Key points
- •
Primary amenorrhea is diagnosed if no menstrual function has occurred by age 15, or 5 years after initial breast development.
- •
Menarche is delayed approximately 0.4 year for each year of premenarchal athletic training.
- •
Gonadal failure is the most common cause of primary amenorrhea, accounting for almost 50% of patients with this disorder.
- •
Individuals with gonadal failure should have a peripheral karyotype obtained to determine whether a Y chromosome is present. If it is present, or if there are signs of hyperandrogenism, the gonads should be removed to prevent the development of malignancy.
- •
Amenorrhea with low estrogen levels is associated with decreased bone density.
- •
If signs of pubertal progression (precocious puberty) are present in a girl, a workup is warranted by the age of 8 years.
- •
The two primary concerns of parents of children with precocious puberty are the social stigma associated with the child being physically different from her peers and the diminished ultimate height caused by the premature closure of epiphyseal centers.
- •
The exact cause of the majority of cases of GnRH-dependent (true or central) precocious puberty is unknown; however, approximately 30% of cases are secondary to central nervous system disease.
- •
The most common cause of gonadotropin-releasing hormone–independent precocious puberty is a functioning ovarian tumor. Granulosa cell tumors are the most common type accounting for 60% of neoplasms.
Primary and seconday amenorrhea
Amenorrhea is defined as the absence of menstrual bleeding and may be primary (never occurring) or secondary (cessation sometime after initiation).
Primary amenorrhea is defined as the absence of menses in a woman who has never menstruated by the age of 15 years ( .) Another definition includes girls who have not menstruated within 5 years of breast development, if occurring by age 10. Breast development (thelarche) should occur by age 13 or otherwise requires evaluation as well. The incidence of primary amenorrhea is less than 0.1%. Secondary amenorrhea is defined as the absence of menses for an arbitrary period, usually longer than 6 to 12 months. The incidence of secondary amenorrhea of more than 6 months’ duration in a survey of a general population of Swedish women of reproductive age was found to be 0.7% but has been cited to be as high as 3% ( ). The incidence is significantly higher in women younger than 25 years and those with a history of menstrual irregularity.
Outside the United States, it is common to see women who have been categorized according to the World Health Organization (WHO) classification. WHO type I usually refers to women with low estrogen levels and low follicle-stimulating hormone (FSH) and normal prolactin (PRL) levels without central nervous system (CNS) lesions; type II refers to a normal estrogen status with normal FSH and PRL levels; WHO type III refers to low estrogen levels and a high FSH level, denoting ovarian failure.
Physiology leading up to menarche
Before the onset of menses, the normal female goes through a progressive series of morphologic changes produced by the pubertal increase in estrogen and androgen production. In 1969 Marshall and Tanner defined five stages of breast development and pubic hair development ( ; ) ( Fig. 36.1 ; Table 36.1 ). These changes sometimes are combined and called Tanner , or pubertal , stages 1 through 5 . The first sign of puberty is usually the appearance of breast budding, followed within a few months by the appearance of pubic hair.
| Classification | Description |
|---|---|
| Breast Growth | |
| B1 | Prepubertal: elevation of papilla only |
| B2 | Breast budding |
| B3 | Enlargement of breasts with glandular tissue, without separation of breast contours |
| B4 | Secondary mound formed by areola |
| B5 | Single contour of breast and areola |
| P UBIC H AIR G ROWTH | |
| PH1 | Prepubertal—no pubic hair |
| PH2 | Labial hair present |
| PH3 | Labial hair spreads over mons pubis |
| PH4 | Slight lateral spread |
| PH5 | Further lateral spread to form inverse triangle and reach medial thighs |
Thereafter the breasts enlarge, the external pelvic contour becomes rounder, and the most rapid rate of growth occurs (peak height velocity). These changes precede menarche. Thus breast budding is the earliest sign of puberty and menarche the latest. The mean ages of occurrence of these events in American women are shown in Table 36.2 and the mean intervals (with standard deviation [SD]) between the initiation of breast budding and other pubertal events are shown in Table 36.3 ( ). The mean interval between breast budding and menarche is 2.3 years, with an SD of approximately 1 year. Some individuals can progress from breast budding to menarche in 18 months, and others may take 5 years. As stated previously, if thelarche has not occurred by age 13, a diagnostic evaluation should be performed.
| Event | Mean Age ± SD (yr) |
|---|---|
| Initiation of breast development | 10.8 ± 1.10 |
| Appearance of pubic hair | 11.0 ± 1.21 |
| Menarche | 12.9 ± 1.20 |
| Interval | Mean Age ± SD (yr) |
|---|---|
| B2—peak height velocity | 1.0 ± 0.77 |
| B2—menarche | 2.3 ± 1.03 |
| B2-PH2 | 3.1 ± 1.04 |
| B2-B5 (average duration of puberty) | 4.5 ± 2.04 |
The mean time of onset of menarche was previously thought to occur when a critical body weight of approximately 48 kg (106 lb) was reached; however, it is now believed that body composition is more important than total body weight in determining the time of onset of puberty and menstruation. Thus the ratio of fat to both total body weight and lean body weight is probably the most relevant factor that determines the time of onset of puberty and menstruation. Individuals who are moderately obese, between 20% and 30% more than the ideal body weight, have an earlier onset of menarche than women who are not obese. Malnutrition, such as occurs with anorexia nervosa or starvation, is known to delay the onset of puberty.
