INTRODUCTION — Amenorrhea (absence of menses) can be a transient, intermittent, or permanent condition resulting from dysfunction of the hypothalamus, pituitary, ovaries, uterus, or vagina (table 1 and table 2). It is often classified as either primary (absence of menarche by age 15 years) or secondary (absence of menses for more than three months in girls or women who previously had regular menstrual cycles or six months in girls or women who had irregular menses). Missing a single menstrual period may not be important to assess, but amenorrhea lasting three months or more and oligomenorrhea (fewer than nine menstrual cycles per year or cycle length greater than 35 days) require investigation. An intermenstrual interval greater than 45 days is considered abnormal in adolescent girls who are ≥2 years postmenarche [1]. The etiologic and diagnostic considerations for oligomenorrhea are the same as for secondary amenorrhea.
The epidemiology and causes of secondary amenorrhea are reviewed here. The evaluation and management of secondary amenorrhea and the causes, evaluation, and management of primary amenorrhea are discussed separately. (See "Evaluation and management of secondary amenorrhea" and "Causes of primary amenorrhea" and "Evaluation and management of primary amenorrhea".)
EPIDEMIOLOGY — The most common causes of secondary amenorrhea, based upon a series of 262 patients with amenorrhea of adult onset, include [2]:
●Hypothalamus – 35 percent (almost all functional hypothalamic amenorrhea) (see 'Functional hypothalamic amenorrhea' below)
●Pituitary – 17 percent (13 percent hyperprolactinemia, 1.5 percent "empty sella," 1.5 percent Sheehan syndrome, 1 percent Cushing's syndrome) (see 'Pituitary disease' below)
●Ovary – 40 percent (30 percent polycystic ovary syndrome [PCOS], 10 percent primary ovarian insufficiency [POI, also known as premature ovarian failure]) (see 'Polycystic ovary syndrome' below and 'Primary ovarian insufficiency (premature ovarian failure)' below)
●Uterus – 7 percent (all due to intrauterine adhesions) (see 'Uterine disorders' below)
●Other – 1 percent (congenital adrenal hyperplasia, ovarian and adrenal tumors, hypothyroidism) (see 'Other hyperandrogenic disorders' below and 'Thyroid disease' below)
Similar results have been seen in other studies [3,4]. The breakdown may be slightly different in adolescents with irregular menses, 50 percent of whom have hyperandrogenism likely attributed to PCOS [5].
CAUSES
Pregnancy — Pregnancy is the most common cause of secondary amenorrhea. It may occur even in women who claim that they have not been sexually active or are positive that intercourse occurred at a "safe" time. It is also important to note that apparent menstrual bleeding does not exclude pregnancy, since a substantial number of pregnancies are associated with some early first trimester bleeding. Thus, a pregnancy test (measurement of serum or urinary human chorionic gonadotropin [hCG]) is recommended as a first step in evaluating any woman with amenorrhea. (See "Evaluation and management of secondary amenorrhea", section on 'Initial evaluation'.)
Hypothalamic dysfunction
●One of the most common types of secondary amenorrhea is functional hypothalamic amenorrhea, which, by definition, excludes pathologic disease. (See 'Functional hypothalamic amenorrhea' below.)
●Although isolated gonadotropin-releasing hormone (GnRH) deficiency most commonly presents as primary amenorrhea, it extremely rarely presents as secondary amenorrhea. There have been some reports of a single menstrual bleed in selected cases (eg, with GnRH receptor mutations, which may not cause complete receptor dysfunction [6]). (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)
●Benign and malignant tumors in the hypothalamus, such as craniopharyngiomas, radiation of sellar tumors, and infiltrative diseases of the hypothalamus, can cause secondary amenorrhea. (See 'Hypothalamic tumors and infiltrative lesions' below.)
●Systemic illness may be associated with menstrual cycle disorders when it is severe enough to result in a decrease in hypothalamic GnRH secretion and/or when it is associated with nutritional deficiencies. (See 'Systemic illness' below.)
Functional hypothalamic amenorrhea — Functional hypothalamic amenorrhea, or functional hypothalamic GnRH deficiency, is a disorder that, by definition, excludes pathologic disease. It is characterized by a presumed decrease in hypothalamic GnRH secretion [7,8].
