CHAPTER 34
Amenorrhea
KEY POINTS
1 Primary amenorrhea is defined as absence of menses at age 13 years when there is no
visible development of secondary sexual characteristics or age 15 years in the
presence of normal secondary sexual characteristics.
2 Absent or irregular menses may be an indication that a woman has a medical
condition that can affect her overall health. The health implications can vary
depending on the etiology of the amenorrhea. Therefore, a cause for amenorrhea
should be established whenever possible.
3 When gonadal failure occurs in conjunction with primary amenorrhea, it is associated
with a high incidence of abnormal karyotype.
4 The most important elements in the diagnosis of amenorrhea include physical
examination for secondary sexual characteristics and anatomic abnormalities,
measurement of human chorionic gonadotropin (hCG) to rule out pregnancy, serum
prolactin and thyroid stimulating hormone (TSH) levels, and assessment of folliclestimulating hormone (FSH) levels with estradiol to differentiate between
hypergonadotropic and hypogonadotropic forms of hypogonadism. It may be helpful
to measure anti-müllerian hormone (AMH).
20355 Therapeutic measures may include specific therapies (medical or surgical) aimed at
correcting the primary cause of amenorrhea, hormone therapy to initiate and
maintain secondary sexual characteristics and provide symptomatic relief,
treatments to maximize and maintain peak bone mass including hormone therapy,
calcium, and vitamin D for women or girls with low circulating estrogen levels, and
ovulation induction for patients desiring pregnancy.
6 The anatomic causes of amenorrhea are relatively few, and may be diagnosed by
history, physical examination, and imaging.
A complex hormonal interaction must take place in order for normal menstruation
to occur. The hypothalamus must secrete gonadotropin-releasing hormone
(GnRH) in a pulsatile fashion, which is modulated by neurotransmitters and
hormones. The GnRH stimulates secretion of follicle-stimulating hormone (FSH)
and luteinizing hormone (LH) from the pituitary, which promotes ovarian
follicular development and ovulation. A normally functioning ovarian follicle
secretes estrogen prior to ovulation. After ovulation, the follicle is converted into
a corpus luteum, and progesterone is secreted in addition to estrogen. These
hormones stimulate endometrial development and maturation for embryo
implantation. If pregnancy does not occur, estrogen and progesterone secretion
decrease and withdrawal bleeding begins. If any of the components
(hypothalamus, pituitary, ovary, uterus, and outflow tract) are nonfunctional,
bleeding cannot occur.
The mean age of menarche became younger during the previous several
decades. Therefore, [1] primary amenorrhea is now defined as the absence of
menses by 13 years of age when there is no visible development of secondary
sexual characteristics or by 15 years of age in the presence of normal
secondary sexual characteristics. The ages defining primary amenorrhea
were decreased by 1 year to continue to represent two standard deviations
above the mean age of developing secondary sexual characteristics and
menses (1). To detect the cause of primary amenorrhea, it is useful to
determine whether secondary sexual characteristics are present (Fig. 34-1).
The absence of secondary sexual characteristics indicates that a woman was
never exposed to estrogen. Failure to begin breast development by age 13
always warrants investigation. [2] Absent or irregular menses may be an
indication that a woman has a medical condition that can affect her overall
health. The health implications can vary depending on the etiology of the
amenorrhea. Therefore, a cause for amenorrhea should be established
whenever possible.
A woman who previously menstruated can develop secondary
amenorrhea, which is defined as absence of menstruation for three
2036menstrual cycles or 3 months (2). A woman with regular cycles and a delay of
menses of even a week may warrant assessment with a pregnancy test. It is
advisable to evaluate a woman who has fewer than nine cycles per year or
cycle length longer than 35 days. With a few exceptions, the causes of
primary amenorrhea are similar to the causes of secondary amenorrhea (Fig.
34-2). Therefore, it is important not to overemphasize a distinction between
primary and secondary amenorrhea.
Patients may develop slight alterations in the hypothalamic– pituitary–ovarian
axis that are not severe enough to cause amenorrhea but instead cause irregular
menses (oligomenorrhea) associated with absent or infrequent ovulation. These
patients may bleed excessively during menstruation because estrogen is
unopposed. The etiologies of oligomenorrhea overlap with the etiologies of
amenorrhea, with the exception that certain anatomic (e.g., absent uterine
development) and karyotypic abnormalities (e.g., Turner syndrome), are largely
associated with primary amenorrhea.
The World Health Organization (WHO) described three classes of
amenorrhea. WHO group I (hypogonadotropic hypogonadism) includes
women with no evidence of endogenous estrogen production, normal or low
FSH levels, normal prolactin levels, and no lesion in the hypothalamicpituitary region. WHO group II (normogonadotropic anovulation) is
associated with evidence of estrogen production and normal levels of
prolactin and FSH. WHO group III (hypergonadotropic hypogonadism)
includes individuals with elevated serum FSH indicating gonadal
insufficiency or failure. Not originally included in the classification, a fourth
category (hyperprolactinemic anovulation) was added to include women who
are anovulatory specifically because of hyperprolactinemia. While not often
used clinically, this historic classification system can be helpful in the
understanding of the etiology of amenorrhea.
AMENORRHEA WITHOUT SECONDARY SEXUAL
CHARACTERISTICS
Disorders associated with hypogonadism may present as primary amenorrhea.
Because breast development is the first sign of estrogen exposure in puberty,
patients without secondary sexual characteristics typically have primary, not
secondary, amenorrhea (Fig. 34-1). It is helpful to categorize the causes of
amenorrhea in the absence of breast development on the basis of gonadotropin
status.
Causes of Primary Amenorrhea
2037Hypergonadotropic Hypogonadism Associated With Absence of Secondary Sexual
Characteristics
Gonadal dysgenesis is a term typically used to describe abnormal
development of the gonads, typically resulting in streak gonads. Gonadal
dysgenesis is associated with high levels of LH and FSH because the gonad
fails to produce the steroids and inhibin that would normally feed back to the
hypothalamus and pituitary gland to suppress pituitary production of GnRH, LH
and FSH. [3] Karyotypic abnormalities are common in women with primary
amenorrhea associated with gonadal failure (Table 34-1). In one series,
approximately 30% of patients with primary amenorrhea had an associated
karyotypic abnormality (3). Turner syndrome (45,X) and its variants represent
the most common form of hypergonadotropic hypogonadism in women with
primary amenorrhea (3,4). Other disorders associated with primary amenorrhea
include structurally abnormal X chromosomes, mosaicism (e.g., 45,X in some
cells and another karyotype such as 46,XX or 46,XXX in other cells), pure
gonadal dysgenesis (46,XX and 46,XY individuals with gonadal streaks resulting
from lack of gonad development), enzyme deficiencies that prevent normal
estrogen production, and gonadotropin-receptor inactivating mutations.
Individuals with these conditions have gonadal failure and cannot synthesize
ovarian steroids. Gonadotropin levels are elevated because of the lack of negative
estrogen feedback on the hypothalamic–pituitary axis. Most patients with these
conditions have primary amenorrhea and lack secondary sexual characteristics.
Occasionally patients with a partial deletion of the X chromosome, mosaicism, or
pure gonadal dysgenesis (46,XX) may synthesize enough estrogen in early
puberty to induce breast development and a few episodes of uterine bleeding and
thus have secondary amenorrhea. Ovulation and, occasionally, pregnancy are
possible.
Genetic Disorders
Turner Syndrome
Patients with Turner syndrome (45,X) initially have normal ovarian development
in utero. Amenorrhea is the result of accelerated atresia of the follicles. The
fibrotic ovaries are called streak ovaries.
In addition to gonadal failure, there are associated stigmata with Turner
syndrome that include short stature, webbed neck, shield chest, cubitus
valgus (increased carrying angle of the arms), low hair line, high-arched
palate, multiple pigmented nevi, and short fourth metacarpals (4,5). X
inactivation is a process that inactivates most of the genes on one X chromosome.
Of the genes on the X chromosome, 20% escape X inactivation, and it is believed
2038that loss of the second copy of these genes in a 45, X patient causes the stigmata
associated with Turner syndrome (6). Reports about the relationship between
karyotype and dysmorphic features have shown conflicting results, with a general
finding of a more severe phenotype associated with monosomy 45X0 compared
with a mosaic karyotype (7,8). A Y cell line should be excluded by karyotype,
fluorescence in situ hybridization, and DNA analysis if necessary (9).
Gonadectomy is recommended if a Y cell line is present because of the increased
risk of gonadoblastoma and subsequent gonadal germ cell tumors.
20392040FIGURE 34-1 Decision tree for evaluation of amenorrhea. FSH, follicle-stimulating
hormone; HCG, human chorionic gonadotropin; HSG, hysterosalpingogram; TSH, thyroidstimulating hormone; PRL, prolactin; CT, computed tomography; MRI, magnetic
resonance imaging; EEG, electroencephalogram; SHG, saline hysterogram (also known as
saline infusion sonogram).
After the diagnosis of Turner syndrome is confirmed by karyotype, studies
should be performed to ensure that cardiac (30% have coarctation of the
aorta), renal (especially horseshoe kidney), and autoimmune (thyroiditis)
abnormalities are diagnosed and treated. Evaluation should be performed in
childhood to identify potential attention-deficit or nonverbal learning disorders.
Women with Turner syndrome should be screened for diabetes mellitus,
aortic enlargement, hypertension, and hearing loss throughout their lives
(5,8).
2041Abnormal X Chromosome
Those 46,XX individuals with partial deletions of the X chromosome have
variable phenotypes, probably depending on the amount and location of the
missing genetic material. Smaller X chromosome deletions cause distinct
features which overlap with features of Turner syndrome, but women with these
smaller deletions are not considered to be within the definition of Turner
syndrome (8). The pseudoautosomal region of the short arm of the X
chromosome escapes X inactivation, thus resulting in two copies remaining
transcriptionally active. The effective monosomy created by the deletion of Xp is
thought to lead to some of the phenotypic features of Turner syndrome (6). The
short stature homeobox (SHOX) gene is located in the distal region of Xp, with
deletion directly associated with short stature and skeletal deformities. However,
women and girls with a small distal deletion of the short arm of the X
chromosome do not appear to be at higher risk for cardiac anomalies or ovarian
failure, which are often present in women with Turner syndrome and a 45,X
karyotype. Most patients with a ring X have ovarian failure and some phenotypic
features similar to Turner syndrome, although some are able to reproduce
successfully. These patients differ from those with Turner syndrome in that they
are more likely to have intellectual disability. Patients with isochrome of the long
arm of the X chromosome (i[Xq]) are similar to XO patients, with the exception
that autoimmune disorders are more common. A balanced translocation of the X
chromosome to an autosome may lead to gonadal failure (10). Gonadal failure can
be caused by the chromosomal break occurring in a gene that is required for
ovarian function, abnormal meiosis, or X inactivation of the translocated X and
adjacent autosomal genes (6,10). Despite these and other reported associations
between karyotype and phenotype, it is important to emphasize that a specific
karyotype does not always predict phenotype (8).
