% of patients with
hypothyroid autoimmune thyroiditis, 45% to 80% of patients with Graves disease,
and 10% to 15% of the general population (364–366). These antibodies can cause
artifact in the measurement of thyroid hormone levels. Antithyroid peroxidase
(anti-TPO) antibodies are used clinically in the diagnosis of Graves disease, the
diagnosis of chronic autoimmune thyroiditis, in conjunction with TSH testing as a
means to predict future hypothyroidism in subclinical hypothyroidism, and to
assist in the diagnosis of autoimmune thyroiditis in euthyroid patients with goiter
or nodules (360).
Another group of antibodies important in ATD bind the TSH receptor (TSHR).
The TSHR belongs to the family of G-protein–coupled receptors. TSHRAb are
pathogenic and capable of activating (TSI) or blocking (TBI) TSHR functions.
TBIs are detectable in two varieties: those that block TSH binding and those that
block prereceptor and postreceptor processes. Several investigators have detected
such blocking antibodies in patients with primary hypothyroidism and atrophic
thyroid glands (367,368). The nomenclature and detection assay of TSHRAb are
listed in Table 35-11. Anti-TSH receptor antibodies were reported in 6% to 60%
of patients with hypothyroid autoimmune thyroiditis, 70% to 100% of patients
with Graves disease, and 1% to 2% of the general population (369–373).
Untreated Graves disease patients tested with third-generation immunometric
assays are uniformly positive (374). TSHRAb are classified as binding inhibitory
immunoglobulins by competitive binding assays (TBII); and in functional assays:
stimulating (TSI)—which possesses capacity to increase cyclic adenosine
monophosphate (cAMP) production; blocking (TBI)—which possesses the
capacity to reduce TSH effects; and, neutral (TNI)—with no effect on TSH
binding or alteration of cAMP levels. A number of competitive and functional
assays are available to determine the levels of each antibody type, which, in toto,
correlate with severity of disease, extraglandular signs, risk of fetal effects, and
chances for remission and recurrence. TSHRAb are used clinically to distinguish
postpartum thyroiditis from Graves disease, to predict the risk of fetal and
neonatal thyrotoxicosis in women with prior ablative treatment or current
thionamide therapy in the setting of Graves disease, and in the diagnosis of
euthyroid Graves opthalmopathy (360). These assays will increasingly optimize
individual patient testing and treatment (375).
Table 35-11 Nomenclature of Anti-TSH Receptor Antibodies
2170Abbreviation Term Assay Used Refers To
LATS Long-acting
thyroid
stimulator
In vivo assay
of stimulation
of mouse
thyroid
Original description of serum
molecule able to stimulate mouse
thyroid; no longer used
TSHRAb,
TRAb
TSHR antibodies Competitive
and functional
assays
described
below
All antibodies recognizing the
TSH receptor (includes TBII
(competitive) and TSI, TBI, and
TNI (competative) based on assay
method)
TBII TSHR-binding
inhibitory
immunoglobulin
Competitive
binding assays
with TSH
Antibodies able to compete with
TSH for TSH receptor binding
irrespective of biologic activity
TSI (also
TSAb)
TSHRstimulating
immunoglobulins
Competitive
and functional
bioassays of
TSH receptor
activation
Antibodies able to block TSH
receptor binding, induce cAMP
production, and nonclassical
signaling cascades
TBI (also
TSBAb,
TSHBAb)
TSHR
stimulationblocking
antibodies
Functional
bioassays of
TSH receptor
activation
Antibodies able to block TSH
receptor binding, induce cAMP
production with ± effects on
nonclassical cascades
TNI TSHR
nonbinding
immunoglobulin
Binding and
functional
assays
No TSH binding, no effect on
cAMP levels, and variable effects
on nonclassical cascades
TSH, thyroid-stimulating hormone.
Antibodies to the NIS are prevalent in a number of thyroid conditions. AntiNISAbs were detected in 24% of patients with Hashimoto disease and 22% of
patients with Graves disease (376). Anti-NISAbs are used experimentally (360).
Autoimmune Thyroid Disease
The most common thyroid abnormalities in women, autoimmune thyroid
disorders, represent the combined effects of the multiple thyroid autoantibodies
(377). The various antigen–antibody reactions result in the wide clinical spectrum
of these disorders. Transplacental transmission of some of these immunoglobulins
may affect thyroid function in the fetus. The presence of autoimmune thyroid
2171disorders, particularly Graves disease, is associated with other autoimmune
conditions: Hashimoto thyroiditis, Addison disease, ovarian failure, rheumatoid
arthritis, Sjögren syndrome, diabetes mellitus (type 1), vitiligo, pernicious
anemia, myasthenia gravis, and idiopathic thrombocytopenic purpura. Other
factors that are associated with the development of autoimmune thyroid disorders
include low birth weight, iodine excess and deficiency, selenium deficiency,
parity, OC pill use, reproductive age span, fetal microchimerism, stress, seasonal
variation, allergy, smoking, radiation damage to the thyroid, and viral and
bacterial infections (378).