One of the major links between body composition and the hypothalamic-pituitary-ovarian (HPO) axis, and thus menstrual cyclicity, is the adipocyte hormone leptin . Leptin is produced by adipocytes and correlates well with body weight. Leptin is also important for feedback involving gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) pulsatility and also binds to specific receptor sites on the ovary and endometrium. Leptin administration has been shown to affect LH pulsatile activity ( ) and to restore cyclicity in women with amenorrhea. Another hormone, a gastric peptide, ghrelin, interacts with leptin in this regard particularly when menstrual function is perturbed ( ).
Body weight and body fat content have been shown to be important for menstruation; a fatness nomogram is depicted in Fig. 36.2 ( ). Well-nourished individuals with prepubertal strenuous exercise programs resulting in less total body fat have also been shown to have a delayed onset of puberty. Warren and colleagues have reported that ballet dancers, swimmers, and runners have menarche delayed to approximately age 15 if they began exercising strenuously before menarche ( ) ( Fig. 36.3 ). It is greater in those athletic activities requiring lower body weight and where success is more subjective (ballet, gymnastics) compared with swimming. It was also determined that stress per se is not the cause of the delayed menarche in these exercising girls, because girls of the same age with stressful musical careers did not have a delayed onset of menarche ( ). Young women with strenuous exercise programs have sufficient estrogen to produce some breast development and thus do not need extensive endocrinologic evaluation if concern arises about the lack of onset of menses. Frisch and coworkers have reported that for girls engaged in premenarchal athletic training, menarche is delayed 0.4 year for each year of training. Individuals who exercise strenuously should be counseled that they will usually have a delayed onset of menses, but it is not a health problem. They should be told that they will most likely have regular ovulatory cycles when they stop exercising or become older.
The metabolic features of amenorrheic athletes, who are considered to be in a state of negative energy balance, are fairly characteristic. These include elevated serum FSH and insulin-like growth factor-binding protein 1 (IGFBP-1) and lowered insulin-like growth factor (IGF) levels.
Emotional stress can lead to inhibition of the GnRH axis. The mechanism involves an increased secretion of corticotropin-releasing hormone (CRH), releasing adrenocorticotropic hormone (ACTH), opioid peptides such as beta-endorphin, and cortisol. CRH itself is known to inhibit GnRH.
Before puberty, circulating levels of LH and FSH are low, with an FSH/LH ratio greater than 1. The CNS-hypothalamic axis is extremely sensitive to the negative feedback effects of low levels of circulating estrogen. As the critical weight or body composition is approached, the CNS-hypothalamic axis becomes less sensitive to the negative effect of estrogen and GnRH is secreted in greater amounts, causing an increase in LH and, to a lesser extent, FSH levels. This release from the prepubertal “brake” on GnRH secretion is depicted in Fig. 36.4 , which also illustrates the integral role of neuropeptides such as kisspeptin ( ). The initial endocrinologic change associated with the onset of puberty is the occurrence of episodic pulses of LH during sleep ( ) ( Fig. 36.5 ). These pulses are absent before the onset of puberty. After menarche, the episodic secretions of LH occur during sleep and while awake. The last endocrinologic event of puberty is activation of the positive gonadotropin response to increasing levels of estradiol (E 2 ), which results in the midcycle gonadotropic surge and ovulation.
Primary amenorrhea
Causes
Although numerous classifications have been used for the various causes of primary amenorrhea, it has been found useful to group causes on the basis of whether secondary sexual characteristics (breasts) and female internal genitalia (uterus) are present or absent ( Box 36.1 ). Thus the findings on a physical examination can alert the clinician to possible causes and indicate which laboratory tests should be performed. In a series of 62 individuals reported by Mashchak, the largest subgroup with primary amenorrhea (29; 47%) were individuals in whom breasts were absent but where a uterus was present; the second largest subgroup (22; 35%) had both breasts and a uterus; lack of a uterus together with breast development accounted for the third largest category (9; 14.5%); and individuals without breasts or a uterus were the least common (2; <1%) ( ). This breakdown of the various accompanying conditions of primary amenorrhea reflects the referral pattern to the center. In one study, a “physiologic delay” occurring in 14% and polycystic ovary syndrome (PCOS) in 7% ( ).
I absent breast development; uterus present
- A.
Gonadal failure
- 1.
45,X (Turner syndrome)
- 2.
46,X, abnormal X (e.g., short- or long-arm deletion)
- 3.
Mosaicism (e.g., X/XX, X/XX,XXX)
- 4.
46,XX or 46,XY pure gonadal dysgenesis
- 5.
17α-hydroxylase deficiency with 46,XX
- 1.