2042FIGURE 34-2 Schematic illustrating the overlap of the causes of primary and secondary
amenorrhea.
Table 34-1 Amenorrhea Associated With a Lack of Secondary Sexual Characteristics
Abnormal pelvic examination
5α-reductase deficiency, 17,20-lyase deficiency, or 17α-hydroxylase deficiency in
XY individual
Congenital lipoid adrenal hyperplasia
Luteinizing hormone receptor defect
Hypergonadotropic hypogonadism
Gonadal dysgenesis
Follicle-stimulating hormone receptor defect
Partial deletion of X chromosome
Sex chromosome mosaicism
Environmental and therapeutic ovarian toxins
204317α-hydroxylase deficiency in XX individual
Galactosemia
Congenital lipoid adrenal hyperplasia in XX individual
Hypogonadotropic hypogonadism
Physiologic delay
Kallmann syndrome
Central nervous system tumors
Hypothalamic/pituitary dysfunction
Mosaicism
Primary amenorrhea is associated with various mosaic states, the most
common of which is 45,X/46,XX (11). The clinical findings in 45,X/47,XXX
and 45,X/46,XX/47,XXX are similar to those in 45,X/46,XX and vary in estrogen
and gonadotropin production, depending on the number of follicles which
ultimately survive in the gonads. When compared with the pure 45,X cell line,
individuals with 45,X/46,XX are taller and have fewer abnormalities, although
many of those with 45,X/46,XX mosaics are shorter than their peers.
Pure Gonadal Dysgenesis
Individuals who are phenotypically female with sexual infantilism, primary
amenorrhea, normal stature, and no karyotypic abnormalities (46,XX or
46,XY) have pure gonadal dysgenesis. The gonads are usually streaks, but there
may be some development of secondary sexual characteristics, and a few episodes
of uterine bleeding. Pure gonadal dysgenesis in a 46,XY individual (previously
known as Swyer syndrome) can occur when mutations in the SRY (sexdetermining region gene on the Y chromosome) located at Yp11 result in XY
females without proper gonad development (12,13). Mutations in many other
genes such as SOX9, DAX1, WT1, and SF1, which affect testicular
differentiation and inhibit anti-müllerian hormone production, result in XY pure
gonadal dysgenesis (14).
With XX gonadal dysgenesis, the condition is likely to be caused by gene
mutations that lead to ovarian insufficiency before pubertal development or after
the development of secondary sexual characteristics. Perrault syndrome is a rare
autosomal recessive disease with pure gonadal dysgenesis (46,XX) and
sensorineural hearing loss (15). XX pure gonadal dysgenesis can be caused by the
presence of small Y chromosome fragments in the genome. If Y sequences are
2044present, gonadectomy is recommended.
Mixed Gonadal Dysgenesis
Most patients with mixed gonadal dysgenesis are XY and have ambiguous
genitalia with a streak gonad on one side and a malformed testis on the opposite.
A small proportion of these patients have mutations in the SRY gene.
Rare Enzyme Deficiencies
Congenital Lipoid Adrenal Hyperplasia
Patients with this autosomal recessive disorder are unable to convert
cholesterol to pregnenolone, which is the first step in steroid hormone
biosynthesis. The initial rate-limiting step in steroidogenesis is the transport of
cholesterol from the outer to the inner mitochondrial membrane facilitated by
steroidogenic acute regulatory protein (StAR). 48 different mutations have been
identified in the StAR (16). Once in the mitochondria, cholesterol is cleaved by
the p450scc enzyme. Several cases of p450scc deficiency have been reported
(17). These patients present in infancy with hyponatremia, hyperkalemia, and
acidosis. Both XX and XY individuals have external female genitalia, however 46
XY patients do not have a uterus and without hormone replacement they will
remain sexually infantile. XX patients may acquire secondary sexual
characteristics at puberty but develop large ovarian cysts and early ovarian failure
(18). Genetic clusters of the disorder are found in the Japanese, Korean, and
Palestinian Arab populations. With appropriate mineralocorticoid and
glucocorticoid replacement, these patients can survive into adulthood.
17α-Hydroxylase and 17,20-Lyase Deficiency
Mutations in the CYP17 gene cause abnormalities in the 17α-hydroxylase and
17,20-lyase functions of the protein that is active in the adrenal and gonadal
steroidogenic pathways. Over 100 mutations that alter the reading frame of the
gene have been associated with combined 17-hydroxylase/17,20-lyase deficiency
(19). Patients have either 46,XX or 46,XY karyotypes. The uterus is absent in
individuals with 46,XY karyotype, a feature distinguishing them from individuals
with the 46,XX karyotype. Individuals with CYP17 mutations have primary
amenorrhea, no secondary sexual characteristics, female phenotype, hypertension,
and hypokalemia (19). The diminished levels of 17α-hydroxylase that
characterize this disorder lead to a reduction in cortisol production, which in turn
causes an increase in adrenocorticotropic hormone (ACTH). 17α-hydroxylase is
not required for production of mineralocorticoids; thus, excessive amounts of
mineralocorticoid are produced, resulting in sodium retention, loss of potassium,
and hypertension. Patients with 17α-hydroxylase deficiency have primordial
2045follicles, but gonadotropin levels are elevated because the enzyme deficiency
prevents synthesis of sex steroids.
Aromatase Deficiency
This very rare autosomal recessive abnormality prevents the affected individual
from aromatizing androgens to estrogen (20). This syndrome may be suspected
even before birth because most mothers of affected children become virilized
during pregnancy. This occurs because the placenta cannot convert the fetal
androgens to estrogen and they diffuse into the maternal circulation. At birth, a
female child has clitoromegaly and posterior labioscrotal fusion (ambiguous
genitalia). At puberty, there is no breast development, primary amenorrhea,
worsening virilization, absent growth spurt, delayed bone age, and multicystic
ovaries. The diagnostic hormonal pattern consists of an elevation of FSH, LH,
testosterone, and dehydroepiandrosterone sulfate (DHEAS) levels, and
undetectable levels of estradiol. Estrogen therapy improves the ovarian and
skeletal abnormalities but must be titrated to mimic normal estrogen levels.
Estrogen administration should be minimal during childhood and increased at
puberty (21).
Galactosemia
In girls, galactosemia often is associated with ovarian failure, but this
condition usually is detected by newborn screening programs. A galactose-1-
phosphate uridyltransferase level can be measured to assess the patient for
galactosemia or carrier status (22).
Rare Gonadotropin Receptor Mutations
Luteinizing Hormone Receptor Mutation
Inactivation of LH receptors is identified in XY patients who have disorders
of sexual development (DSD) with primary amenorrhea in the absence of
secondary sexual characteristics caused by homozygous premature stop codon,
deletions, and missense mutations in the LHR gene located on chromosome 2.
The Leydig cells in these individuals are unable to respond to LH, causing Leydig
cell hypoplasia. This leads to early testicular failure and prevents masculinization.
XX siblings with the same mutations develop normal secondary sexual
characteristics but are amenorrheic with elevated LH levels, normal FSH levels,
and cystic ovaries (23,24).
Follicle-Stimulating Hormone Receptor Mutation
An autosomal recessive single amino acid substitution in the extracellular domain
of the FSH receptor, which prevents FSH binding, was identified in six families
2046in Finland. This condition leads to primary or early secondary amenorrhea,
variable development of secondary sexual characteristics, and high levels of FSH
and LH (25). A novel homozygous mutation in the FSH receptor gene leading to
primary ovarian insufficiency (POI) has been reported (26).
Other Causes of Primary Ovarian Failure Without Secondary Sexual Characteristics
Severe damage to the ovaries before the onset of puberty can lead to ovarian
insufficiency and failure to develop secondary sexual characteristics. Ovarian
dysfunction can occur in association with irradiation of the ovaries, chemotherapy
with alkylating agents (e.g., cyclophosphamide), or combinations of radiation and
other chemotherapeutic agents (27). Other causes of premature ovarian failure
(also known as POI) are more commonly associated with amenorrhea after the
development of secondary sexual characteristics, as described below.
Hypogonadotropic Hypogonadism Associated With the Absence of Secondary Sex
Characteristics
Primary amenorrhea resulting from hypogonadotropic hypogonadism
occurs when the hypothalamus fails to secrete adequate amounts of GnRH or
when a pituitary disorder associated with inadequate production or release
of pituitary gonadotropins is present.
Physiologic Delay
Physiologic or constitutional delay of puberty is the most common
manifestation of hypogonadotropic hypogonadism. Amenorrhea may result
from the lack of physical development caused by delayed reactivation of the
GnRH pulse generator. Levels of GnRH are functionally deficient in relation to
chronologic age but normal in terms of physiologic development.
Kallmann Syndrome
The second most common hypothalamic cause of primary amenorrhea
associated with hypogonadotropic hypogonadism is insufficient pulsatile
secretion of GnRH (Kallmann syndrome), which has varied modes of genetic
transmission. Insufficient pulsatile secretion of GnRH leads to deficiencies in
FSH and LH (28). Kallmann syndrome is often associated with anosmia (inability
to perceive odors), although a woman may not be aware of her impaired sense of
smell. The hypogonadism and anosmia arise because of failure of proper neuronal
migration during fetal development.
Other Causes of Gonadotropin-Releasing Hormone Deficiency
Deficiencies in GnRH may be caused by developmental or genetic defects,
inflammatory processes, tumors, vascular lesions, or trauma. Central nervous
2047system (CNS) tumors that lead to primary amenorrhea, the most common of
which is craniopharyngioma, are usually extracellular masses that interfere
with the synthesis and secretion of GnRH or stimulation of pituitary
gonadotropins. Virtually all of these patients have disorders in the production of
other pituitary hormones and LH and FSH (29,30). Prolactin-secreting pituitary
adenomas are rare in childhood and more commonly occur after development of
secondary sexual characteristics.
Genetic Disorders
5α-Reductase Deficiency
The possibility of 5α-reductase deficiency should be considered in the evaluation
of amenorrhea. 5α-Reductase converts testosterone to its more potent form,
dihydrotestosterone which is the hormone responsible for triggering
masculinization of the male external genitalia during early sexual development
(31). Patients with 5α-reductase deficiency are genotypically XY with ambiguous
genitalia, frequently experience virilization at puberty, have testes (because of
functioning Y chromosomes), and have no müllerian structures as a result of
functioning AMH. Patients with 5α-reductase deficiency differ from patients
with androgen insensitivity because they do not develop breasts at puberty
(Fig. 34-3). These patients have low gonadotropin levels as a result of
testosterone levels that are sufficient to suppress breast development and
allow normal feedback mechanisms to remain intact. Normal male
differentiation of the urogenital sinus and external genitalia do not occur because
dihydrotestosterone is required for this development. Normal internal male
genitalia derived from the wolffian ducts are present because this development
requires only testosterone. Male pattern hair growth, muscle mass, and voice
deepening are testosterone dependent.
