Amenorrhea (Case 42)
Case: A 28-year-old woman presents with amenorrhea after discontinuing her oral contraceptive pills (OCPs). She desires pregnancy but has not conceived after 9 months of unprotected intercourse with her husband. Further questioning reveals a history of menarche at 13 years of age and normal development of secondary sexual characteristics. She believes breast development began around age 11 years. The patient’s menses were initially irregular; during the first year following menarche, she had fluctuations in cycle length and intermittently light and heavy menses. By the age of 15 years, however, her menses had become regular, occurring every 28 to 30 days and lasting about 5 days. She started OCPs when she was 20 years old both for contraception and to help with premenstrual cramping and mood swings. She continued on combination estrogen-progestin OCPs until the age of 27 years. Since stopping her OCPs, she has not had any regular menstrual cycles, with only two occasions of light bleeding lasting about 2 days each.
The patient has been feeling anxious about her inability to conceive and about her absent menses. Her husband has been evaluated and has been found to have a normal semen analysis. The patient reports that she has a history of headaches that began while she was in college but have worsened in the past 2 years. Currently she has headaches almost daily that are retro-orbital, dull, and aching. She denies any recent vision problems but has noticed occasional discharge from her breasts, which sometimes has a white, milky appearance. She has maintained a stable weight and is eating a balanced diet. She has not been sleeping well for the past 3 months, which she attributes to stress, and often feels fatigued during her workday as a high school teacher. She becomes tearful during the interview, and her husband, who accompanied her to the visit, holds her hand throughout the evaluation.
Hypothalamic amenorrhea (HA)
Primary ovarian insufficiency (POI)
Amenorrhea refers to the absence or abnormal cessation of the menstrual cycle. Evaluation for primary amenorrhea, the absence of menarche, should be initiated when there is failure to menstruate by 15 years of age in the presence of normal secondary sexual characteristics or within 5 years after breast development if that occurs before 10 years of age.
Secondary amenorrhea, cessation of menses after menarche that lasts 3 months or more, should be evaluated, but sometimes it should be evaluated after 1 to 2 weeks in patients with regular cycles to exclude pregnancy. Oligomenorrhea, less than nine menstrual cycles per year, also requires investigation. Pregnancy, lactation, and menopause account for about 96% to 97% of secondary amenorrhea. Of the remaining 3% to 4%, most will have one of several common causes for amenorrhea including hypothalamic-pituitary-ovarian (HPO) axis disorders, structural abnormalities, and disorders of androgen excess.
• Secondary amenorrhea usually occurs in patients with normal breast and uterine development and often involves an acquired or progressive disease process that halts or prevents regular menstrual cycles.
• When considering a patient with secondary amenorrhea, determine whether there is a hypothalamic, pituitary, or ovarian problem, or abnormal menses due to a hormonal excess or deficiency outside of the HPO axis.
• If the patient has never had menstrual cycles, review of secondary sexual characteristic development is particularly important. In a younger patient, parents may need to assist in this portion of the history.
• If the patient has experienced menarche, her subsequent menstrual pattern must be reviewed to determine whether she has achieved regular cycles or has had persistently irregular menses for months or years following menarche.
• The presence of headache, visual changes, galactorrhea, hirsutism, acne, weight changes, heat or cold intolerance, diarrhea or constipation, palpitations, or menopausal symptoms may help the physician focus the evaluation.
• Careful review of the patient’s medication list is also important to assess for any agents that may impact hormone levels and/or signal underlying medical problems that have not been mentioned by the patient.
• The exam should specifically target the findings that could signal an underlying cause. For example, short stature, dysmorphic facial features, wide-set nipples, low hairline, or low-set ears should increase suspicion for Turner syndrome, one of the more common genetic causes for amenorrhea.
• Other physical findings that could relate to an underlying cause for amenorrhea include abnormal BMI or body habitus, neurologic defects (especially impaired visual fields), an abnormal thyroid exam, expressible breast discharge, acne, hirsutism, abnormal body fat distribution, abdominal striae, and abnormal reflexes.
