Chapter 54. Amenorrhea

• Amenorrhea is literally defined as the absence of menses.
• Primary amenorrhea (seen in approximately 2.5% of the population) is clinically defined as the absence of menses by age 13 years in the absence of normal growth or secondary sexual development, or the absence of menses by age 15 years in the setting of normal growth and secondary sexual development.
  • Traditionally, evaluation was usually initiated by age 16 years if normal growth and secondary sexual characteristics were present, and at age 14 years if absent.
  • Because of secular trends toward earlier menarche over the past half century, the evaluation should begin at age 15 years, the age when more than 97% of girls should have experienced menarche.
  • The decision to evaluate should be made with a full understanding of the patient's clinical presentation.
  • Evaluation should not be delayed in the setting of neurologic symptoms (suggestive of hypothalamic–pituitary lesion) or pelvic pain (suggestive of outflow obstruction).
• Secondary amenorrhea is clinically defined as the absence of menses for more than 3 cycle intervals, or 6 consecutive months, in a previously menstruating woman.
  • The incidence of secondary amenorrhea can be quite variable, from 3% in the general population to 100% under conditions of extreme physical or emotional stress.
  • Table 54–1 lists the most common causes of secondary amenorrhea.

Menstruation has long been an important societal marker of female sexual development, as well as one of the most tangible signs of female endocrine and reproductive tract maturation. Regular and spontaneous menstruation requires (1) functional hypothalamic–pituitary–ovarian endocrine axis, (2) an endometrium competent to respond to steroid hormone stimulation, and (3) an intact outflow tract from internal to external genitalia.

The human menstrual cycle is susceptible to environmental influences and stressors. Thus missing a single or occasional menstruation rarely reflects a significant pathology. However, prolonged or persistent absence of menses may be one of the earliest signs of neuroendocrine or anatomic abnormality.

Diagnosing and treating amenorrhea is important because of the implications for future fertility; risks of unopposed estrogen, including endometrial hyperplasia and neoplasia; risks of hypoestrogenism, including osteoporosis and urogenital atrophy; and impact on psychosocial development. Because of their significant overlap in etiology and treatment, primary and secondary amenorrhea are discussed collectively in this chapter.

Pregnancy is the most common cause of amenorrhea and must be considered in every patient presenting for evaluation of amenorrhea. Amenorrhea caused by aberrations of the normal menstrual cycle is discussed in Chapter 4. Chapters 37 and 55 discuss developmental anomalies of the reproductive organs and masculinization, respectively. This chapter discusses amenorrhea associated with 46, XX and 46, XY karyotypes, anatomic defects, and dysfunction of the hypothalamic–pituitary–ovarian axis, as well as systemic disorders that affect menstruation.

Both primary and secondary amenorrhea can result from abnormalities in the compartments linked with the occurrence of menses. This includes the hypothalamic–pituitary axis, the ovaries, and the outflow tract, namely the uterus, cervix, and vagina.

Hypothalamic–Pituitary Dysfunction

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 Defects

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.

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.

Ovarian Dysgenesis

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.

Steroid Enzyme Defects

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.

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

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

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.

Imperforate Hymen

If the hymen is complete, menstrual efflux cannot occur.

Asherman's Syndrome

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.

Testicular Feminization

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.

Anorchia

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.

Figures 54–2 and 54–3 summarize the diagnostic workup for primary and secondary amenorrhea, respectively. It is important at the outset to determine which organ is dysfunctional and then to identify the exact cause. Medical history, patient symptoms and complaints, and physical examination will lead to the correct diagnosis. Applying other assisting tests will substantiate the diagnosis. Once this has been done, specific therapy can be planned.

Any patient with amenorrhea who has a uterus should be tested for pregnancy and for serum levels of thyroid-stimulating hormone (TSH) and prolactin. Galactorrhea should be identified or ruled out by physical examination.

Diagnosis of Primary Amenorrhea

Figure 54–2 outlines the diagnostic scheme for primary amenorrhea. Pelvic examination should be done to establish the presence of a vagina and uterus and no vaginal septum or imperforate hymen that might account for the failure of appearance of menses. Because pelvic examination of an adolescent girl may be difficult, pelvic ultrasound or examination under anesthesia may be required to establish the presence of a uterus. Other diagnostic tools, namely pelvic computed tomography (CT) scan and magnetic resonance imaging (MRI), may be helpful.

