Evaluation and Management of Amenorrhea

Initial Laboratory Workup

• The initial laboratory workup for amenorrhea should include a hormone panel with LH and FSH levels, estradiol, prolactin, TSH, and free T4, as well as total and free testosterone, and anti-Müllerian hormone to assess ovarian reserve, according to the Human Reproduction Update 1
• A pregnancy test should be performed as the first step in all cases of secondary amenorrhea, followed by a hormone panel ideally collected between days 3-6 of the cycle if cycling 1
• The LH/FSH ratio >2 suggests polycystic ovary syndrome (PCOS), and elevated levels of total and free testosterone >2.5 nmol/L suggest hyperandrogenism 1, 2
• Thyroid function tests, including TSH and free T4, should be performed to rule out thyroid dysfunction 3
• Testosterone (total and free) levels should be measured, with elevated levels (>2.5 nmol/L) suggesting hyperandrogenism, common in PCOS or with valproate use 2
• Androstenedione levels should be measured, with levels >10.0 nmol/L warranting investigation for adrenal/ovarian tumors 2
• DHEAS (Dehydroepiandrosterone sulfate) levels should be measured, with age-specific reference ranges, and elevated levels may indicate adrenal hyperplasia or tumors 2
• Glucose/insulin measurements should be performed, with fasting glucose >7.8 mmol/L suggesting diabetes, and glucose/insulin ratio >4 suggesting reduced insulin sensitivity, common in PCOS and obesity 2

Diagnostic Criteria

• Elevated FSH/LH (>40 mIU/mL) suggests primary ovarian insufficiency, and consideration of karyotype testing to rule out Turner syndrome is recommended, as stated in the Journal of Clinical Oncology 4
• Low/normal FSH and LH with elevated prolactin requires evaluation for prolactinoma, medication effects, or hypothyroidism, while normal prolactin levels suggest functional hypothalamic amenorrhea (FHA) 1
• Normal FSH/LH with LH/FSH ratio >2 suggests PCOS, and checking androgens and insulin resistance markers, as well as evaluating for polycystic ovarian morphology on ultrasound, is necessary 1, 2
• Progesterone levels <6 nmol/L in the mid-luteal phase indicate anovulation 2
• Polycystic ovary syndrome (PCOS) is characterized by LH/FSH ratio >2, elevated androgens (testosterone, androstenedione), polycystic ovaries on ultrasound, normal to high estrogen levels, and insulin resistance common 2, 5
• Functional hypothalamic amenorrhea is characterized by low or normal LH and FSH, normal to low androgens, history of weight loss, excessive exercise, or stress, low estrogen levels, and normal insulin sensitivity 1
• Hyperprolactinemia is characterized by elevated prolactin levels, normal or low gonadotropins, and consideration of medication effects, pituitary tumors, or hypothyroidism 2
• Hypothyroidism or hyperthyroidism can cause menstrual irregularities, diagnosed by abnormal TSH and free T4 levels 6

Imaging Studies

• Pelvic ultrasonography should be performed to evaluate for polycystic ovaries, endometrial abnormalities, and structural pathologies 2, 7
• Transvaginal ultrasound is more sensitive than transabdominal for identifying structural abnormalities, and can be used to evaluate for polycystic ovaries, endometrial abnormalities, and structural pathologies 2, 7
• MRI should be considered if ultrasound is inconclusive, and can visualize the endometrium even in the presence of leiomyomas and adenomyosis 7
• Pituitary MRI should be considered if clinical features or laboratory results suggest hypothalamic-pituitary abnormality 2

Progesterone Challenge Test

• The progesterone challenge test helps determine estrogen status and endometrial responsiveness, using medroxyprogesterone acetate 10 mg orally twice daily for 5-10 days, as a standard dosage 1
• Withdrawal bleeding occurs in approximately 93% of women with adequate estrogen levels and responsive endometrium, and typically occurs within 2-7 days after completing the course 1

Therapeutic Management

• For therapeutic management of amenorrhea when withdrawal bleeding is desired, addressing underlying energy balance issues before hormonal therapy is necessary for functional hypothalamic amenorrhea 1
• Patients with PCOS may require combined hormonal contraceptives for cycle regulation, while those with hyperprolactinemia require treatment of the underlying cause (medication adjustment, prolactinoma treatment) 1, 2
• Primary ovarian insufficiency patients can maintain unpredictable ovarian function and should not be presumed infertile, according to the Human Reproduction Update 1
• Treatment should be directed at the underlying cause, with combined hormonal contraceptives recommended for PCOS to regulate cycles, and progesterone therapy used to induce withdrawal bleeding 8
• For functional hypothalamic amenorrhea, addressing energy balance issues and considering nutritional counseling is recommended 9
• For hyperprolactinemia, identifying and treating the underlying cause, such as medication adjustment or treatment of pituitary tumor, is recommended 2

Common Pitfalls

• Failing to rule out pregnancy before initiating workup, missing functional hypothalamic amenorrhea in normal-weight women, and confusing isolated polycystic ovarian morphology with PCOS are common pitfalls to avoid, as stated in the Human Reproduction Update 1
• Not considering medication effects (antiepileptics, hormonal contraceptives, antipsychotics) is also a common mistake, and should be taken into account during the evaluation and management of amenorrhea 2, 6
• Failing to distinguish between isolated polycystic ovaries and PCOS, as polycystic ovaries occur in 17-22% of the general female population, and PCOS requires additional clinical or biochemical features 2
• Missing functional hypothalamic amenorrhea in normal-weight women, which can occur without obvious weight loss if energy expenditure exceeds intake 10, 1
• Low energy availability (LEA) states are common in female athletes, with a prevalence of 6-45%, and can cause disruptions of LH pulsatility and menstrual dysfunction 9
• BMI <18.5 kg/m² suggests energy deficiency, and recent weight loss >10% in 1 month is a high-risk factor 10
• Oligomenorrhea is defined as menstrual cycles occurring at intervals greater than 35 days, with a comprehensive hormone panel and targeted laboratory testing recommended to identify the underlying cause, particularly focusing on ruling out polycystic ovary syndrome (PCOS), thyroid dysfunction, hyperprolactinemia, and functional hypothalamic amenorrhea 2
• In adolescents, oligomenorrhea may be normal in the first 2-3 years post-menarche, while in women >35, perimenopause should be considered 10
• Antiepileptics (particularly valproate) can cause reproductive dysfunction, and hormonal contraceptives, antipsychotics, and other medications can affect menstrual cycles 2, 6