Recommendations for Testing and Treatment
Overt and subclinical hypothyroidism are defined as an elevated TSH with a
low T4 and an elevated TSH and normal T4, respectively, using appropriate
patient ranges (nonpregnant and pregnant). A number of professional
organizations published various recommendations for thyroid function assessment
via a TSH in women. Because of the long interval from development of disease to
diagnosis, the nonspecific nature of symptoms, and the potential adverse neonatal
and maternal outcomes associated with untreated hypothyroidism in pregnancy,
the American Association of Clinical Endocrinologists (AACE) recommended
screening women prior to conceiving or at the first prenatal appointment
(379,380). The AACE recommended screening for the presence of
hypothyroidism in patients with type 1 diabetes mellitus (3-fold increased risk of
postpartum thyroid dysfunction and 33% prevalence overall) and patients taking
lithium therapy (35% prevalence), and consideration of testing in patients
presenting with infertility (>12% prevalence) or depression (10% to 12%
prevalence), as these populations are at an increased risk of hypothyroidism
(380). A screening TSH was recommended in women starting at the age of 50
because of the increased prevalence of hypothyroidism in this population
(381). Thyroid function testing at 6-month intervals was recommended for
patients taking amiodarone, as hyperthyroidism or hypothyroidism occurs in 14%
to 18% of these patients (380). Any woman with a history of postpartum
thyroiditis should be offered annual surveillance of thyroid function, as 50% of
these patients will develop hypothyroidism within 7 years of diagnosis (382).
Because there is a high prevalence of hypothyroidism in women with Turner and
Down syndromes, an annual check of thyroid function is recommended for these
patients (383,384).
Alternatively, the Endocrine Society’s clinical practice guidelines regarding the
management of thyroid dysfunction during pregnancy and postpartum
recommends targeted screening for the following individuals: history of thyroid
disorder, family history of thyroid disease, goiter, thyroid autoantibodies, clinical
2172signs or symptoms of thyroid disease, autoimmune disorders, infertility, head
and/or neck radiation, and preterm delivery (385). The American Congress of
Obstetricians and Gynecologists accepted these recommendations for TSH testing
(386). Because of the (i) potentially significant neurologic effects on the fetus and
other adverse pregnancy events, (ii) physiologic rise in TBG and the hCG like
activity of TSH in pregnancy, and (iii) potential for the targeted screening groups
to have overt or subclinical hypothyroidism defined by the reference ranges for
pregnancy (TSH <2.5, 3.1, and 3.5 mU/L for the first, second, and third
trimesters, respectively), targeted maternal testing for hypothyroidism is
encouraged. The targeted screening protocol allows that 30% of subclinical
hypothyroidism cases may be missed. According to these recommendations,
preconceptionally diagnosed hypothyroid women (overt or subclinical) should
have their T4 dosage adjusted such that the TSH value is less than 2.5 mU/L
before pregnancy. The T4 dosage in women already on replacement will routinely
require a dose escalation (30% to 50%) at 4 to 6 weeks gestation in order to
maintain a TSH value less than 2.5 mU/L. Pregnant women with overt
hypothyroidism should be normalized as rapidly as possible to maintain TSH at
less than 2.5 and 3 mU/L in the first, second, and third trimesters, respectively.
Euthyroid women with thyroid autoantibodies are at risk of hypothyroidism and
should have TSH screening in each trimester. After delivery, hypothyroid women
need a reduction in T4 dosage used during pregnancy. Because subclinical
hypothyroidism is associated with adverse outcomes for the mother and the fetus,
T4 replacement is recommended. The American Thyroid Association (ATA) has
recommended an alternative approach that states that therapy may be considered
for TPO antibody-positive women with TSH concentrations greater than 2.5
mU/L. Treatment is also recommended for TPO antibody-negative women with
TSH concentrations greater than 4 mU/L. The ATA does not recommend
levothyroxine therapy for TPO antibody-negative women with a TSH less than
4.0 mU/L (387).
Hashimoto Thyroiditis
Hashimoto thyroiditis, or chronic lymphocytic thyroiditis, was first described in
1912 by Dr. Hakaru Hashimoto. Hashimoto thyroiditis can manifest as
hyperthyroidism, hypothyroidism, euthyroid goiter, or diffuse goiter. High levels
of antimicrosomal and antithyroglobulin antibody are usually present, and
TSHRAb may also be present (365,388,389). Hashimoto thyroiditis is
characterized by a direct T-cell attack on the thyroid gland, leading to thyroiditis
and subsequent exposure of thyroid antigens (TPO and thyroglobulin) against
which antibodies are produced. Thyroglobulin antibodies (TgAbs) and thyroid
2173peroxidase antibodies (TPOAbs) are commonly associated with a destructive
pattern and are considered diagnostic for this disease. In any iodine-sufficient
population, however, the prevalence of TPOAbs and TgAbs is much higher than
that of clinical disease, amounting to approximately 15% to 25%, with the highest
prevalence found in females and increasing with age. Typically, glandular
hypertrophy is found, but atrophic forms are also present. Three classic types of
autoimmune injury are found in Hashimoto thyroiditis: (i) complement-mediated
cytotoxicity, (ii) antibody-dependent cell-mediated cytotoxicity, and (iii)
stimulation or blockade of hormone receptors, which results in hypo- or
hyperfunction or growth (Fig. 35-11).
FIGURE 35-11 Types of autoimmune injury found in Hashimoto thyroiditis. A:
Complement-mediated cytotoxicity, which can be abolished by inactivating the
complement system. B: Antibody-dependent cell-mediated cytotoxicity (ADCC) function
through killer T cells, monocytes, and natural killer cells that have immunoglobulin G
fragment receptors. C: Stimulation of blockade of hormone receptors leading to
hyperfunction or hypofunction or growth, depending on the types of immunoglobulins
acting on the target cell. TBII, TSH-binding inhibitor immunoglobulin; TGI, thyroid
2174growth–promoting immunoglobulin; TSAb, thyroid-stimulating antibodies; TSH, thyroidstimulating hormone. (From IMMUNOLOGICAL OBSTETRICS, edited by W.B. Coulam
et al. Copyright © 1992 by W.W. Norton & Company Inc. Used by permission of W. W.
Norton & Company, Inc.)