If no uterus is present, serum testosterone levels should be measured and karyotyping done to differentiate between müllerian agenesis and testicular feminization.

Diagnosis of Amenorrhea Associated with Galactorrhea-Hyperprolactinemia

Figure 54–3 outlines the diagnostic workup of patients with galactorrhea or hyperprolactinemia. Table 54–4 summarizes the differential diagnosis of galactorrhea-amenorrhea.

Patients with primary hypothyroidism have elevated thyroid-releasing hormone (TRH) levels. TRH acts to stimulate the release of prolactin and may thereby lead to galactorrhea-amenorrhea syndrome. TSH is also elevated and easier to measure and thus is the screening test for hypothyroidism.

Once hypothyroidism is adequately treated, serum prolactin must be measured again after thyroid function has become normal. If prolactin remains elevated or is initially higher than 50–200 ng/mL, the patient should be further studied via cone view of the sella or CT or MRI scan of the sella to rule out pituitary micro- or macroadenoma.

A meticulous history must be taken to ascertain whether the hyperprolactinemia is caused by ingestion of drugs. Prolactin secretion is inhibited by dopamine and stimulated by serotonin and TRH. Any drug that blocks the synthesis or binding of dopamine will increase the prolactin level. Prolactin is increased by serotonin agonists and decreased by serotonin antagonists. Pituitary macroadenoma should be ruled out if prolactin levels are higher than 50–100 ng/mL, even if the patient is taking drugs that lead to raised prolactin levels.

Diagnosis of Amenorrhea Caused by Primary Ovarian Failure

Table 54–3 lists the causes of primary ovarian failure.

Karyotyping is indicated for all women who present with premature menopause, particularly if their amenorrhea is primary. Patients with primary amenorrhea may have a steroid enzyme defect. Autoimmune oophoritis is a reversible cause of ovarian failure that must be investigated.

Diagnosis of Amenorrhea Associated with Hypothalamic–Pituitary Dysfunction

Table 54–5 summarizes the differential diagnosis of hypoestrogenic amenorrhea. The category includes amenorrhea associated with athletic activity, weight loss, or stress. Differentiation of hypothalamic from pituitary dysfunction can be achieved by giving GnRH, but is generally not a worthwhile effort, as pituitary causes are rare and can often be diagnosed on the basis of the history. Moreover, in Kallmann's syndrome, a single bolus dose of GnRH may not elicit a normal response. Up to 40 doses of GnRH have been required to prime the pituitary so that it will respond normally. A GnRH pump also has been used.

If there is a significant history consistent with Sheehan's syndrome, pituitary function testing is indicated in order to determine the functional capacity of the gland—particularly the integrity of the pituitary–adrenal axis.

In girls with primary amenorrhea, observing the pattern of LH and FSH release after administration of GnRH will help to determine whether the patient is undergoing late pubertal changes.

Diagnosis of Secondary Amenorrhea

These patients are studied according to the scheme outlined in Figure 54–3. The first step is the progestin challenge, which indirectly determines whether the ovary is producing estrogen. If the endometrium has been primed with estrogen, exogenous progestin will produce menses. Give either medroxyprogesterone acetate 10 mg orally daily for 5–7 days, or progesterone 100 mg intramuscularly as a single dose. Other progestative preparations can be used as well (Table 54–6). If vaginal bleeding follows, the ovaries are secreting estrogen. If it does not, it can be concluded that there is no estrogen or that the patient has Asherman's syndrome.

From a practical standpoint, if a patient has not had a D&C, it is virtually impossible for her to have Asherman's syndrome, so the diagnostic steps summarized in the following paragraphs can be disregarded.

Asherman's syndrome can be ruled out by administration of conjugated estrogen 2.5 mg orally daily or estradiol 4 mg daily for 21 days, followed by a progestational agent for 7–10 days (Table 54–6). Patients with Asherman's syndrome do not bleed after this regimen.

