Gonadotropin-releasing hormone (GnRH)–secreting neurons of the hypothalamus originate in the olfactory bulb and migrate along the olfactory tract into the mediobasal hypothalamus and the arcuate nucleus. Under normal physiologic circumstances, the arcuate nucleus releases pulses of GnRH into the hypophyseal portal system approximately every hour. Discharge of GnRH releases luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary; LH and FSH, in turn, stimulate ovarian follicular growth and ovulation. The ovarian hormones estradiol and progesterone stimulate the development and shedding of the endometrium, culminating in the withdrawal bleeding of menses. Anovulation and amenorrhea occur as a result of interference with GnRH transport, GnRH pulse discharge, or congenital absence of GnRH (Kallmann's syndrome). Any of these situations leads to hypogonadotropic hypogonadism, resulting in amenorrhea.
Defects of GnRH Transport
Interference with the transport of GnRH from the hypothalamus to the pituitary may occur with pituitary stalk compression or destruction of the arcuate nucleus. Pituitary stalk transsection from trauma, compression, radiation, tumors (craniopharyngioma, germinoma, glioma, teratomas), and infiltrative disorders (sarcoidosis, tuberculosis) may either destroy areas of the hypothalamus or prevent transport of hypothalamic hormones to the pituitary.
Defects of GnRH Pulse Production
The metabolic consequence of any significant reduction in the normal GnRH pulse frequency or amplitude is that little or no LH or FSH can be released, with the result that no ovarian follicles develop, virtually no estradiol is secreted, and the patient is amenorrheic. This is the biochemical status in normal prepubertal girls and those with constitutional delayed puberty, such as in anorexia nervosa, severe stress, extreme weight loss, or prolonged vigorous athletic exertion, and in hyperprolactinemia. Amenorrhea on this basis may also be an idiopathic phenomenon.
Less severe reductions in GnRH pulse amplitude and frequency result in diminished LH and FSH secretion with some follicular stimulation. The stimulation is insufficient to result in full follicular development and ovulation, but estradiol is secreted. This may occur with stress, hyperprolactinemia, as a result of vigorous athletic activity, or in the early stages of eating disorders. It may also be idiopathic.
Functional or hypothalamic amenorrhea results from abnormal hypothalamic GnRH secretion in the absence of pathologic processes. As a result, patients demonstrate decreased gonadotropin pulsations, absent follicular development and ovulation, and low estradiol secretion. Serum FSH levels are usually in the normal range; the setting of high FSH:LH ratio is consistent with prepubertal patterns. A number of environmental stressors are associated, including eating disorders and physical or psychologic stress. Weight loss, especially to a level of at least 10% below ideal body weight, and excessive exercise are also associated with hypothalamic amenorrhea. The female athlete triad syndrome is defined by amenorrhea, eating disorder, and osteopenia or osteoporosis.
Congenital GnRH deficiency is called idiopathic hypogonadotropic hypogonadism when it occurs as an isolated phenomenon and Kallmann's syndrome when it is associated with anosmia. These patients lack GnRH secretion and express low, prepubertal levels of serum gonadotropins. Follicular recruitment and ovulation do not occur. Although more than 60% of cases are sporadic, congenital GnRH deficiency can also be inherited in an autosomal dominant trait or X-linked recessive pattern.
Autosomal recessive mutations of the GnRH receptor gene have also been reported. This defect appears to produce a wider spectrum of physical symptoms than with the other gene defects, and the defect lies in the ability of the pituitary gland to recognize GnRH, rather than the ability of the hypothalamus to produce GnRH. It is debatable whether this is in fact Kallmann's syndrome, as the GnRH receptor development is not related to anosmia. More common in boys with delayed puberty, constitutional delay of puberty is an uncommon etiology of primary amenorrhea in girls. Patients demonstrate delayed adrenarche and gonadarche, but ultimately go on to have normal, albeit delayed, pubertal development.