The histologic picture of Hashimoto thyroiditis includes cellular hyperplasia,
disruption of follicular cells, and infiltration of the gland by lymphocytes,
monocytes, and plasma cells. Occasionally, adjacent lymphadenopathy may be
noted. Some epithelial cells are enlarged and demonstrate oxyphilic changes in
the cytoplasm (Askanazy cells or Hürthle cells, which are not specific to this
disorder). The interstitial cells show fibrosis and lymphocytic infiltration. Graves
disease and Hashimoto thyroiditis may cause very similar histologic findings
manifested by a similar mechanism of injury.
Clinical Characteristics and Diagnosis of Hashimoto Thyroiditis
Patients with Hashimoto thyroiditis may present with typical symptoms of
hypothyroidism or may be relatively asymptomatic. Patients often present with a
goiter, which can involve the parietal lobe. At later stages of the disease,
hypothyroidism can be found without a goiter. Notable clinical manifestations
associated with Hashimoto thyroiditis include fatigue, weight gain,
hyperlipidemia, dry hair, dry skin, cold intolerance, depression, menstrual
irregularities, bradycardia, and or memory impairment. Hashitoxicosis, the
hyperthyroid manifestation of Hashimoto thyroiditis, may occur after a
hypothyroid state and development into a euthyroid or hyperthyroid state and is
thought to be the result of development of TSH-stimulating antibodies (TSI)
associated with Graves disease (380). This variant is estimated to occur in 4% to
8% of patients with Hashimoto thyroiditis. In the setting of Hashitoxicosis, the
patient requires frequent follow-up and the potential for adjustments in thyroid
supplementation. These patients often become hypothyroid during the course of
treatment.
In many cases, an elevated serum TSH is detected during routine
screening. Elevated serum anti-TPO antibodies confirm the diagnosis, and
free T4 and T3 document overt or subclinical hypothyroidism. The
sedimentation rate may be elevated, depending on the course of the disease at the
time of recognition. Other causes of hypothyroidism should be considered, as
listed in Table 35-12. Progression from subclinical to clinically overt
hypothyroidism is reported to vary from 3% to 20%, with a higher risk noted in
patients with goiter or thyroid antibodies (341,390). Treatment of subclinical
hypothyroidism is somewhat controversial, but clinical studies suggested
treatment of subclinical hypothyroidism is associated with a reduction in
2175neurobehavioral abnormalities, a reduction in cardiovascular risk factors, and an
improvement in lipid profile (391,392).
Hashimoto thyroiditis is one of the most frequent autoimmune diseases
and has been reported to be associated with gastric disorders in 10% to 40%
of patients. About 40% of patients with autoimmune gastritis also present with
Hashimoto thyroiditis. Chronic autoimmune gastritis (CAG) is characterized by
the partial or complete disappearance of parietal cells leading to impairment of
hydrochloric acid and intrinsic factor production. The patients develop
hypochlorhydria-dependent iron-deficient anemia, leading to pernicious anemia,
and severe gastric atrophy. This entity is known as polyglandular autoimmune
syndrome (393).
Table 35-12 Potential Causes of Hypothyroidism
Primary
Congenital absence of thyroid gland
External thyroid gland radiation
Familial disorders and thyroxine synthesis
Hashimoto thyroiditis
Iodine-131 ablation for Graves disease
Ingestion of antithyroid drugs
Iodine deficiency
Idiopathic myxedema (autoimmune)
Surgical removal of thyroid gland
Secondary
Hypothalamic thyrotropin-releasing hormone deficiency
Pituitary or hypothalamic tumors or disease
Treatment
Thyroxine replacement is initiated in patients with clinically overt
hypothyroidism or subclinical hypothyroidism with a goiter. Regression of gland
size usually does not occur, but treatment often prevents further growth of the
2176thyroid gland. Treatment is recommended for patients with subclinical
hypothyroidism in the setting of a TSH greater than 10 mIU/L on repeat
measurements, pregnant patients, a strong habit of tobacco use, signs or
symptoms associated with thyroid failure, or patients with severe hyperlipidemia
(394). All pregnant patients with an elevated TSH level should be treated with
levothyroxine. Treatment does not slow progression of the disease. The initial
dosage of levothyroxine may be as little as 12.5 μg per day up to a full
replacement dose. The mean replacement dosage of levothyroxine is 1.6 μg/kg of
body weight per day, although the dosage varies greatly between patients (380).
Aluminum hydroxide (antacids), cholestyramine, iron, calcium, and sucralfate
may interfere with absorption. Rifampin and sertraline hydrochloride may
accelerate the metabolism of levothyroxine. The half-life of levothyroxine is
nearly 7 days; therefore, nearly 6 weeks of treatment are necessary before the
effects of a dosage change can be evaluated.
Hypothyroidism appears to be associated with decreased fertility resulting from
disruption in ovulation, and thyroid autoimmune disease is associated with an
increased risk of pregnancy loss with or without overt thyroid dysfunction (395).
A meta-analysis of case–control and longitudinal studies performed since 1990
reveals a possible association between miscarriage and thyroid antibodies with an
odds ratio of 2.73 (95% CI 2.20 to 3.40). This association may be explained by a
heightened autoimmune state affecting the fetal allograft or a slightly higher age
of women with antibodies compared with those without antibodies (0.7 ± 1 year,
p < 0.001) (396). Studies suggest that early subclinical hypothyroidism may be
associated with menorrhagia (397).
Severe primary hypothyroidism is associated with menstrual irregularities in
23% of women, with oligomenorrhea being the most common (396).
Reproductive dysfunction in hypothyroidism may be caused by a decrease in the
binding activity of SHBG, resulting in increased estradiol and free testosterone as
well as from hyperprolactinemia (396). The increase in prolactin levels is the
result of enhanced sensitivity of the prolactin-secreting cells to TRH (with
elevated TRH seen in primary hypothyroidism) and defective dopamine turnover
resulting in hyperprolactinemia (398–401). Hyperprolactinemia-induced luteal
phase defects are associated with less severe forms of hypothyroidism (402,403).
