Amenorrhea: A Systematic Approach to Diagnosis and Management


Menstrual patterns can be an indicator of overall health and self-perception of well-being. Primary amenorrhea, defined as the lifelong absence of menses, requires evaluation if menarche has not occurred by 15 years of age or three years post-thelarche. Secondary amenorrhea is characterized by cessation of previously regular menses for three months or previously irregular menses for six months and warrants evaluation. Clinicians may consider etiologies of amenorrhea categorically as outflow tract abnormalities, primary ovarian insufficiency, hypothalamic or pituitary disorders, other endocrine gland disorders, sequelae of chronic disease, physiologic, or induced. The history should include menstrual onset and patterns, eating and exercise habits, presence of psychosocial stressors, body weight changes, medication use, galactorrhea, and chronic illness. Additional questions may target neurologic, vasomotor, hyperandrogenic, or thyroid-related symptoms. The physical examination should identify anthropometric and pubertal development trends. All patients should be offered a pregnancy test and assessment of serum follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone levels. Additional testing, including karyotyping, serum androgen evaluation, and pelvic or brain imaging, should be individualized. Patients with primary ovarian insufficiency can maintain unpredictable ovary function and may require hormone replacement therapy, contraception, or infertility services. Functional hypothalamic amenorrhea may indicate disordered eating and low bone density. Treatment should address the underlying cause. Patients with polycystic ovary syndrome should undergo screening and intervention to attenuate metabolic disease and endometrial cancer risk. Amenorrhea can be associated with clinically challenging pathology and may require lifelong treatment. Patients will benefit from ample time with the clinician, sensitivity, and emotional support.

Menstrual patterns can be an indicator of overall health status and self-perception of well-being.1,2 A broad differential is important to avoid missing rare or emergent pathology because many underlying conditions can present as amenorrhea.3 Primary amenorrhea is the lifelong absence of menses.3 Evaluation should be considered if menarche has not occurred by 15 years of age or three years post-thelarche.1,4 Lack of any pubertal development by 13 years of age should prompt investigation for delayed puberty.4,5

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Clinical recommendationEvidence ratingComments

Patients who have not reached menarche by 15 years of age (or three years post-thelarche), or who have experienced cessation of regular menses for three months or previously irregular menses for six months, should be evaluated.1,3,4,6


Recommendation from consensus guidelines

Pregnancy should be excluded in all patients with amenorrhea, and serum follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone levels should be obtained.13,6,1012


Recommendation from consensus guidelines

Patients with primary ovarian insufficiency should be treated with hormone therapy until the age of natural menopause (50 to 51 years of age) to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy.3639


Recommendation from consensus guideline based on observational studies and a randomized controlled trial

In patients with functional hypothalamic amenorrhea, 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


Recommendations from consensus guideline based on observational studies

In patients with functional hypothalamic amenorrhea, combined oral contraceptives do not improve bone density and should not be used solely for this purpose.2,22,47,48


Recommendations from consensus guideline based on a randomized controlled trial (disease-oriented outcome) and a systematic review of observational studies

In patients with polycystic ovary syndrome and an elevated body mass index, weight loss and regular exercise are recommended and may restore regular menses and improve metabolic comorbidities.12,49,50


Recommendation from consensus guidelines based on observational studies and randomized controlled trials

In patients with polycystic ovary syndrome and infertility, letrozole (Femara) is a first-line treatment because it confers higher ovulation, pregnancy, and live birth rates than clomiphene.12,50,52


Recommendation from consensus guidelines based on meta-analysis of randomized trials

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case

The Authors

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DAVID A. KLEIN, MD, MPH, is an associate program director of the National Capital Consortium Family Medicine Residency Program at Fort Belvoir (Va.) Community Hospital and an assistant professor in the Departments of Family Medicine and Pediatrics at the Uniformed Services University of the Health Sciences, Bethesda, Md....

SCOTT L. PARADISE, MD, is a third-year resident in the National Capital Consortium Family Medicine Residency Program at Fort Belvoir Community Hospital.

RACHEL M. REEDER, MD, is a third-year resident in the National Capital Consortium Family Medicine Residency Program at Fort Belvoir Community Hospital.

Address correspondence to David A. Klein, MD, MPH, Fort Belvoir Community Hospital, 9300 DeWitt Loop, Fort Belvoir, VA 22060 (e-mail: Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.


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