- B.
Hypothalamic failure secondary to inadequate GnRH release
- 1.
Insufficient GnRH secretion because of neurotransmitter defect
- 2.
Inadequate GnRH synthesis (Kallmann syndrome)
- 3.
Congenital anatomic defect in central nervous system
- 4.
CNS neoplasm (craniopharyngioma)
- 1.
- C.
Pituitary failure
- 1.
Isolated gonadotrophin insufficiency (thalassemia major, retinitis pigmentosa)
- 2.
Pituitary neoplasia (chromophobe adenoma)
- 3.
Mumps, encephalitis
- 4.
Newborn kernicterus
- 5.
Prepubertal hypothyroidism
- 1.
II breast development; uterus absent
- A.
Androgen resistance (testicular feminization)
- B.
Congenital absence of uterus (uterovaginal agenesis)
III absent breast development; uterus absent
- A.
17,20-desmolase deficiency
- B.
Agonadism
- C.
17α-hydroxylase deficiency with 46,XY karyotype
IV breast development; uterus present
- A.
Hypothalamic cause
- B.
Pituitary cause
- C.
Ovarian cause
- D.
Uterine cause
Breasts absent and uterus present
It would seem logical, because breast development is a biomarker of ovarian estrogen production, that individuals with no breast development and a uterus present have no estrogen production. This is either the result of a primary ovarian disorder or an abnormality of the CNS hypothalamic–pituitary axis, which provides the normal signal to the ovary. The phenotype of individuals with either of these causes of low estrogen status is similar.
Gonadal failure (hypergonadotropic hypogonadism)
Failure of gonadal development is the most common cause of primary amenorrhea , occurring in almost 50% of those with this symptom. Gonadal failure is most commonly caused by a chromosomal disorder or deletion of all or part of an X chromosome, but it is sometimes caused by another chromosomal genetic defect and, rarely, defective CYP-17 leading to 17α-hydroxylase deficiency. The chromosomal disorders are usually caused by a random meiotic or mitotic abnormality (e.g., nondisjunction, anaphase lag) and thus are not inherited; however, if gonadal development is absent in the presence of a 46,XX (called pure gonadal dysgenesis ), a gene disorder may be present, because it has been reported to occur in siblings. Reindollar reported that all individuals with gonadal failure and an X chromosome abnormality were shorter than 63 inches in height ( ). Approximately one-third also had major cardiovascular or renal anomalies.
Deletion of the entire X chromosome (as occurs in Turner syndrome) or of the short arm (p) of the X chromosome results in short stature. Deletions of only the long arm (q) usually do not affect height. In place of the ovary a band of fibrous tissue called a gonadal streak is present ( ) ( Fig. 36.6 ). When ovarian follicles are absent, synthesis of ovarian steroids and inhibin does not occur. Breast development does not occur because of the low circulating E 2 levels. Because the negative hypothalamic-pituitary action of estrogen and inhibin is not present, gonadotropin levels are markedly elevated, with FSH levels being higher than LH. Estrogen is not necessary for müllerian duct development or wolffian duct regression, so the internal and external genitalia are phenotypically female.
An occasional individual with mosaicism, an abnormal X chromosome, pure gonadal dysgenesis (46,XX), or even Turner syndrome (45,X) may have a few follicles that develop under endogenous gonadotropin stimulation early in puberty and may synthesize enough estrogen to induce breast development and a few episodes of uterine bleeding, resulting early in premature ovarian failure , usually before age 25. Rarely, ovulation and pregnancy can occur.
Goldenberg reported that all individuals with primary amenorrhea and plasma FSH levels higher than 40 mIU/mL have no functioning ovarian follicles in the gonadal tissue. Thus in women with primary amenorrhea, the diagnosis of gonadal failure can be established if the FSH levels are consistently elevated, without requiring ovarian tissue evaluation.
45,X and related abnormalities
Turner syndrome occurs in approximately 1 per 2000 to 3000 live births but is much more common in abortuses . In addition to primary amenorrhea and absent breast development, these individuals have other somatic abnormalities, the most prevalent being short stature (<60 inches in height), webbing of the neck, a short fourth metacarpal, and cubitus valgus. Cardiac abnormality, renal abnormalities, and hypothyroidism are also more prevalent.
A wide variety of chromosomal mosaics are associated with primary amenorrhea and normal female external genitalia, the most common being X/XX. In addition, individuals with X/XXX and X/XX/XXX mosaicism have primary amenorrhea. These individuals are generally taller and have fewer anatomic abnormalities than individuals with a 45,X karyotype. In addition, some of them may have a few gonadal follicles and approximately 20% have sufficient estrogen production to menstruate. Occasionally, ovulation may occur, as stated earlier. Isolated phenotypic features of Turner syndrome (without gonadal failure) may also occur in males and is known as Noonan syndrome.
