Evaluation and management 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 thereafter) 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 [1]). 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. The etiologic and diagnostic considerations for oligomenorrhea are the same as for secondary amenorrhea.

The evaluation of secondary amenorrhea and a brief summary of treatment options are reviewed here. The epidemiology and causes of secondary amenorrhea and overviews of primary amenorrhea and abnormal uterine bleeding in adolescents are discussed separately. (See "Epidemiology and causes of secondary amenorrhea" and "Evaluation and management of primary amenorrhea" and "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis".)

INITIAL EVALUATION — Once pregnancy has been ruled out, a logical approach to women with either primary or secondary amenorrhea is to consider disorders based upon the levels of control of the menstrual cycle: hypothalamus, pituitary, ovary, and uterus. Determining the site of the defect is important because it determines the appropriate therapeutic regimen. While the most common causes of secondary amenorrhea are likely to be functional hypothalamic amenorrhea or polycystic ovary syndrome (PCOS), disorders with an anatomic or pathologic cause must be ruled out (algorithm 1) [2,3].

Rule out pregnancy — A pregnancy test is recommended as a first step in evaluating any woman with secondary amenorrhea. Measurement of serum beta subunit of human chorionic gonadotropin (hCG) is the most sensitive test. Commercially available home kits for measurement of hCG in urine are improving, but the clinician who suspects pregnancy should order a serum hCG measurement, even if the woman had a negative home test. (See "Clinical manifestations and diagnosis of early pregnancy", section on 'Types of pregnancy tests'.)

History — The woman should be asked about any past medical history, risk factors, or symptoms that might suggest any of the major causes of secondary amenorrhea or oligomenorrhea (algorithm 1 and table 1). The history should include the following questions:

●Has there been stress, change in weight, diet, or exercise habits, or is there an eating disorder or illness (that might result in functional hypothalamic amenorrhea) [4]? (See "Epidemiology and causes of secondary amenorrhea", section on 'Functional hypothalamic amenorrhea'.)

●Is the woman taking any drugs that might cause or be associated with amenorrhea? The drug may be taken for a systemic illness that itself can cause hypothalamic amenorrhea. Newly initiated or discontinued oral contraceptives can be associated with several months of amenorrhea, as can androgenic drugs like danazol or a high-dose progestin. Other drugs cause amenorrhea by increasing serum prolactin (PRL) concentrations, including metoclopramide and antipsychotic drugs. (See "Causes of hyperprolactinemia".)

●Is there hirsutism, acne, and a history of irregular menses (suggestive of hyperandrogenism)? (See "Clinical manifestations of polycystic ovary syndrome in adults".)

●Are there symptoms of hypothalamic-pituitary disease, including headaches, visual field defects, fatigue, or polyuria and polydipsia? (See "Causes, presentation, and evaluation of sellar masses".)

●Are there any symptoms of estrogen deficiency, including hot flashes, vaginal dryness, poor sleep, or decreased libido? These symptoms may be prominent with primary ovarian insufficiency (POI). In contrast, women with hypothalamic amenorrhea do not usually have these symptoms, despite the presence of similarly low serum estradiol (E2) concentrations. (See "Autoimmune primary ovarian insufficiency (premature ovarian failure)" and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)

●Has the patient had galactorrhea, which suggests hyperprolactinemia?

●Is there a history of obstetrical catastrophe, severe bleeding, dilatation and curettage, or endometritis or other infection that might have caused scarring of the endometrial lining (Asherman syndrome)? (See "Intrauterine adhesions: Clinical manifestation and diagnosis".)

Physical examination — In addition to the medical history, the physical examination may provide clues about the possible cause of amenorrhea (algorithm 1 and table 1). The examination in women with secondary amenorrhea should include measurements of height and weight. A body mass index (BMI) greater than 30 kg/m² is observed in 50 percent or more of women with PCOS, depending on the population studied. Women with a BMI less than 18.5 kg/m² may have functional hypothalamic amenorrhea due to an eating disorder, strenuous exercise, or a systemic illness associated with weight loss. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations".)