Asherman's syndrome can also be diagnosed by weekly serum progesterone tests. Any value in the ovulatory range (>3 ng/mL) not associated with menses is indicative of Asherman's syndrome. Hysterosalpingography, sonohysterography, and hysteroscopy can also lead to a diagnosis of Asherman's syndrome. Three dimensional ultrasound (3D US) is a non invasive tool and may also help in diagnosis. In a patient who does not have Asherman's syndrome and who does not respond to the progestin challenge, ovarian dysfunction may be of hypothalamic or ovarian origin. The distinction is based on the FSH level. Primary ovarian dysfunction resulting in low estradiol secretion is associated with high serum FSH. Values vary in different laboratories, but in general an FSH level higher than 40 mIU/mL indicates primary ovarian failure. POF resulting in secondary amenorrhea can be due to genetic cause such as XO/XX mosaicism and 47XXX. Carriers of fragile X permutation are at an increased risk to develop POF, with a reported prevalence of 10–20%. Therefore, patients with secondary amenorrhea and high gonadotropin levels should have karyotype analysis and screened for the fragile X mutation. In addition, POF can be due to an autoimmune process, ovarian infectious disease such as mumps oophoritis, or a physical insult such as surgery, irradiation, or chemotherapy.

Patients who bleed in response to the progestin challenge (ie, whose ovaries are secreting estrogen) fit into one of 4 categories: (1) virilized, with or without ambiguous genitalia; (2) hirsute, with polycystic ovaries, hyperthecosis, or mild maturity-onset adrenal hyperplasia; (3) nonhirsute, with hypothalamic dysfunction; or (4) amenorrheic secondary to systemic disease.

Table 54–7 sets forth the differential diagnosis for patients with amenorrhea who respond to progestin challenge test and are considered to have anovulation. Clinical examination, transvaginal ultrasound, and hormonal profile (FSH, LH, androgens, insulin) may be helpful in establishing the diagnosis of PCOS.

The complications of amenorrhea can be numerous, including infertility and psychosocial developmental delays with lack of normal physical sexual development. Hypoestrogenic patients can develop severe osteoporosis and fractures, the most hazardous to life being femoral neck fracture (see Chapter 59). The complications associated with amenorrhea in patients who respond to progestin challenge are endometrial hyperplasia and carcinoma (see Chapter 59) resulting from unopposed estrogen stimulation.

Management of Patients Desiring Pregnancy–Ovulation Induction

Ovulation Induction in Patients with Amenorrhea-Galactorrhea with Pituitary Macroadenoma

Dopamine agonist drugs such as cabergoline and bromocriptine remain the first-line treatment of hyperprolactinemia of any cause, including macroadenomas. These drugs can decrease prolactin secretion and tumor size. Surgical therapy–transsphenoidal or frontal removal of the pituitary adenoma or the entire gland–may be required if tumor size or secretion are resistant to dopamine agonists, the lesion is rapidly enlarging or causing symptoms such as visual changes or headaches, or in women with giant adenomas (>3 cm) who wish to discontinue agonist treatment for conception and the duration of pregnancy. Approximately half of surgically treated patients will menstruate normally after this procedure.

Ovulation Induction in Patients with Amenorrhea-Galactorrhea Without Macroadenoma (Including Patients with Microadenomas)

These patients ovulate readily in response to dopamine agonist treatment, with dose titrated until serum prolactin is normal. Patients are maintained on the lowest dose necessary to maintain normal prolactin levels. Once pregnancy has been achieved, the agent can be discontinued. Patients with macroadenomas may need to continue therapy throughout pregnancy to avoid further growth of the lesion.

Patients taking drugs that raise the prolactin level should discontinue them if possible, but continued use of such drugs is not a contraindication to therapy.

Ovulation Induction in Patients with Hypothyroidism

Amenorrheic patients with hypothyroidism frequently respond to thyroid replacement therapy.

Ovulation Induction in Patients with Primary Ovarian Failure

According to Rebar and associates, patients with primary ovarian failure can be made to ovulate only under very rare circumstances. Patients with reversible ovarian failure include those with autoimmune oophoritis, who can be successfully treated with corticosteroids. Otherwise, almost all patients with primary ovarian failure fall into the category of idiopathic premature ovarian failure and cannot be made to ovulate. In vitro fertilization (IVF) with donor oocytes is the only way they can have children.

Any patient with a Y chromosome should undergo oophorectomy to prevent tumor development.

