Secondary amenorrhea is defined as the cessation of menses sometime after menarche has occurred. Oligomenorrhea is defined as menses occurring at intervals longer than 35 days. No consensus has been reached regarding the point at which oligomenorrhea becomes amenorrhea. Some authors suggest the absence of menses for 6 months constitutes amenorrhea, but the basis for this recommendation is unclear. Practically speaking, a woman aged 16-40 years who experiences loss of an established regular menstrual pattern should have an evaluation to seek the cause. By 1 year after menarche, if a young girl experiences 3 months of oligomenorrhea or polymenorrhea, an evaluation is indicated.
This article addresses the evaluation and treatment of women with secondary amenorrhea who have no evidence of androgen excess. Women with amenorrhea who do have evidence of androgen excess, such as hirsutism, virilization, or sexual ambiguity, should be evaluated differently from women with amenorrhea alone.
For related information see Medscape's Pregnancy and Women's Sexual Health Resource Centers.< Sexual Women?s>
Regular and predictable menstrual cycles occur if the ovarian hormones estradiol and progesterone are secreted in an orderly fashion in response to stimulation by the hypothalamus and pituitary. Circulating estradiol stimulates growth of the endometrium. Progesterone, produced by the corpus luteum formed after ovulation, transforms proliferating endometrium into secretory endometrium. If pregnancy does not occur, this secretory endometrium breaks down and sheds during the ensuing menstrual period.
Amenorrhea occurs if the hypothalamus and pituitary fail to provide appropriate gonadotropin stimulation to the ovary, resulting in inadequate production of estradiol or in failure of ovulation and progesterone production. Amenorrhea can also occur if the ovaries fail to produce adequate amounts of estradiol despite normal and appropriate gonadotropin stimulation by the hypothalamus and pituitary. In some cases, the hypothalamus, pituitary, and ovaries all may be functioning normally, yet amenorrhea occurs because of uterine abnormalities such as adhesions in the endometrial cavity, cervical defects, uterine septum, and imperforate hymen.
- Hypothalamic or pituitary dysfunction results in decreased or inhibited GnRH secretion, which affects the pulsatile release of LH causing anovulation. This can be caused by a number of reasons.
- A common cause of primary amenorrhea is functional hypothalamic amenorrhea (66%).
- This can be caused by eating disorders, exercise, or high levels of prolonged physical or mental stress. This can also include major psychiatric disorders such as depression. (See eMedicine’s article Amenorrhea, Primary)
- Pituitary tumors such as prolactinoma (13%) or in Cushing disease or hypothalamic tumors
- Other intracranial tumors such as craniopharyngioma, brain injury, or cranial irradiation
- Congenital GnRH deficiency leads to low gonadotropin levels. When this occurs with anosmia, it is considered Kallman syndrome.
- Other pituitary causes include empty sella syndrome, pituitary infarct, or hyperprolactinemia.
Ovarian causes (12%)39
- Absence of ovaries, oocytes, or follicles are all conditions that cause amenorrhea.
- Estradiol needed to maintain regular cycles is deficient or absent.
- Gonadal dysgenesis most commonly occurs in Turner syndrome (45,XO). It can also be seen in XX gonadal dysgenesis and XY gonadal dysgenesis. “Pure” gonadal dysgenesis occurs when the syndrome affects the gonad only and no other dysmorphic features are noted.
- Fragile X leading to ovarian failure.
- Polycystic ovarian syndrome (PCOS) usually presents as secondary amenorrhea but may rarely present as primary amenorrhea.
Anatomical/congenital abnormalities (7%)39
- Female reproductive tract abnormalities account for about one fifth of primary amenorrhea cases.39 Pelvic pain is common in girls with disorders of the reproductive tract that have outflow obstruction. A uterus and patent vaginal tract are needed for normal menstrual flow to occur.
- Imperforate hymen causes an outflow obstruction. These patients can have blood in the vagina that collects and can result in a perirectal mass.