Gonadotropin-Releasing Hormone Receptor Mutations
Mutations have been identified in the GnRH receptor gene, which lead to
abnormal GnRH function (32). Most affected patients are compound
heterozygotes, but homozygous autosomal recessive mutations have been
identified. The GnRH receptor is a G-protein–coupled receptor. Functional
studies show that the mutations cause marked decrease in binding of GnRH to its
receptor or prevent second messenger signal transduction. Without a functional
signal transduction, FSH and LH are not stimulated and are unable to promote
follicular growth. All patients are normosomic.
Follicle-Stimulating Hormone Deficiency
Patients with FSH deficiency usually seek treatment for delayed puberty and
2048primary amenorrhea associated with hypoestrogenism. Patients with this rare
disorder are distinguished from other hypoestrogenic patients by having
decreased FSH levels and increased LH levels. These patients have low serum
androgen levels despite the abnormal LH-to-FSH ratio, indicating that FSHstimulated follicular development is a prerequisite for thecal cell androgen
production. In some of these patients, autosomal recessive mutations in the FSHβ
subunit, which impair dimerization of α and β subunits and prevent binding to the
FSH receptor, have been identified (33). Pregnancy has been reported after
induction of ovulation with injectable gonadotropins (34).
Other Hypothalamic/Pituitary Dysfunctions
Functional gonadotropin deficiency results from malnutrition,
malabsorption, weight loss or anorexia nervosa, excessive exercise, chronic
disease, neoplasia, and marijuana use, although these conditions are more
commonly associated with amenorrhea accompanied by secondary sexual
characteristics that developed before the onset of the problem (35,36).
Hypothyroidism, polycystic ovarian syndrome (PCOS), Cushing syndrome,
hyperprolactinemia, and infiltrative disorders of the CNS are more
commonly associated with amenorrhea in the presence of development of
secondary sexual characteristics, but have been reported to lead to
amenorrhea accompanied by delayed puberty (37,38). Constitutional delay
without underlying causes is less common in girls than in boys, and the
reason for lack of development should be vigorously pursued.
Evaluation of Women With Amenorrhea Associated With the Absence of
Secondary Sexual Characteristics
A careful history and physical examination are necessary to appropriately
diagnose and treat primary amenorrhea associated with hypogonadism. The
physical examination may be particularly helpful in patients with Turner
syndrome. A history of short stature but consistent growth rate, a family history
of delayed puberty, and normal physical findings (including assessment of smell,
optic discs, and visual fields) may suggest physiologic delay. Headaches, visual
disturbances, short stature, symptoms of diabetes insipidus, and weakness of one
or more limbs suggest CNS lesions (39). Galactorrhea may be seen with
prolactinoma, a condition more commonly associated with secondary amenorrhea
in the presence of normal secondary sexual characteristics.
2049FIGURE 34-3 A well-developed patient with complete androgen insensitivity. Note the
characteristic paucity of pubic hair and well-developed breasts. (From Souhail R, Amine
S, Nadia A, et al. Complete androgen insensitivity syndrome or testicular feminization:
Review of literature based on a case report. Pan Afr Med J 2016;25:199. Figure 1 used
with permission.)
2050The diagnostic workup for primary amenorrhea is summarized as follows:
[4] The initial laboratory test should be assessment of serum FSH and LH
levels unless the history and physical examination suggest otherwise to
differentiate hypergonadotropic and hypogonadotropic forms of
hypogonadism. If the FSH level is elevated, a karyotype should be obtained. An
elevated FSH level in combination with a 45,X karyotype confirms the diagnosis
of Turner syndrome. Partial deletion of the X chromosome, mosaicism, pure
gonadal dysgenesis, and mixed gonadal dysgenesis are diagnosed by obtaining a
karyotype.
1. Because of the association with coarctation of the aorta (up to 30%) and
thyroid dysfunction, patients with Turner syndrome should undergo
echocardiography every 3 to 5 years and thyroid function studies yearly.
Cardiac MRI is considered an important component of the cardiac
evaluation (5,8). Patients with Turner syndrome should be evaluated for
hearing loss, renal malformations, diabetes, and hypertension.
2. If the karyotype is abnormal and contains the Y chromosome, as in
gonadal dysgenesis, the gonads should be removed to prevent tumors (14).
3. If the karyotype is normal and the FSH level is elevated, it is important to
consider the diagnosis of 17α-hydroxylase deficiency because it may be a
life-threatening disease if untreated. The characteristic symptoms of 17α-
hydroxylase deficiency include hypertension, hypokalemia, and abnormal
sexual development. The hormone imbalances include an elevated serum
progesterone (>2.0 ng/mL) level, a low to normal 17α-hydroxyprogesterone
(10 to 100 ng/mL) level, an elevated serum 11-deoxycorticosterone (100 to
1,000 ng/dL) level, an elevated corticosterone (4,000 to 40,000 ng/dL), and
low levels of cortisol, DHEAs, testosterone, and estradiol (19,40). The
diagnosis is confirmed with an ACTH stimulation test. After ACTH bolus
administration, affected individuals have markedly increased levels of
corticosterone and 11-deoxycorticosterone compared with baseline levels and
no change in serum 17α-hydroxyprogesterone levels.
4. If the screening FSH level is low, the diagnosis of hypogonadotropic
hypogonadism is established. CNS lesions should be ruled out by imaging
using computed tomography (CT) or MRI, especially if galactorrhea,
headaches, or visual field defects are identified. Pituitary adenomas account
for over 80% of all sellar and parsellar lesions (41). Rathke cleft cyst,
craniopharyngioma, and meningioma are the most common nonadenomatous
sellar masses. CNS malignancy and cancer metastases can impact pituitary
function and result in hypogonadotropic hypogonadism.
5. Physiologic delay is a diagnosis of exclusion that is difficult to distinguish
2051from insufficient GnRH secretion. The diagnosis can be supported by a
history suggesting physiologic delay, an x-ray showing delayed bone age, and
the absence of a CNS lesion on CT or MRI scanning.
Treatment of Amenorrhea Associated With the Absence of Secondary Sexual
Characteristics
[5] Individuals with primary amenorrhea associated with all forms of
gonadal failure and hypergonadotropic hypogonadism need cyclic estrogen
and progestogen therapy to initiate, mature, and maintain secondary sexual
characteristics. Prevention of osteoporosis is an additional benefit of estrogen
therapy:
1. Therapy is usually initiated with 0.3 to 0.625 mg per day of oral
conjugated estrogens or 0.5 to 1 mg per day of oral estradiol.
2. If the patient is short in stature, higher doses should not be used because
premature closure of the epiphyses should be avoided. Most of these
patients are of normal height, and higher estrogen doses may be used initially
and reduced to the maintenance doses after several months.
3. Estrogen can be given daily in combination with progestogen
(medroxyprogesterone acetate or progesterone) to prevent hyperplasia that
could result from unopposed estrogen stimulation of the endometrium in
patients with a uterus. Medroxyprogesterone acetate may be administered at
a dose of 2.5 mg daily every day of the month or 5 to 10 mg for 12 to 14 days
per month. Oral micronized progesterone may be administered at a daily dose
100 mg every day of the month or 200 mg daily for 12 to 14 days per month.
Cyclic hormone therapy (with 12 to 14 days of progestogen per month) more
closely mimics the natural menstrual cycle. Progesterone vaginal suppositories
may be administered at a dose of 50 mg daily or 100 mg for 12 to 14 days
monthly. Progesterone bioadhesive vaginal gel is another option indicated for
the treatment of secondary amenorrhea, with a starting dose of 4% (45 mg),
and possible increase to 8% (90 mg) for women who have failed to respond to
the 4% dose, both used in a cyclic fashion.
4. Occasionally, individuals with mosaicism and gonadal streaks may
ovulate and be able to conceive either spontaneously or after the
institution of estrogen therapy.
5. If 17α-hydroxylase deficiency is confirmed, treatment is instituted with
corticosteroid replacement and estrogen. Progestogen should be added to
protect the endometrium from hyperplasia.
[5] If possible, therapeutic measures are aimed at correcting the primary
2052cause of amenorrhea:
1. Craniopharyngiomas may be resected with a transsphenoidal approach
or during craniotomy, depending on the size of the tumor. Studies show
similar survival rates with limited tumor removal followed by adjuvant
radiotherapy compared to radical gross total resection with an improved
quality of life after treatment (42,43).
2. Germinomas are highly sensitive to radiation and chemotherapy,
therefore surgery is rarely indicated (44).
3. Prolactinomas and hyperprolactinemia often may respond to dopamine
agonists (bromocriptine or cabergoline) (45).
4. Specific therapies are directed toward malnutrition, malabsorption,
weight loss, anorexia nervosa, exercise amenorrhea, neoplasia, and
chronic diseases. Logically, it would appear that patients with
hypogonadotropic hypogonadism of hypothalamic origin should be treated
with long-term administration of pulsatile GnRH. This form of therapy is
impractical because it requires the use of an indwelling catheter and a portable
pump for prolonged periods and there is a lack of availability of this
equipment in the United States. The primary focus of treatment should be to
correct the underlying problem that is causing the menstrual dysfunction (e.g.,
malnutrition). For individuals with anorexia, intensive treatment to
achieve weight gain and emotional well-being is preferable to long-term
treatment with hormone therapy (46). If a patient is unable to correct the
underlying condition, she may be treated with cyclic estrogen and progestogen
therapy at least until sexual maturity is achieved. When sexual maturation is
achieved, hormone therapy can be continued to treat hypoestrogenic
symptoms until the underlying disorder leading to amenorrhea can be
adequately treated.
5. Patients with Kallmann syndrome, and patients with other etiologies for
hypothalamic amenorrhea, can be treated with hormone replacement.
6. If the patient has physiologic delay of puberty, the only management
required is reassurance that the anticipated development will occur
eventually.
Individuals whose karyotypes contain a Y cell line (45,X/46,XY mosaicism,
or pure gonadal dysgenesis 46,XY) are predisposed to gonadal ridge tumors,
such as gonadoblastomas, dysgerminomas, and yolk sac tumors. The gonads
of these individuals should be removed when the condition is diagnosed to
prevent malignant transformation. There is some evidence that hirsute
individuals without Y chromosomes should undergo gonad removal. One patient
2053with hirsutism and the karyotype 45,X was noted to have a streak gonad; the
contralateral gonad was dysgenic and contained developing follicles, welldifferentiated seminiferous tubules, and Leydig cells. This patient was found to be
HY antigen–positive (47).
Clomiphene citrate is often ineffective for inducing ovulation in patients with
hypogonadism who desire pregnancy because such patients are hypoestrogenic. In
patients with hypogonadism, ovulation induction with injectable gonadotropins is
generally successful. In patients without ovarian function, oocyte donation may
be appropriate. There are reports of death in pregnant patients with Turner
syndrome resulting from aortic dissection and rupture (48,49). Careful
counseling and investigation should be undertaken in patients with Turner
syndrome before treating them with donated oocytes.
AMENORRHEA WITH SECONDARY SEXUAL
CHARACTERISTICS AND ABNORMALITIES OF PELVIC
ANATOMY
Causes
Outflow and Müllerian Anomalies
[6] Primary amenorrhea is caused by a congenital abnormality of the female
reproductive organs in approximately 20% of cases. Amenorrhea occurs if
there is blockage of the outflow tract, if the outflow tract is missing, or if
there is no functioning uterus (Table 34-2). Most women with müllerian
abnormalities will have normal ovarian function and thus will have normal
secondary sexual characteristic development.