Replacement therapy appears to reverse the hyperprolactinemia and correct
ovulatory defects (404,405).
Combined thyroxine and triiodothyronine therapy is no more effective than
thyroxine therapy alone, and patients with hypothyroidism should be treated with
thyroxine alone (406). Treatment should target normalizing TSH values, and a
daily dose of 0.012 mg up to a full replacement dose of levothyroxine (1.6 μg/kg
of body weight per day) may be required with dosage dependent on the patient’s
2177weight, age, cardiac status, and duration and severity of hypothyroidism (380).
Graves Disease
Graves disease, characterized by exophthalmos, goiter, and hyperthyroidism,
was first identified as an association of findings in 1835. A heritable specific
defect in immunosurveillance by suppressor T lymphocytes is believed to result
in the development of a helper T-cell population that reacts to multiple epitopes of
the thyrotropin receptor. This activity induces a B-cell–mediated response,
resulting in the clinical features of Graves disease (403). The TSHRAb bind to
conformational epitopes in the extracellular domain of the thyrotropin receptor
and are uniformly detected in patients with untreated Graves disease (404). Thus,
Graves disease is primarily caused by a T-cell abnormality, but the
hyperthyroidism associated with the disease is caused by the production of the
pathognomonic thyrotropin receptor autoantibodies (TRAbs) produced by B cells.
Graves disease is a complex autoimmune disorder in which several genetic
susceptibility loci and environmental factors are likely to play a role in the
development of the disease. Human leukocyte antigen and polymorphisms in the
cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene were established as
susceptibility loci; however, the magnitude of their contributions seems to vary
among patient populations and study groups. Additional loci are likely to be
identified by a combination of genome-wide linkage analyses and allelic
association analyses of candidate genes. The rate of concordance for Graves
disease is only 20% in monozygotic twins and even lower in dizygotic twins,
consistent with a multifactorial inheritance pattern highly influenced by
environmental factors. Linkage analysis identified loci on chromosomes 14q31,
20q11.2, and Xq21 that are associated with susceptibility to Graves disease (407).
Clinical Characteristics and Diagnosis
The classic triad in Graves disease consists of exophthalmos, goiter, and
hyperthyroidism. The symptoms associated with Graves disease include frequent
bowel movements, heat intolerance, irritability, nervousness, heart palpitations,
impaired fertility, vision changes, sleep disturbances, tremor, weight loss, and
lower extremity swelling. Physical findings may include lid lag, nontender
thyroid enlargement (two to four times normal), onycholysis, dependent lower
extremity edema, palmar erythema, proptosis, staring gaze, and thick skin. A
cervical venous bruit and tachycardia may be noted. The tachycardia does not
respond to increased vagal tone produced with a Valsalva maneuver. Severe cases
may demonstrate acropachy, chemosis, clubbing, dermopathy, exophthalmos with
ophthalmoplegia, follicular conjunctivitis, pretibial myxedema, and vision loss.
Approximately 40% of patients with new onset of Graves disease and many of
2178those previously treated have elevated T3 and normal T4 levels. Abnormal T4 or
T3 results are often caused by protein binding changes rather than altered thyroid
function; therefore, assessment of free T4 and free T3 is indicated in conjunction
with TSH. In Graves disease, the TSH levels are suppressed, and levels may
remain undetectable for some time even after the initiation of treatment. Thyroid
autoantibodies, including TSI, may be useful during pregnancy to more accurately
predict fetal risk of thyrotoxicosis (380). Autonomously functioning, benign
thyroid neoplasms that exhibit a similar clinical picture include toxic adenomas
and toxic multinodular goiter. A radioactive iodine uptake thyroid scan may help
differentiate these two conditions from Graves disease. Rare conditions resulting
in thyrotoxicosis include metastatic thyroid carcinoma causing thyrotoxicosis,
amiodarone-induced thyrotoxicosis, iodine-induced thyrotoxicosis, postpartum
thyroiditis, a TSH-secreting pituitary adenoma, an hCG-secreting
choriocarcinoma, struma ovarii, and “de Quervan’s” or subacute thyroiditis (408).
Factitious ingestion of thyroxine or desiccated thyroid should be considered in
patients with eating disorders. Patients with thyrotoxicosis factitia demonstrate
elevated T3 and T4, suppressed TSH, and a low serum thyroglobulin level,
whereas other causes of thyroiditis and thyrotoxicosis demonstrate high levels of
thyroglobulin. Potential causes of hyperthyroidism are listed in Table 35-13.
Treatment
Iodine-131 Ablation
Treatment of women with hyperthyroidism of an autoimmune origin presents
unique challenges to the physician who must consider the patient’s needs and her
reproductive plans. Because the drugs used to treat this disorder have potentially
harmful effects on the fetus, special attention must be given to the use of
contraception and the potential for pregnancy.