- Transverse vaginal septum can be anywhere along the tract between the hymenal ring and cervix.39
- Vaginal agenesis/Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is caused by agenesis or partial agenesis of the mullerian duct system. It is characterized by complete lack of vagina with differing amounts of uterine development. This can be distinguished from androgen insensitivity with total testosterone levels.
Receptor and enzyme defects (2-3%)
- Congenital adrenal hyperplasia as a result of 17-alpha hydroxylase deficiency (CYP 17) causes an excess of deoxycortisone to be produced and deficiency of cortisol and adrenal and gonadal sex steroids. Patients with this disorder who experience primary amenorrhea can be either genotypic males (XY) or females (XX) with genitalia that are only partially developed.39
- Vanishing testes syndrome is characterized by genotypic males whose gonads do not develop completely. As a result, there is no testosterone, estrogen, or müllerian-inhibiting substance produced. These patients appear phenotypically female.39
- Patients who have Ullrich Turner syndrome are 46,XY and have a deletion or mutation on chromosome 6 in the testis determining factor. These patients do not make mullerian-inhibiting factor or testosterone. They have primary gonadal failure and feminized internal and external genitalia.39
- Androgen insensitivity syndrome occurs when patients are resistant to testosterone. It is an X-linked disease in which patients appear as phenotypically normal females. The testes, located internally and sometimes in the labia or inguinal area, do make mullerian-inhibiting hormone, so all mullerian structures, fallopian tubes, uterus, and upper third of the vagina are absent.39
- 5-alpha reductase deficiency in 46,XY patients causes ambiguous genitalia in newborns. These patients cannot convert testosterone to dihydrotestosterone, which is a more potent androgen. This leads to feminization of the genitalia.39
- Gonadotropin resistance is very rare, but inactivating mutations of the receptors for LH and FSH can cause anovulatory amenorrhea.40
- Aromatase deficiency is also a very rare disorder. Aromatase catalyzes the conversion of androgen to estrogen. When estrogen synthesis cannot occur, increased levels of testosterone result and virilization of the female occurs. Girls often have cystic ovaries and resultant amenorrhea.41
Each year, approximately 5-7% of menstruating women experience 3 months of secondary amenorrhea.
No evidence indicates that the prevalence of amenorrhea varies according to national origin or ethnic group. However, local environmental factors related to nutrition and the prevalence of chronic disease undoubtedly have an effect. For instance, the age of the first menses varies by geographic location, as demonstrated by a World Health Organization study comparing 11 countries, which reported a median age of menarche of 13-16 years across centers.
Menstrual suppression has become common with oral contraceptives that are designed for such an effect. Menstrual suppression due to oral contraceptives is not considered secondary amenorrhea.
The regular occurrence of spontaneous menses is a sign of good health. It means that the hypothalamic-pituitary-ovarian axis is functioning normally to produce ovarian hormones and support ovulation. The ovary functions as both an endocrine organ and a reproductive organ. When menstrual cycle regularity is lost, this means the ovaries are not functioning normally in either their endocrine role or their reproductive role. Loss of menstrual regularity has been associated with reduced bone density and increased fracture rates. Thus, loss of menstrual regularity has associated morbidity and may contribute to increased mortality.
- Estrogen, androgens, and progesterone play an important role in building and maintaining bone mass. Menstrual cycle duration of longer than 31 days has been associated with a 2-fold increase in wrist fracture. Similar correlations exist for the risk of hip fracture, a potentially fatal occurrence.
- Regular menstruation is a sign that the ovaries support ovulation and that they contain a normal store of primordial follicles. Primordial follicles are composed of an oocyte surrounded by a single layer of granulosa cells. The number of primordial follicles in the human ovary peaks during the fifth gestational month at approximately 7 million. After this initial finite pool is in place, no additional primordial follicles are formed. In some cases, loss of menstrual regularity is an early sign of declining fertility and impending premature ovarian failure. Also in some cases, this follicle depletion progresses to cause irreversible infertility. Approximately 10% of women evaluated for amenorrhea in a tertiary center are found to have premature ovarian failure.