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Amenorrhea caused by hypothalamic dysfunction probably represents a spectrum of related disorders including functional hypothalamic amenorrhea (FHA), amenorrhea in the female athlete, and amenorrhea associated with eating disorders. The precise mechanism of these disorders is not known, but all share a reduction in hypothalamic gonadotropin-releasing hormone (GnRH) production. FHA accounts for about 15% to 35% of cases of amenorrhea, making it one of the most common causes. The blunted GnRH release pattern leads to decreased FSH and LH but an increased FSH/LH ratio similar to that seen before puberty. Estradiol levels are also decreased, and patients are usually anovulatory. Leptin, an adipocyte hormone that acts as a satiety factor and a cofactor in the maturation of the reproductive system, has been implicated in the development of HA. Leptin can stimulate GnRH pulsatility and gonadotropin secretion and is decreased in patients across the spectrum of HA.
Amenorrhea in the female athlete is part of the “female athlete triad,” which also includes disordered eating and osteoporosis. Elite athletes in sports such as gymnastics, diving, and marathon running, as well as ballet dancers, are particularly vulnerable to this triad. In these patients, body fat often is below the 10th percentile.
Patients with anorexia nervosa also have severely reduced body fat, and often their body weight is <85% of normal for age and height. These patients have a distorted body image, fear weight gain, and exist in a self-imposed starvation state. In addition to low body weight and wasting, they may also have bradycardia, hypothermia, constipation, and dry skin. Patients with bulimia may have normal weight and physical exam findings but can still have neuroendocrine abnormalities leading to irregular menses.
FHA can be related to strenuous exercise or poor nutrition without falling into either of the previous two categories but can also result from psychological stress. Often, these patients are high achievers with an impaired ability to cope with the stress of daily life and/or acutely stressful situations.
GnRH pulsatility cannot be measured, so LH pulsatility is used as a surrogate, and in clinical practice the FSH/LH ratio is used to assess problems with hypothalamic function. In HA, the FSH/LH ratio is >1 in the setting of hypoestrogenemia, although the absolute concentrations of both gonadotropins are decreased. In patients with FHA who have mild perturbations in the HPO axis, these lab data may be normal. In that case HA can be diagnosed when other causes of anovulation are ruled out and the history of amenorrhea coincides with increased physical or psychological stress.
Treatment of the underlying problem with counseling, behavior modification, stress management strategies, or inpatient care in the case of eating disorders should be tailored to the patient’s individual needs. With elite athletes with amenorrhea, the underlying problem will probably not be corrected until they retire from competition. All patients with HA should be treated with cyclic estrogen-progestin therapy to protect against bone loss caused by estrogen deficiency. Patients desiring pregnancy should target optimal weight and nutrition, but may need ovulation induction with clomiphene citrate to stimulate endogenous gonadotropins or treatment with exogenous gonadotropins or pulsatile GnRH. See Cecil Essentials 61, 71.
Hyperprolactinemia accounts for 15% to 30% of amenorrhea. About 50% of patients with elevated prolactin levels have evidence of a pituitary mass on MRI, and about 40% to 50% of these masses are prolactinomas. Under normal circumstances, prolactin release is under tonic inhibition by dopamine, but these tumors are able to function autonomously. They can be classified as microadenomas when <10 mm in diameter and as macroadenomas when >10 mm in diameter. The serum prolactin level can help physicians predict tumor size; microprolactinomas are more likely with prolactin levels <100 ng/mL, while higher values raise suspicion for a macroprolactinoma. This cutoff is not definitive, however. The precise mechanism of prolactin’s action on the menstrual cycle is not known.
In addition to experiencing amenorrhea, patients with a prolactinoma often present with galactorrhea. This milky discharge can sometimes be expressed by the physician on breast exam. If the prolactinoma is large, it may cause headache, visual disturbances by compression on the optic chiasm, or other CNS perturbations. If the patient has a microprolactinoma, she will probably have normal visual fields and may have no CNS disturbances.