The patient should also be examined for hirsutism, acne, striae, acanthosis nigricans, vitiligo, and easy bruisability. Breasts should be examined for evidence of galactorrhea, and a vulvovaginal examination should look for signs of estrogen deficiency. Parotid gland swelling and/or erosion of dental enamel would suggest an eating disorder (bulimia nervosa). (See "Clinical manifestations of polycystic ovary syndrome in adults" and "Bulimia nervosa and binge eating disorder in adults: Medical complications and their management", section on 'Physical examination'.)

Laboratory testing — The initial laboratory evaluation (after ruling out pregnancy) for women with secondary amenorrhea should include follicle-stimulating hormone (FSH), serum PRL, E2, and thyroid-stimulating hormone (TSH) to test for POI, hyperprolactinemia, and thyroid disease, respectively. In women with prolonged amenorrhea, this is measured on a random day. However, if menses occurs, testing is ideally performed on day 3 (although any day between 1 and 5 would be reasonable) (algorithm 1).

The clinical utility of this approach (measuring FSH, PRL, and TSH) was examined in a study of 127 women with adult-onset amenorrhea [5]. High serum FSH concentrations, high PRL, and abnormal TSH were seen in 10, 7.5, and 2.5 percent of patients, respectively, suggesting that this is a reasonable approach to initial testing in women with secondary amenorrhea.

We measure serum E2 as one of the initial tests with serum FSH to evaluate the pituitary-ovarian axis. Low or normal E2 that is associated with an elevated FSH indicates POI, while low or normal E2 associated with FSH that is normal or low suggests the possibility of secondary (pituitary or hypothalamic) hypogonadism, either structural or functional. Interpretation of the serum E2 should also take into account that levels change across the menstrual cycle and it may be variable in women with either early POI or functional hypothalamic amenorrhea (during recovery). In addition, a single sample may not reflect exposure to E2 over weeks. For this reason, E2 status sometimes is assessed by measurement of endometrial thickness on pelvic ultrasound. Although we no longer routinely perform the progestin withdrawal test, in the absence of E2 testing and/or pelvic ultrasound availability, it is a reasonable option. (See 'Assessment of estrogen status' below.)

If there is clinical evidence of hyperandrogenism (hirsutism, acne, scalp hair loss [alopecia]), serum total testosterone should be measured in addition to the initial laboratory tests listed for women without hyperandrogenism. In addition, many measure 17-hydroxyprogesterone at the initial visit to rule out nonclassic 21-hydroxylase deficiency (algorithm 1). (See 'High serum androgens' below and "Evaluation of premenopausal women with hirsutism", section on 'Biochemical testing'.)

ADDITIONAL EVALUATION

Prolactin high — Prolactin (PRL) secretion can be transiently increased by stress, eating, sexual intercourse, and exercise. Therefore, if prolactin is mildly elevated (<50 ng/mL [<50 mcg/L]) we recommend that it be repeated fasting, in the morning, and without exercise before pituitary magnetic resonance imaging (MRI) is ordered. All of these women should be screened for thyroid disease because hypothyroidism can sometimes cause hyperprolactinemia. (See 'Abnormal TSH' below.)

If a mildly elevated serum PRL is confirmed to be high on a second sample, or if the initial sample is >50 ng/mL (>50 mcg/L), a pituitary MRI should be performed unless a very clear explanation is found for the elevation (eg, untreated hypothyroidism or antipsychotic drug use). The goal of imaging is to evaluate the possibility of a hypothalamic or pituitary lesion. In the case of a lactotroph adenoma, the image will allow determination of whether it is a microadenoma or a macroadenoma (≤1 or >1 cm, respectively). (See "Clinical manifestations and evaluation of hyperprolactinemia", section on 'Laboratory/imaging tests'.)