No evidence suggests that the incidence of either primary or secondary amenorrhea is related to race.
Amenorrhea occurs only in women.
Loss of menstrual regularity is an indication for a careful review of systems. The menstrual cycle should be viewed as a vital sign. Loss of menstrual regularity may be the first clear symptom heralding the onset of a major illness or systemic disease. Viewing the menstrual cycle as a vital sign may lead to earlier diagnosis of, and intervention for, several potentially life-threatening disorders. An arbitrarily defined duration of amenorrhea need not pass before taking corrective action.
Amenorrhea can be due to pregnancy, anatomic defects of the outflow tract, ovarian disorders, and pituitary or hypothalamic disorders. In some cases, the cause is functional, meaning that the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator has shut down the reproductive system in its role as an integrator of metabolic and psychogenic stress. Attributing the loss of menstrual regularity to a recent stressful life event is tempting; however, this approach can delay the detection of significant pathology that can have long-term health consequences. One study has shown that one third of women in a control group report a significant stressful life event in the preceding year.
Pregnancy is the most common cause of amenorrhea. Determining whether the patient is sexually active and whether she is using contraceptive methods is important. In some cases, the hormonal contraception itself may be the cause of the amenorrhea.
Often, time constraints do not permit practitioners to obtain a thorough history and review of symptoms on the first visit. Scheduling a repeat visit to permit a more thorough evaluation may be necessary.
Another option is to use standardized history-taking instruments to collect this information in preparation for a return visit. In other cases, patients may be asked to keep a menstrual calendar and return in 3 months for reassessment. The importance of the ovary as an endocrine organ that helps maintain bone density should be stressed to the patient to help ensure her return.
- Disorders of the outflow tract: Prior history of a surgical procedure involving the endometrial cavity, especially if performed in the presence of infection, raises the possibility of uterine synechiae (Asherman syndrome).
- Ovarian disorders
- Symptoms of vaginal dryness, hot flashes, night sweats, or disordered sleep may be a sign of ovarian insufficiency or premature ovarian failure. The presence of these symptoms in young women demands timely further evaluation.
- Prior history of chemotherapy or radiation therapy may be associated with ovarian failure.
- Hypothalamic/pituitary disorders
- Associated galactorrhea, headaches, or reduced peripheral vision could be a sign of intracranial tumor. These symptoms require immediate further evaluation.
- A history of hemorrhage after childbirth can lead to failure of regular menses to return. This may be an indication of postpartum pituitary necrosis. Failure of lactation is an even earlier sign. Detecting this condition early is important because of the possible development of associated central adrenal insufficiency, a potentially fatal condition.
- Sarcoidosis can manifest insidiously, with development of mild fatigue, malaise, anorexia, weight loss, and fever. Because 90% of patients with sarcoidosis have pulmonary involvement at some stage of the disorder, cough and dyspnea may be present.
- Hemochromatosis may manifest as weakness, lassitude, weight loss, and a change in skin color.
- Functional impairment of the hypothalamic GnRH pulse generator
- Dieting with excessive restriction of energy intake, especially fat restriction, may lead to loss of menstrual regularity and associated bone loss. In extreme cases, the process may advance to anorexia nervosa, a potentially fatal condition. Associated symptoms are an intense fear of fatness and a body image that is heavier than observed. Eating disorders can be restrictive in nature or can be of a binge-eating/purging type.
- Major psychiatric disorders such as depression, obsessive-compulsive disorder, or schizophrenia may disrupt the menstrual cycle. Symptoms associated with these conditions may be detected upon review of systems.
- Autoimmune adrenal insufficiency, a potentially fatal condition, often manifests as vague and nonspecific symptoms. Loss of menstrual regularity may be the first clear symptom indicating a need for further evaluation to detect this condition.
- Loss of menstrual regularity may herald the onset of other autoimmune endocrine disorders such as hyperthyroidism, hypothyroidism, or autoimmune lymphocytic hypophysitis. The same is true for other endocrine disorders such as Cushing syndrome or pheochromocytoma. A careful review of symptoms may help uncover these disorders.