The abnormal GnRH secretion characteristic of functional hypothalamic amenorrhea leads to decreased pulses of gonadotropins, absent midcycle surges in luteinizing hormone (LH) secretion, absence of normal follicular development, anovulation, and low serum estradiol concentrations [9]. Variable neuroendocrine patterns of LH secretion can be seen [10]. Serum concentrations of follicle-stimulating hormone (FSH) are low or normal and often exceed those of LH, similar to the pattern in prepubertal girls.
One of the main clinical concerns in women with functional hypothalamic amenorrhea is bone loss due to hypoestrogenemia. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Functional hypothalamic amenorrhea: Evaluation and management" and "Anorexia nervosa: Endocrine complications and their management", section on 'Bone'.)
Risk factors — Multiple factors may contribute to the pathogenesis of functional hypothalamic amenorrhea, including eating disorders (such as anorexia nervosa), excessive exercise, and stress. However, in a few women with functional hypothalamic amenorrhea, no obvious precipitating factor is evident. The term hypothalamic amenorrhea is often used interchangeably with functional hypothalamic amenorrhea.
●Both weight loss below a certain target level (approximately 10 percent below ideal body weight) and excessive exercise are associated with amenorrhea. Most cases of amenorrhea associated with exercise are also associated with weight loss, with evidence that normal cycles are maintained when caloric intake is sufficient to match the energy expenditure [11,12]. The "female athlete triad" is defined as the presence of amenorrhea, disordered eating, and osteoporosis or osteopenia (table 3) [13]. This syndrome is especially common in amenorrhea associated with activities that tend to be associated with low body weight (eg, running, ballet dancing) and sports in which scoring is subjective (eg, figure skating or gymnastics). (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".)
●Hypothalamic amenorrhea can be caused by nutritional deficiencies that are not associated with weight loss or strenuous exercise. As an example, in two studies, the diet and body composition of nonathletic women with hypothalamic amenorrhea and normal body mass index (BMI) were compared with similar women who had regular menstrual cycles [14,15]. In contrast with their menstruating counterparts, the women with amenorrhea severely restricted their fat consumption and had lower body fat mass. Another cause of amenorrhea due to nutritional deficiencies is celiac disease. (See 'Celiac disease' below.)
●Emotional stress and stress induced by illness (eg, myocardial infarction, severe burns) are additional causes of hypothalamic amenorrhea. With severe illness, the hypothalamic GnRH deficiency is transient; the hypothalamic-pituitary-ovarian axis recovers once the patient is well.
Role of leptin deficiency — Women with hypothalamic amenorrhea have lower serum concentrations of leptin, a protein derived from adipose tissue, which probably contributes to their low gonadotropin secretion as compared with similar-weight women who have normal menstrual cycles [16,17]. The chronic energy deficit and hypoleptinemia seen with hypothalamic amenorrhea are also associated with bone loss and neuroendocrine dysfunction, including abnormalities of the thyroid, growth hormone, and adrenal axes [13-16,18]. (See "Evaluation and management of secondary amenorrhea", section on 'Functional hypothalamic amenorrhea' and "Physiology of leptin", section on 'Hypothalamic amenorrhea'.)
Genetic basis — There is marked interpatient variability in the degree of weight loss or exercise required to induce amenorrhea. This may in part be due to an underlying genetic predisposition in susceptible individuals. A number of gene mutations have been identified in patients with congenital GnRH deficiency; heterozygous mutations in some of the same genes (KAL1, FGFR1, PROKR2, GNRHR) have now been identified in women with functional hypothalamic amenorrhea, as well [19]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Genetics'.)
Recovery — The natural history of hypothalamic amenorrhea has been studied in a retrospective, questionnaire-based analysis of 28 patients [20]. Women with a history of hypothalamic amenorrhea with a clear precipitant (eating disorder, stress, and/or weight loss) had a better prognosis for recovery than those with no clear precipitant (71 and 29 percent, respectively). Reversal of the inciting factor appeared necessary but not sufficient for recovery (83 percent recovery if the factor was reversed). In a second study of 93 women with hypothalamic amenorrhea, baseline predictors of recovery included a greater BMI, a higher serum androstenedione concentration, and a lower serum cortisol concentration [21].
