Amenorrhea

para>Pregnancy is by far the most common cause of secondary amenorrhea.

EPIDEMIOLOGY

Prevalence

Primary amenorrhea: <1% of female population
Secondary amenorrhea: 3-5% of female population
No evidence for race and ethnicity affecting prevalence

ETIOLOGY AND PATHOPHYSIOLOGY

Primary amenorrhea
- Hypothalamic-pituitary abnormalities
- Constitutional delay of puberty
  - Eating disorder
  - Stress/exercise
  - Central lesions (tumors, hypophysitis, granulomas)
  - Pituitary dysfunction (hyperprolactinemia, abnormal secretion of follicle-stimulating hormone [FSH], luteinizing hormone [LH], or GnRH)
  - Thyroid dysfunction
- Gonadal abnormalities
  - Chromosomal abnormalities (androgen insensitivity syndrome)
  - Euchromosomal gonadal agenesis or dysgenesis (Turner syndrome, Swyer syndrome, and pure gonadal dysgenesis)
  - Polycystic ovarian syndrome (PCOS)
  - Abnormal gonadotropin function
  - Autoimmune gonadal failure
  - Idiopathic gonadal failure
- Anatomic abnormalities
  - Imperforate hymen
  - Transverse vaginal septum
  - Congenital absence of the cervix
  - M ¼llerian agenesis
Secondary amenorrhea
- Pregnancy
- Thyroid disease
- Functional hypothalamic amenorrhea (stress, weight loss, and/or excessive exercise)
- Hyperprolactinemia (altered metabolism, ectopic production, breastfeeding/stimulation, hypothyroidism, medications, empty sella syndrome, pituitary adenoma)
- If pregnancy, thyroid disease, and hyperprolactinemia are ruled out, consider the following:
  - Normogonadotropic amenorrhea: hyperandrogenic anovulation (acromegaly, androgen-secreting tumors, Cushing disease, exogenous androgens, nonclassical congenital adrenal hyperplasia, PCOS); outflow tract obstruction (Asherman syndrome, cervical stenosis, fibroids, polyps)
  - Hypergonadotropic hypogonadism: normal menopause; premature ovarian failure (autoimmune, chemotherapy, galactosemia, fragile X premutation and other genetic causes, 17-hydroxylase deficiency, idiopathic, mumps oophoritis, pelvic radiation)
  - Hypogonadotropic hypogonadism: eating disorders, CNS tumors, chronic illness, cranial radiation, excessive weight loss/exercise/malnutrition, hypothalamic or pituitary destruction, Sheehan syndrome
Pathophysiology varies, depending on etiology.
Primary amenorrhea should be evaluated in the context of presence or absence of secondary sexual characteristics.
Can result from dysfunction in hypothalamic-pituitary-gonadal axis, anatomic abnormalities, or another endocrine gland disorder

Genetics
May occur with Turner syndrome or testicular feminization

RISK FACTORS

Obesity
Overtraining (prolonged, excessive exercise)
Eating disorders
Malnutrition
Anovulatory disorders
Psychosocial crisis
Treatment with antipsychotic medications

GENERAL PREVENTION

Maintenance of proper body mass index (BMI) and healthy lifestyle with respect to food and exercise

COMMONLY ASSOCIATED CONDITIONS

Premature ovarian failure may be associated with autoimmune abnormalities (autoimmune thyroiditis, type 1 diabetes).
PCOS is associated with insulin resistance and obesity.
Decreased exposure to estrogen may increase risk for osteopenia or osteoporosis.

DIAGNOSIS

HISTORY

Review of systems including weight change, symptoms of pregnancy or menopause, virilizing changes, cyclic pelvic pain, galactorrhea, headaches, vision changes, fatigue, palpitations, polyuria/polydipsia
Growth and pubertal development history, including age of breast development, pubertal growth spurt, and adrenarche
History of chronic illness, trauma, surgery, medications, prior chemotherapy or radiation
Psychiatric history
Social history, including diet and exercise history, drug abuse, and sexual history
Family history of delayed or absent puberty

PHYSICAL EXAM

General appearance
Vital signs, height, weight, growth percentile and BMI, hypotension, bradycardia, hypothermia (anorexia nervosa)
HEENT exam: evidence of dental erosions, trauma to palate (bulimia), visual field defect, funduscopic changes, cranial nerve findings (prolactinoma), webbed neck (Turner syndrome), thyromegaly
Skin exam: evidence of androgen excess (acne, hirsutism), acanthosis nigricans (PCOS), fine downy hair on body (anorexia nervosa), striae
Breast: state of development, evidence of galactorrhea (prolactinoma), shield chest (Turner syndrome)
Pelvic exam: presence or absence of pubic hair (if sparse: androgen insensitivity or deficiency); clitoromegaly (androgen excess); distention or bulging of external vagina (imperforate hymen); thin, pale vaginal mucosa without rugae (estrogen deficiency and ovarian failure); presence of cervical mucus (evidence for estrogen production); blind vaginal pouch (m ¼llerian agenesis, androgen insensitivity syndrome); ovarian enlargement (tumors, PCOS, autoimmune oophoritis)