- Strenuous exercise related to a wide variety of athletic activities can be associated with the development of amenorrhea. Elicit a history regarding the type of exercise activity and its duration per week.
- Abuse of drugs such as cocaine and opioids have central effects that may disrupt the menstrual cycle.
- Malnutrition and cirrhosis associated with alcoholism may cause loss of menstrual regularity.
- AIDS, HIV disease, or other types of immune-deficiency states may induce systemic infection leading to chronic disease and loss of menstrual regularity.
- Occult malignancy with progressive weight loss and a catabolic state may lead to loss of menstrual regularity. A careful review of systems may help uncover such a disorder.
Physical examination should begin with an overall assessment of nutritional status and general health. Measure height and weight and seek evidence for chronic disease or cachexia.
Hypothermia, bradycardia, hypotension, and reduced subcutaneous fat can be observed in persons with severe anorexia nervosa. In cases of frequent vomiting, look for possible dental erosion, reduced gag reflex, trauma to the palate, subconjunctival hemorrhage, and metacarpophalangeal calluses or bruises.
- Examine the skin for evidence of androgen excess, such as hirsutism, hair loss, and acne. Acanthosis nigricans may be present in association with androgen excess related to insulin resistance.
- Skin examination findings can also give clues to other endocrine disorders. Vitiligo or increased pigmentation of the palmar creases may herald primary adrenal insufficiency. Thin, parchmentlike skin, striae, and evidence of easy bruising may be signs of Cushing syndrome. Warm, moist skin radiating excessive heat may be a sign of hyperthyroidism.
- Large pituitary tumors can cause visual-field cuts by impinging on the optic tract. In some cases, these visual-field cuts can be detected by simple confrontational testing.
- Assess the state of breast development. Also examine the breasts for galactorrhea. In some cases, breast discharge can be expressed, yet the condition is not true galactorrhea. If the discharge is indeed milk, this can be confirmed by finding fat globules in the fluid using low-power microscopy.
- Examine for the presence of axillary and pubic hair. These are a marker of adrenal and ovarian androgen secretion. In cases of panhypopituitarism, sources of androgen are low and pubic and axillary hair is sparse. Also, some women develop the combination of autoimmune premature ovarian failure and autoimmune primary adrenal insufficiency. These women are also markedly androgen-deficient and have scant axillary and pubic hair. The same is true for persons with androgen insensitivity syndrome (testicular feminization), 17-hydroxylase deficiency, and 17,20-desmolase deficiency.
- Pelvic examination findings can provide physical evidence indicating the adequacy of estrogen production. Thin and pale vaginal mucosa with absent rugae is evidence of estrogen deficiency. The presence of cervical mucus with spinnbarkeit is good evidence of estrogen effect. However, evidence of estrogen effect detected on physical examination findings can be misleading in some cases because estrogen is being produced as a result of higher than normal follicle-stimulating hormone (FSH) levels (compensated ovarian insufficiency). Women with well-established premature ovarian failure often have intermittent ovarian follicle function that produces enough estrogen to have vaginal and cervical effects.
- Measuring the clitoris is an effective method for determining the degree of androgen effect. The clitoral index can be determined by measuring the glans of the clitoris in the anteroposterior and transverse diameter. A clitoral index greater than 35 mm2 is evidence of increased androgen effect. A clitoral index greater than 100 mm2 is evidence of virilization.
- Ovarian enlargement may be found upon pelvic examination in cases of autoimmune oophoritis, 17-hydroxylase deficiency, or 17,20-desmolase deficiency. In these disorders, inadequate negative feedback supplied by the ovary permits excessive gonadotropin stimulation that may cause ovarian enlargement with multiple follicular cysts. In some cases, these disorders manifest with an acute onset of pain related to ovarian torsion.
- A general physical examination may uncover unexpected findings that are indirectly related to the loss of menstrual regularity (eg, discovery of hepatosplenomegaly, which may lead to detection of a chronic systemic disease).