Hypothalamic tumors and infiltrative lesions — Hypothalamic tumors, (eg, craniopharyngiomas, lymphomas) and infiltrative diseases (eg, Langerhans cell histiocytosis, sarcoidosis) may result in decreased GnRH secretion, low or normal serum gonadotropin concentrations, and amenorrhea. However, these lesions are uncommon compared with functional hypothalamic amenorrhea. Most women with infiltrative disease of the hypothalamus who have amenorrhea will have one or more neurologic symptoms, such as severe headache, change in personality, or marked mood changes. (See "Neurologic sarcoidosis", section on 'Clinical features' and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Diabetes insipidus and other endocrinopathies'.)
Systemic illness — Systemic illness may be associated with menstrual cycle disorders when it is severe enough to result in a decrease in hypothalamic GnRH secretion and/or when it is associated with nutritional deficiencies. Examples include type 1 diabetes mellitus and celiac disease, which may also present with autoimmune ovarian insufficiency. (See 'Primary ovarian insufficiency (premature ovarian failure)' below and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Autoimmune adrenalitis'.)
Type 1 diabetes mellitus — Adolescent girls with type 1 diabetes mellitus have an increased prevalence of oligomenorrhea and amenorrhea. In one study, 39 of 56 (70 percent) adolescents with type 1 diabetes mellitus had amenorrhea or oligomenorrhea compared with 12 of 56 (22 percent) controls. The adolescents with type 1 diabetes mellitus and glycated hemoglobin (A1C) concentrations >7.6 percent were more likely to have menstrual abnormalities [22]. Even in well-controlled adults with type 1 diabetes mellitus, the prevalence of amenorrhea is 20 percent [23]. (See "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Miscellaneous'.)
Type 2 diabetes in adolescent girls may be associated with polycystic ovary syndrome (PCOS) and menstrual cycle disorders. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents".)
Celiac disease — It is estimated that approximately 40 percent of women with untreated celiac disease have menstrual cycle disorders [24]. Other reproductive problems in these women include delayed menarche, infertility, miscarriage, and pregnancy complications. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Menstrual and reproductive issues'.)
Pituitary disease — Among pituitary disorders that cause secondary amenorrhea, lactotroph adenomas (prolactin-secreting pituitary adenomas, prolactinomas) are the most common. They are responsible for 13 percent of cases of secondary amenorrhea and 90 percent of the cases due to pituitary disease [2]. Other types of pituitary adenomas and other sellar masses, and other types of pituitary disease, account for the majority of the remaining cases of pituitary origin. (See "Causes of hypopituitarism".)
Hyperprolactinemia — Hyperprolactinemia has a similar presentation to functional hypothalamic amenorrhea, except for the additional finding of galactorrhea in some women. As a result, serum prolactin should be measured in every woman with amenorrhea. The normal range should be consulted for the prolactin assay used, as the upper limit of normal for women of reproductive age can range from 20 to 27 ng/mL (20 to 27 mcg/L). Stress, sleep, and intercourse can also raise serum prolactin. Thus, we recommend that serum prolactin be measured at least twice before sellar imaging is ordered, particularly in women with borderline high values (<50 ng/mL [<50 mcg/L]).
Prolactin appears to cause amenorrhea by suppressing hypothalamic GnRH secretion, leading to low gonadotropin and estradiol concentrations [25]. Unlike the other pituitary hormones, prolactin release is mostly controlled by inhibition, primarily by hypothalamic dopamine. The negative regulation by dopamine is so potent that disruption of the pituitary stalk, by trauma or a large tumor, leads to hyperprolactinemia. Several drugs, estrogen, and increased thyrotropin-releasing hormone (TRH) release due to hypothyroidism can also reversibly stimulate prolactin secretion. (See "Causes of hyperprolactinemia".)
Magnetic resonance imaging (MRI) of the pituitary should, therefore, be performed in any woman with persistent hyperprolactinemia. As a general rule, the serum prolactin concentration correlates with pituitary adenoma size. Thus, a minimal increase in the serum prolactin concentration in a woman with a large tumor suggests that the mass is probably not a lactotroph adenoma. (See "Clinical manifestations and evaluation of hyperprolactinemia".)