Ovulation Induction in Patients with Hypoestrogenic Hypothalamic Amenorrhea (Progestin-Challenge Negative)

In these patients with low estrogen levels, the pituitary does not release high quantities of LH and FSH (as would be expected with an intact, normally functioning, negative feedback mechanism). Therefore, even though clomiphene citrate (an antiestrogen) is unlikely to stimulate gonadotropin release, many reproductive endocrinologists treat such patients successfully with a single course of clomiphene citrate, 150 or 250 mg daily for 5 days, on the chance that ovulation will occur.

Injections of exogenous gonadotropins (human recombinant follicle-stimulating hormone combined with human recombinant luteinizing hormone or human menopausal gonadotropin [hMG]) is usually first-line therapy. Patients showing some ovarian stimulation by clomiphene can be treated with a combination of clomiphene and hMG–the advantage being a reduction in the amount of hMG required and thus a substantial cost savings. Ovulation induction with gonadotropins must be carefully monitored with serial ultrasound and estradiol determinations to avoid hyperstimulation. Hyperstimulation is the stimulation of too many follicles, with associated ovarian enlargement and ascites, as well as other systemic abnormalities.

If a specific and potentially reversible cause of amenorrhea can be identified (eg, marked weight loss), it should be corrected.

Ovulation Induction in Patients WHO Bleed in Response to Progestin Challenge

Virtually all of these patients respond to clomiphene citrate. The starting dose is 50 mg orally daily for 5 days. This can be increased to a maximum of 250 mg orally daily in 50-mg increments until ovulation is induced. Efficacy of clomiphene, however, plateaus at 100 mg/d. This medication is approved by the US Food and Drug Administration for use up to 150 mg/d. Ovulation occurs 5–10 days after the last dose. Patients with elevated androgens who do not respond to clomiphene citrate may respond to combined treatment with an oral hypoglycemic agent and clomiphene. If clomiphene therapy with or without oral hypoglycemic agents is ineffective, gonadotropin therapy may be attempted. Care must be taken in using FSH in these patients, as they are likely to become hyperstimulated.

Laparoscopic ovarian drilling (LOD) is a surgical method of ovulation induction in PCOS patients. LOD involves electrocautery or laser drilling of the ovarian cortex, with the goal of creating foci of laser or thermal damage in the cortex and ovarian stroma. In general, at least 6 puncture sites 2–4 mm in depth are made in the ovary away from the hilum. The mechanism of action is unknown, but may involve destruction of androgen-producing stromal cells, a sudden drop in ovarian androgen levels, improved follicular microenvironment, or increased gonadotropin secretion. This procedure may cause postoperative pelvic adhesions, resulting in tubal compromise.

Management of Patients Not Desiring Pregnancy

Patients who are hypoestrogenic must be treated with a combination of estrogen and progesterone to maintain bone density and prevent genital atrophy. The dose of estrogen varies with the age of the patient. Oral contraceptives are good replacement therapy for most women. Combinations of 0.625–1.25 mg of conjugated estrogens orally daily on days 1 through 25 of the cycle with 5–10 mg of medroxyprogesterone acetate on days 16 through 25 are a suitable alternative. Calcium intake should be adjusted to 1–1.5 g of elemental calcium daily.

Patients who respond to the progestin challenge require occasional progestin administration to prevent the development of endometrial hyperplasia and carcinoma. Oral contraceptive pills may be used to regulate the menstrual cycle. Oral contraceptives also help with management of hirsutism. Alternatively, progestational medication in a dose detailed in Table 54–6 for 10–13 days every month or every other month is sufficient to induce withdrawal bleeding and to prevent the development of endometrial hyperplasia. Patients with hyper-prolactinemia need periodic prolactin measurements and radiographic cone views of the sella turcica to rule out the development of macroadenoma.

The prognosis for amenorrhea is good. It is not usually a life-threatening clinical event, as with proper evaluation, tumors can be recognized and treated. Many patients with hypothalamic amenorrhea will spontaneously recover normal menstrual cycles.

Virtually all amenorrheic women who do not have premature ovarian failure can be made to ovulate with a dopamine agonist, clomiphene citrate, insulin-sensitizing agents, and gonadotropins.