Table 35-13 Potential Causes of Hyperthyroidism
Factitious hyperthyroidism
Graves disease
Metastatic follicular cancer
Pituitary hyperthyroidism
Postpartum thyroiditis
Silent hyperthyroidism (low radioiodine uptake)
2179Struma ovarii
Subacute thyroiditis
Toxic multinodular goiter
Toxic nodule
Tumors secreting human chorionic gonadotropin (molar pregnancy, choriocarcinoma)
A single dose of radioactive iodine-131 is an effective cure in about 80% of
cases and is the definitive treatment in nonpregnant women. Any woman of
childbearing age should be tested for pregnancy before undergoing diagnostic or
therapeutic administration of iodine. Ablation of a second-trimester fetal thyroid
gland and congenital hypothyroidism (cretinism) from treatment during the first
trimester were reported (409). Nuclear medicine professionals provide expertise
in the administration of the radioactive isotope, and because the effect of the
radioactive iodine is not immediate, the endocrinologist continues to provide
suppressive medical treatment for 6 to 12 weeks after administration of iodine
while the patient remains hyperthyroid. As early as 2 to 3 months after treatment,
patients may become hypothyroid and should be supplemented with thyroxine as
indicated by serum levels of free thyroid hormone levels (380). TSH testing is not
sensitive for predicting thyroid function during this time as changes in TSH lag 2
weeks to several months behind thyroid function changes (380). Failure to
respond to iodine 6 months after treatment may require a repeat treatment with
radioactive iodine (408). Postablative hypothyroidism develops in 50% of patients
within the first year after iodine therapy and in more than 2% of patients per year
thereafter.
A higher rate of miscarriage was noted in women treated with iodine therapy in
the year preceding therapy, but there is no reported increase in the rate of
stillbirths, preterm birth, low birth weight, congenital malformation, or death after
therapy (410). Many thyroidologists and nuclear medicine specialists are willing
to allow pregnancy earlier than 1 year after therapy if patients receive
replacement therapy with levothyroxine.
Thyroid-Stimulating Receptor Antibody in Graves Disease
The level of TSHRAb of the TBII class grossly parallels the degree of
hyperthyroidism as assessed by the serum levels of thyroid hormones and total
thyroid volume. Studies suggest that the combination of a small goiter volume
(<40 mL) and a low TBII level (<30 U/L) results in a 45% chance of remission
during the 5 years after completion of a 12- to 24-month course of antithyroid
drug therapy (411). In contrast, the overall rate of relapse exceeded 70% in
2180patients with a large goiter volume (>70 mL) and a higher TBII level (>30 U/L).
The subgroup of patients with larger goiters and higher TBII levels had less than a
10% chance to remain in remission in the 5 years after treatment. Although it is
not necessary for the diagnosis of Graves disease, except in some cases of
multinodular goiter, a TSHRAb measurement may be a useful marker of disease
severity. Used in combination with other clinical factors, it may contribute to
initial decisions regarding treatment. See Table 35-11 for a review of the
nomenclature and assay methods for TSHRAb.
Measurements of TSHRAb (TBII category) during treatment with antithyroid
drugs are predictive of subsequent outcome. In one series, 73% of TBII-negative
patients had remission compared with only 28% of TBII-positive patients who
achieved remission after 12 months of antithyroid drug therapy (412). The
duration of a course of antithyroid drug therapy may be modified according to the
TSHRAb status. In patients whose TSHRAb status became negative and
antithyroid drug therapy was discontinued, the relapse rate was 41% compared
with a rate of 92% for those patients who remained TSHRAb positive (413).
Regardless of the rapidity of the disappearance of TSHRAb, it does seem that
antithyroid drug therapy should be maintained for 9 to 12 months to minimize the
risk of relapse. TSHRAb status appears to determine, in an inverse relationship,
the reduction in thyroid volume after radioactive iodine therapy.
Third-generation TSHRAb assays have been developed, and their utility in
evaluation and treatment monitoring is being evaluated. Some patients with
Graves disease have or will develop antineutrophil cytoplasmic antibodies
(ANCA) after treatment, which may be associated with small-vessel vasculitides,
such as Wegener granulomatosis and microscopic polyangiitis. Smoking appears
to be an independent risk factor for relapse after medical therapy and should be
considered when planning treatment.
Antithyroid Drugs
Antithyroid drugs of the thioamide class include propylthiouracil (PTU) and
methimazole. Low doses of either agent block the secondary coupling reactions
that form T3 and T4 from MIT and DIT. At higher doses, they also block
iodination of tyrosyl residues in thyroglobulin. PTU additionally blocks the
peripheral conversion of T4 to T3. Approximately one-third of patients treated by
this approach alone go into remission and become euthyroid (411).
In 2009, the FDA published a warning on the use of PTU because of 32
reported cases of serious liver injury associated with its use (414,415). The
average daily dose associated with liver failure was 300 mg, and liver failure was
reported to occur anywhere from 6 days to 450 days after initiation of therapy
(416). Traditionally, PTU was the drug of choice to treat hyperthyroidism for the
2181duration of pregnancy because it less readily crosses the placenta, and
methimazole was associated with an increased risk of choanal atresia and aplasia
cutis (417–420). Because of the case reports of PTU-related liver failure and
the increased risk of birth defects associated with methimazole use during
embryogenesis, the FDA and the Endocrine Society recommend PTU never
be used as first-line medical treatment of hyperthyroidism for nonpregnant
patients. It is recommended that its use be limited to pregnant women during
the first trimester, situations where surgery or radioactive iodine treatment
are contraindicated, and individuals who have developed a toxic reaction to
methimazole (414,416). The FDA recommends monitoring patients closely for
signs and symptoms of liver injury while taking PTU. If liver injury is suspected,
PTU should be promptly discontinued (414). The ATA recommends an initial
dose of 100 to 600 mg per day in three divided doses with a goal to maintain T4
in the upper limit of normal using the lowest possible dose. Minor reactions such
as pruritus affect 3% to 5% of patients treated with thionamide therapy, and
antihistamines may eliminate symptoms and allow continued use.
Agranulocytosis is a rare and potentially fatal complication of PTU and
methimazole therapy, developing in 0.2% of women treated, and it mandates
immediate discontinuation of the drug (417). Agranulocytosis most commonly
presents with fever and a sore throat followed by sepsis; the occurrence of fever,
sore throat, or a viral-like syndrome should prompt an urgent evaluation.