Other sellar masses — Any other sellar mass (such as other kinds of pituitary adenomas, craniopharyngiomas, meningiomas, cysts, etc) can also cause deficient gonadotropin secretion and therefore amenorrhea, with or without hyperprolactinemia. (See "Causes, presentation, and evaluation of sellar masses".)
Other diseases of the pituitary — Sheehan syndrome, radiation, infarction, and infiltrative lesions of the pituitary gland, such as hemochromatosis and lymphocytic hypophysitis, are all uncommon causes of gonadotropin deficiency. (See "Causes of hypopituitarism".)
Thyroid disease — Menstrual cycle disorders are common in women with thyroid disease. This was illustrated in a report of over 1000 women with a thyroid disorder [26]. Menstrual disturbances were common in women with hypothyroidism (35 and 10 percent for severe and mild-moderate hypothyroidism, respectively) [26] (see "Clinical manifestations of hypothyroidism", section on 'Reproductive abnormalities'). In women with severe hyperthyroidism, amenorrhea and hypomenorrhea occurred in 2.5 and 3.7 percent, respectively. Rates were lower in those with mild to moderate hyperthyroidism (0.2 and 0.9 percent, respectively).
Although heavy bleeding is the typical bleeding pattern seen with hypothyroidism, secondary amenorrhea can also occur [27]. It is important to recognize hypothyroidism as a potential cause of a reversibly enlarged pituitary gland (due to thyrotroph hyperplasia, lactotroph hyperplasia, or both) and hyperprolactinemia and not to confuse this entity with a lactotroph adenoma [28,29]. (See "Clinical manifestations of hypothyroidism", section on 'Reproductive abnormalities'.)
Polycystic ovary syndrome — PCOS, the most common reproductive disorder in women, accounts for approximately 20 percent of cases of amenorrhea but may account for approximately 50 percent of cases of oligomenorrhea [5] (see 'Epidemiology' above). Of note, PCOS is not simply an ovarian disorder; its pathogenesis is complex. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults", section on 'Pathogenesis'.)
The principal features of PCOS include androgen excess, ovulatory dysfunction, and/or polycystic ovaries. In addition, many women with PCOS are overweight or obese and have insulin resistance. Women with PCOS may present with amenorrhea, but they more commonly have irregular menses (oligomenorrhea). (See "Clinical manifestations of polycystic ovary syndrome in adults".)
The minimal criteria for the diagnosis of PCOS are two out of three of the following: (1) hyperandrogenism, (2) oligomenorrhea or amenorrhea, and (3) polycystic ovaries on ultrasound [30]. Other causes of irregular menses and hyperandrogenism must be ruled out as PCOS is a diagnosis of exclusion. Hyperandrogenism is usually manifested clinically as acne or hirsutism and sometimes as a high serum concentration of at least one androgen. PCOS is a diagnosis of exclusion. (See "Diagnosis of polycystic ovary syndrome in adults".)
Other hyperandrogenic disorders — Disorders other than PCOS that are associated with hyperandrogenism (eg, classic or nonclassic 21-hydroxylase deficiency and androgen-secreting tumors) may cause menstrual cycle disorders by causing anovulation or endometrial atrophy [31,32]. Exogenous androgens (eg, androgen abuse) can have the same effect. (See "Use of androgens and other hormones by athletes", section on 'Reproductive (women)' and "Pathophysiology and causes of hirsutism", section on 'Causes'.)
Ovarian disorders
Primary ovarian insufficiency (premature ovarian failure) — The depletion of oocytes before age 40 years is called primary ovarian insufficiency (POI, or premature ovarian failure). Most women experience intermittent follicular development, estradiol production, LH surges, ovulation, and menstrual bleeding between months of hypoestrogenemia. When POI is complete, lack of ovarian function leads to estrogen deficiency, endometrial atrophy, and cessation of menstruation. Despite the intermittent ovarian function, conception is rare once a diagnosis of POI has been made. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)
Loss of the negative feedback effect of estradiol and inhibin on the hypothalamus and pituitary results in high serum FSH concentrations, which distinguishes ovarian insufficiency from hypothalamic amenorrhea (low or normal FSH). (See "Clinical manifestations and diagnosis of menopause", section on 'Menstrual cycle and endocrine changes'.)