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Primary amenorrhea
- Serum prolactin (PRL) and thyroid-stimulating hormone (TSH)
- If no secondary sexual characteristics, measure serum FSH and LH.
  - FSH/LH <5 IU/L suggests primary hypothalamic or pituitary etiology.
  - FSH >20 and LH >40 IU/L suggests gonadal failure, and karyotype analysis should be performed.
- If secondary sexual characteristics are present, evaluate for anatomic abnormalities. If uterus is absent or abnormal, perform karyotype analysis, testosterone level, and dehydroepiandrosterone sulfate (DHEA-S).
Secondary amenorrhea
- Exclude pregnancy with hCG.
- Serum TSH: Elevated in hypothyroidism, decreased in hyperthyroidism
- Consider (low yield): serum chemistry, CBC, urinalysis to rule out underlying disease
- PRL:
  - >100 ng/mL suggests empty sella syndrome or pituitary adenoma; perform MRI for evaluation.
  - <100 ng/mL: Evaluate for other etiologies, of which medications are most common.
If PRL and TSH are normal, perform progestin challenge (see "Treatment"¯).
- If withdrawal bleed: normogonadotropic amenorrhea related to hyperandrogenic chronic anovulation, most commonly PCOS
- If no withdrawal bleed: Follow up with estradiol priming (see "Diagnostic Procedures/Other"¯ and "Treatment"¯) and repeat progestin challenge:
  - If no bleed: Consider outflow tract obstruction.
  - If bleed occurs: Check FSH/LH: elevated in hypergonadotropic hypogonadism, decreased in pituitary tumors or hypogonadotropic hypogonadism
If virilizing signs and significant acne are present, measure free testosterone, DHEA-S, and 17-OH progesterone levels. Initiate evaluation for androgen-secreting tumor if testosterone >200 ng/dL.
Imaging is not generally indicated as a first approach.
US may show ovarian cysts (PCOS), presence or absence of uterus, and endometrial thickness.
An MRI of the pelvis can clarify any uterine or vaginal anomalies suggested by US or if pediatric patient is unable to tolerate transvaginal US probe.
An MRI of the sella turcica if prolactinoma suspected (elevated PRL >100), and consider with functional hypothalamic amenorrhea (other adenomas)

Follow-Up Tests & Special Considerations

Women <30 years with ovarian failure (see below) should have karyotype analysis and be investigated for premutations of FMR1 gene (fragile X syndrome) and for adrenal antibodies.
If absence of uterus or foreshortened vagina, karyotype analysis should also be performed.
Laparoscopy: diagnosis of streak ovaries (Turner syndrome) or polycystic ovaries
Hysterosalpingogram: Rule out Asherman syndrome and other etiologies of outflow obstruction.

Diagnostic Procedures/Other

If constitutional delay is suspected, obtain bone age.
If hypothalamic amenorrhea from functional suppression is suspected, consider dual-energy x-ray absorptiometry (DEXA) scan to assess bone loss (1).

TREATMENT

GENERAL MEASURES

Treatment depends on the underlying cause.

