Amenorrhea: A Systematic Approach to Diagnosis and Management

David A. Klein, MD, MPH; Scott L. Paradise, MD; Rachel M. Reeder, MD

Disclosures

Am Fam Physician. 2019;100(1):39-48. 

In This Article

Differential Diagnosis and Management

Outflow Tract Abnormalities

Outflow tract abnormalities are generally associated with 46,XX chromosomal patterns and normal pubertal progression. Müllerian agenesis occurs in approximately one in 5,000 females and in 15% of females diagnosed with primary amenorrhea.[25,26] It is characterized by the abnormal development of reproductive anatomy and is associated with urologic and skeletal malformations.[16,25] Transverse septum and imperforate hymen may present with cyclic pelvic pain. Intrauterine adhesions can occur after endometrial instrumentation and are corrected using hysteroscopy. Cervical stenosis can occur after cervical procedures, radiation, or vaginal birth.[6,27]

Androgen insensitivity syndrome is characterized by the resistance of peripheral tissues to testosterone in patients with 46,XY chromosomal patterns.[28–30] Patients with 5α-reductase deficiency are phenotypic females that develop male secondary sex characteristics at puberty. Both of these rare conditions are confirmed by genetic analysis or enzyme assays.[28] Prophylactic gonadectomy may require evaluation by a pediatric urologist based on malignancy risk and patient or guardian preferences.[31]

Primary Ovarian Insufficiency

Primary ovarian insufficiency affects approximately one in 100 females and is defined by follicle dysfunction or depletion.[10,17,32] It is diagnosed in patients younger than 40 years with two serum follicle-stimulating hormone levels in the menopausal range obtained at least one month apart.[10,17] Vasomotor symptoms and vaginal dryness are common.[10,11]

Most cases are idiopathic; however, irradiation, chemotherapy, infections, tumors, autoimmune processes, and chromosomal irregularities can also cause primary ovarian insufficiency.[10] A karyotype is abnormal in approximately one-third of patients with primary amenorrhea, and it should be offered to all patients with a diagnosis of primary ovarian insufficiency to identify Turner syndrome (or variants).[10,21]

Patients diagnosed with primary ovarian insufficiency should be offered testing for FMR1 gene premutation, which confers the risk of fragile X syndrome in children.[10,11,33,34] Testing for thyroid and adrenal antibodies and annual or biennial screening for hypothyroidism may be considered given how often these conditions coexist.[10,11,35]

Hormone replacement therapy (HRT) may reduce associated vasomotor symptoms, bone mineral density loss, and cardiovascular risk and should be continued until the age of natural menopause (50 to 51 years).[3,20,36–39] A common post-pubertal regimen of HRT is 100 mcg of daily transdermal estradiol or 0.625 mg of daily oral conjugated estrogens, adding 200 mg of micronized oral progesterone daily for 12 days each month.[3,37,38] Transdermal estrogen may be associated with lower venous thromboembolism risk than oral formulations.[40] It is also reasonable to recommend 1,200 mg of calcium daily and 1,000 IU of vitamin D daily with regular weight-bearing exercises to maintain bone mineral density in accordance with guidelines for postmenopausal women.[10,41]

Approximately 10% of females diagnosed with primary ovarian insufficiency retain fertility.[10] HRT may not adequately suppress ovulation; therefore, barrier or intrauterine contraceptives may augment HRT for contraceptive purposes.[10,38,42] Combined hormonal contraceptives may be substituted for HRT to adequately prevent pregnancy and provide the noncontraceptive benefits of HRT; this approach requires higher doses of estrogen, which may confer additional venous thromboembolic risk.[38,43] A primary ovarian insufficiency diagnosis introduces long-term challenges for patients and families. Clinicians should offer ample time, sensitivity, and emotional support to the patient.[11]

Hypothalamic and Pituitary Causes

Functional Hypothalamic Amenorrhea. Functional hypothalamic amenorrhea is a disorder of chronic anovulation caused by suppression of the hypothalamic-pituitary axis from body weight loss, excessive exercise, or stress and may result in infertility or bone density loss.[2,44–46] The pathology is similar to the female athlete triad; both are characterized by menstrual dysfunction, low energy availability, and decreased bone mineral density.[2,22,46] Although functional hypothalamic amenorrhea is a diagnosis of exclusion, evaluation typically reveals low or low-normal serum-luteinizing hormone and follicle-stimulating hormone levels and low serum estradiol.[2] Bone mineral density testing should be considered after six months of amenorrhea, severe nutritional deficit, or history of stress fracture.[2,22]

Treatment should correct the underlying cause to restore ovulatory function through behavior change, nutritional repletion (e.g., caloric intake, vitamin D), stress reduction, and weight gain.[2,22,46]A multidisciplinary team including a clinician, nutritionist or registered dietician, and therapist may be optimal.[2,22] Patients with severe bradycardia, hypotension, orthostasis, or electrolyte abnormalities may require inpatient treatment.[2] A return to play tool to guide recommendations for athletes is provided in eTable A.