Transverse Blockages
Any transverse blockage of the müllerian system will cause amenorrhea.
Such outflow obstructions include imperforate hymen, transverse vaginal
septum, and absence of the cervix or vagina. Transverse blockage of the
outflow tract with an intact endometrium frequently causes cyclic pain without
menstrual bleeding in adolescents. The blockage of blood flow can cause
hematocolpos, hematometra, or hemoperitoneum, and endometriosis.
Müllerian Anomalies
Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome includes vaginal
agenesis with variable development of the uterus accompanied in some cases
by renal, skeletal, and auditory abnormalities (50,51). Karyotype is 46,XX.
Müllerian agenesis accounts for approximately 10% to 15% of cases of primary
2054amenorrhea (2). Two subtypes are recognized: (1) isolated müllerian aplasia; and
(2) müllerian anomaly accompanied by other anomalies which may include renal
malformations (such as an absent, pelvic, horseshoe kidney, or double urinary
collecting system) skeletal abnormalities, congenital heart defects, and hearing
impairment. The exact cause of MRKH syndrome remains largely unknown (52).
One study demonstrated a low prevalence of mutations in two known causative
genes (WNT4 and HNF1B), but found copy number variants (CNVs) in certain
regions that may be involved (53). Other promising candidate genes and the
possibility of epigenetic changes will require further study before any conclusions
can be drawn.
Table 34-2 Anatomic Causes of Amenorrhea
Secondary sexual characteristics present
Müllerian anomalies
Imperforate hymen
Transverse vaginal septum
Mayer–Rokitansky–Küster–Hauser syndrome
Androgen insensitivity
Ovotesticular disorder
Absent endometrium
Asherman syndrome
Secondary to prior uterine or cervical surgery
Curettage, especially postpartum
Cone biopsy/ loop electroexcision procedure
Secondary to infections
Pelvic inflammatory disease
Tuberculosis
Schistosomiasis
Absence of Functioning Endometrium
2055Amenorrhea may occur if there is no functioning endometrium. When the
findings of the physical examination are normal, anatomic abnormalities of the
uterine cavity should be considered. A congenitally absent endometrium is a rare
finding in patients with primary amenorrhea (54). Intrauterine adhesions,
referred to as Asherman syndrome, is more common with secondary
amenorrhea or hypomenorrhea. Adhesions typically result from endometrial
trauma during a surgical procedure, but may also result from infection. The most
common cause of Asherman syndrome is uterine curettage for pregnancy-related
complications (55). Adhesions can develop following myomectomy, curettage of
the nongravid uterus, infections related to use of an intrauterine device,
tuberculosis, and schistosomiasis. Cervical stenosis resulting from surgical
removal of dysplasia (cone biopsy, loop electroexcision procedure) may lead to
amenorrhea.
Androgen Insensitivity
Phenotypic females with complete congenital androgen insensitivity
(previously called testicular feminization) have breast development, little or
no axillary and pubic hair, and primary amenorrhea (Fig. 34-3) (56).
Genotypically, they are male (XY) but have a defect that prevents normal
androgen receptor function, leading to the development of the female
external phenotype. The testes, often palpable in the inguinal area or labia,
produce müllerian-inhibiting substance that induces the regression of the
müllerian structures (fallopian tubes, uterus and upper 1/3 of the vagina).
Serum testosterone is in the normal male range.
The gene for the androgen receptor is located on the X chromosome and
inheritance is X-linked recessive. Defects in the androgen receptor gene include
complete absence of the gene and mutations that disrupt the binding domains of
the receptor. Androgen receptor deficits are diverse and may result from
diminished receptor function or concentration. The diagnosis of this disorder is
based on physical examination, serum testosterone concentration, and
karyotype. On physical examination, the patients have a blind vaginal pouch,
scant or absent axillary and pubic hair, and breast development at puberty.
The breasts, however, have pale areolae and the nipples are immature. At puberty,
the conversion of testosterone to estrogen stimulates breast growth. Patients are
unusually tall with eunuchoidal tendency (long arms with big hands and feet).
The testes should be removed after puberty because of the increased risk of
developing testicular cancer (2% to 5%). Research suggests that gonadectomy
may be deferred until adulthood because of the low risk of malignancy (57).
Ovotesticular Disorder of Sexual Development
2056Ovotesticular disorder of sexual development is a rare condition that should
be considered as a possible cause of amenorrhea (58). Both male and female
gonadal tissues are present in these patients. Both müllerian and wolffian
structures are present and correspond to the ipsilateral gonad. Genotypes are
variable with the majority being 46,XX, with the remaining mosaic and 46,XY.
Patients with 46,XX karyotype may menstruate. The external genitalia usually are
ambiguous, and breast development frequently occurs in these individuals.
Evaluation of Women With Amenorrhea, Normal Secondary Sexual
Characteristics, and Suspected Anatomic Abnormalities
[6] Most congenital abnormalities can be diagnosed by physical examination.
In the evaluation of primary amenorrhea, the single most important step is
to determine if the uterus is present. In addition, the vagina and cervix
should be examined. Ultrasonography or MRI is useful to identify the müllerian
anomaly when the abnormality cannot be found by physical examination. The
patient should be examined for skeletal malformations and assessed with
intravenous pyelography or renal ultrasound to detect concomitant renal
abnormalities.
1. An imperforate hymen can be differentiated from other transverse
blockages by the finding of a perirectal mass that protrudes from the
introitus with Valsalva.
2. It is difficult to differentiate a transverse septum or complete absence of
the cervix and uterus in a female from a blind vaginal pouch in a
genotypic male (46,XY) with female sex reversal caused by androgen
insensitivity syndrome. Androgen insensitivity is likely when pubic and
axillary hair is absent. To confirm the diagnosis, a karyotype determination
should be performed to see whether a Y chromosome is present. In some
patients, the defect in the androgen receptor is not complete and virilization
occurs.
3. A congentially absent endometrium is an outflow tract abnormality that
cannot be diagnosed by physical examination in a patient with primary
amenorrhea. This abnormality is very rare and is seen in a patient who has
normal physical findings (normal vagina, cervix, and uterus), and a normal
endocrine evaluation. Although in most cases performance of the progestogen
challenge test is not recommended, this test may be of value to confirm the
rare diagnosis of congenitally absent endometrium. In this case, progestogen
can be administered to a woman who appears to have normal estrogen
production (or if estrogen status is questioned, 2.5 mg conjugated estrogen or
2 mg micronized estradiol can be given for 25 days with 5 to 10 mg of
2057medroxyprogesterone acetate added for the last 10 days). Congenital absence
of the endometrium is confirmed if no bleeding occurs with this regimen in a
patient with primary amenorrhea and no physical abnormalities. Transvaginal
ultrasound to assess endometrial thickness may be helpful, with a thickened
endometrial lining indicating endometrial response to estrogen. Hysteroscopy
with endometrial biopsy should be performed to confirm the diagnosis (54).
4. Asherman syndrome cannot be diagnosed by physical examination. It is
diagnosed by performing hysterosalpingography, saline infusion
sonography (also known as saline hysterogram), or hysteroscopy. These
tests will show either complete obliteration or multiple filling defects caused
by synechiae. If tuberculosis or schistosomiasis is suspected, endometrial
cultures should be performed.
Treatment of Women With Amenorrhea, Normal Secondary Sexual
Characteristics, and Abnormalities of Pelvic Anatomy
The treatment of congenital anomalies can be summarized as follows:
1. Treatment of an imperforate hymen involves making a cruciate incision
to open the vaginal orifice. Most imperforate hymens are not diagnosed until
a hematocolpos forms. It is unwise to place a needle into a hematocolpos
without completely removing the obstruction because a pyocolpos may occur.
2. If a transverse septum is present, surgical removal is required. Forty-six
percent of transverse septa occur in the upper third of the vagina, and 40%
occur in the middle third of the vagina (59). Vaginal dilators should be used to
distend the vagina until it is healed to prevent vaginal adhesions and prevent
reobstruction (60,61). Patients have a fully functional reproductive system
after surgery. Early studies suggested that patients with a repaired complete
transverse septum in the middle or upper vagina may have an increased risk of
infertility, but other studies have demonstrated normal conception rates
following surgical repair (62).
3. Hypoplasia or absence of the cervix in the presence of a functioning
uterus is more difficult to treat than other outflow obstructions.
Previously, a hysterectomy was thought to be required. Conservative
laparoscopic uterovaginal anastomosis has been described and is the
recommended first-line treatment (63,64). Hysterectomy may be needed if
conservative surgery is not successful. Endometriosis is a common finding,
and it is questionable whether this condition should be treated initially with
surgery or if it will resolve spontaneously after surgical repair of the
obstruction. If hysterectomy is needed, the ovaries should be retained to
provide the benefits of estrogen and permit the possibility of future
2058childbearing by removing mature oocytes for in vitro fertilization and transfer
of embryos to a gestational carrier.
4. If the vagina is absent or short, progressive dilation is usually successful
in making it functional (60,65,66). If dilation fails or the patient is unable to
perform dilation, the McIndoe split thickness graft technique, the Vecchietti
procedure, or other surgical approaches may be considered (67–69). The initial
use of vaginal dilators is required to maintain a functional vagina.
5. In patients with complete androgen insensitivity, the testes should be
removed after pubertal development is complete to prevent malignant
degeneration (57). In patients with testes, approximately 14% develop a
neoplasia, most often a gonadoblastoma. Almost one-half of the testicular
neoplasms are malignant (dysgerminomas), but transformation usually does
not occur until after puberty (70). In patients who develop virilization and
have a XY karyotype, GnRH agonist therapy can be utilized to delay puberty
until the individual can develop and determine their gender identity. After
puberty the testes should be removed. Bilateral laparoscopic gonadectomy is
the preferred procedure for removal of intra-abdominal testes.
6. Adhesions in the cervix and uterus (Asherman syndrome) can be removed
using hysteroscopic resection with scissors or electrocautery (71,72). It is
reasonable to place a pediatric Foley catheter in the uterine cavity for 7 to 10
days postoperatively (along with systemic administration of broad-spectrum
antibiotic therapy). A month course of high-dose estrogen therapy with
progestogen withdrawal is used to prevent reformation of adhesions. Forty
percent to 80% of patients thus treated achieve pregnancy, but complications
including miscarriage, preterm labor, placenta previa, and placenta accreta can
occur. Cervical stenosis can be treated by cervical dilation.
AMENORRHEA WITH SECONDARY SEXUAL
CHARACTERISTICS AND NORMAL PELVIC ANATOMY
Although the complete list of potential causes is long, the most common
causes of amenorrhea in women with normal secondary sexual
characteristics and normal pelvic examination are pregnancy, PCOS,
hyperprolactinemia, thyroid disease, POI (also known as premature ovarian
failure), and hypothalamic dysfunction. Pregnancy must be considered in all
women of reproductive age with amenorrhea.