A serum prolactin level should be checked as a screening test for all women presenting with amenorrhea. Certain medications, including estrogen-containing OCPs, neuroleptics, tricyclic antidepressants, metoclopromide, methyldopa, and verapamil, can cause elevations in prolactin level. Prolactin can also be transiently elevated in response to stress, exercise, breast stimulation, or eating, and is elevated normally in pregnancy and during lactation. Prolactin is most reliably measured in the midmorning and in a fasting state. The test should be repeated under these ideal circumstances if the initial prolactin level is mildly or moderately elevated without an obvious cause. All patients with a confirmed elevation in prolactin level should have a dedicated pituitary MRI. If a macroprolactinoma is present, the patient’s other pituitary axes should be checked with FSH, LH, TSH, insulin-like growth factor 1 (IGF-1, a surrogate for growth hormone), and an 8:00 AM ACTH with cortisol.
The treatment of choice is administration of a dopamine agonist; the two dopamine agonists used most often in clinical practice are cabergoline and bromocriptine. These medications are very effective in reducing the prolactin level, shrinking tumor size, and resolving any associated symptoms. Prolactin level should be checked about 6 weeks after initiation of therapy to ensure that it has returned to the normal range. Pituitary MRI scans and visual field testing should be obtained periodically, especially in response to any increase in serum prolactin level. See Cecil Essentials 65, 71.
Pituitary adenomas, which are not prolactin-secreting, can also impact the menstrual cycle. Since prolactin release is under tonic inhibition by dopamine, anything that interrupts this inhibition can cause elevated prolactin and lead to abnormal menses. Most commonly, dopamine inhibition is blocked when a pituitary mass expands in such a way as to apply pressure to the infundibulum (the pituitary stalk). The dopaminergic neurons that inhibit prolactin release travel through this stalk, so their function is impaired when the stalk is compressed. Pituitary adenomas can also cause abnormal menses by compressing gonadotropin-releasing cells in the anterior pituitary.
If an adenoma is impacting the menses by direct effects on the gonadotrophs, galactorrhea would not be expected. If the mass is a macroadenoma, the patient can have symptoms including headaches and visual changes. A macroadenoma may cause growth hormone deficiency, central hypothyroidism, and, rarely, central adrenal insufficiency. Because the adrenal axis is the most crucial for survival, this is the last axis to manifest dysfunction due to pituitary compression by a mass.
Serum prolactin level may be elevated in the setting of a pituitary adenoma that is not a prolactinoma, although the elevation is often not as pronounced; pituitary MRI should follow. If the patient has a macroadenoma with only mildly elevated prolactin levels and evidence that the adenoma is causing compression of the pituitary stalk and/or the pituitary itself, this is most likely a non-prolactin-producing macroadenoma. If the patient has a microadenoma with mildly elevated prolactin levels, further investigation may be necessary to determine the type of adenoma present. In either case, the patient requires evaluation of the other pituitary hormones, with measurement of FSH, LH, IGF-1, and TSH as well as a 24-hour urine free cortisol to assess the adrenal axis. In addition, the α-subunits of FSH and LH should be measured, because these are typically elevated in a “nonfunctioning” pituitary adenoma.
Treatment for pituitary adenomas depends on the size and location of the mass, as well as any associated symptoms. Non–prolactin-secreting tumors do not respond well to medical therapy. Trans-sphenoidal resection is the treatment of choice for macroadenomas and is usually performed urgently if the patient has evidence of optic chiasm compression and visual field defects. Microadenomas do not require urgent surgery and sometimes can be observed with serial pituitary MRI scans to assess for growth. If the adenoma is producing another type of hormone, resection is recommended in most cases. Additional therapy may be needed after resection for further management of hormone excess caused by any tumor that is left behind. See Cecil Essentials 65, 71.
Primary hypothyroidism is caused by decreased production of thyroid hormone by the thyroid gland, most often secondary to autoimmune destruction of the thyroid cells. Low circulating thyroid hormone levels lead to increased thyrotropin-releasing hormone (TRH) production by the hypothalamus and increased TSH release by the pituitary, but also act on lactotrophs to increase prolactin secretion. If the primary hypothyroidism persists, prolactin levels can rise significantly enough to cause menstrual irregularities.
Patients may present with galactorrhea, as well as menstrual irregularities, if the prolactin level is high enough. Symptoms typical of hypothyroidism including weight gain, fatigue, constipation, cold intolerance, brittle nails, coarse and dry hair, and dry skin may also be experienced.
