Amenorrhea: A Systematic Approach to Diagnosis and Management

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

Am Fam Physician. 2019;100(1):39-48.

Chronic Disease, Physiologic, and Induced Causes

Patients with chronic disease may experience amenorrhea; however, these conditions are often recognized by individual signs and symptoms. Menopause should be considered in patients older than 40 years.^[15,16,54] Pregnancy, lactation, hormonal contraceptives, and exogenous androgens (e.g., transgender care) may also cause amenorrhea.^[2,3,6]

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This article updates previous articles on this topic by Klein and Poth,³ and Master-Hunter and Heiman.⁵⁵

Data Sources: A PubMed search was completed using the MeSH function with the key phrase amenorrhea and one of the following: diagnosis, evaluation, management, or treatment. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews published after August 1, 2011. Also searched were Essential Evidence Plus, and the Cochrane Database of Systematic Reviews. Search dates: April 18 to July 16, 2018, and January 20, 2019.

The contents of this article are solely the views of the authors and do not necessarily represent the official views of the Uniformed Services University of the Health Sciences, the U.S. Air Force, the U.S. Army, the U.S. Navy, the U.S. military at large, the U.S. Department of Defense, or the U.S. government.

Abstract and Introduction
Evaluation
Differential Diagnosis and Management
Chronic Disease, Physiologic, and Induced Causes
References
Sidebar

Table 1. Select Causes of Amenorrhea*
Outflow tract abnormalities
Acquired
Cervical stenosis
Intrauterine adhesions
Congenital
5α-reductase deficiency
Androgen insensitivity syndrome
Imperforate hymen
Müllerian agenesis
Transverse vaginal septum
Primary ovarian insufficiency
Acquired
Autoimmune
Chemotherapy or radiation
Congenital
Gonadal dysgenesis (other than Turner syndrome)
Turner syndrome or variant
Hypothalamic or pituitary disorders
Autoimmune disease
Brain radiation
Constitutional delay of puberty
Empty sella syndrome
Functional (overall energy deficit or stress)
Eating disorder
Stress
Vigorous exercise
Weight loss
Gonadotropin deficiency (e.g., Kallmann syndrome)
Hyperprolactinemia
Adenoma (prolactinoma)
Chronic kidney disease
Medications or illicit drugs (e.g., antipsychotics, opiates)
Physiologic (pregnancy, stress, exercise)
Infarction (e.g., Sheehan syndrome)
Infiltrative disease (e.g., sarcoidosis)
Infection (e.g., meningitis, tuberculosis)
Medications or illicit drugs (e.g., cocaine)
Trauma or surgery
Tumor (primary or metastatic)
Other endocrine gland disorders
Adrenal insufficiency
Androgen-secreting tumor (e.g., ovarian or adrenal)
Cushing syndrome
Diabetes mellitus, uncontrolled
Late-onset congenital adrenal hyperplasia
Polycystic ovary syndrome (multifactorial)
Thyroid disease
Amenorrhea attributed to chronic disease
Celiac disease
Inflammatory bowel disease
Other chronic disease
Physiologic or induced
Breastfeeding
Contraception
Exogenous androgens
Menopause
Pregnancy

*—Conditions may span multiple categories.
Adapted with permission from Klein DA, Poth MA. Amenorrhea: an approach to diagnosis and management. Am Fam Physician. 2013;87(11):782, with additional information from references 1, 2, 5, 6, and 10–12.