Pituitary causes of amenorrhea are rare; most are secondary to hypothalamic dysfunction. However, acquired pituitary dysfunction can ensue from previous local radiation or surgery. Excess iron deposition due to hemochromatosis or hemosiderosis may destroy gonadotropes.
Congenital Pituitary Dysfunction
Congenital absence of the pituitary is a rare and lethal condition. Isolated defects of LH or FSH production do occur (rarely), resulting in anovulation and amenorrhea.
Acquired Pituitary Dysfunction
Sheehan's syndrome, characterized by postpartum amenorrhea, results from postpartum pituitary necrosis secondary to severe hemorrhage and hypotension and is a rare cause of amenorrhea. Surgical ablation and irradiation of the pituitary as management of pituitary tumors also can cause amenorrhea.
Iron deposition in the pituitary may result in destruction of the cells that produce LH and FSH. This occurs only in patients with markedly elevated serum iron levels (ie, hemosiderosis), usually resulting from extensive red cell destruction. Thalassemia major is an example of a disease that causes hemosiderosis.
Pituitary microadenomas and macroadenomas also lead to amenorrhea because of elevated prolactin levels, but the mechanism(s) underlying this cause of amenorrhea are unclear. Isolated hyperprolactinemia in the absence of adenoma is an uncommon cause of primary amenorrhea. However, the diagnosis is strongly suggested by a history of galactorrhea. Diagnosis is readily made by evaluating a serum prolactin level. Drugs given to treat medical conditions may induce hyperprolactinemia to result in amenorrhea. Discontinuation of the medication if possible or adequate treatment to reduce prolactin level may solve the problem. Table 54–2 lists the most common drugs associated with hyperprolactinemia.
Hypothyroidism may also lead to elevated prolactin levels and thereby lead to amenorrhea.
Table 54–2. Drug-Induced Hyperprolactinemia.
Ovarian and Ovulatory Dysfunction
A variety of gonadal disorders can result in amenorrhea. The most common cause of primary amenorrhea is gonadal dysgenesis. This group of disorders is usually associated with sex chromosomal abnormalities, resulting in streak gonad development, premature depletion of ovarian follicles and oocytes, and absence of estradiol secretion. Patients usually present with hypergonadotropic amenorrhea regardless of degree of pubertal development. Primary ovarian failure is characterized by elevated gonadotropins and low estradiol (hypergonadotropic hypogonadism). Secondary ovarian failure is almost always caused by hypothalamic dysfunction and is characterized by normal or low gonadotropins and low estradiol (hypogonadotropic hypogonadism).
Table 54–3 lists the causes of primary ovarian failure.
Table 54–3. Causes of Primary Ovarian Failure (Hypergonadotrophic Hypogonadism). ||Download (.pdf)
Table 54–3. Causes of Primary Ovarian Failure (Hypergonadotrophic Hypogonadism).
|Idiopathic premature ovarian failure|
|Steroidogenic enzyme defects (primary amenorrhea)|
|Cholesterol side-chain cleavage|
|Testicular regression syndrome|
|Pure gonadal dysgenesis (Swyer's syndrome) (46,XY)|
|Turner's syndrome (45,XO)|
|Mixed gonadal dysgenesis|
|Ovarian resistance syndrome (Savage's syndrome)|
|Post infection (eg, mumps)|
|Post oophorectomy (also wedge resections and bivalving)|
If the primitive oogonia do not migrate to the genital ridge, the ovaries fail to develop. Streak gonads, which do not secrete hormones, develop instead, and the result is primary amenorrhea. Cytogenetic abnormalities of the X chromosome account for the majority of abnormal ovarian development and function, and studies show that 2 intact X chromosomes are required to maintain normal oocytes. Fetuses with 45,X karyotype demonstrate normal oocyte number at 20–24 weeks' gestation, but there is rapid atresia resulting in absence of oocytes at birth. Similarly, women with deletions in either the long or short arm of one X chromosome also develop either primary or secondary amenorrhea.
a. Gonadal Dysgenesis with No Y Chromatin–
Turner's syndrome (45,XO or 45,XO,XX mosaics) and 46,XX gonadal dysgenesis are the most common karyotypes. Patients with Turner's syndrome usually present with primary amenorrhea. However, some patients with mosaic abnormalities may menstruate briefly, and a few have conceived.