Methimazole is the first-line drug for the treatment of hyperthyroidism,
except in the first trimester of pregnancy, as it has been shown to be more
effective than PTU at controlling severe hyperthyroidism and is associated
with higher adherence rates and less toxicity (421). The ATA recommends
initial daily doses of 10 to 40 mg per day in a single dose. Like treatment with
PTU, the goal is to maintain a free T4 level in the upper limits of normal using the
lowest possible dose. Free T4 levels show improvement 4 weeks after therapy,
and TSH levels take 6 to 8 weeks to normalize (417). Methimazole use in
pregnancy is associated with an 18-fold risk of fetal choanal atresia compared
with the general population (95% CI 3 to 121) (422). Congenital aplasia cutis was
associated with maternal use of methimazole during pregnancy; however, it is not
known whether the risk (0.03%) is greater than that seen in the general population
(423).
Studies suggest a potential role for an intrathyroid dexamethasone injection to
prevent relapse (424). Other medical therapies include iodide and lithium, both of
which reduce thyroid hormone release and inhibit the organification of iodine.
Iodide leads to the secondary coupling of T3 and T4. Iodide inhibition of thyroid
metabolism is only transient, and complete escape from inhibition occurs within 1
2182to 2 weeks of iodide therapy, making this useful only for acute management of
severe thyrotoxicosis (408). Lithium may be used when thionamide therapy is
contraindicated or in combination with PTU or methimazole (408). To avoid
toxicity during treatment, serum lithium levels should be monitored. Lithium has
been associated with fetal Ebstein anomaly, and iodide has been associated with
congenital goiter; these medications should not be used in pregnant women and
should be used with caution in women of reproductive age. Because of the
complications related to medical therapy of hyperthyroidism, women desiring
pregnancy should be counseled to strongly consider surgical treatment or
radioactive iodine treatment prior to pregnancy (416).
Breastfeeding and Use of Anti-Thyroid Drugs
Studies have shown that only limited quantities of PTU and methimazole are
secreted in milk, and therefore the neonatal exposure to ATD is minimal and
clinically insignificant. Furthermore, a few studies, albeit small scale, have shown
normal TFTs and no increased risk of malformations in neonates whose mothers
received methimazole in pregnancy (425).
Surgery
Thyroidectomy was used for the treatment of Graves disease but is now rarely
used unless there is a suspicion for coexisting thyroid malignancy (380). Potential
candidates for surgical intervention include pregnant women refusing or not
tolerating antithyroid medical therapy, pediatric patients presenting with Graves
disease, or patients who refuse radioactive iodine therapy. Surgery is the most
rapid and consistent method of achieving a euthyroid state in Graves disease and
avoids the possible long-term risks of radioactive iodine. Surgical intervention
may be considered in severe Graves ophthalmopathy. Patients should be rendered
euthyroid before a thyroidectomy. The risks of surgery include postoperative
hypoparathyroidism, recurrent laryngeal nerve paralysis, routine anesthetic and
surgical risks, hypothyroidism, and failure to relieve thyrotoxicosis.
β-Blockers
Propranolol occasionally is used with or without concurrent antithyroid
medications before radioactive iodine or surgery to provide relief of symptoms.
Larger and more frequent doses may be required because of a relative resistance
to β-adrenergic antagonists in the setting of hyperthyroidism.
Thyroid Storm
Thyroid storm is an acute, life-threatening exacerbation of hyperthyroidism
and should be treated as a medical emergency in an intensive care unit
setting. Symptoms include tachycardia, tremor, diarrhea, vomiting, fever,
2183dehydration, and altered mental status that may proceed to coma. Patients with
poorly controlled hyperthyroidism are most susceptible. Beta-blocker agents,
glucocorticoids, PTU (the action of which includes inhibition of T4–T3
conversion), and iodides are all key elements of therapy.
Hyperthyroidism in Gestational Trophoblastic Disease and Hyperemesis Gravidarum
Because of the weak TSH-like activity of hCG, conditions with high levels of
hCG, such as molar pregnancy, may be associated with biochemical and
clinical hyperthyroidism. Symptoms regress with removal of the abnormal
trophoblastic tissue and resolution of elevated levels of hCG. In a similar fashion,
when hyperemesis gravidarum is associated with high levels of hCG, mild
biochemical and clinical features of hyperthyroidism may be seen (426,427).
Gestational trophoblastic disease is reviewed in Chapter 41.
Thyroid Function in Pregnancy
Physicians should be aware of the changes in thyroid physiology during
pregnancy. Pregnancy is associated with reversible changes in thyroid physiology
that should be noted before diagnosing thyroid abnormalities (see Fig. 35-12 for
pregnancy-associated changes in TBG, total T4, hCG, TSH, and free T4) (417).
Women with a history of hypothyroidism often require increased thyroxine
replacement (25% to 50%) during pregnancy, and patients should have thyroid
function tests performed at the first prenatal visit and during each trimester
thereafter. Evidence suggests that optimal fetal and infant neurodevelopmental
outcomes may require careful titration of replacement thyroxine that meets the
frequently increased requirements of pregnancy (428,429). Postpartum, women
should return to their prepregnancy dosage of levothyroxine and have a follow-up
TSH checked 6 weeks postpartum.
2184FIGURE 35-12 Pregnancy-associated changes in TSH relative to hCG and free T4 in
relation to TBG. Relative serum concentration changes throughout pregnancy highlighting
a fall in TSH associated with an increase in hCG early in pregnancy and a fall in free T4 as
TBG levels rise during pregnancy. hCG, human chorionic gonadotropin; TSH, thyroidstimulating hormone; TBG, thyroid-binding globulin total T4, total thyroxine; free T4, free
thyroxine. (Based on data from Brent GA. Maternal thyroid function: interpretation of
thyroid function tests in pregnancy. Clin Obstet Gynecol 1997;40:3–15.)