Causes
Polycystic Ovarian Syndrome
2059PCOS is one of the most common endocrine disorders affecting women with
a prevalence between 6% and 10%. The syndrome is characterized by
hyperandrogenism, ovulatory dysfunction, and polycystic-appearing ovaries
(73–75). All definitions of PCOS exclude patients with significantly elevated
prolactin, significant thyroid dysfunction, adult-onset congenital adrenal
hyperplasia, and androgen-secreting neoplasms from being classified as PCOS.
The National Institutes of Health (NIH) 1990 criteria required hyperandrogenism
and oligomenorrhea or amenorrhea for the diagnosis for PCOS. The Rotterdam
2003 criteria required two of three of the following for the PCOS diagnosis:
hyperandrogenism, oligomenorrhea or amenorrhea, polycystic ovaries by
ultrasound (76). In 2012, an expert panel workshop at the NIH agreed to utilize
the Rotterdam criteria (77). The number of antral follicles to define a polycystic
ovary has been debated given the fact that ultrasound is now capable of
visualizing small antral follicles accurately (78).
Although insulin resistance and obesity is noted among women with PCOS, it
is not included in any of the diagnostic criteria. Insulin resistance is more
prevalent in women who are obese with hyperandrogenism and chronic
anovulation. Women with PCOS are often subfertile caused by infrequent or
absent ovulation. PCOS can have other general health implications, including
increased risk for endometrial hyperplasia and cancer, diabetes, and
cardiovascular disease.
Even though PCOS usually causes irregular bleeding rather than
amenorrhea, it remains one of the most common causes of amenorrhea (2).
The etiology of PCOS remains largely unknown.
Not all patients who are hirsute and amenorrheic have PCOS. The
possibility of androgen-secreting adrenal tumors or congenital adrenal
hyperplasia (79) should be considered. Elevations in androgens (e.g., Sertoli–
Leydig, hilus, and lipoid cell tumors) and estrogens (e.g., granulosa cell tumors)
by ovarian tumors may lead to abnormal menstrual patterns, including
amenorrhea. A history of rapid onset of hirsutism is suggestive of a tumor.
Hyperprolactinemia
Hyperprolactinemia is a common cause of anovulation in women. Elevation
of prolactin produces abnormal GnRH secretion, which can lead to
menstrual disturbances (80). Prolactin levels rise in pregnancy, but typically
return to normal within 6 months after delivery in nursing mothers and within
weeks in nonnursing mothers. Dopamine release suppresses prolactin secretion.
Levels of prolactin can be increased by pituitary adenomas that produce prolactin,
by other CNS lesions that disrupt the normal transport of dopamine down the
pituitary stalk, and by medications that interfere with normal dopamine secretion
2060(such as antidepressants, antipsychotics including risperidone, metoclopramide,
some antihypertensives, opiates, and H2 receptor blockers).
If elevated TSH and elevated prolactin levels are found together, the
hypothyroidism should be treated before hyperprolactinemia is treated.
Often, the prolactin level will normalize with treatment of hypothyroidism
because thyroid-releasing hormone, which is elevated in hypothyroidism,
stimulates prolactin secretion.
Primary Ovarian Insufficiency (Premature Ovarian Failure)
POI is suggested as a preferred term for the condition that otherwise was
referred to as premature ovarian failure or premature menopause (81,82).
Others have suggested premature ovarian insufficiency. POI is defined as the
presence of amenorrhea for 4 months or more accompanied by two serum FSH
levels in the menopausal range for a woman who is less than 40 years of age.
Ovarian “insufficiency” is suggested to be more appropriate than “failure” in part
because ovarian function can wax and wane, and function can resume even after it
appears that a woman transitioned into menopause. In one large cohort, 24% of
women had some resumption of ovarian function after diagnosis of POI (83).
Ovarian insufficiency may be caused by decreased follicular endowment,
accelerated follicular atresia, or follicle dysfunction (81). Over 75% of women
with POI will have at least intermittent symptoms including hot flushes, night
sweats, and emotional lability (84). Symptoms are uncommon among women
with primary amenorrhea who never received estrogen. The incidence of POI has
been estimated to be about 1% (85,86).
If the ovary does not develop or stops its hormone production before
puberty, the patient will not develop secondary sexual characteristics without
exogenous hormone therapy. If ovarian insufficiency begins later in life, the
woman will have normal secondary sexual characteristics.
POI clearly compromises the chance of a woman conceiving with autologous
oocytes. However, 5% to 10% of women with a diagnosis of premature ovarian
failure achieve pregnancy, with approximately 80% of these pregnancies resulting
in the delivery of a healthy child (87). It can be difficult to determine which
women will be able to conceive. Published studies of testing for ovarian reserve
have not specifically focused on the POI populations, and pregnancies may occur
with or without treatment despite very unfavorable results for tests of ovarian
reserve such as serum FSH, estradiol, and AMH (88). In general, there is no
convincing evidence that adjuvant therapies are effective in inducing ovulation
for women with premature ovarian failure who no longer respond to gonadotropin
therapy (89). Greater understanding of the factors affecting primordial follicle
activation may lead to improvements in the success of experimental treatments
2061such as in vitro activation (90–92). Oocyte donation and embryo donation are the
only proven effective fertility treatments for women with POI (93).
POI is a heterogeneous disorder with many potential causes (81,94). POI
may be caused by sex chromosome disorders, by fragile X mental retardation 1
(FMR1) premutations, and mutations of single genes (52). Radiation or
chemotherapy may lead to POI. The cause of POI may be autoimmune. The
cause remains unknown in a majority of cases (Table 34-3).
Sex Chromosome and Single Gene Disorders Associated with Primary Ovarian
Insufficiency
Absence of one X chromosome (Turner syndrome) is associated with POI,
despite normal initial development of the ovaries, because of accelerated
atresia of the follicles (95). Although Turner syndrome may often be associated
with primary amenorrhea with absence of secondary sexual characteristics, breast
development may occur if ovarian function is initially present. Mosaicism of an
XO or XY cell line may cause ovarian insufficiency. Individuals with a 47,XXX
karyotype may develop ovarian failure (96). The most common physical
features of 47,XXX are tall stature, epicanthal folds, hypotonia, and clinodactyly.
Table 34-3 Causes of Ovarian Insufficiency or Failure After Development of
Secondary Sexual Characteristics
Chromosomal etiology (e.g., Turner mosaic)
FMR1 premutation
Iatrogenic causes: radiation, chemotherapy, surgical damage to ovarian blood supply or
removal of ovaries
Infections
Autoimmune-lymphocytic oophoritis
Infections
Galactosemia
Perrault syndrome
Idiopathic (80–90% of cases, includes genetic mutations not detected in routine clinical
care)
At least 23 genes are known to have mutations associated with POI and many
more are likely to be identified (52,97). However, only two of these genes (FMR1
2062and NR5A1) account for >3% to 4% of POI patients. A deletion of a portion of the
X chromosome may be present in patients with POI. The Xq21-28 region appears
to be critical, with several genes in this region identified as the cause of early
ovarian insufficiency in humans (POF1B gene located at Xq21, the DIAPH2 gene
located at distal Xq21, and the XPNPEP2 gene located at Xq25 (98,99). Other
examples of known mutations are BMP15 gene (100) and FOXL2 leading to
ovarian failure and ptosis (101). An autosomal recessive form of POI is
associated with hearing loss in Perrault syndrome (102).
FMR1 Premutation Carriers
The most clinically significant gene known to be associated with POI is the
FMR1 gene. Fragile X syndrome, the most common cause of inherited (Xlinked) intellectual disability, is caused by inactivation of the FMR1 gene
located on Xq27.3. This inactivation occurs as a result of expansion of a
cytosine–guanine–guanine (CGG) triplet repeat of more than 200 copies
(103). FMR1 premutation carriers (typically defined as greater than 55 but
under 200 CGG repeats) may have POI and impaired fertility. The
prevalence of POI in women who carry the FMR1 premutation is estimated to be
between 13% and 26%. The risk of having POI appears to increase with
increasing premutation repeat size between 59 and 99. It is possible that there is
an increased risk of POI among women who carry intermediate-size allele
(approximately 41 to 58 repeats), but this is not conclusively proven. The risk
plateaus or decreases for women with repeat sizes of 100. Women with full
mutations (200 or more CGG repeats) are not at higher risk for POI. It is
hypothesized that expression of abnormal FMR1 mRNA produced by patients
with the premutation causes dysfunction in the ovary, which does not occur when
the FMR1 gene is inactivated and not transcribed. The incidence of having a
premutation is 0.8% to 7.5% of women with sporadic POI and up to 13% of
women with familial POI.
FMR1 premutations carried by women are unstable and can expand in the
next generation to transmit fragile X syndrome to the male offspring,
especially if women have more than 100 repeats. The smallest repeat to expand to
the full mutation in one generation is approximately 59. In contrast to potential
expansion in women, the repeat sequence is transmitted from fathers to daughters
in a relatively stable manner.
Iatrogenic Causes of Primary Ovarian Insufficiency
Radiation and chemotherapy (especially alkylating agents such as
cyclophosphamide) may lead to POI (104,105). Other iatrogenic causes of POI
include surgical interference with ovarian blood supply or removal of ovarian
2063tissue which can cause ovarian insufficiency or failure from early loss of
follicles. Ovarian suppression with GnRH agonists has been tried, but has not
been clearly proven to preserve fertility (106). Although cigarette smoking
decreases the age at which menopause will occur, smoking would not be expected
to be the primary cause of amenorrhea occurring before the age of 40. In rare
cases, infections have been suggested to be associated with POI.
Autoimmune Disorders
In one series, 4% of women with POI were noted to have steroidogenic cell
immunity with lymphocytic oophoritis as the mechanism for follicle
dysfunction (107). Autoimmune lymphocytic oophoritis is associated with a
theca cell infiltrate that spares granulosa cells (108). Ultrasound examination
reveals the presence of numerous ovarian follicles, despite elevated serum FSH
levels and hypoestrogenism (81). Ovarian antibody testing is not clinically
reliable for diagnosing the disorder, as women with biopsy-proven autoimmune
oophoritis may have a negative test for ovarian antibody. However, women with
autoimmune lymphocytic oophoritis appear to reliably test positive for adrenal
antibodies. The most readily available antibody is the 21-hydroxylase antibody.
Ideally, antibody to the adrenal gland itself, as assessed by indirect
immunofluorescence, is reasonable to test if available. Testing for 21-hydroxylase
antibody is strongly recommended for women who are determined to have POI
because women who test positive for this antibody are at risk for potentially fatal
hypoadrenalism. Signs that suggest a risk for potentially fatal adrenal
insufficiency include hyperpigmentation, weakness, nausea, vomiting, diarrhea,
and weight loss.
POI may be part of a polyglandular autoimmune syndrome. Antibodies
are present in a variable number of patients with POI, depending on the
autoimmune studies performed. Presence of antithyroid antibodies does not
confirm that there is an autoimmune cause for POI.