B. Gonadal Dysgenesis with Y Chromatin–
Normal female sexual differentiation depends on testicular secretion of antimüllerian hormone (AMH) by Sertoli cells and testosterone by Leydig cells. AMH causes regression of müllerian structures, whereas testosterone and its metabolite dihydrotestosterone (DHT) promote differentiation of male internal and external genitalia, respectively. A variety of disorders can result in the presentation of amenorrhea in phenotypic females possessing Y chromatin material.
The vanishing testes syndrome occurs in 46,XY males with failed gonadal development. Although anorchia commonly occurs at approximately 7 weeks' gestational age, the patient's presentation depends on the timing of gonadal regression. Failure occurring later in development might result in male genitalia at birth, but absence of puberty as a consequence of gonadal failure. On the other hand, typical early gonadal failure before testicular development would result in absent secretion of testis-determining factor (TDF) and AMH. These patients would demonstrate feminization of internal and external genitalia and primary amenorrhea.
Swyer's syndrome, which presents as a form of early-onset vanishing testes syndrome, results from a deletion mutation in the TDF region of Y chromosome. These patients possess the 46,XY genotype but do not secrete testosterone or AMH, resulting in feminization of internal and external genitalia. Patients present with primary amenorrhea and gonadal failure. The syndrome is diagnosed by DNA hybridization studies showing abnormality in the short arm of the Y chromosome.
Premature Ovarian Failure
Menopause occurs when the ovaries fail secondary to depletion of ova. If this occurs before age 40 years, it is considered premature and affects 1–5% of women. It is marked by amenorrhea, increased gonadotropin levels, and estrogen deficiency. Woman presented with premature ovarian failure (POF) should be tested for karyotype to rule out sex chromosome translocations, short arm deletions, or the presence of an occult Y chromosome fragment, which is associated with an increased risk of gonadal tumors. Approximately 16% of women having fragile X permutation experience POF. Thus this permutation as well as other genetic trait reported to be associated with POF should be tested in some patients. Surgery affecting the ovaries, chemotherapy, and pelvic irradiation are iatrogenic causes of POF and should be discussed with the patient in order to use modalities aimed at preserving fertility.
Figure 54–1 depicts normal steroidogenesis in the ovary. Genetic females with defects in enzymes 1–4 have normal internal female genitalia and 46,XX karyotype. However, they cannot produce estradiol, and thus they fail to menstruate or have breast development.
Steroidogenesis in the ovary.
Congenital lipoid adrenal hyperplasia describes 1 of 15 known defects in the steroidogenic acute regulatory protein, which facilitates cholesterol transport from the outer to the inner mitochondrial membrane. This enzyme catalyzes an early, rate-limiting step in tropic hormone-stimulated steroidogenesis. Patients thus present with hyponatremia, hyperkalemia, and acidosis in infancy. Both XX and XY individuals are phenotypically female. These patients can survive into adulthood given appropriate glucocorticoid and mineralocorticoid supplementation. XX patients may exhibit some secondary sexual characteristics at puberty, but present with amenorrhea and premature ovarian failure due to intraovarian accumulation of cholesterol.
Ovarian Resistance (Savage's Syndrome)
Patients with this syndrome have elevated LH and FSH levels, and the ovaries contain primordial germ cells. A defect in the cell receptor mechanism is the presumed cause.