Reproductive Effects of Hyperthyroidism
High levels of TSAb (TSI) in women with Graves disease are associated with
fetal–neonatal hyperthyroidism (430,431). Despite both the inhibition and
elevation of gonadotropins seen in thyrotoxicosis, most women remain ovulatory
and fertile (401,432). Severe thyrotoxicosis can result in weight loss, menstrual
cycle irregularities, and amenorrhea. An increased risk of spontaneous abortion is
noted in women with thyrotoxicosis. An increased incidence of congenital
anomalies, particularly choanal atresia and possibly aplasia cutis, can occur in the
offspring of women treated with methimazole (418,419,422).
Autoimmune hyperthyroid Graves disease may improve spontaneously, in
which case antithyroid drug therapy may be reduced or stopped. TSHRAb
production may persist for several years after radioactive iodine therapy or radical
surgical treatment for hyperthyroid Graves disease. In this circumstance, there is a
risk of exposing a fetus to TSHRAb. Fetal–neonatal hyperthyroidism is observed
2185in 2% to 10% of pregnancies occurring in mothers with a current or previous
diagnosis of Graves disease, secondary to the transplacental passage of maternal
TSHRAb. This is a serious condition with a 16% neonatal mortality rate and a
risk of intrauterine fetal death, stillbirth, and skeletal developmental
abnormalities, such as craniosynostosis. Caution against overtreatment with
antithyroid medication is warranted, as these medications may cross the placenta
in sufficient quantities to induce fetal goiter. Guidelines for TSHRAb testing
during pregnancy in women with previously treated Graves disease are found in
Table 35-14. Fetal goiters and the associated fetal hypo- or hyperthyroid status
were diagnosed accurately in mothers with Graves disease using a combination of
fetal ultrasonography of the thyroid with Doppler, fetal heart rate monitoring,
bone maturation, and maternal TSHRAb and antithyroid drug status (433).
Postpartum Thyroid Dysfunction
Postpartum thyroid dysfunction is much more common than recognized; it is
often difficult to diagnose because its symptoms appear 1 to 8 months postpartum
and are often confused with postpartum depression and difficulties adjusting to
the demands of the neonate and infant. Postpartum thyroiditis appears to be
caused by the combination of a rebounding immune system in the postpartum
state and the presence of thyroid autoantibodies. Histologically, lymphocytic
infiltration and inflammation are found and anti-TPO antibodies are often present
(434,435). The following are criteria for the diagnosis of postpartum thyroiditis:
(i) no history of thyroid hormonal abnormalities either before or during
pregnancy, (ii) documented abnormal TSH level (either depressed or elevated)
during the first year postpartum, and (iii) absence of a positive TSH-receptor
antibody titer (Graves disease) or a toxic nodule. A number of studies describe
clinical and biochemical evidence of postpartum thyroid dysfunction in 5% to
10% of new mothers (436,437).
Table 35-14 Guidelines for TSHRAb Testing During Pregnancy With Previously
Treated Graves Disease
1. In the woman with antecedent Graves disease in remission after ATD treatment, the
risk for fetal–neonatal hyperthyroidism is negligible, and systematic measurement of
TSHRAb is not necessary. Thyroid function should be evaluated during pregnancy to
detect an unlikely but possible recurrence. In that case, TSHRAb assay is mandatory
2. In the woman with antecedent Graves disease previously treated with radioiodine or
thyroidectomy and regardless of the current thyroid status (euthyroidism with or
without thyroxine substitution), TSHRAb should be measured early in pregnancy to
evaluate the risk for fetal hyperthyroidism. If the TSHRAb level is high, careful
2186monitoring of the fetus is mandatory for the early detection of signs of thyroid
overstimulation (tachycardia, impaired growth rate, oligohydramnios, goiter).
Cardiac echography and measurement of circulatory velocity may be confirmatory.
Ultrasonographic measurements of the fetal thyroid have been defined from 20
weeks gestational age but require a well-trained operator, and thyroid visibility may
be hindered because of fetal head position. Color Doppler ultrasonography is helpful
in evaluating thyroid hypervascularization. Because of the potential risks of fetal–
neonatal hyperthyroid cardiac insufficiency and the inability to measure the degree
of hyperthyroidism in the mother because of previous thyroid ablation, it may be
appropriate to consider direct diagnosis in the fetus. Fetal blood sampling through
cordocentesis is feasible as early as 25–27 weeks gestation with less than 1% adverse
effects (fetal bleeding, bradycardia, infection, spontaneous abortion, in utero death)
when performed by experienced clinicians. ATD administration to the mother may
be considered to treat the fetal hyperthyroidism
3. In the woman with concurrent hyperthyroid Graves disease, regardless of whether it
has preceded the onset of pregnancy, ATD treatment should be monitored and
adjusted to keep free T4 in the high-normal range to prevent fetal hypothyroidism
and minimize toxicity associated with higher doses of these medications. TSHRAb
should be measured at the beginning of the last trimester, especially if the required
ATD dosage is high. If the TSHRAb assay is negative or the level low, fetal–
neonatal hyperthyroidism is rare. If antibody levels are high (TBII ≥40 U/L or TSAb
≥300%), evaluation of the fetus for hyperthyroidism is required. In this condition,
there is usually a fair correlation between maternal and fetal thyroid function such
that monitoring the ATD dosage according to the mother’s thyroid status is
appropriate for the fetus. In some cases in which a high dose of ATD >20 mg/d of
methimazole or >300 mg/d of PTU is necessary, there is a risk of goitrous
hypothyroidism in the fetus, which might be indistinguishable from goitrous Graves
disease. The correct diagnosis relies on the assay of fetal thyroid hormones and TSH,
which allows for optimal treatment
4. In any woman who has previously given birth to a newborn with hyperthyroidism, a
TSHRAb assay should be performed early in the course of pregnancy
TSHRAb, thyroid-stimulating hormone receptor antibodies; ATD, autoimmune thyroid
disease; T4, thyroxine; TBII, TSH-binding inhibitory immunoglobulin; TSAb, thyroidstimulating antibody; PTU, propylthiouracil.