Structurally abnormal X chromosome
Although individuals with this disorder have a 46,XX karyotype, part of one X chromosome is structurally abnormal. If there is deletion of the long arm of the X chromosome (Xq), normal height has been reported to occur, but, in Reindollar’s series, these individuals were all relatively short ( ). They have no somatic abnormalities; however, if there is deletion of the short arm of the X chromosome (Xp), the individual will be short. A similar phenotype occurs in those with isochromosome of the long arm of the X chromosome. Other X chromosome abnormalities include a ring X and minute fragmentation of the X chromosome.
Pure gonadal dysgenesis (46,XX and 46,XY with gonadal streaks)
As noted, this abnormality may have a familial/genetic association and has been reported in siblings. Abnormalities in genes involved in gonadal development are expected to be involved. These individuals have normal stature and phenotype, absence of secondary sexual characteristics, and primary amenorrhea. Some of these women have a few ovarian follicles, develop breasts, and may even menstruate spontaneously for a few years.
46,XY gonadal dysgenesis is the result of an abnormal testis in utero. There can be incomplete forms with some degree of testicular tissue, but in this context the “pure” form as a dysgenetic streak as in other forms of ovarian dysgenesis and previously has been referred to as Swyer syndrome.
If a Y chromosome is present (as in 46,XY gonadal dysgenesis) or is found as part of a mosaic karyotype, with or without any clinical signs of androgenization, gonadectomy should be performed.
17α-hydroxylase deficiency with 46,XX karyotype
A rare gonadal cause of primary amenorrhea without breast development and normal female internal genitalia is deficiency of the enzyme 17α-hydroxylase (P450 CYP-17) in an individual with a 46,XX karyotype (it can also occur in genetic males 46,XY), who may present in a similar fashion. Only a few such individuals have been described in the literature, but it is important for the clinician to be aware of this entity because, in contrast to those described earlier, these individuals have hypernatremia and hypokalemia. Because of decreased cortisol, ACTH levels are elevated. The mineralocorticoid levels are also elevated, because 17α-hydroxylase is not necessary for the conversion of progesterone to deoxycortisol or corticosterone. Thus there is excessive sodium retention and potassium excretion, leading to hypertension and hypokalemia. Serum progesterone levels are also elevated because progesterone is not converted to cortisol. In addition to sex steroid replacement, these individuals need cortisol administration. They usually have cystic ovaries and viable oocytes. Pregnancies have been documented after in vitro fertilization–embryo transfer (IVF-ET), despite low levels of endogenous sex steroids.
Genetic disorders with hyperandrogenism
Hyperandrogenism occurs in approximately 10% of women with gonadal dysgenesis. Most have a Y chromosome or fragment of a Y chromosome, but some may only have a DNA fragment that contains the testes-determining gene (probably SRY ) without a full Y chromosome. Those with hypergonadotropic hypogonadism and a female phenotype who have any clinical manifestation of hyperandrogenism, such as hirsutism, should have a gonadectomy , even if a Y chromosome is not present, because gonadal neoplasms are common.
CNS-hypothalamic-pituitary disorders
With CNS-hypothalamic-pituitary disorders, the low estrogen levels are caused by an abnormal or absent signal to the ovary, resulting in very low circulating gonadotropin levels. The cause of low gonadotropin production may be morphologic or endocrinologic.
CNS lesions
Any anatomic lesion of the hypothalamus or pituitary can cause low gonadotropin production. These lesions can be congenital (e.g., stenosis of aqueduct, absence of sellar floor) or acquired (tumors). Many of these lesions, particularly pituitary adenomas, result in elevated PRL levels (see Chapter 37 ); however, non–PRL-secreting pituitary tumors ( chromophobe adenomas ) and craniopharyngiomas may not be associated with hyperprolactinemia and can rarely be the cause of primary amenorrhea with low gonadotropin levels. Thus all individuals with primary amenorrhea and low gonadotropin levels, with or without an elevated PRL level, should have computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the hypothalamic-pituitary region to rule out the presence of a lesion.
Inadequate GnRH release (hypogonadotropic hypogonadism)
Those without a demonstrable lesion and a low gonadotropin level were previously thought to have primary pituitary failure ( hypogonadotropic hypogonadism ); however, when they are stimulated with GnRH, there is an increase in FSH and LH levels, indicating that the basic defect is primarily hypothalamic with insufficient GnRH synthesis or a CNS neurotransmitter defect , resulting in inadequate GnRH synthesis, release, or both. This can also be the result of abnormal kisspeptin, as noted earlier. Although a single bolus of GnRH may not initially cause a rise in gonadotropin level in these individuals, after 4 days of GnRH administration (priming), the women will have a rise in gonadotropin levels after a single GnRH bolus. Because GnRH secretion occurs after migration of these specific cells from the olfactory lobe to the hypothesis during embryogenesis, anosmia may also occur in some patients with gonadotropin deficiency. This is caused by a specific defect of the KAL gene (Xp 22-3), which is responsible for neuronal migration. Other genetic defects resulting in gonadotropic deficiency may occur on the X chromosome or autosomes and include FGFR1, PROKR2, and GNRHR ( ) as well as loss of function mutations in the kisspeptin-1 receptor.