Because thyroid dysfunction is common in women, TSH is part of the routine testing done at initial screening for causes of amenorrhea. Patients with an elevated prolactin level should be tested for TSH level, if not already done, to determine whether hypothyroidism could be the cause for the prolactin elevation. The TSH will be elevated in hypothyroidism, with a low thyroid hormone (free T4) level.
Treatment of the hypothyroidism with levothyroxine will reverse the thyroid dysfunction and correct the menstrual irregularities. See Cecil Essentials 66, 71.
Primary hyperthyroidism results from overproduction of thyroid hormone by the thyroid gland. Most commonly this is due to Graves disease, an autoimmune process mediated by antibodies that bind to the TSH receptor and stimulate thyroid hormone release. The mechanism(s) causing irregular menses in hyperthyroid patients is not known.
Patients with hyperthyroidism can present with weight loss, fatigue, irritability, impaired concentration, tachycardia, palpitations, diarrhea, heat intolerance, diaphoresis, hair loss, and warm, moist skin, and addition to amenorrhea.
As is the case with hypothyroidism, TSH level should be used as a screening tool for all women presenting with amenorrhea. Primary hyperthyroidism is diagnosed with an elevated free T4 and a low or undetectable TSH.
Treatment is aimed at reversing the hyperthyroid state. This can be accomplished with medication, radioactive iodine ablation of the overactive thyroid, and, rarely, surgery. Once the thyroid abnormality is corrected, the menstrual irregularities will resolve. See Cecil Essentials 66, 71.
Polycystic Ovarian Syndrome
Androgen excess accounts for over 30% of amenorrhea and up to 75% of anovulation and is most often caused by PCOS. In 1990 the National Institutes of Health (NIH) developed criteria for the diagnosis of PCOS that included chronic anovulation and clinical and/or biochemical signs of hyperandrogenism with exclusion of other etiologies. In 2003 the Rotterdam consensus conference amended the criteria to require two out of three of the following: oligo-ovulation or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries with exclusion of other etiologies (i.e., CAH, androgen-secreting tumors, Cushing syndrome). Hyperinsulinemia does seem to play a major role in the pathogenesis of PCOS, with a prevalence of 50% to 60% in this population, compared with 10% to 25% in the general population. Also, increasing evidence points to a strong genetic component to disease development.
In addition to experiencing amenorrhea, patients with PCOS may have physical signs of androgen excess such as acne and/or hirsutism. Patients with PCOS can have normal pubertal development and menarche but often experience irregular menses thereafter. Patients may be placed on OCPs for cycle regulation without further investigation into the cause of their irregular menses, since irregular cycles are not necessarily abnormal in the years following menarche. In some cases PCOS is not diagnosed until patients present for evaluation of amenorrhea or oligomenorrhea when they stop OCPs and are trying to conceive.
PCOS often can be diagnosed on clinical grounds in the setting of amenorrhea or oligomenorrhea, acne, and hirsutism. Additional information can be obtained through pelvic ultrasonography, which may demonstrate polycystic ovaries, although this is not required to make the diagnosis. Biochemical abnormalities associated with PCOS include elevated total and free testosterone, dehydroepiandrosterone sulfate (DHEAS), insulin, and LH/FSH ratio. These are not present in all women with the syndrome, however, and some can be present in the absence of PCOS. Patients should be evaluated for other causes of anovulation. If these can be ruled out, and the clinical setting and additional tests suggest PCOS, the diagnosis can then be established.
In patients desiring regular menstrual cycles, OCPs are an excellent choice for therapy. These will restore the normal cyclic nature of estrogen and progesterone and also can help treat acne and hirsutism. Spironolactone can also be used to treat hirsutism and functions by inhibiting androgen biosynthesis and competitively inhibiting the androgen receptor. If pregnancy is desired, treatment with metformin can help promote ovulatory cycles. In some cases, however, strategies for ovulation induction similar to those used in HA must be employed (see above). If these measures are not successful, patients may also need to consider in vitro fertilization. See Cecil Essentials 71.