Abnormal TSH — Both hypo- and hyperthyroidism can be associated with oligo- or amenorrhea. A third-generation thyroid-stimulating hormone (TSH) assay is usually all that is needed to diagnose hypo- or hyperthyroidism. The only exception would be in central hypothyroidism, where free thyroxine (T4) and TSH will both be low. In severe eating disorders, a suppressed TSH and free T4 may also be seen.

In some cases of profound hypothyroidism, there may be a slight increase in serum PRL (due to a presumed increase in hypothalamic thyrotropin-releasing hormone [TRH], which stimulates both TSH and PRL secretion) [6]. Treatment of the hypothyroidism restores serum PRL to normal. Therefore, a pituitary MRI should not be performed unless hyperprolactinemia persists after the patient is euthyroid. (See 'Prolactin high' above.)

High serum FSH — A high serum follicle-stimulating hormone (FSH) concentration indicates primary ovarian insufficiency (POI), formerly referred to as premature ovarian failure. It should be kept in mind, however, that intermittent follicular development does occur in women with POI, resulting in transient normalization of serum FSH concentrations. During times of ovarian inactivity and amenorrhea, FSH is high and serum estradiol (E2) is low, similar to what is seen in normal menopause. The presence of hot flashes and/or vaginal dryness is suggestive of POI as these symptoms are uncommon in women with menstrual disturbances due to other causes (algorithm 1). (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)

For patients without an obvious precipitating factor for POI (gonadotoxic chemotherapy or radiotherapy), additional testing to rule out the most common etiologies of POI should be performed, including a karyotype to look for Turner syndrome (including mosaicism). In women with 46,XX spontaneous POI, we also suggest testing for antiadrenal antibodies and the fragile X premutation. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Diagnosis' and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)

Low or normal serum FSH — Women with normal serum PRL and TSH, a low or normal serum follicle-stimulating hormone (FSH) concentration, and no history of uterine instrumentation are likely to have a hypothalamic-pituitary disorder or polycystic ovary syndrome (PCOS). A serum FSH concentration that is low or "normal" is inappropriately low in the presence of a low serum E2 concentration and indicates secondary (hypogonadotropic) hypogonadism. This constellation is one of the most common outcomes of laboratory testing in women with amenorrhea (algorithm 1).

Although we do not recommend measuring serum luteinizing hormone (LH) level as one of our initial laboratory tests, it can be helpful in the occasional patient who has features of both functional hypothalamic amenorrhea and PCOS (eg, amenorrhea with mild hirsutism and/or acne, but normal/low body mass index [BMI] and a history of exercise) [7,8]. Serum FSH concentrations are low or normal in both functional hypothalamic amenorrhea and PCOS. Serum FSH is typically higher than LH in women with functional hypothalamic amenorrhea; in women with PCOS, serum FSH is typically lower than LH. In addition, women with functional hypothalamic amenorrhea are hypoestrogenic, while women with PCOS are typically well estrogenized. (See 'Assessment of estrogen status' below.)

Hypothalamic amenorrhea can also be seen with systemic illness such as celiac disease and type 1 diabetes mellitus. We therefore suggest measurement of fasting blood glucose or glycated hemoglobin (A1C) to rule out diabetes mellitus if the patient has polyuria, polydipsia, and serologic screening for celiac disease with immunoglobulin A antibodies against tissue transglutaminase (tTG-IgA). Other specific tests may be done, depending upon the clinical history. As an example, iron studies to test for hemochromatosis should be performed if there is an appropriate family history or if the patient has manifestations of iron overload (bronzed skin, diabetes mellitus, or unexplained heart or liver disease). (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Diagnosis of celiac disease in children" and "Approach to the patient with suspected iron overload".)

MRI of the sella region is indicated in all women without a clear explanation for hypogonadotropic hypogonadism, such as weight loss, exercise, or stress, and in all women who have normal laboratory findings and symptoms such as visual field defects, headaches, or other signs of hypothalamic-pituitary dysfunction. In contrast, no further testing is required if the onset of amenorrhea occurred recently or is easily explained and there are no symptoms suggestive of other disease (algorithm 1). (See "Epidemiology and causes of secondary amenorrhea".)