POI may be due to complete or partial loss of an X chromosome (Turner syndrome), the fragile X premutation, autoimmune ovarian destruction, or, most commonly, unknown and rare causes. Radiation therapy or chemotherapy with alkylating agents such as cyclophosphamide may also result in POI. POI is reviewed in detail separately. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)" and "Management of primary ovarian insufficiency (premature ovarian failure)".)
Ovarian tumors — Rare cases of ovarian tumors secreting inhibin may present with secondary amenorrhea. In one patient, an ovarian fibrothecoma producing inhibin B resulted in suppressed FSH and estradiol concentrations, amenorrhea, and hot flashes [33]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)
Uterine disorders — Intrauterine adhesions (Asherman syndrome) are the only uterine cause of secondary amenorrhea. This syndrome results from acquired scarring of the endometrial lining, usually secondary to postpartum hemorrhage or endometrial infection followed by instrumentation such as a dilatation and curettage. This abnormality prevents the normal build-up and shedding of endometrial cells, leading to very light or absent menses. The etiology of and evaluation for intrauterine adhesions is reviewed separately. (See "Intrauterine adhesions: Clinical manifestation and diagnosis", section on 'Etiology and risk factors' and "Evaluation and management of secondary amenorrhea", section on 'Normal laboratory results and history of uterine instrumentation'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Amenorrhea".)
SUMMARY
●Pregnancy is the most common cause of secondary amenorrhea. (See 'Pregnancy' above.)
●Estimated frequencies of the different causes of secondary amenorrhea include:
•Hypothalamic – 35 percent (almost all functional hypothalamic amenorrhea) (see 'Functional hypothalamic amenorrhea' above)
•Pituitary – 17 percent (13 percent hyperprolactinemia, 1.5 percent "empty sella," 1.5 percent Sheehan syndrome, 1 percent Cushing's syndrome) (see 'Pituitary disease' above)
•Ovary – 40 percent (30 percent polycystic ovary syndrome [PCOS], 10 percent primary ovarian insufficiency [POI, also known as premature ovarian failure]) (see 'Polycystic ovary syndrome' above and 'Primary ovarian insufficiency (premature ovarian failure)' above)
•Uterus – 7 percent (all due to intrauterine adhesions) (see 'Uterine disorders' above)
•Other – 1 percent (classic or nonclassic 21-hydroxylase deficiency, hypothyroidism, ovarian and adrenal tumors)
●A number of hypothalamic or pituitary disorders can result in secondary amenorrhea, including:
•Functional hypothalamic amenorrhea or functional hypothalamic gonadotropin-releasing hormone (GnRH) deficiency, which by definition excludes pathologic disease. One of the main clinical concerns in women with functional hypothalamic amenorrhea is bone loss due to hypoestrogenemia. Risk factors for functional hypothalamic amenorrhea include weight loss, exercise associated with low weight (running, ballet dancing), nutritional deficiencies, and stress. (See 'Functional hypothalamic amenorrhea' above.)
•Systemic illness when it is severe enough to result in a decrease in hypothalamic GnRH secretion and/or when it is associated with nutritional deficiencies. Examples include type 1 diabetes mellitus and celiac disease. (See 'Systemic illness' above.)
•Hyperprolactinemia, most commonly due to lactotroph adenomas (prolactinomas). (See 'Hyperprolactinemia' above.)
●Ovarian disorders that may result in secondary amenorrhea include:
•PCOS, one of the most common endocrine disorders in women. PCOS is not simply an ovarian disorder; its pathogenesis is complex. The principal features of PCOS include ovulatory dysfunction, androgen excess, polycystic ovaries on ultrasound, and metabolic issues, including obesity. Women with PCOS may present with amenorrhea, but they more commonly have irregular menses (oligomenorrhea). (See 'Polycystic ovary syndrome' above.)
•POI refers to menopause prior to age 40 years. It may be due to complete or partial loss of an X chromosome (Turner syndrome), the fragile X premutation, autoimmune ovarian destruction, or, most commonly, unknown causes. (See 'Primary ovarian insufficiency (premature ovarian failure)' above.)
●Intrauterine adhesions (Asherman syndrome) are the only uterine cause of secondary amenorrhea. This syndrome results from acquired scarring of the endometrial lining, usually secondary to postpartum hemorrhage or endometrial infection followed by instrumentation such as a dilatation and curettage. (See 'Uterine disorders' above.)