Amenorrhea can be divided into 2 groups: (1) amenorrhea without evidence of associated androgen excess and (2) amenorrhea with evidence of androgen excess (eg, hirsutism, virilization, sexual ambiguity). For a review of the causes of amenorrhea associated with androgen excess, see androgen excess.
Pregnancy is the most common cause of secondary amenorrhea. A pregnancy test (measurement of serum or urinary human chorionic gonadotropin) is recommended as a first step in evaluation of a secondary amenorrhea.
Since regular menstruation reflects a properly functioning hypothalamic-pituitary-gonadal axis, a logical approach is to consider disorders based upon the levels of control of the menstrual cycle: uterus, ovary, pituitary, and hypothalamus.
- Uterine causes
- Intrauterine adhesions (Asherman syndrome): This results from acquired scarring of the endometrium, usually secondary to postpartum hemorrhage or infection followed by procedures such as dilatation and excessive curettage. This abnormality prevents the normal build up and shedding of the endometrium leading to scant or absent menses. The diagnosis is suggested by absence of endometrial stripe on uterine ultrasonography and confirmed by hysteroscopy evaluation or by absence of bleeding after cyclic therapy with estrogen and later progestin for several weeks.
- Recently, a case report of a woman in whom persistent secondary amenorrhea developed due to intrauterine adhesions after selective embolization of the uterine arteries for control of refractory primary postpartum hemorrhage is described. Adverse effects of these new lifesaving technologies remain to be evaluated long term.36
- Ovarian causes
- Prodromal premature ovarian failure: This is a state of ovarian insufficiency in which FSH levels are elevated and menses are irregular but not to the degree required to make a diagnosis of premature ovarian failure. It is also referred to as primary ovarian insufficiency. For a more in-depth discussion, see Ovarian Insufficiency.
- Karyotypically normal spontaneous premature ovarian failure: For an in-depth discussion, see Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure.
- Turner syndrome
- Pure gonadal dysgenesis: The term pure here refers to the fact that the syndrome seems to have purely affected the gonad. No associated dysmorphic findings exist as are noted in Turner syndrome, which is often referred to as gonadal dysgenesis. Pure gonadal dysgenesis can occur with either a 46,XX or a 46,XY karyotype.
- Autoimmune oophoritis
- 17,20-desmolase deficiency or 17-hydroxylase deficiency
- Radiation or chemotherapy (refer to iatrogenic premature ovarian failure)
- FSH receptor mutation
- Pituitary causes
- Prolactinoma: This is the most common pituitary etiology and accounts for almost 20% of cases of secondary amenorrhea.26 Elevated prolactin levels may suppress GnRH secretion, leading to low gonadotropin and low estradiol levels. However, hyperprolactinemia may also occur secondarily based on hypothalamic dysfunction.
- Other pituitary tumors (Cushing syndrome, acromegaly, thyrotropin)
- Postpartum pituitary necrosis (Sheehan syndrome)
- Autoimmune hypophysitis
- Pituitary radiation
- Hypothalamic causes
- Tumors such as craniopharyngioma or teratoma
- Infiltrative disorder such as sarcoidosis, Langerhans cell histiocytosis, lymphoma
- Kallmann syndrome
- Functional causes
- Chronic disease
- Weight loss
- Depression or other psychiatric disorders
- Recreational drug abuse
- Psychotropic drug use
- Excessive exercise
- Severe stress or severe illness
- Women with hypothalamic amenorrhea have lower serum leptin concentrations, which may contribute to their low gonadotropin secretion. Leptin administration resulted in improvement of the reproductive axis in a study of women with functional hypothalamic amenorrhea.