Assessment of estrogen status — An assessment of estrogen status should be done in some cases to help with interpreting the FSH values and in others to help guide therapy (eg, hypoestrogenic patients need estrogen therapy for prevention of bone loss, while those making estrogen need endometrial protection with progesterone).

Some clinicians use endometrial thickness on pelvic ultrasound (<4 mm is consistent with hypoestrogenism), but this is not performed routinely [9,10].

Serum E2 measurements can also be used to assess estrogen status, as described above. (See 'Laboratory testing' above.)

High serum androgens — Depending upon the clinical picture, a high serum androgen value may be consistent with the diagnosis of PCOS, or if it is extremely high, it may raise the question of an androgen-secreting tumor of the ovary or adrenal gland. Of note, many women with PCOS present with hyperandrogenism (acne, hirsutism) without hyperandrogenemia (algorithm 1). (See "Clinical manifestations of polycystic ovary syndrome in adults" and "Diagnosis of polycystic ovary syndrome in adults", section on 'Diagnosis'.)

Androgen-secreting tumors are typically associated with the rapid onset of virilizing symptoms and, in some adrenal cases, with glucocorticoid excess. Most clinicians initiate evaluation for a tumor if the serum concentration of testosterone is greater than 150 to 200 ng/dL (5.2 to 6.9 nmol/L). This topic is discussed in detail separately. (See "Evaluation of premenopausal women with hirsutism", section on 'Biochemical testing' and "Evaluation of premenopausal women with hirsutism", section on 'Additional evaluation for severe hyperandrogenemia'.)

Normal laboratory results and history of uterine instrumentation — Women with normal laboratory results and a history of uterine instrumentation should be evaluated for intrauterine adhesions (Asherman syndrome). One approach that many clinicians use is to start with a progestin challenge (medroxyprogesterone acetate 10 mg for 10 days). If withdrawal bleeding occurs, an outflow tract disorder has been ruled out.

If bleeding does not occur, estrogen and progestin may be administered. The endometrium may be primed with estradiol 1 mg/day or transdermal estradiol 0.05 mg/day patch twice weekly for 35 days. A progestin is then added from days 26 to 35 (typically medroxyprogesterone 10 mg/day). Failure to bleed upon cessation of this therapy strongly suggests endometrial scarring. In this situation, a hysterosalpingogram or direct visualization of the endometrial cavity with a hysteroscope can confirm the diagnosis of intrauterine adhesions (algorithm 1). (See "Intrauterine adhesions: Clinical manifestation and diagnosis".)

MANAGEMENT

Goals — The overall goals of management in women with secondary amenorrhea include:

●Correcting the underlying pathology, if possible

●Helping the woman to achieve fertility, if desired

●Preventing complications of the disease process (eg, estrogen replacement to prevent osteoporosis); or in polycystic ovary syndrome (PCOS), management of obesity, hirsutism, oligomenorrhea, and metabolic disorders

A brief summary of treatment options is presented here. More detailed discussions are found separately.

Functional hypothalamic amenorrhea

●Lifestyle changes – For many athletic women, explaining the need for adequate caloric intake to match energy expenditure sometimes results in increased caloric intake or reduced exercise, followed by resumption of menses. However, many women are reluctant to modify their behaviors. (See "Functional hypothalamic amenorrhea: Evaluation and management", section on 'Weight gain/lifestyle changes'.)

Nonathletic women who are underweight or who appear to have nutritional deficiencies should have nutritional counseling, and they can be referred to a multidisciplinary team specializing in the assessment and treatment of individuals with eating disorders. (See "Eating disorders: Overview of prevention and treatment".)

●Cognitive behavioral therapy – Cognitive behavioral therapy (CBT) may be effective for restoring ovulatory cycles in some women.

●Management of low bone density – The effect of estrogen therapy on bone and the approach to women with exercise-associated amenorrhea are discussed separately. An overview of low bone density is also reviewed separately. (See "Functional hypothalamic amenorrhea: Evaluation and management", section on 'Low bone density'.)