Galactosemia
Galactosemia is caused by a lack of functional galactose-1-phosphate
uridyltransferase (22). Galactosemia is a rare cause of POI and is typically
diagnosed in childhood prior to presentation with amenorrhea. Galactose
metabolites appear to have toxic effects on ovarian follicles, causing their
premature destruction. Although about 90% of women with classic galactosemia
develop POI, the pregnancy rate for these women may be higher than for other
causes of POI (109).
Pituitary and Hypothalamic Lesions
2064Hypothalamic Tumors
For normal menstruation to occur, the hypothalamus must be able to secrete
GnRH, and the pituitary must be able to respond with production and
release of FSH and LH. Tumors of the hypothalamus or pituitary, such as
craniopharyngiomas, germinomas, tubercular or sarcoid granulomas, or
dermoid cysts, may prevent appropriate hormonal secretion. Patients with
these disorders may have neurologic abnormalities, and secretion of other
hypothalamic and pituitary hormones may be abnormal. Craniopharyngiomas are
the most common tumors. They are located in the suprasellar region and
frequently cause headaches and visual changes. The surgical and radiologic
treatment of tumors may in itself cause further abnormalities in hormone secretion
(Table 34-4).
Table 34-4 Pituitary and Hypothalamic Lesions
Pituitary and hypothalamic
Craniopharyngioma
Germinoma
Tubercular granuloma
Sarcoid granuloma
Dermoid cyst
Pituitary
Nonfunctioning adenomas
Hormone-secreting adenomas
Prolactinoma
Cushing disease
Acromegaly
Infarction
Lymphocytic hypophysitis
Surgical or radiologic ablations
2065Sheehan syndrome
Diabetic vasculitis
Pituitary Lesions
Hypopituitarism is rare because a large portion of the gland must be
destroyed before decreased hormonal secretion affects the patient clinically.
The pituitary gland may be destroyed by tumors (nonfunctioning or hormone
secreting), infarction, or infiltrating lesions such as lymphocytic hypophysitis,
granulomatous lesions, and surgical or radiologic ablations. Sheehan syndrome
is associated with postpartum necrosis of the pituitary resulting from a
hypotensive episode that, in its severe form (pituitary apoplexy), presents
with the patient in shock. The patient may develop a localized, severe, retroorbital headache or abnormalities in visual fields and visual acuity. Patients with a
mild form of postpartum pituitary necrosis cannot lactate, lose pubic and axillary
hair, and do not menstruate after delivery.
Diabetic vasculitis and sickle cell anemia rarely manifest as pituitary failure.
Hypopituitarism is associated with hyposecretion of ACTH and thyroidstimulating hormone (TSH) and gonadotropins; therefore, thyroid and adrenal
function must be evaluated. If hypopituitarism occurs before puberty, menses
and secondary sexual characteristics will not develop.
Growth hormone (GH), TSH, ACTH, and prolactin are secreted by the
pituitary, and the excess production of each by pituitary tumors causes menstrual
abnormalities. The menstrual abnormalities are caused by adverse effects of these
hormones on the GnRH pulse generator and not by direct effects on the ovary.
Prolactinomas are the most common hormone-secreting tumors in the pituitary, as
described above.
Altered Hypothalamic Gonadotropin-Releasing Hormone Secretion
Abnormal secretion of GnRH is a common cause of amenorrhea. The term
functional hypothalamic amenorrhea implies that correction of causal factors will
restore ovulatory function (110). Chronic disease, malnutrition, stress, psychiatric
disorders, eating disorders, and exercise inhibit GnRH pulses, thus altering the
menstrual cycle (Table 34-5). Other hormonal systems that produce excess or
insufficient hormones can cause abnormal feedback and adversely affect GnRH
secretion. In hyperprolactinemia, Cushing disease (excess ACTH), and
acromegaly (excess GH), excess pituitary hormones are secreted that inhibit
GnRH secretion.
Table 34-5 Abnormalities Affecting Release of Gonadotropin-Releasing Hormone
2066Variable estrogen statusa
Anorexia nervosa
Exercise induced
Stress induced
Pseudocyesis
Malnutrition
Chronic diseases
Diabetes mellitus
Renal disorders
Pulmonary disorders
Liver disease
Chronic infections
Addison disease
Hyperprolactinemia
Thyroid dysfunction
Euestrogenic states
Obesity
Hyperandrogenism
Polycystic ovary syndrome
Cushing syndrome
Congenital adrenal hyperplasia
Androgen-secreting adrenal tumors
Androgen-secreting ovarian tumors
Granulosa cell tumor
2067Idiopathic
aSeverity of the condition determines estrogen status–-the more severe, the more likely to
manifest as hypoestrogenism.
When the decrease in GnRH pulsatility is severe, amenorrhea results.
With less severe alterations in GnRH pulsatility, anovulation and
oligomenorrhea can occur. The pulsatile secretion of GnRH is modulated by
interactions with neurotransmitters and peripheral gonadal steroids. Kisspeptin
plays a critical role in the initiation of GnRH secretion during puberty (110).
Endogenous opioids, corticotropin-releasing hormones (CRH), melatonin, and α-
aminobutyric acid (GABA) inhibit the release of GnRH, whereas catecholamine,
acetylcholine, and vasoactive intestinal peptide stimulate GnRH pulses.
Dopamine and serotonin have variable effects (111).
Decreased leptin levels are associated with hypothalamic amenorrhea,
regardless of whether it is caused by exercise, eating disorders, or is idiopathic
(112). Leptin is a hormone secreted by adipocytes that is involved in energy
hemostasis. Receptors are found in the hypothalamus and bone, making it an
excellent candidate for a modulator of menstrual function and bone mass. Levels
correlate with nutritional changes and body mass index. Administration of leptin
to women with hypothalamic amenorrhea increased levels of LH, estradiol,
insulin-like growth factor-1 (IGF-1), and thyroid hormone. Ovulation and
increased bone mass occurred in these patients (113). However, weight loss
occurring with leptin administration limits the utility of using leptin as a potential
therapeutic agent.
Eating Disorders
Anorexia nervosa is an eating disorder that affects many adolescent women.
The criteria for diagnosis of anorexia nervosa in the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5) include low body weight
(defined in a somewhat open-ended fashion as less than minimally normal weight
in adults, or less than minimally expected weight in children and adolescents) and
a refusal to maintain a minimally normal or expected weight (114). Patients
with anorexia may either state the refusal or demonstrate behavior which
indicate a refusal to maintain a normal weight. Patients attempt to maintain
their low body weight by food restriction, laxative abuse, and intense exercise.
Anorexia nervosa is a life-threatening disorder with a significant mortality
rate (115). Amenorrhea may precede, coincide, or follow the weight loss.
Multiple hormonal patterns are altered. The 24-hour patterns of FSH and LH may
show constantly low levels as seen in childhood or increased LH pulsatility
during sleep consistent with the pattern seen in early puberty. Hypercortisolism is
2068present despite normal ACTH levels, and the ACTH response to CRH
administration is blunted. Circulating triiodothyronine (T3) is low, yet circulating
inactive reverse T3 concentrations are high. Patients may develop cold and heat
intolerance, lanugo hair, hypotension, bradycardia, and diabetes insipidus. They
may have yellowish discoloration of the skin resulting from elevated levels of
serum carotene caused by altered vitamin A metabolism.
Binge eating is associated with bulimia consisting of vomiting, laxative
abuse, and diuretics to control weight. Signs of bulimia include tooth decay,
parotid gland hypertrophy (chipmunk jowls), hypokalemia, and metabolic
alkalosis.
Weight Loss and Dieting
Weight loss can cause amenorrhea even if weight does not decrease below
normal. Loss of 10% body mass in 1 year is associated with amenorrhea.
Some but not all of these women have an underlying eating disorder. Prognosis is
good for the return of menses if the patients recover from the weight loss. Dieting
without weight loss and changes in diet can lead to amenorrhea (116).
Exercise
In patients with exercise-induced amenorrhea, there is a decrease in the
frequency of GnRH pulses, which is assessed by measuring a decreased
frequency of LH pulses. These patients are usually hypoestrogenic, but less
severe alterations may cause minimal menstrual dysfunction (anovulation or
luteal phase defect). The decrease in GnRH pulsatility can be caused by hormonal
alterations, such as low levels of leptin or high levels of ghrelin, neuropeptide Y,
and corticotrophin-releasing hormone (117). Runners and ballet dancers are at
higher risk for amenorrhea than swimmers (118). It was previously suggested that
a minimum of 17% body fat is required for the initiation of menses and 22% body
fat for the maintenance of menses (119). However, studies suggest that
inappropriately low caloric intake during strenuous exercise is more important
than body fat (120). Higher-intensity training, poor nutrition, stress of
competition, and associated eating disorders increase an athlete’s risk for
menstrual dysfunction. Osteoporosis may result in stress fractures during
training and lifelong increased fracture risk. Stress fractures most commonly
occur in the weight-bearing cortical bone such as the tibia, metatarsal, fibula, and
femur. These athletes may fail to reach peak bone mass and have abnormal bone
mineralization.
Stress
Stress-related amenorrhea can be caused by abnormalities in
2069neuromodulation in hypothalamic GnRH secretion, similar to those that
occur with exercise and anorexia nervosa. Excess endogenous opioids and
elevations in CRH secretion inhibit the secretion of GnRH (111). These
mechanisms are not fully understood but appear to be the common link between
amenorrhea and chronic diseases, pseudocyesis, and malnutrition. Cognitive
behavioral therapy has shown some promise in initiating neuroendocrine recovery
(121).
Obesity
Most obese patients have normal menstrual cycles, but the percentage of women
with menstrual disorders increases for women with obesity compared with
women of normal weight. The menstrual disorder is more often irregular uterine
bleeding with anovulation rather than amenorrhea. Obese women have an excess
number of fat cells in which extraglandular aromatization of androgen to
estrogen occurs. They have lower circulating levels of sex hormone–binding
globulin, which allows a larger proportion of free androgens to be converted
to estrone. Excess estrogen creates a higher risk for endometrial cancer for
these women. The decrease in sex hormone–binding globulin allows an increase
in free androgen levels, which initially are eliminated by an increased rate of
metabolic clearance. This compensatory mechanism diminishes over time, and
hirsutism can develop. Frequently, these patients are classified as having PCOS.
Alterations in the secretion of endorphins, cortisol, insulin, GH, and IGF-1 may
interact with the abnormal estrogen and androgen feedback to the GnRH pulse
generator to cause menstrual abnormalities.
Other Hormonal Factors
The secretion of hypothalamic neuromodulators can be altered by feedback
from abnormal levels of peripheral hormones. Excesses or deficiencies of
thyroid hormone, glucocorticoids, androgens, and estrogens can cause
menstrual dysfunction. Excess secretion of GH, TSH, ACTH, and prolactin
from the pituitary gland can cause abnormal feedback inhibition of GnRH
secretion, leading to amenorrhea. GH excess causes acromegaly, which may be
associated with anovulation, hirsutism, and polycystic-appearing ovaries as a
result of stimulation of the ovary by IGF-1. More commonly, GH excess is
accompanied by amenorrhea, low gonadotropin levels, and elevated
prolactin levels. Acromegaly is recognized by enlargement of facial features,
hands, and feet; hyperhidrosis; visceral organ enlargement; and multiple
skin tags. Cushing disease is caused by an ACTH-secreting pituitary tumor,
which is manifested by truncal obesity, moon facies, hirsutism, proximal
weakness, depression, and menstrual dysfunction.