- In most cases, clinical variables alone are not adequate to define the pathophysiologic mechanism disrupting the menstrual cycle. All women who present with 3 months of secondary amenorrhea should have a diagnostic evaluation initiated at that visit. As stated by Speroff et al, "Few problems in gynecologic endocrinology are as challenging or taxing to the clinician as amenorrhea. The clinician must be concerned with an array of potential diseases and disorders involving, in many instances, unfamiliar organ systems, some carrying morbid and even lethal consequences for the patient."29
- Perform a pregnancy test. Once pregnancy is excluded, a thorough history, review of symptoms, and physical examination are important. If the history and physical examination findings do not reveal the cause of the amenorrhea, a complete blood cell count, urinalysis, and serum chemistries should be evaluated to help rule out systemic disease. Serum prolactin, FSH, estradiol, and thyrotropin levels should also be measured routinely in the initial evaluation of amenorrhea once pregnancy has been excluded.
- Prolactin levels in excess of 200 ng/mL are not observed except in the case of prolactin-secreting pituitary adenoma (prolactinoma). In general, the serum prolactin level correlates with the size of the tumor.
- Psychotropic drugs, hypothyroidism, stress, and meals can also raise prolactin levels. Repeatedly elevated prolactin levels require further evaluation if the cause is not readily apparent.
- Follicle-stimulating hormone
- An FSH level in the menopausal range is indicative of ovarian insufficiency. Check the reference range for the laboratory where the test is performed.
- If a repeat value in 1 month confirms this finding (taking in consideration the above laboratory-dependent caveat) and the patient has experienced at least 4 months of disordered menstrual cycles (oligomenorrhea, polymenorrhea), then the diagnosis of premature ovarian failure or primary ovarian insufficiency is confirmed.
- Luteinizing hormone: Luteinizing hormone level is elevated in cases of 17,20-lyase deficiency, 17-hydroxylase deficiency, and premature ovarian failure.
- Generally, when considering measurement of the estradiol level, concomitantly obtain and measure FSH level. Serum estradiol levels within the reference range can be found intermittently despite the presence of well-documented primary ovarian insufficiency. Finding a concomitantly elevated FSH level brings this to light.
- Serum estradiol levels undergo wide fluctuations during the normal menstrual cycle. During the early follicular phase of the menstrual cycle, levels may be lower than 50 pg/mL. During the preovulatory estradiol surge, levels in the range of 400 pg/mL are not uncommon. In healthy menopausal women, estradiol levels are routinely lower than 20 pg/mL.
- Testosterone and dehydroepiandrosterone sulfate: Obtaining these tests is not necessary in a woman with no evidence of androgen excess.
- Thyrotropin and free thyroxine (T4)
- Ovarian causes: The information obtained with ovarian ultrasonography does not change clinical management in the evaluation of amenorrhea, and ovarian ultrasonography should be reserved for investigational use.
- MRI for pituitary or hypothalamic causes
- MRI of the pituitary and hypothalamus is often indicated in the evaluation of amenorrhea.
- Request imaging of the hypothalamic/pituitary area specifically, rather than a study of the entire brain. This achieves higher resolution.
- MRI is indicated in the following circumstances:
- Associated headaches or visual-field cuts
- Profound estrogen deficiency with otherwise unexplained amenorrhea
- Progesterone withdrawal test: Prior to the development of readily available assays to measure serum levels of estradiol, the progesterone challenge test was used as a bioassay with which to demonstrate estrogen effect at the level of the endometrium. Progesterone has been shown to predictably induce a withdrawal bleed if the circulating serum estradiol level is at least 50 pg/mL. However, the progesterone withdrawal test can provide inappropriately reassuring information that may delay the etiology of ovarian insufficiency. The progesterone withdrawal test is no substitute for evaluating ovarian health. Demonstrating the presence of normally functioning ovaries requires the concurrent measurement of serum estradiol and FSH.
- Minnesota Nutrition Data Systems evaluation: This can be used to assess dietary intake. This is a 24-hour recall and analysis of total energy, protein, fat, and carbohydrate content.
- Beck Depression Inventory: This can be used to assess the patient's mood.
- Modifiable Activity Questionnaire and Paffenbarger Questionnaire: The Modifiable Activity Questionnaire15 and the Paffenbarger Questionnaire can be used to assess the patient's level of physical activity.
- Multidimensional eating disorder inventory for anorexia and bulimia9
- The bulimia test revised (ie, BULIT-R)