Amenorrhea: A Systematic Approach to Diagnosis and Management

Key points

• Primary amenorrhea should be evaluated if menarche has not occurred by 15 years of age or three years after thelarche. Secondary amenorrhea is the cessation of regular menses for three months or of irregular menses for six months.
• Pregnancy should be excluded in all patients, and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin and thyroid-stimulating hormone (TSH) levels should be obtained.
• Causes are grouped as outflow tract abnormalities, primary ovarian insufficiency, hypothalamic or pituitary disorders, other endocrine gland disorders, sequelae of chronic disease, and physiologic or induced causes.
• Primary ovarian insufficiency affects approximately one in 100 females and is treated with hormone therapy until the age of natural menopause (50 to 51 years).
• In functional hypothalamic amenorrhea, treatment corrects the underlying cause, and combined oral contraceptives do not improve bone density.

Overview

Amenorrhea is the absence of menses and can signal many underlying conditions, from pregnancy to ovarian, pituitary, endocrine or anatomic disorders. A systematic approach starts with a history, examination and a pregnancy test, followed by the hormone tests above, and treatment addresses the underlying cause. This American Family Physician review updates earlier articles on the topic and rates its key recommendations with the SORT system, mostly as consensus-based (rating C).

Definitions and evaluation

Oligomenorrhea is the lack of menstruation for intervals longer than 35 days in adults or 45 days in adolescents, and cycle intervals are typically 21 to 34 days. The history covers menstrual patterns, pregnancy and breastfeeding, eating and exercise habits, psychosocial stressors, weight changes, fractures, medicines and substances, chronic illness and the timing of breast and pubic hair development. Galactorrhea, headaches or visual field defects suggest hypothalamic or pituitary disease, acne or hirsutism suggest hyperandrogenism, and hot flashes or night sweats suggest primary ovarian insufficiency. The examination reviews trends in height, weight and body mass index and looks for signs of estrogen exposure, virilization or a congenital syndrome.

Tests

All patients are offered a pregnancy test and FSH, LH, prolactin and TSH levels, which identify most endocrine causes. Free and total testosterone and dehydroepiandrosterone sulfate are checked if hyperandrogenism is suspected, an 8 a.m. 17-hydroxyprogesterone level assesses late-onset congenital adrenal hyperplasia, and a low anti-Müllerian hormone level correlates with low ovarian reserve. Karyotyping is considered in patients of short stature to look for Turner syndrome. Pelvic ultrasonography or MRI can show abnormal anatomy or an androgen-secreting tumour, brain MRI can identify pituitary tumours and dual energy x-ray absorptiometry can establish baseline fracture risk.

Main causes and management

Outflow tract abnormalities include Müllerian agenesis (about one in 5,000 females and 15% of those diagnosed with primary amenorrhea), transverse septum, imperforate hymen, intrauterine adhesions and androgen insensitivity syndrome. Primary ovarian insufficiency is diagnosed in patients younger than 40 years with two FSH levels in the menopausal range at least one month apart. A karyotype is offered to all of them, testing for the FMR1 premutation is offered, and hormone therapy is continued until the age of natural menopause. Calcium 1,200 mg and vitamin D 1,000 IU daily with weight-bearing exercise are also reasonable, and about 10% of patients retain fertility, so contraception may be needed. Functional hypothalamic amenorrhea results from weight loss, excessive exercise or stress and typically shows low or low-normal LH and FSH with low estradiol. Bone density testing is considered after six months of amenorrhea, a severe nutritional deficit or a stress fracture, and the Endocrine Society recommends against bisphosphonates. Hyperprolactinemia usually needs a pituitary MRI unless prolactin normalises at least three days after stopping the causative medicine, and symptomatic prolactinomas are treated with dopamine agonists or resection.

Polycystic ovary syndrome

PCOS is diagnosed by the Rotterdam criteria (two of ovulatory dysfunction, androgen excess and polycystic ovaries), and ultrasonography is not required. In adolescence, hyperandrogenism and persistent oligomenorrhea are key to diagnosis. Patients should be screened for hypertension and raised BMI at each visit and for dyslipidemia and impaired glucose tolerance every three to five years. Weight loss and regular exercise may restore regular menses, and combined hormonal contraceptives are first-line for menstrual abnormalities, hirsutism, acne and protection from endometrial cancer. Metformin may suit selected patients but is ineffective for acne or hirsutism. For infertility, letrozole is first-line because it gives higher ovulation, pregnancy and live birth rates than clomiphene.

Frequently asked questions

When should amenorrhea be evaluated?

Primary amenorrhea needs evaluation if menarche has not occurred by 15 years of age or three years after thelarche, and secondary amenorrhea after three months without previously regular menses or six months without previously irregular menses.

Which tests come first?

A pregnancy test and serum FSH, LH, prolactin and TSH levels, with further testing individualised.

How is primary ovarian insufficiency treated?

With hormone therapy until the age of natural menopause (50 to 51 years) to reduce the risk of osteoporosis, cardiovascular disease and urogenital atrophy, with contraception or fertility advice as needed.

Source

Klein DA, Paradise SL, Reeder RM. Amenorrhea: A Systematic Approach to Diagnosis and Management. American Family Physician 2019;100(1):39-48. This page is a summary prepared by Medpresso from the original publication. It is not a substitute for the full text or for medical advice.