2070Evaluation for Women With Amenorrhea in the Presence of Normal Pelvic
Anatomy and Normal Secondary Sexual Characteristics
A pregnancy test (urine or serum human chorionic gonadotropin [hCG])
should be performed in a reproductive-age woman who has amenorrhea with
normal secondary sexual characteristics and a normal pelvic examination. If
the results of the pregnancy test are negative, the evaluation of amenorrhea
is as follows:
1. Clinical assessment of estrogen status
2. Serum TSH
3. Serum prolactin
4. Serum FSH level
5. Vaginal ultrasound for assessment of antral follicle count in the ovaries
can be considered (may help establish the diagnosis of PCOS or suggest
POI)
6. [4] Imaging of the pituitary and hypothalamic assessment if prolactin is
elevated or if hypothalamic amenorrhea is suspected (particularly if CNS
symptoms are present or there is no clear explanation for hypothalamic
amenorrhea).
Assessment of Estrogen Status
The presence of vaginal dryness or hot flashes increases the likelihood of a
diagnosis of hypoestrogenism. A serum estradiol level higher than 40 pg/mL is
considered indicative of significant estrogen production, but interassay
discrepancies often exist and serum estrogen levels can vary greatly on a day-today basis for a given woman. Vaginal ultrasound demonstrating a thin
endometrium suggests that a patient is hypoestrogenic, unless there is reason to
suspect that the patient lacks functional endometrium. A dual-energy x-ray
absorptiometry (DEXA) scan to determine bone mineral density should be
considered for a patient in whom long-term hypoestrogenism is suspected.
There is little utility in routine performance of a progestogen challenge test
to determine the patient’s estrogen status. False positives and false negatives
are common.
Thyroid and Prolactin Disorders
Consideration should be given to thyroid disorders and hyperprolactinemia
in women with amenorrhea because of the relatively common incidence of
these conditions.
1. Sensitive TSH assays can be used to evaluate hypothyroidism and
2071hyperthyroidism. Further evaluation of a thyroid disorder is required if
abnormalities in TSH levels are found. Mild degrees of thyroid dysfunction
are unlikely to cause amenorrhea. Given the general health implications of
thyroid dysfunction and readily available treatments, routine assessment of
TSH is reasonable for women with amenorrhea.
2. Prolactin is most accurately obtained in a patient who is fasting and who
has not had any recent breast stimulation to avoid concluding that a
patient is hyperprolactinemic on the basis of a transient prolactin
elevation. If a patient still has some menstrual cycles, it is advisable to obtain
the prolactin level in the follicular phase.
Follicle-Stimulating Hormone Levels
Assessment of serum FSH levels is required to determine whether the patient has
hypergonadotropic, hypogonadotropic, or eugonadotropic amenorrhea. A
circulating FSH level of greater than 25 to 40 mIU/mL indicated on at least
two blood samples is indicative of hypergonadotropic amenorrhea.
Hypergonadotropism implies that the cause of amenorrhea is ovarian
insufficiency. The history should establish whether the cause of ovarian
insufficiency is chemotherapy or radiation therapy.
Anti-müllerian hormone (AMH) is a circulating biomarker, which correlates
with the size of the pool of ovarian follicles (122). AMH is produced by the
granulosa cells of preantral and early antral follicles (123). Although it is not
formally included in the diagnosis of POI, AMH becomes undetectable several
years before the final menses and thus may aid in the early diagnosis of POI.
AMH levels are low in women with POI and high in women with PCOS.
If the diagnosis of POI is confirmed, the patient should be tested for:
1. FMR1 premutation
2. Karyotype
3. 21-hydroxylase antibody
FMR1 premutation testing will reveal women at risk for bearing a child with
fragile X syndrome, which may be important information for other family
members. The goal of the peripheral blood karyotype is to identify an absent or
abnormal X chromosome and to identify whether or not any portion of a Y
chromosome is present. It is important to identify Y chromosomal material so it
may be removed to prevent malignant degeneration. Although commonly
suggested that karyotype only be performed if the patient is younger than the age
of 30, it should be noted that rare patients with Turner syndrome developed
amenorrhea after age 35. In addition, some patients who present older than the
2072age of 30 may have actually had the onset of POI at a younger age but were
unaware because of the use of oral contraceptives. Therefore, consideration
should be given to performance of karyotype, regardless of the patient’s age.
Testing for 21-hydroxylase antibody will identify women at risk for adrenal crisis.
If a diagnosis of PCOS is suspected, the patient should have:
1. Documentation of hyperandrogenism—either by serum total testosterone
and sex hormone binding globulin or free testosterone and/or by presence of
physical findings such as acne, hirsutism, and androgenic alopecia.
2. Serum 17-hydroxyprogesterone to exclude congenital adrenal hyperplasia
resulting from 21-hydroxylase deficiency, particularly if the patient is at
increased risk—highest prevalence is among Ashkenazi Jews, Hispanics,
Yugoslavs, Native American Inuits in Alaska, and Italians.
3. If the diagnosis of PCOS is made, the patient should undergo screening
for diabetes and a fasting lipid profile.
Assessment of the Pituitary and Hypothalamus
If the patient is hypoestrogenic and the FSH level is not high, pituitary and
hypothalamic lesions should be excluded.
1. A complete neurologic examination may help localize a lesion.
2. Either CT or MRI scanning should be performed to confirm the presence
or absence of a tumor. MRI will identify smaller lesions than CT; if a lesion is
too small for identification by CT, it may be clinically insignificant. MRI
offers the advantage of avoiding exposure to x-ray.
3. The patient’s history of weight changes, exercise, eating habits, and body
image is an important factor in determining whether anorexia nervosa,
malnutrition, obesity, exercise, or stress may be responsible for
amenorrhea.
Patients with certain specific clinical findings should undergo screening for
other hormonal alterations:
1. Androgen levels should be assessed in any hirsute patient to ensure that
adrenal and ovarian tumors are not present and to aid in the diagnosis of
PCOS.
2. Acromegaly is suggested by coarse facial features, large doughy hands, and
hyperhidrosis and may be confirmed by measuring IGF-1 levels.
3. In patients with truncal obesity, hirsutism, hypertension, and erythematous
striae, Cushing syndrome should be ruled out by assessing 24-hour urinary
2073cortisol levels or performing a 1-mg overnight dexamethasone suppression test
or late night salivary cortisol (124). It is important to confirm that the patient is
not taking exogenous glucocorticoid.
Treatment for Women With Amenorrhea in the Presence of Normal Pelvic
Anatomy and Normal Secondary Sexual Characteristics
The treatment of nonanatomic causes of amenorrhea associated with normal
secondary sexual characteristics varies widely according to the cause. The
underlying disorder should be treated whenever possible. Patients who are
pregnant may be counseled regarding the options for continued care. When
thyroid abnormalities are detected, thyroid hormone, radioactive iodine, or
antithyroid drugs may be administered as appropriate. If
hyperprolactinemia is present, treatment may include discontinuation of
contributing medications, treatment with dopamine agonists such as
bromocriptine or cabergoline, and, rarely, surgery for particularly large pituitary
tumors. When POI causes amenorrhea, hormone replacement should be
considered to improve quality of life and to prevent osteoporosis (125).
Counseling regarding the risks and benefits of hormone replacement therapy is
indicated. Gonadectomy is required when a Y cell line is present.
Surgical removal, radiation therapy, or a combination of both is advocated for
treatment of CNS tumors other than prolactinomas. It may be necessary to treat
individuals who have panhypopituitarism with various replacement regimens after
all the deficits are elucidated. These regimens include estrogen and progestogen
replacement for lack of gonadotropins, corticosteroid replacement for lack of
ACTH, thyroid hormone for lack of TSH, and desmopressin acetate (1-deamino-
8-D-AVP [DDAVP]) to replace vasopressin.
The treatment of amenorrhea associated with hypothalamic dysfunction
depends on the underlying cause:
1. Hormonally active ovarian tumors are surgically removed (rare).
2. Obesity, malnutrition or chronic disease, Cushing syndrome, and
acromegaly should be specifically treated.
3. Stress-induced amenorrhea may respond to psychotherapy.
4. Exercise-induced amenorrhea may improve with moderation of activity
and weight gain, when appropriate. If hypoestrogenism persists, higher
doses of estrogen may be needed in these women than in older menopausal
women to maintain bone density. In addition, 1,200 to 1,500 mg of calcium
and 400 to 800 IU of vitamin D daily are advised. Bisphosphonates do not
improve bone density in amenorrheic athletes because it is lack of bone
formation rather than increased resorption that causes the osteopenia. In
2074addition, the use of bisphosphonates is not advised because they can be
deposited into the bone, and long-term effects, especially during pregnancy,
are unknown.
5. Treatment of eating disorders such as anorexia nervosa generally
demands a multidisciplinary approach, with outpatient family-based
therapy, the first line particularly for adolescents, and hospitalization
reserved for severe cases (126).
6. Chronic anovulation associated with PCOS may be treated after
identifying the desires of the patient. Patients may be concerned about their
lack of menstruation, not hirsutism, or infertility. The endometrium of these
individuals should be protected from the environment of unopposed
estrogen that accompanies the anovulatory state. Oral contraceptives are a
good alternative for those patients who require contraception. For those
patients who are not candidates for oral contraceptive use, cyclic
administration of progestogen is advised. Progestogen withdrawal will occur if
there is an adequate estrogenic environment to induce proliferation of the
endometrium, and it is not sufficient to cause withdrawal bleeding in patients
who are hypoestrogenic (e.g., those who have amenorrhea associated with
anorexia nervosa). Women with PCOS may require treatment for insulin
resistance, dyslipidemia, and obesity. Regular periodic screening for diabetes
and a lipid panel is recommended for women with PCOS. Reduction in weight
in obese women with PCOS leads to improved pregnancy rates, decreases
hirsutism, and improves glucose and lipid levels. Insulin-sensitizing
medications such as metformin and cholesterol-lowering medications such as
statins can be considered. Ovulation induction is performed if pregnancy is
desired, as described below.
A common progestogen used to induce withdrawal bleeding and thus
protect the endometrium from hyperplastic transformation is
medroxyprogesterone acetate (10 mg for 12 to 14 days per month). Occasionally,
ovulation may occur; therefore, patients should be made aware that pregnancy is
possible, and appropriate contraceptive measures should be used.
Medroxyprogesterone acetate should not be used in early pregnancy.
Alternatively, progesterone suppositories (50 to 100 mg) or oral micronized
progesterone (200 mg) can be given for 12 to 14 days per month to protect the
endometrium from hyperplasia and induce withdrawal bleeding.