Females with Kallmann syndrome and related forms of gonadotropic deficiency have normal height and an increase in growth of long bones, resulting in a greater wingspan-to-height ratio. Men affected by gonadotropic deficiency have hypogonadism, an increased wingspan-to-height ratio, and altered spatial orientation abilities. Anosmia in Kallmann syndrome must be tested for by blinded testing of certain characteristic smells, such as coffee, cocoa, or orange. Not all women in this category of GnRH deficiency states will have anosmia, which is specific for some patients with Kallmann syndrome.
There is a tendency for GnRH deficiency to be familial/inherited through a variety of mechanisms, although the majority of cases, more than two-thirds, are sporadic.
Isolated gonadotropin deficiency (pituitary disease)
Rarely, individuals with primary amenorrhea and low gonadotropin levels do not respond to GnRH, even after 4 days of administration. This is known as isolated gonadotropin deficiency . They almost always have an associated disorder such as thalassemia major (with iron deposits in the pituitary) or retinitis pigmentosa. Occasionally this pituitary abnormality has been associated with prepubertal hypothyroidism, kernicterus, or mumps encephalitis.
Estrogen resistance
This rare condition was first described in men and now has been described in a woman (breast absent, uterus present). A mutation in estrogen receptor alpha (ERα) does not allow estrogen signaling or a biologic response to estrogen action. Endogenous estrogen levels are high, gonadotropins are higher than the normal range (to try to provoke an estrogen response), and the ovaries are cystic. Exogenous estrogen does not normally induce changes except minimal changes with high pharmacologic doses ( ).
Breast development present and uterus absent
Two disorders present with primary amenorrhea associated with normal breast development and the absence of a uterus: androgen resistance and congenital absence of the uterus. The former is a genetically inherited disorder, whereas the latter is an accident of development and does not have an established pattern of inheritance.
Androgen resistance
Androgen resistance syndrome , originally termed testicular feminization, is a genetically transmitted disorder in which androgen receptor synthesis or action does not occur. It is rare, with an incidence of 1 in 60,000. The syndrome is caused by the absence of an X-chromosome gene responsible for cytoplasmic or nuclear testosterone receptor function. It is an X-linked recessive or sex-linked autosomal dominant disorder, with transmission through the mother. These individuals have an XY karyotype and normally functioning male gonads that produce normal male levels of testosterone and dihydrotestosterone; however, because of a lack of receptors in target organs, there is lack of male differentiation of the external and internal genitalia ( ). The external genitalia remain feminine, as occurs in the absence of sex steroids. Wolffian duct development, which normally occurs as a result of testosterone stimulation, fails to take place. Because müllerian duct regression is induced by antimüllerian hormone (AMH), also called müllerian-inhibiting substance (MIS, a glycoprotein synthesized by the Sertoli cells of the fetal testes), this process occurs normally in these individuals because steroid receptors are unnecessary for the action of glycoproteins. Thus women with this disorder have no female or male internal genitalia, normal female external genitalia, and a short or absent vagina. Pubic hair and axillary hair are absent or scanty as a result of a lack of androgenic receptors, but breast development is normal or enhanced. It is known that testosterone is responsible for inhibiting breast proliferation. Thus with androgen resistance, the absence of androgen action allows even low levels of estrogen to cause unabated breast stimulation. Estrogen levels here are in the normal male range, and LH is slightly elevated.
Testes that are intraabdominal or that occur in the inguinal canal have an increased risk of developing a malignancy (gonadoblastoma or dysgerminoma ), with an incidence reported to be approximately 20%; however, these malignancies rarely occur before age 20. Therefore it is usually recommended that the gonads be left in place until after puberty is completed to allow full breast development and epiphyseal closure to occur. After these events occur, which is typically around age 18, the gonads should be removed. It is recommended that those with androgen resistance be informed that they have an abnormal sex chromosome, without specifically mentioning a Y chromosome, because it is widely known that an XY karyotype indicates maleness; however, some families choose to have full disclosure and a complete understanding of the abnormality. In addition, because psychologically and phenotypically these individuals are female and have been raised as such, the term gonads should be used instead of testes. These individuals should also be informed that they can never become pregnant because they do not have a uterus and that their gonads must be removed after age 18 because of their high potential for malignancy.
Congenital absence of the uterus (uterine agenesis, uterovaginal agenesis, mayer-rokitansky-küster-hauser syndrome)
The Hox genes are important for uterine development, and mutations (e.g., in HOXA13 ) have been found in genetic syndromes that include uterine abnormalities (e.g., hand-foot-genital and Guttmacher syndromes) and also in cases of bicornuate uterus. To date, however, no abnormalities have been found in cases of congenital absence of the uterus.