Primary Ovarian Insufficiency
POI is the preferred term for a condition previously called premature menopause or premature ovarian failure. This condition is considered to be present when a woman under 40 years of age has had amenorrhea for ≥4 months and two FSH level measurements at least 1 month apart that are in the menopausal range. In 90% of cases, the cause for POI is unknown, but 46,XX POI occasionally occurs as part of a syndrome such as Fragile X or autoimmune polyendocrine syndrome. Spontaneous 46,XX POI affects approximately 1 in 100 women by 40 years of age. Two major mechanisms resulting in POI are follicle dysfunction and follicle depletion. The latter may be the result of inadequate primordial follicles in utero, accelerated use of available follicles, or autoimmune or toxic (i.e., chemotherapy, radiation, ovarian torsion) effects leading to destruction of follicles.
The condition usually develops after normal puberty, menarche, and a period of regular menses. Most commonly, women progress to amenorrhea gradually with a prodrome of irregular menses, but the condition occasionally presents with an abrupt cessation of menses. In some women, POI presents when menses fail to resume after pregnancy or cessation of OCPs. Women may experience symptoms of estrogen deficiency such as hot flashes, night sweats, sleep disturbance, and dyspareunia. Not all patients have severe estrogen deficiency, however, so some women have no symptoms other than amenorrhea.
After pregnancy has been ruled out, FSH, TSH, and prolactin levels should be checked. If the FSH is elevated into the postmenopausal range, levels should be checked again in 1 month with an estradiol level measurement. Patients with POI that is not associated with a known syndrome should have a karyotype analysis, testing for gene mutations associated with Fragile X syndrome, and adrenal antibodies. Pelvic ultrasonography is also recommended. About 10% to 15% of patients will have a positive family history with a first-degree relative affected. These patients should be queried about a personal or family history of other components of the autoimmune polyglandular syndrome, including hypothyroidism, adrenal insufficiency, and hypoparathyroidism.
Many women diagnosed with POI require both physical and psychological treatment. Early menopause with prolonged estrogen deficiency is associated with a higher risk of osteoporotic fractures and mortality from ischemic heart disease. These patients should receive physiologic estrogen and progestin replacement until the age when menopause usually occurs. Pregnancy may occur while the patient is taking these hormones, and they should be stopped when pregnancy is confirmed. OCPs provide more steroid hormone than is necessary for physiologic replacement, so these are not recommended as first-line hormonal management. About 5% to 10% of patients with POI will have spontaneous remission, allowing for pregnancy. See Cecil Essentials 71.
a. Asherman syndrome: Patients have intrauterine adhesions that obliterate the uterine cavity and result from damage to the endometrial basal layer, most commonly after a surgical procedure that disrupts the uterine lining. Patients can have a range of menstrual disturbances, infertility, and spontaneous abortions. Treatment involves lysis of adhesions and hormonal therapy.
b. Nonclassical CAH: The clinical features of this disease are similar to those observed in PCOS, including menstrual irregularities, hyperandrogenism, and polycystic ovaries. CAH is an autosomal-recessive disorder that is most often caused by mutations in the gene encoding 21-hydroxylase, an enzyme in the steroidogenesis pathway. Most patients with nonclassical CAH do not have cortisol deficiency or ACTH excess. The diagnosis can be made by measuring early-morning 17-hydroxyprogesterone levels. This is the substrate for 21-hydroxylase and will be elevated, usually over 800 ng/dL, in CAH. Treatment for nonclassical CAH is similar to that for PCOS.
c. Androgen-secreting tumors: These can be present in the adrenal gland or ovary, and should be suspected with rapid onset of androgenic symptoms and with associated symptoms like weight loss, anorexia, and bloating. Elevated testosterone > 200 ng/dL and DHEAS > 700 ng/mL raise suspicion for a tumor and should be followed by abdominal and pelvic CT. Pelvic ultrasonography can also help make the diagnosis of an ovarian tumor. Treatment involves surgical resection, mitotane (an adrenal cortex suppressor), and steroid synthesis inhibitors.
d. Kallmann syndrome: This syndrome occurs most often in an X-linked recessive inheritance pattern. It involves a mutation of the KAL1 gene, which codes for anosmin, an adhesion molecule involved in migration of GnRH and olfactory neurons to the hypothalamus. The specific mutation has not been identified in females, but it results in GnRH deficiency and amenorrhea. Patients are treated with hormone replacement therapy to stimulate secondary sexual characteristics and to increase bone mineral density. If pregnancy is desired, patients will be treated with exogenous pulsatile GnRH or exogenous gonadotropins.