MEDICATION

Progesterone challenge and replacement: medroxyprogesterone (Provera): 10 mg/day for 10 days will result in withdrawal bleed if hypothalamic-pituitary-gonadal axis is intact although experts disagree (2).
Estrogen replacement: Cycling with a combination oral contraceptive (containing 35 or 50 Ī¼g of estrogen) or conjugated estrogen (Premarin) 0.625 mg for 25 days with progesterone added as above for the last 10 days will result in a withdrawal bleed if the uterus and lower genital tract are normal.
Use of hormonal therapies will not correct the underlying problem. Other drugs might be required to treat specific conditions (e.g., bromocriptine for hyperprolactinemia).
Use of hormonal replacement therapy is not recommended for long-term management of amenorrhea in older women.
- May be safe for symptom management in young women
- Give to maintain secondary sex characteristics and to prevent osteoporosis in adolescents and young women (3)[A].
Combination estrogen/progesterone contraceptives (oral contraceptive pills [OCPs], patch, ring) replace estrogen and prevent pregnancy.
- Have a positive effect on bone mineral density in oligo-/amenorrheic women but not in functional hypothalamic amenorrhea (4)[A]
- Can decrease hirsutism in PCOS
Calcium supplementation: 1,500 mg/day if cause is hypoestrogenism
Because PCOS is related to insulin resistance, metformin (Glucophage) has been used (start at 500 mg BID) to correct metabolic abnormalities, improve ovulation, and restore normal menstrual patterns. Of note, treatment with metformin has shown an increase in clinical pregnancy rates but not in live birth rates (5)[A].
Functional hypothalamic amenorrhea appears to improve with administration of exogenous leptin (still under investigation) (6)[C].
Contraindications to estrogen administration
- Pregnancy, thromboembolic disease, previous myocardial infarct or cerebrovascular accident, estrogen-dependent malignancy, severe hepatic impairment or disease
Precautions
- Patients with amenorrhea who desire pregnancy should not be given hormone replacement therapy but should receive treatment for infertility based on the specific cause.

ISSUES FOR REFERRAL

Many causes of amenorrhea require referral to specialists in ob/gyn, endocrine, surgery, and/or psychiatry.

SURGERY/OTHER PROCEDURES

Hymenectomy for primary amenorrhea if due to imperforate hymen
Lysis of adhesions in Asherman syndrome is often effective in restoring regular menses and fertility.
If karyotype is XY, gonads must be removed due to increased risk of tumors.
Patients with congenital short vagina can undergo surgery to create a functioning vagina.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

If overtraining is suspected, activity level should be reduced by 25-50%.
Patient Monitoring

Depends on the cause and treatment chosen
If hormonal replacement is used, discontinue after 6 months to assess spontaneous resumption of menses.

DIET

Correct overweight or underweight by dietary management and behavior modification.
If PCOS is the etiology, a weight-loss diet will help restore ovulation.

PATIENT EDUCATION

Educate on the circumstances and complications of her condition and its underlying etiology.
Specific educational resources are helpful (e.g., prenatal classes and menopause support groups).
Discuss the expected duration of amenorrhea (temporary or permanent), effect on fertility, and the long-term sequelae of untreated amenorrhea (e.g., osteoporosis, vaginal dryness).
Appropriate contraceptive advice should be given because fertility returns before menses.
Additional support may be needed if the amenorrhea is associated with a reduction in, or loss of, fertility.

PROGNOSIS

Reflects the underlying cause. In functional hypothalamic amenorrhea, one study demonstrated 83% reversal rate in presence of obvious contributing factor.

COMPLICATIONS

Estrogen-deficiency symptoms (e.g., hot flashes, vaginal dryness) and osteoporosis in prolonged hypoestrogenic amenorrhea
Increased risk of endometrial cancer in patients whose amenorrhea is secondary to anovulation with estrogen excess (obesity, PCOS)
Premature ovarian failure may increase cardiovascular risk.

REFERENCES

11 Gordon CM. Clinical practice. Functional hypothalamic amenorrhea. N Engl J Med. 2010;363(4):365-371.22 Klein DA, Poth MA. Amenorrhea: an approach to diagnosis and management. Am Fam Physician. 2013;87(11):781-788.33 Marjoribanks J, Farquhar C, Roberts H, et al. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012;(7):CD004143.44 Liu SL, Lebrun CM. Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review. Br J Sports Med. 2006;40(1):11-24.55 Tang T, Lord JM, Norman RJ, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2012;(5):CD003053.66 Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A. 2011;108(16):6585-6590.

ADDITIONAL READING

Practice Committee of American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2008;90(Suppl 5):S219-S225.
Santoro N. Update in hyper- and hypogonadotropic amenorrhea. J Clin Endocrinol Metab. 2011;96(11):3281-3288.

CODES

ICD10

N91.2 Amenorrhea, unspecified
N91.0 Primary amenorrhea
N91.1 Secondary amenorrhea
E28.8Other ovarian dysfunction

ICD9

626.0Absence of menstruation
256.8Other ovarian dysfunction

SNOMED

14302001Amenorrhea (finding)
8913004Primary physiologic amenorrhea (finding)
86030004Secondary physiologic amenorrhea (finding)
444769001anovulatory amenorrhea (finding)
413487000Amenorrhea associated with obesity (finding)
57260004Dietary amenorrhea (finding)

CLINICAL PEARLS

First evaluate whether amenorrhea is primary or secondary and exclude pregnancy. TSH and PRL are usual first blood tests.
Progestin challenge may cause withdrawal bleed in women with intact hypothalamic-pituitary-gonadal axis.

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