Hyperprolactinemia — The management of women with amenorrhea due to hyperprolactinemia depends upon the cause of the hyperprolactinemia and the patient's goals (eg, pursuing fertility or not). This topic is reviewed in detail separately. (See "Management of hyperprolactinemia".)

Primary ovarian insufficiency (premature ovarian failure) — Women with primary ovarian insufficiency (POI) should receive estrogen therapy for prevention of bone loss. This can be either an oral contraceptive (if the patient is having intermittent ovarian function and does not wish to become pregnant) or replacement doses of estrogen and progestin. Regimens for the latter are reviewed separately. (See "Management of primary ovarian insufficiency (premature ovarian failure)".)

Intrauterine adhesions — Therapy of Asherman syndrome (intrauterine adhesions) consists of hysteroscopic lysis of adhesions followed by a course of estrogen treatment to stimulate regrowth of endometrial tissue [11]. (See "Intrauterine adhesions: Clinical manifestation and diagnosis".)

Polycystic ovary syndrome — Treatment of hyperandrogenism is directed toward achieving the woman's goal (eg, relief of hirsutism, resumption of menses, fertility) and preventing the long-term consequences of PCOS, such as endometrial hyperplasia, obesity, and metabolic disorders. For women with PCOS, the type of therapy depends upon whether fertility is desired. (See "Treatment of polycystic ovary syndrome in adults".)

Thyroid disease — The management of thyroid disorders is reviewed separately. (See "Treatment of primary hypothyroidism in adults" and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment".)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Absent or irregular periods (The Basics)")

●Beyond the Basics topics (see "Patient education: Absent or irregular periods (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Secondary amenorrhea is defined as the 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 previously had irregular menses. A stepwise approach to the history, physical examination, and laboratory testing usually results in a specific diagnosis (algorithm 1). (See 'Initial evaluation' above.)

●Initial laboratory evaluation

•Rule out pregnancy – Pregnancy is a common cause of secondary amenorrhea and should be excluded based on a sensitive pregnancy test (human chorionic gonadotropin [hCG]). (See 'Rule out pregnancy' above.)

•Patients without hyperandrogenism – After ruling out pregnancy, initial laboratory testing for women with amenorrhea without hyperandrogenism should include serum prolactin (PRL), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH) to test for hyperprolactinemia, ovarian failure, and thyroid disease, respectively. (See 'Laboratory testing' above.)

We also typically measure serum estradiol (E2) to help with interpreting the FSH values in some patients, and in others to help guide therapy (eg, hypoestrogenic patients need estrogen therapy for prevention of bone loss, while those making estrogen need endometrial protection with progesterone). (See 'Assessment of estrogen status' above.)

•Patients with hyperandrogenism – If there is clinical evidence of hyperandrogenism (hirsutism, acne, scalp hair loss [alopecia]), serum total testosterone should be measured in addition to the initial laboratory tests. (See "Evaluation of premenopausal women with hirsutism", section on 'Hirsutism with oligomenorrhea/amenorrhea' and 'High serum androgens' above.)

●Additional evaluation based upon initial results – Further evaluation depends upon the results of the initial evaluation. Important categories include normal or low serum FSH, high FSH, high serum PRL, normal laboratory results with a history of uterine instrumentation, high serum androgen concentrations, and abnormal TSH. (See 'Additional evaluation' above.)

●Treatment options – Detailed discussions of treatment options for each disorder are found elsewhere. Treatment depends upon the cause of the secondary amenorrhea and the patient's goals. The overall goals of management include (see 'Management' above):

•Correcting the underlying pathology, if possible

•Helping the woman to achieve fertility, when desired

•Preventing complications of the disease process (eg, estrogen replacement to prevent osteoporosis); or in polycystic ovary syndrome (PCOS), management of obesity, hirsutism, oligomenorrhea, and metabolic disorders