Congenital absence of the uterus is the second most common cause of primary amenorrhea . It occurs in 1 in 4000 to 5000 female births and accounts for approximately 15% of individuals with primary amenorrhea. Individuals with complete uterine agenesis have normal ovaries, with regular cyclic ovulation and normal endocrine function. Women with this disorder have normal breast and pubic and axillary hair development but have a shortened or absent vagina, in addition to absence of the uterus ( ) ( Fig. 36.7 ). Although often there are no bulbous structures, but merely streaklike tissue, in 7% to 10% of cases there are two nonfused rudimentary horns as in the figure. On occasion one or both horns may have some functioning endometrium . In this setting of obstructed outflow, cyclic pelvic pain, which may be severe at times, may be encountered. Congenital renal abnormalities occur in approximately one-third of these individuals and skeletal abnormalities in approximately 12%. Cardiac and other congenital abnormalities also occur with increased frequency. Occasional defects in the bones of the middle ear can also occur, resulting in some degree of deafness. The overwhelming majority of these disorders are caused by an isolated developmental defect, but on occasion the condition is genetically inherited. It is usually easy to differentiate these individuals from those with androgen resistance by the presence of normal pubic hair, but some with incomplete androgen resistance have some pubic hair.
Women in this category are normal endocrinologically and have been able to have children using a surrogate or gestational carrier. A woman underwent a uterine transplantation from a donated postmenopausal uterus and was able to have a live birth ( ).
Absent breast and uterine development
Individuals with no breast or uterine development are rare. They usually have a male karyotype, elevated gonadotropin levels, and testosterone levels in the normal or below-normal female range. The differential diagnosis for this phenotype includes deficiencies in CYP17 (17α-hydroxylase deficiency/17,20-desmolase deficiency) and agonadism ( ). Individuals with predominant deficiency in 17 α- hydroxlase activity have testes present but lack the enzyme necessary to synthesize sex steroids and thus have female external genitalia. Because they have testes, AMH is produced and the female internal genitalia regress; with low testosterone levels, the male internal genitalia do not develop. Insufficient estrogen is synthesized to develop breasts. A similar lack of sex steroid synthesis occurs in males with a 17,20-desmolase deficiency.
Individuals with agonadism, sometimes called the vanishing testes syndrome, have no gonads present, but because the female internal genitalia are also absent, it has been postulated that testicular AMH-MIS production occurred during fetal life but the gonadal tissue subsequently regressed.
Secondary sex characteristics (breasts) present and female internal genitalia (uterus) present
Individuals with secondary sex characteristics and female internal genitalia present are the second largest category of individuals with primary amenorrhea, accounting for approximately one-third of them. In the series reported by Mashchak, approximately 25% of these individuals had hyperprolactinemia and prolactinomas ( ). The remaining women had profiles similar to those with secondary amenorrhea, including PCOS, and thus should be subcategorized and treated similarly as women with secondary amenorrhea, which will be discussed later.
Primary amenorrhea with absent endometrium
Primary amenorrhea with absent endometrium is a rare condition in this category of primary amenorrhea with uterus and breast present. Endocrine function is completely normal, as are the uterus, ovaries, and fallopian tubes; however, in two reported cases the endometrium was found to be absent, after repeated biopsies ( ; ). It is likely that some genetic defect is responsible for this rare finding, but the reported association of a translocation between chromosomes 4 and 20 ( ) is unlikely to be the cause.
Differential diagnosis and management
After a history is obtained and a physical examination performed, including measurement of height, span, and weight, those with primary amenorrhea can be grouped into one of the four general categories listed in Box 36.1 , depending on the presence or absence of breasts and a uterus. If breasts are absent but a uterus is present, the diagnostic evaluation should differentiate between CNS-hypothalamic-pituitary disorders and failure of normal gonadal development. Although individuals with both these disorders have similar phenotypes because of low E 2 levels, a single serum FSH assay can differentiate between these two major diagnostic categories ( ) ( Fig. 36.8 ). Women with hypergonadotropic hypogonadism (FSH > 40 mIU/mL), not those with hypogonadotropic hypogonadism, should have a peripheral white blood cell karyotype obtained to determine whether a Y chromosome is present. If a Y chromosome is present, the streak gonads should be excised. If a Y chromosome is absent, it is unnecessary to remove the gonads unless there are signs of hyperandrogenism. It is also unnecessary to perform a karyotype on the gonadal tissue to detect possible mosaicism with a Y chromosome in the gonad unless there is some evidence of hyperandrogenism.
All women with an elevated FSH level and an XX karyotype should have electrolyte and serum progesterone levels measured to rule out 17α-hydroxylase deficiency; a clue is if the patient is hypertensive. In addition to hypernatremia and hypokalemia, individuals with 17α-hydroxylase deficiency have an elevated serum progesterone level (>3 ng/mL), a low 17α-hydroxyprogesterone level (<0.2 ng/mL), and an elevated serum deoxycorticosterone level (>17 ng/100 mL) and usually have hypertension. Doses of conjugated equine estrogen (CEE) in the range of 0.625 mg or its equivalent are usually sufficient to cause breast proliferation. These rare individuals with 17α-hydroxylase deficiency need to have adequate cortisol replacement in addition to sex steroid treatment.