Table 2. Findings in the Evaluation of Amenorrhea
Findings	Associations
History
Chemotherapy or radiation	Impairment of specific organ or structure, (e.g., brain, pituitary, ovary)
Family history of early or delayed menarche	Constitutional delay of puberty
Galactorrhea	Pituitary tumor
Hirsutism, acne	Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome
Illicit or prescription drug useLoss of smell (anosmia)	Multiple associations, consider effect on prolactin
Loss of smell (anosmia)	Kallman syndrome (GnRH deficiency)
Menarche and menstrual history	Primary vs. secondary amenorrhea
Sexual activity	Pregnancy
Significant headaches or vision changes	Central nervous system tumor, empty sella syndrome
Temperature intolerance, palpitations, diarrhea, constipation, tremor, depression, skin changes	Thyroid disease
Vasomotor symptoms (e.g., hot flashes or night sweats)	Primary ovarian insufficiency, natural menopause
Weight loss, excessive exercise, poor nutrition, psychosocial distress, diets	Functional hypothalamic amenorrhea
Physical examination
Abnormal thyroid examination	Thyroid disorder
Acanthosis nigricans or skin tags	Hyperinsulinemia (PCOS)
Anthropomorphic measurements; growth charts	Multiple associations; Turner syndrome, constitutional delay of puberty
Body mass index	High: PCOSLow: Functional hypothalamic amenorrhea
Bradycardia	Functional hypothalamic amenorrhea (e.g., anorexia nervosa)
Breast development (normal progression)	Presence of circulating estrogen*
Dysmorphic features (e.g., webbed neck, short stature, low hairline)	Turner syndrome
Male pattern baldness, increased facial hair, acne	Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome
Pelvic examination
Absence or abnormalities of cervix or uterus	Rare congenital causes including Müllerian agenesis or androgen insensitivity syndrome
Clitoromegaly	Androgen-secreting tumor; CAH; 5α-reductase deficiency
Presence of transverse septum or imperforate hymen	Outflow tract obstruction
Reddened or thin vaginal mucosa	Decreased endogenous estrogen
Sexual maturity rating abnormal	Turner syndrome, constitutional delay of puberty, rare causes
Striae, buffalo hump, central obesity, hypertension	Cushing syndrome

CAH = congenital adrenal hyperplasia; GnRH = gonadotropin-releasing hormone; PCOS = polycystic ovary syndrome.
*—Absence of breast buds may not indicate nonfunctioning ovaries or future functionality.
Adapted with permission from Klein DA, Poth MA. Amenorrhea: an approach to diagnosis and management. Am Fam Physician. 2013;87(11):783, with additional information from references 1, 2, 5, 6, and 10–12.

Table 3. Laboratory and Radiographic Testing in the Evaluation of Amenorrhea
Findings	Associations
Laboratory testing (refer to local reference values)
17-hydroxyprogesterone level (collected at 8 a.m.)	High: late-onset CAH
Anti-Müllerian hormone	High: Functional hypothalamic amenorrhea, PCOSLow: Primary ovarian insufficiency
Complete blood count and metabolic panel	Abnormal: chronic disease (e.g., elevated liver enzymes in functional hypothalamic amenorrhea)
Estradiol	Low: Poor endogenous estrogen production (suggestive of poor current ovarian function)
Follicle-stimulating hormone and luteinizing hormone	High: Primary ovarian insufficiency; Turner syndrome Low: Functional hypothalamic amenorrhea Normal: PCOS; intrauterine adhesions; multiple others
Free and total testosterone; dehydroepiandrosterone sulfate	High: Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome
Karyotype	Abnormal: Turner syndrome, rare chromosomal disorders
Pregnancy test	Positive: Pregnancy, ectopic pregnancy
Prolactin	High: Pituitary adenoma, medications, hypothyroidism, other neoplasm
Thyroid-stimulating hormone	High: Hypothyroidism Low: Hyperthyroidism
Radiographic testing
Dual energy x-ray absorptiometry	Evaluation of fracture risk
MRI of the adrenal glands	Androgen-secreting adrenal tumor
MRI of the brain (including sella)*	Tumor (e.g., microadenoma)
Pelvic organ ultrasonography or magnetic resonance imaging	Morphology of pelvic organs, polycystic ovarian morphology, androgen-secreting ovarian tumor

CAH = congenital adrenal hyperplasia; MRI = magnetic resonance imaging; PCOS = polycystic ovary syndrome.
*—Clinicians may need to specify the need for pituitary (sella) cuts and contrast. Indications for magnetic resonance imaging include severe or persistent headaches, persistent vomiting (not self-induced), lateralizing neurologic signs, clinical signs or laboratory abnormalities to suggest pituitary hormone deficiency or excess, or change in vision, thirst, or urination.2
Information from references 2, 5, 6, and 10–12.