In hypoestrogenic individuals such as those with POI, estrogen
replacement must be added to the progestogen for successful menstrual
regulation and prevention of osteoporosis. The doses of estrogen needed for
relief of symptoms in young women with POI are often higher than those that are
2075used for older menopausal women (127). Women with POI (who would normally
still be making hormone if the ovaries were functioning normally) are different
from those reaching menopause at a median age of 51. Therefore, data regarding
hormone therapy that were collected from women reaching menopause at the
median age should not be extrapolated to younger women. Although there are no
comparative data and no long-term prospectively collected data regarding
hormone therapy for women with POI, the risks of hormone therapy are likely
to be lower and the benefits potentially greater for younger women than for
older women reaching menopause after the age of 50 (125).
When chronic anovulation is caused by congenital adrenal hyperplasia,
glucocorticoid administration (i.e., dexamethasone 0.5 mg at bedtime) is
sometimes successful in restoring the normal feedback mechanisms, thereby
permitting regular menstruation and ovulation.
Hirsutism
Patients who have oligomenorrhea or amenorrhea resulting from chronic
anovulation may have hirsutism. The most common cause of hirsutism and
oligo-ovulation is PCOS. After ruling out androgen-secreting tumors and
congenital adrenal hyperplasia, treatment may be aimed at decreasing coarse
hair growth.
Oral Contraceptives
Oral contraceptives may be effective for hirsutism by decreasing ovarian
androgen production and increasing circulating levels of sex hormone–binding
globulin, leading to decreased free androgen in the circulation.
Antiandrogens
Spironolactone decreases androgen production and competes with androgens at
the androgen receptor. Side effects include diuresis and dysfunctional uterine
bleeding. The use of spironolactone is typically combined with oral
contraceptives to avoid irregular bleeding and to prevent pregnancy from
occurring while on spironolactone. Flutamide is approved by the U.S. Food and
Drug Administration (FDA) for adjuvant therapy in prostatic cancer but not
specifically for treatment of hirsutism. A low dose of flutamide may be effective
in treating hirsutism (128). Liver function should be monitored because of the
rare complication of hepatotoxicity. Cyproterone acetate, a strong progestin and
antiandrogen, is used in some countries, but is not available in the United States.
It is usually administered in combination with ethinyl estradiol in an oral
contraceptive and has a high efficacy (129) by decreasing circulating androgen
and LH levels, and by inducing antagonism of androgen effects at the peripheral
2076level. Finasteride, a 5α-reductase inhibitor, is approved by the FDA for the
treatment of benign prostatic hypertrophy (Proscar) and male pattern baldness
(Propecia). It may be effective in treating hirsutism, but with inconsistent results
(130).
All antiandrogens are teratogenic as they may lead to feminization of the
external genitalia of a male fetus (ambiguous genitalia) if the patient should
conceive while taking the medication. Therefore, antiandrogens are typically used
in combination with oral contraceptives.
Cosmetic Approaches
Medical treatment can be combined with cosmetic treatment for optimal efficacy
(131). Eflornithine hydrochloride is a topical cream that is approved by the FDA
for use on the face and chin. Improvements in facial hirsutism may be seen in 4 to
8 weeks of twice-daily applications. Short-term options include shaving, chemical
depilation, plucking, threading, waxing, and bleaching. Long-term treatments
include electrolysis, laser therapy, and intense pulse light therapy.
Ovulation Induction
A large subset of patients with amenorrhea or oligomenorrhea and chronic
anovulation seek care because they are unable to conceive. Ovulation
induction therapy is generally the treatment of choice for such patients, but
pretreatment counseling should be provided in sufficient detail to ensure realistic
expectations. The patient should be provided with information regarding the
chances of a successful pregnancy (considering age of the patient and treatment
modality), potential complications (hyperstimulation and multiple gestation),
expense, time, and psychological impact involved in completing the course of
therapy. The selective estrogen receptor modulator, clomiphene citrate, is a
common first choice for ovulation induction for many patients because of its
relative safety, efficacy, oral route of administration, and relatively low cost.
Clomiphene citrate is indicated primarily in patients with adequate levels of
estrogen and normal levels of FSH and prolactin. It is less effective in
hypogonadotropic patients who already have a poor estrogen supply.
The aromatase inhibitor, letrozole, has been demonstrated to be effective for
ovulation induction in women with PCOS (132). In systematic reviews and
meta-analyses of randomized trials, ovulation induction with letrozole was
found to result in higher pregnancy rate compared with clomiphene (133,134)
and letrozole can be recommended as first-line treatment because of higher
ovulation pregnancy and live birth rate (134). However, it should be noted that
letrozole is FDA approved only for breast cancer, not for ovulation induction.
As many as 80% of patients can be expected to ovulate after either letrozole or
2077clomiphene citrate therapy. Contraindications to the use of clomiphene citrate or
letrozole include pregnancy, liver disease, and pre-existing large ovarian cysts.
Side effects can include hot flashes. In addition, clomiphene is associated with a
risk of visual changes, which generally are viewed as an indication to discontinue
subsequent clomiphene citrate use. The risk of multiple pregnancy is increased
with clomiphene citrate. The majority of multiple gestations are twins; triplets
and higher order multiple gestations are rare. In a meta-analysis examining use of
letrozole for ovulation induction in anovulatory women, letrozole led to a lower
rate of multiple pregnancy compared with clomiphene (134).
The most commonly recommended treatment regimen for clomiphene citrate is
50 mg daily for 5 days, beginning on the 3rd to 5th day of menstrual or
withdrawal bleeding. Letrozole is typically prescribed at a starting dose of 2.5 mg
or 5 mg daily for 5 days. Cycles may be monitored by measuring midcycle LH
levels to assess the hormonal signal for ovulation. Ovulation may be confirmed
by measuring midluteal progesterone levels. Ultrasonographic monitoring to
assess folliculogenesis may be helpful, especially when hCG is used to induce
ovulation. Endometrial thinning may be detected with midcycle ultrasound. With
these data, it is possible to immediately adjust the dose in the subsequent cycle if
a given regimen is ineffective.
Although a large randomized trial demonstrated that clomiphene alone is
superior to metformin alone in achieving live birth in women with PCOS
(135), a meta-analysis suggests that for some patients with PCOS, metformin
and clomiphene combined may increase the likelihood of ovulation compared
with clomiphene alone (134). Thinning of the endometrium at midcycle in the
face of adequate midcycle estradiol or lack of success with repeated cycles of
letrozole or clomiphene are generally indications to consider injectable
gonadotropins.
Women with PCOS who do not ovulate or become pregnant with
clomiphene citrate or letrozole, and women with hypogonadotropic
hypoestrogenic anovulation, may be candidates for therapy with injectable
gonadotropins. Available preparations include recombinant FSH and LH and
products purified from the urine of menopausal women (FSH or FSH–LH
combinations). Administration protocols and dosages vary widely and should be
adjusted to individual needs. Safe administration requires careful monitoring of
ovarian response with ultrasonography and, in some cases, serial estradiol
measurements. In general, gonadotropins are administered at a dose of 37 to 150
IU per day by subcutaneous injection for 3 to 5 days, after which time estradiol
and follicular monitoring commence. In most cycles, gonadotropin is
administered for 7 to 12 days. Ovulation is triggered by subcutaneous or
intramuscular injection of 5,000 to 10,000 IU hCG or subcutaneous injection of
2078250 μg of recombinant hCG when the lead follicle reaches 16 to 20 mm in
diameter based on ultrasonographic assessments. Ovulation generally occurs
approximately 38 to 40 hours after hCG administration. Luteal phase support may
be provided with the administration of progesterone supplementation.
The two major complications associated with induction of ovulation with
gonadotropins are multiple pregnancy (10% to 30%) and ovarian
hyperstimulation syndrome. The incidence of both of these complications can
be reduced but not eliminated by careful monitoring. Cycles complicated by the
recruitment of numerous follicles or by high estradiol levels may be canceled by
withholding the ovulatory dose of hCG. Selected patients may be converted safely
to in vitro fertilization. Because severe ovarian hyperstimulation syndrome is lifethreatening and may lead to prolonged hospitalization, ovulation induction with
gonadotropins generally is performed by experienced practitioners who devote a
significant portion of their practice to the treatment of infertility.
Ovulation induction with pulsatile GnRH may be effective in patients who
have chronic anovulation associated with low levels of estrogen and
gonadotropins. For therapy to be successful, a functional ovary and pituitary
gland must be present. Patients with ovarian or pituitary failure do not respond to
GnRH therapy. To be effective, GnRH must be administered in a pulsatile
fashion, either intravenously or subcutaneously by a programmable pump.
Ovulation induction with GnRH, as compared with gonadotropins, is associated
with a relatively low incidence of ovarian hyperstimulation and multiple births. In
addition, the need for appropriate timing of the ovulatory dose of hCG is avoided
because patients treated with pulsatile GnRH have an appropriately timed
endogenous LH surge. Disadvantages are mainly related to maintaining the
programmable pump and injection site and lack of availability of an appropriate
pump in the United States. After ovulation, luteal phase support is necessary and
may be provided with hCG, progesterone, or continuation of the GnRH therapy.
For women with overt POI (also known as premature ovarian failure),
there is no good evidence to suggest that any treatment can increase the
chance of conception with autologous oocytes (87,89). Treatments that were
tried include ovulation induction with clomiphene or gonadotropin, initial
suppression of gonadotropin levels by pretreatment with high-dose estrogen
or GnRH agonist followed by expectant management or gonadotropin
stimulation, standard-dose hormone therapy followed by gonadotropin, and
corticosteroid pretreatment followed by gonadotropin. If POI is diagnosed
while a patient still has a significant supply of oocytes, fertility preservation could
be considered if the patient is not able to consider conception at the time of
diagnosis. In most cases, patients with prolonged amenorrhea are not diagnosed at
a time when significant numbers of reproductively competent oocytes are present.
2079Fertility preservation is an option for patients about to undergo gonadotoxic
chemotherapy (136) or if a patient is known (e.g., based on family history) to be
at risk for POI. Either embryos or oocytes can be cryopreserved, but in most
cases, oocyte cryopreservation is preferable so that the source of sperm for
fertilization of the oocytes can be decided at a future time and/or based on
personal feelings about having embryos frozen. Ovarian tissue freezing can be
considered if oocyte cryopreservation is not possible, such as when chemotherapy
must be initiated immediately.
Patients with POI who desire pregnancy will in most cases have a high
chance of having a child with the help of oocyte donation. Oocytes from
donors may be harvested after ovulation induction, fertilized with sperm from the
intended father or sperm donor, and transferred into the recipient’s uterus after the
endometrium is appropriately prepared with estrogen and progesterone. Special
concern is warranted for women with Turner syndrome who have been reported
to have an increased risk of maternal mortality of 2% (49). Rupture of the aorta
may occur even if an echocardiogram shows no dilatation (137). In women with
Turner syndrome who have a spontaneous pregnancy, the risk of cardiovascular
morbidity may be lower (138). It is suggested that all women with Turner
syndrome who are considering pregnancy undergo a full cardiac evaluation at a
center with expertise in cardiovascular imaging (5,8), and that women with
Turner syndrome receive expert consultation regarding whether or not it is safe to
consider carrying a pregnancy.
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