Epidemiology and causes of secondary amenorrhea

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 females who previously had regular menstrual cycles or six months in females 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 females 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. An overview of the normal menstrual cycle, evaluation and management of secondary amenorrhea, and the causes, evaluation, and management of primary amenorrhea are discussed separately. (See "Normal menstrual cycle" and "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 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 females 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 female 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, absence of normal follicular development, absent midcycle surges in luteinizing hormone (LH) secretion, 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 females.

One of the main clinical concerns in females 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 females with functional hypothalamic amenorrhea, no obvious precipitating factor is evident. The term hypothalamic amenorrhea is often used interchangeably with functional hypothalamic amenorrhea (FHA). FHA is reviewed in detail separately. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Functional hypothalamic amenorrhea: Evaluation and management".)

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 females 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 '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 disease)", section on 'Autoimmune adrenalitis'.)

Type 1 diabetes mellitus — Adolescent females 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 [11]. Even in well-controlled adults with type 1 diabetes mellitus, the prevalence of amenorrhea is 20 percent [12]. (See "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Miscellaneous'.)

Type 2 diabetes in adolescent females 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 females with untreated celiac disease have menstrual cycle disorders [13]. Other reproductive problems in these females 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 females. As a result, serum prolactin should be measured in every female with amenorrhea. The normal range should be consulted for the prolactin assay used, as the upper limit of normal for females 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 females with borderline high values (<50 ng/mL [<50 mcg/L]). The causes, clinical manifestations, and evaluation of hyperprolactinemia are reviewed in detail separately. (See "Causes of hyperprolactinemia" and "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 females with thyroid disease. This was illustrated in a report of over 1000 females with a thyroid disorder [14]. Menstrual disturbances were common in females with hypothyroidism (35 and 10 percent for severe and mild-moderate hypothyroidism, respectively) [14] (see "Clinical manifestations of hypothyroidism", section on 'Reproductive abnormalities'). In females 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 [15]. 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 [16,17]. (See "Clinical manifestations of hypothyroidism", section on 'Reproductive abnormalities'.)

Polycystic ovary syndrome — PCOS, the most common reproductive disorder in females, 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 females with PCOS are overweight or obese and have insulin resistance. Females with PCOS may present with amenorrhea, but they more commonly have irregular menses (oligomenorrhea). PCOS is reviewed in detail separately. (See "Clinical manifestations of polycystic ovary syndrome in adults" and "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 [18,19]. 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 females 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 [20]. (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 – Pregnancy is the most common cause of secondary amenorrhea. (See 'Pregnancy' above.)

●Epidemiology – Aside from pregnancy, the 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 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)

●Hypothalamic and pituitary disorders – A number of hypothalamic or pituitary disorders can result in secondary amenorrhea, including:

•Functional hypothalamic amenorrhea – Functional hypothalamic amenorrhea or functional hypothalamic gonadotropin-releasing hormone (GnRH) deficiency, which by definition excludes pathologic disease. One of the main clinical concerns in females 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 – 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 – Hyperprolactinemia, most commonly due to lactotroph adenomas (prolactinomas). (See 'Hyperprolactinemia' above.)

●Ovarian disorders – Ovarian disorders that may result in secondary amenorrhea include:

•PCOS – PCOS, one of the most common endocrine disorders in females. 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. Females with PCOS may present with amenorrhea, but they more commonly have irregular menses (oligomenorrhea). (See 'Polycystic ovary syndrome' above.)

•POI – 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.)

●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. (See 'Uterine disorders' above.)