Combined oral contraceptives have not been shown to improve bone density; however, after a reasonable trial of nonpharmacologic therapy (i.e., six to 12 months), clinicians may recommend short-term use of transdermal 17β-estradiol (e.g., 100-mcg patch if bone age is 15 years or older) and cyclic oral progestin (e.g., medroxyprogesterone, 2.5 mg daily, 10 days per month) for this purpose as it avoids first-pass liver metabolism.[2,46–48] Hormonal contraceptives may mask underlying pathology but should be considered for patients at risk of pregnancy because ovulation may precede menstruation.[2] The Endocrine Society recommends against bisphosphonate use in this population.[2]

Hyperprolactinemia. Elevated serum prolactin may induce amenorrhea by inhibiting gonadotrophs. Common causes include medication use (e.g., antipsychotics), pregnancy, and pituitary adenoma.[13,14] Most patients with elevated serum prolactin will require MRI of the pituitary unless prolactin levels collected at least three days after discontinuing inciting medications have normalized.[14] The risk of withdrawing medications (e.g., psychosis) may exceed the benefits (e.g., bone health).[14] Symptomatic prolactinomas may be treated with dopamine agonists or resection.[13,14]

Other Central Nervous System Causes. Amenorrhea may be caused by hypothalamic-pituitary axis damage through inflammation, ischemia, infiltration, infection, or trauma. Disorders affecting pubertal development, including gonadotropin-releasing hormone deficiency and constitutional delay, have been described previously in American Family Physician.[5]

Other Endocrine Causes

Polycystic Ovary Syndrome. PCOS is a multifactorial endocrine disorder characterized by ovulatory dysfunction, biochemical or clinical androgen access, and polycystic ovaries.[6,8,12,49] The Rotterdam Consensus Criteria require two of the aforementioned features for diagnosis; the Androgen Excess Society requires hyperandrogenism and another feature.[8,12,49] Pelvic ultrasonography is not required for diagnosis.[8,49,50] Diagnostic accuracy in adolescence is challenging because anovulation and polycystic ovarian morphology can be physiologic; therefore, hyperandrogenism and persistent oligomenorrhea are key to diagnosis.[8,49] Benefits of early management may outweigh risks of delay for diagnostic certainty.[8,49]

Markedly elevated serum androgens could indicate other hyperandrogenic conditions, but strict cut-offs are not defined.[2,12,49] PCOS is associated with metabolic syndrome and insulin resistance. Patients should be screened for hypertension and an elevated body mass index at each visit, and should be screened for dyslipidemia and impaired glucose tolerance (i.e., two-hour oral glucose tolerance testing [preferred] or A1C level) every three to five years.[12,49–51]

Healthy eating habits and regular exercise should be recommended for all patients with PCOS. Weight loss may restore regular menses and improve metabolic comorbidities in patients with an elevated body mass index.[12,49,50] Combined hormonal contraceptives are first-line therapy for menstrual abnormalities, hirsutism, acne, and protection from endometrial cancer caused by unopposed estrogen secretion.[12,14,49,50] Metformin may prevent diabetes mellitus and regulate menses, and it may be appropriate for patients with impaired glucose tolerance when lifestyle modification is unsuccessful or for those with contraindications to applicable contraceptives.[12,49]Metformin is ineffective for treating acne or hirsutism.[15,49]For patients with PCOS and infertility, letrozole (Femara) is a first-line therapeutic option, because it confers higher ovulation, pregnancy, and live birth rates than clomiphene.[12,50,52]

Thyroid and Adrenal Disease. Hypo- and hyperthyroidism may cause amenorrhea.[2,6,12] Late-onset congenital adrenal hyperplasia (e.g., 21-hydroxylase deficiency) is a common cause of hyperandrogenic amenorrhea; an elevated serum 17-hydroxyprogesterone level should be followed by confirmatory adrenocorticotropic hormone stimulation testing.[12,49,53] Adrenal or ovarian androgen-secreting tumors are exceedingly rare but should be considered in patients with rapid-onset virilization or markedly elevated serum androgens.[3,12,49] If physical stigmata of cortisol excess are present, Cushing syndrome may be excluded by a 24-hour urinary free cortisol, late-night salivary cortisol, or dexamethasone suppression test.[2,12,49]

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