Women with ovarian failure or hypergonadotropic hypogonadism who wish to become pregnant may undergo egg donation. As long as the uterus is normal, which is usually the case, high pregnancy rates in the range of 60% to 70% per cycle may be expected. If the patient has Turner syndrome, cardiac evaluation is mandatory before pregnancy because of potential risks such as aortic dissection.
If the FSH level is low, the underlying disorder is in the CNS-hypothalamic-pituitary region and PRL should be determined. Even if the PRL level is not elevated, all women with hypogonadotropic hypogonadism should have a head CT scan or MRI to rule out a lesion. It is unnecessary to perform a karyotype because all those with hypogonadotropic hypogonadism are expected to be 46,XX. The use of GnRH testing is optional but is usually clinically unnecessary unless GnRH is going to be used for ovulation induction. Ovulation can be induced in women with this disorder because their ovaries are normal. Initially they should receive estrogen-progestogen treatment to induce breast development and cause epiphyseal closure. When fertility is desired, human menopausal gonadotropins or pulsatile GnRH should be administered. Clomiphene citrate will be ineffective because of low endogenous E 2 levels.
The differential diagnosis of androgen resistance from uterine agenesis can easily be made by the presence in the latter condition of normal body hair, ovulatory and premenstrual-type symptoms, biphasic basal temperature, and a normal female testosterone level. Because women with uterine agenesis have normal female endocrine function, they do not require hormone therapy. A renal scan should be performed because of the high incidence of renal abnormalities. They may need surgical reconstruction of an absent vagina (McIndoe procedure), but progressive mechanical dilation with plastic dilators, as described by Frank, should be tried first and is usually successful in motivated individuals, particularly when using pressure from body weight, as with a bicycle seat. These women can now have their own genetic children. After ovarian stimulation and follicle aspiration, fertilized oocytes can be placed in the uterus of a surrogate recipient (gestational carrier). As noted earlier, a case report of a woman having a live birth after uterus transplantation has been reported ( ).
Individuals with androgen resistance have an XY karyotype and male levels of testosterone. After full breast development is attained and epiphyseal closure occurs, the gonads should be removed because of malignant potential. Thereafter, estrogen therapy should be administered. They do not need progestogen therapy in the absence of a uterus, and lower doses of estrogen are sufficient; typical menopause symptoms are usually not present.
The rare individuals without breast development and no internal genitalia should be referred to an endocrine center for the extensive evaluation necessary to establish the diagnosis. If gonads are present, they should be removed because a Y chromosome is present. Hormone therapy should be administered to these individuals.
Secondary amenorrhea
Causes
The symptom of amenorrhea associated with hyperprolactinemia or excessive androgen or cortisol production is not considered in this chapter because these disorders are discussed in Chapters 37 , 38 , and 39 . If amenorrhea is present without galactorrhea, hyperprolactinemia, or hirsutism, the symptom can result from disorders in the CNS (hypothalamic-pituitary axis), ovary, or uterus. In a review of 262 patients presenting with secondary amenorrhea during a 20-year period at a tertiary medical center, Reindollar reported that 12% of cases resulted from a primary ovarian problem, 62% from a hypothalamic disorder, 16% from a pituitary problem (including prolactinomas), and 7% from a uterine disorder. The uterine cause of secondary amenorrhea is the only one in which normal endocrine function is present and is discussed first.
Uterine factor
Intrauterine adhesions (IUAs) or synechiae (Asherman syndrome) can obliterate the endometrial cavity and produce secondary amenorrhea. A pregnancy complication, prior instrumentation, or, rarely, endometrial tuberculosis can also cause endometrial damage with adhesion formation. The most common antecedent factor of IUAs is endometrial curettage associated with pregnancy —either evacuation of a live or dead fetus by mechanical means or postpartum or postabortal curettage. Curettage for a missed abortion results in a high incidence of IUA formation (30%). IUAs may also occur after diagnostic dilation and curettage (D&C) in a nonpregnant woman, so this procedure should be performed only when indicated and not routinely at the time of other surgical procedures (e.g., diagnostic laparoscopy). A less common cause of IUA is severe endometritis or fibrosis after a myomectomy, metroplasty, or cesarean delivery. This cause of amenorrhea should be considered most likely if a temporal relationship exists between the onset of symptoms and uterine curettage.
Confirmation of the diagnosis is usually made by a hysterosalpingogram ( Fig. 36.9 ) or another form of imaging including hysteroscopy. Although it has been suggested that sequential administration of estrogen-progestogen be used as the initial diagnostic procedure when IUA is suspected, withdrawal bleeding may occur after administration of the estrogen/progestogen in women with IUA and should not be relied on.
CNS and hypothalamic causes
CNS structural abnormalities
The same anatomic lesions in the brainstem or hypothalamus, which have been discussed as causing primary amenorrhea (by interfering with GnRH release), can also cause secondary amenorrhea. Hypothalamic lesions include craniopharyngiomas, granulomatous disease (e.g., tuberculosis, sarcoidosis), and sequelae of encephalitis. When such uncommon lesions are present, circulating gonadotropins and E 2 levels are low and withdrawal uterine bleeding will not occur after progestogen administration.