Clinical Characteristics and Diagnosis
Postpartum thyroiditis usually begins with a transient hyperthyroid phase between
6 weeks and 6 months postpartum followed by a hypothyroid phase. Only onefourth of the cases follow this classic clinical picture, and more than one-third
have either hyperthyroidism or hypothyroidism alone. Individuals with type 1
2187diabetes have a 3-fold increased risk of developing postpartum thyroiditis.
Women with a history of postpartum thyroiditis in a previous pregnancy have
nearly a 70% chance of recurrence in a subsequent pregnancy. Additional risk
factors include a family history of thyroid disorders and TPOAb positivity (438).
Although psychotic episodes are rare, postpartum thyroid dysfunction should be
considered in all women with postpartum psychosis. The thyrotoxic phase may be
subclinical and overlooked, particularly in areas where iodine intake is low (439).
Unlike patients with Graves disease, those with the hyperthyroidism caused by
postpartum thyroiditis have a low level of radioactive isotope uptake. Women
with a history of postpartum thyroiditis should be followed closely as they have a
20% risk of permanent hypothyroidism immediately following the onset of
thyroiditis, up to a 60% risk of permanent hypothyroidism over the next 5 to 10
years, and up to a 70% risk of postpartum thyroiditis in future pregnancies
(440,441).
The absence of thyroid tenderness, pain, fever, elevated sedimentation rate, and
leukocytosis helps to rule out subacute thyroiditis (de Quervain thyroiditis).
Evaluation of TSH, T4, T3, T3 RU, and antimicrosomal antibody titer confirms
the diagnosis.
Treatment
Most patients are diagnosed during the hypothyroid phase and require 6 to 12
months of thyroxine replacement if they are symptomatic (382). Because
approximately 60% of women develop permanent hypothyroidism, TSH should
be evaluated following discontinuation of replacement therapy.
Rarely, patients are diagnosed during the hyperthyroid phase (442). Antithyroid
medications are not routinely used for these women. Propranolol may be used for
relief of symptoms but should be used with appropriate counseling in nursing
mothers.
Antithyroid Antibodies and Disorders of Reproduction
Women who have antithyroid autoantibodies before and after conception appear
to be at an increased risk for spontaneous abortion (443,444). Non-organ–specific
antibody production and pregnancy loss are documented in cases of
antiphospholipid abnormalities (445). The concurrent presence of organ-specific
thyroid antibodies and non-organ–specific autoantibody production is not
uncommon (445–447). In cases of recurrent pregnancy loss, thyroid
autoantibodies may serve as peripheral markers of abnormal T-cell function and
further implicate an immune component as the cause of reproductive failure. The
clinical implications of these findings in the management of patients with
recurrent pregnancy loss are not known. Recurrent pregnancy loss is covered in
2188Chapter 33.
Thyroid Nodules
Thyroid nodules are a common finding on physical examination and are
demonstrated by high-frequency ultrasonography in over two-thirds of patients
(448). Occasionally such nodules are functional, and clinical and laboratory
evaluation should be applied to distinguish these nodules from nonfunctional
nodules, which are occasionally malignant. For nonfunctional “cold” nodules,
fine-needle biopsy and aspiration are required to rule out malignancy. In the case
of indeterminate aspirates, 2% to 20% are malignant; therefore, surgical biopsy is
often indicated (449). Molecular diagnosis screening of the BRAF mutation
improves the diagnosis of cancer on fine-needle aspiration (450).
Turner Syndrome and Down Syndrome
Patients with Turner syndrome (and other forms of hypergonadotropic
hypogonadism associated with abnormalities of the second sex chromosome)
exhibit a high prevalence of autoimmune thyroid disorders. Approximately 50%
of adult patients with Turner syndrome have anti-TPO and antithyroglobulin
(anti-TG) autoantibodies. Of these patients, approximately 30% will develop
subclinical or clinical hypothyroidism. The disorder is indistinguishable from
Hashimoto thyroiditis. A susceptibility locus for Graves disease is noted on
chromosome X (451). Because of the increased risk of ATD, it is recommended
that women with Turner syndrome are screened with yearly TSH testing starting
at the age of 4 (452).
Down syndrome, caused by an extra chromosome 21, is characterized by an
atypical body habitus, mental retardation, cardiac malformations, an increased
risk of leukemia, and a reduced life expectancy. The extra chromosome is almost
always of maternal origin. Autoimmune thyroid disorders are more common in
patients with Down syndrome than in the general population. The gene for
autoimmune polyglandular syndrome I (APECED) has been mapped to
chromosome 21 and is thought to be a transcription factor involved in immune
regulation (AIRE). This gene may play a role in the development of ATD in these
patients (453). Hashimoto thyroiditis is the most common type of thyroid disease
in individuals with Down syndrome. Hypothyroidism develops in as many as
50% of patients older than age 40 with Down syndrome. These clinical
syndromes and other evidence suggest part of the genetic susceptibility to
Hashimoto thyroiditis may reside on chromosomes X and 21. Because of the
increased frequency of hypothyroidism associated with Down syndrome, it is
recommended to screen individuals at 6 months, 12 months, and then annually
thereafter (384).
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