Table 4. Interpretation of Common Laboratory Studies in the Evaluation of Amenorrhea*
	17-OHP	AMH	DHEA-S	ESTRADIOL	LH (IU PER L)	LH/FSH	FSH (IU PER L)	PROLACTIN	TESTOSTERONE	TSH
Congenital adrenal hyperplasia	High	Normal	High normal	Low	< 15	> 1	< 10	Normal	High	Normal
Functional hypothalamic amenorrhea	Normal	High	Normal	Low	< 10†	~ 1	< 10†	Low normal	Low normal	Low normal
Hyperprolactinemia	Normal	Normal	Normal or slightly high	Low	< 10	> 1	< 10	High	Normal	High or normal
Menopause	Normal	Low	Normal	Low	> 15	< 1	> 15	Normal	Low normal	Normal
Polycystic ovary syndrome	Normal	Normal or high	High normal	Low	< 15	> 1	< 10	High normal	High or high normal	Normal
Primary ovarian insufficiency	Normal	Low	Normal	Low	> 15	< 1	> 15	Normal	Low normal	Normal

17-OHP = 17-hydroxyprogesterone; AMH = anti-Müllerian hormone; DHEA-S = dehydroepiandrosterone-sulfate; FSH = follicle-stimulating hormone; LH = luteinizing hormone; TSH = thyroid-stimulating hormone.
*—Clinicians should generally interpret these serum laboratory levels in the context of local reference ranges. Specific ranges for some tests are provided to improve diagnostic accuracy between conditions, but should be interpreted in the appropriate clinical context and per local reference ranges.
†—LH and FSH may be normal in functional hypothalamic amenorrhea.
Adapted with permission from Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(5):1423.

eTable A. The Female Athlete Triad: Proposed Tool to Guide Return to Play Recommendations*
Magnitude of risk
Risk factors	Low risk = 0 points each	Moderate risk = 1 point each	High risk = 2 points each
Low energy availability with or without an eating disorder	No dietary restriction	Some dietary restriction; current or history of disordered eating	Meets DSM-5 criteria for current or history of an eating disorder
Low BMI or expected weight	BMI ≥ 18.5 kg per m², ≥ 90% expected weight, or weight stable	BMI 17.5 kg per m² to < 18.5 kg per m², < 90% expected weight, or 5% to < 10% weight loss per month	BMI ≤ 17.5 kg per m², < 85% expected weight, or ≥ 10% weight loss per month
Delayed menarche	Menarche < 15 years	Menarche 15 to < 16 years	Menarche ≥ 16 years
Oligomenorrhea or amenorrhea (current or history)	> 9 menses in 12 months	6 to 9 menses in 12 months	< 6 menses in 12 months
Low bone mineral density†	Z-score ≥ −1.0	Z-score −1.0 to < −2.0, especially in weight-bearing sports	Z-score ≤ −2.0
Stress reaction/fracture	None	1	2 or more, or 1 high-risk fracture (e.g., trabecular site such as femoral neck, sacrum, or pelvis)
Cumulative risk	# Points +	# Points +	# Points = Total Score

Note: BMI percentile (based on 50th percentile population measurements) is used to calculate expected weight for individuals younger than 20 years. A calculator can be found at: https://www.cdc.gov/healthyweight/bmi/calculator.html.
BMI = body mass index; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, 5th ed.
Full clearance = 0 to 1 point; provisional or limited clearance = 2 to 5 points; restricted from training or competition = 6 or more points.
*—The athlete's overall clinical and psychosocial context should guide application of this proposed decision tool. Athletes with an eating disorder and BMI < 16 kg per m² or an athlete who is purging more than 4 times per week should be categorically restricted from training and participation.
†—Bone density testing is indicated for individuals with 2 or more moderate risk factors or 1 high risk factor. Osteoporosis is defined as a bone mineral density Z-score of −2.0 or less (or −1.0 or less if weight-bearing sport) and a clinically significant stress fracture (5 to 19 years of age) or presence of a secondary cause (20 years or older).
Adapted with permission from De Souza MJ, Nattiv A, Joy E, et al.; Expert Panel. 2014 female athlete triad coalition consensus statement on treatment and return to play of the female athlete triad: 1st international conference held in San Francisco, California, May 2012 and 2nd international conference held in Indianapolis, Indiana, May 2013. Br J Sports Med. 2014;48(4):289.

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Sort: Key Recommendations for Practice

Clinical recommendation	Evidence rating	Comments
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	C	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.^{1–3,6,10–12}	C	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.^36–39	C	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	B	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	C	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	B	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	A	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 series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

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Amenorrhea: A Systematic Approach to Diagnosis and Management

Chronic Disease, Physiologic, and Induced Causes

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