Drugs
Phenothiazine derivatives, certain antihypertensive agents, and other drugs listed in Chapter 37 can also produce amenorrhea without hyperprolactinemia, although usually PRL is elevated. Therefore women with secondary amenorrhea should have a detailed medication history obtained, even if galactorrhea is not present. Oral contraceptive steroids inhibit ovulation by acting on the hypothalamus to suppress GnRH and directly on the pituitary to suppress FSH and LH. Occasionally this hypothalamic-pituitary suppression persists for several months after oral contraceptives are discontinued, producing the syndrome termed postpill amenorrhea. This oral contraception–induced suppression should not last longer than 6 months. It has been reported that the incidence of amenorrhea persisting more than 6 months after discontinuation of oral contraceptives (0.8%) is approximately the same as the incidence of secondary amenorrhea in the general population (0.7%). Thus the reason for amenorrhea persisting more than 6 months after discontinuation of oral contraceptives is probably unrelated to their use, except that the regular withdrawal bleeding produced by oral contraceptives masks the development of this symptom.
Stress and exercise
Stressful situations, including a sudden change in a normal routine, can produce amenorrhea. A high percentage of women who were in concentration camps or those sentenced for execution also became amenorrheic as a result of stress.
Feicht and colleagues reported that the incidence of secondary amenorrhea in runners has a positive correlation with the number of miles run per week ( ) ( Fig. 36.10 ). In a comparison of amenorrheic and eumenorrheic athletes, they reported that physical parameters such as age, weight, lean body mass, and body fat were similar. The only significant difference between the two groups was the fact that the amenorrheic athletes ran more miles weekly . McArthur and associates have also reported there is no significant difference in the percentage of body fat in amenorrheic runners compared with runners who were menstruating. Both stress and exercise can increase brain-derived factors that can inhibit GnRH release (CRH, opioid peptides etc.) If the cause of GnRH inhibition is stress related, when the stressful situation abates, whether emotional in origin or related to strenuous exercise, normal cyclic ovarian function and regular menses usually resume in a few months.
Weight loss
Both male and female animals that are malnourished have decreased reproductive capacity. Weight loss is also associated with amenorrhea in women and has been classified into two groups: the moderately underweight group, which includes individuals whose weight is 15% to 25% less than ideal body weight, and severely underweight women, whose weight loss is more than 25% of ideal body weight. Weight loss can occur from excessive dietary restrictions and from malnutrition. An extreme form of this is anorexia nervosa, which is a psychiatric disorder. Vigersky demonstrated that women with amenorrhea associated with simple weight loss have direct and indirect evidence of hypothalamic dysfunction , but pituitary and end organ function is normal. Mason showed that in contrast to women with normal cycles, a group of women with weight loss amenorrhea had similar mean levels of LH and LH pulse amplitude, but they had a decreased frequency of LH pulses. Thus the amenorrhea associated with weight loss appears to be caused mainly by failure of normal GnRH release, with the lack of a pituitary response under extreme conditions. Hypoleptinemia, alterations in ghrelin, and GH and thyroid dysfunction contribute to these findings.
Polycystic ovary syndrome
PCOS is a heterogenous disorder that may present with prolonged periods of amenorrhea, although the more typical menstrual pattern is one of irregularity or oligomenorrhea. Women need not be overweight or obese, or have symptoms and signs of hyperandrogenism, which typically occurs. Although many women with PCOS have an elevated serum LH level, this level may be normal, particularly in women who are obese, and measurement of LH is not required as a diagnostic criterion. Nevertheless, the diagnosis of PCOS may be confirmed by visualizing polycystic ovaries on ultrasound, particularly in the absence of classic findings such as hyperandrogenism. According to the European Society of Human Reproduction and Embryology–American Society for Reproductive Medicine (ESHRE-ASRM) Rotterdam criteria for the diagnosis of PCOS, women may be diagnosed as having PCOS with only the menstrual disturbance (in this case amenorrhea) and polycystic ovaries seen with ultrasound. This subject is discussed in detail in Chapter 39 . PCOS in a more severe form may present early and has been noted to be a cause of primary amenorrhea as well.
Functional hypothalamic amenorrhea
Women with secondary amenorrhea who have no anatomic abnormalities, are not on drugs, and have no history of excessive exercise, stress, or large changes in body have an entity called functional hypothalamic amenorrhea (FHA). In the final analysis, these women have an alteration of hypothalamic GnRH release and do not exhibit characteristic cyclic alterations in LH pulsatility. They either have no pulses ( ) ( Fig. 36.11 ) or have a persistent pattern of pulsatility that is normally found in only one portion of the ovulatory cycle, usually the slow frequency normally found in the luteal phase, despite having a steroid milieu similar to that in the follicular phase (see Fig. 36.11 ). As reported by Ferin and colleagues, administration of the opioid antagonists naloxone and naltrexone to women with FHA is followed by an increase in frequency of LH pulses and by induction of ovulation ( ).