Polycystic Ovary Syndrome
One of the most common causes of secondary amenorrhea is polycystic ovary syndrome (PCOS). PCOS is the most common cause of ovulatory dysfunction in reproductive-age women. After exclusion of other etiologies (congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome), the diagnosis is based on the presence of at least 2 of the following characteristics: (a) oligo- or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism, (3) polycystic ovaries. Although the exact mechanism is unknown, it appears that insulin resistance and hyperinsulinemia play a permissive role. Abnormally elevated baseline insulin leads to increased androgens via decreased sex hormone-binding globulin and stimulation of ovarian insulin and insulinlike growth factor-I receptors. Insulin-sensitizing agents such as metformin and rosiglitazone are used as a sole or adjuvant agent for ovulation induction in PCOS.
Anatomic Abnormalities Associated with Amenorrhea (See Chapter 37)
Müllerian dysgenesis is characterized by congenital absence of the uterus and the upper two-thirds of the vagina. Affected individuals may ovulate regularly, have normal development of the secondary sex characteristic, and have a 46, XX karyotype.
Vaginal agenesis is characterized by failure of the vagina to develop.
Transverse Vaginal Septum
This anomaly results from failure of fusion of the müllerian and urogenital sinus-derived portions of the vagina.
If the hymen is complete, menstrual efflux cannot occur.
In Asherman's syndrome, amenorrhea is caused by intrauterine synechiae. The usual cause is a complicated dilatation and curettage (D&C) (eg, infected products of conception, vigorous elimination of the endometrium), but the syndrome can occur after myomectomy, caesarean section, and tuberculous endometritis.
Amenorrhea in Women with 46, Xy Karyotype
The details of embryonic sexual differentiation are discussed in Chapter 2. Briefly, the sexually undifferentiated male fetal testis secretes müllerian-inhibiting factor (MIF) and testosterone. MIF promotes regression of all müllerian structures: the uterine tubes, the uterus, and the upper two-thirds of the vagina. Testosterone and its active metabolite DHT are responsible for embryonic differentiation of the male internal and external genitalia.
In testicular feminization, a condition also addressed as complete androgen insensitivity syndrome, all müllerian-derived structures are absent because MIF is present. The external genital and mesonephric ducts cannot respond to androgens, because androgen receptors are either absent or defective. Affected individuals are therefore phenotypic females lacking a uterus and a complete vagina. They produce some estrogen, develop breasts, and are reared as girls and therefore present with primary amenorrhea. The syndrome is inherited in an X-linked recessive trait. In contrast to other dysgenetic gonads with a Y chromosome, the occurrence of gonadal malignancy is late (rarely before the age of 25) and the incidence is less, approximately 5–10%. Therefore, the removal of the nonfunctioning testes can be postponed until the age of 16–18 years to allow completion of puberty.
Pure Gonadal Dysgenesis (Swyer Syndrome)
If the primitive germ cells do not migrate to the genital ridge or the SRY gene is not functioning harboring a mutation, a testis will not develop, and a streak gonad will be present. Affected individuals have normal female internal and external genitalia, as neither MIF nor androgens are secreted by the streaks. Because these individuals produce no estrogen, they will not develop breasts. They are reared as girls and present clinically with either delayed puberty or primary amenorrhea. Removal of the streak gonads should be done as soon as the diagnosis is made to prevent the possible development of tumor in such gonads.
If the fetal testes regress before 7 weeks' gestation, neither MIF nor testosterone is secreted, and affected individuals will present with a clinical picture identical to that of pure gonadal dysgenesis. Individuals whose testes regress between 7 and 13 weeks' gestation present with ambiguous genitalia.
Testicular Steroid Enzyme Defects
A testis with defective enzymes 1–4 will produce MIF but not testosterone (Fig. 54–1). Affected individuals have female external genitalia and no müllerian structures. They will be reared as girls and present clinically with either delayed puberty or primary amenorrhea.
A defect in enzyme 6 (17-hydroxysteroid dehydrogenase) results in ambiguous genitalia and virilization at puberty.