Amenorrhea, Secondary & Menopause

Essentials of Diagnosis

• Secondary amenorrhea: absence of menses for 3 consecutive months in women who have passed menarche

• Menopause: termination of naturally occurring menses; usually diagnosed after 12 months of amenorrhea

General Considerations

Causes of secondary amenorrhea

• High human chorionic gonadotropin (hCG)

  • Pregnancy most common cause

  • Rarely caused by ectopic secretion of hCG by choriocarcinoma or bronchogenic carcinoma

• Hypothalamic-pituitary causes (low-normal follicle-stimulating hormone [FSH])

• "Hypothalamic amenorrhea"

  • Idiopathic

  • Stress

  • Strict dieting

  • Vigorous exercise

  • Organic illness

  • Anorexia nervosa

• Hyperprolactinemia, pituitary tumors, and corticosteroid excess can suppress gonadotropins

• Hyperandrogenism (low-normal FSH)

  • Polycystic ovarian syndrome

  • Use of anabolic steroids

  • Rarely caused by

    • Adrenal P-450c21 deficiency

    • Ovarian or adrenal malignancy

    • Cushing disease

• Endometritis (normal FSH)

  • Scarring (Asherman syndrome) occurring spontaneously

  • Following delivery or D&C

  • Tuberculosis or schistosomiasis in endemic areas

• Early and premature menopause (high FSH) (primary ovarian failure before age 45)

  • Autoimmune

  • XO/XX chromosome mosaicism

  • Bilateral oophorectomy

  • Pelvic radiation therapy

  • Chemotherapy

  • Frequently familial

  • Additional causes

    • Myotonic dystrophy

    • Galactosemia

    • Mumps oophoritis

• Normal menopause (high FSH) (primary ovarian failure after age 45)

Demographics

• Normal age of menopause in the United States is 48–55 years (average 51.5 years)

Symptoms and Signs

• Vasomotor symptoms (hot flushes)

  • Experienced by 60–80% of women

  • May last seconds to many minutes

  • Severity varies; may be most severe at night

  • Median duration of moderate-to-severe hot flushes is about 10 years; tend to continue longer in thin versus obese women and in black versus white women

• Sleep disturbances, fatigue, insomnia, headache, diminished libido, or joint pains

• Depression and irritability

• Urogenital atrophy with vaginal dryness and dyspareunia

• Some women report mild cognitive impairment, which may be related to decreased cerebral blood flow noted in hypogonadal women, particularly during hot flushes

• Increased bone osteoclastic activity increases the risk for osteoporosis and fractures

• Skin becomes more wrinkled

• Increases in the LDL:HDL cholesterol ratio cause an increased risk for atherosclerosis

• Perform pelvic examination to check for uterine or adnexal enlargement

Differential Diagnosis

• Pregnancy

• Menopause or perimenopause

• Polycystic ovary syndrome

• Hypothalamic amenorrhea, eg, stress, weight change, exercise

• Hyperprolactinemia

• Hypothyroidism or hyperthyroidism

• Diabetes mellitus

• Premature ovarian failure

• Anorexia nervosa

Laboratory Tests

Premature amenorrhea

• An elevated hCG indicates pregnancy

• Laboratory evaluation for nonpregnant women includes

  • Serum prolactin

  • Follicle-stimulating hormone, luteinizing hormone (both elevated in menopause)

  • Thyroid-stimulating hormone

• Routine testing of kidney and liver function (blood urea nitrogen, serum creatinine, bilirubin, alkaline phosphatase, and alanine aminotransferase) is also performed

• A serum testosterone level is obtained in hirsute or virilized women

• Patients with manifestations of hypercortisolism receive a 1-mg overnight dexamethasone suppression test for initial screening

Typical menopause

• No laboratory testing when amenorrhea occurs at the expected age

• An elevated serum FSH with a low or low-normal serum estradiol helps confirm the diagnosis

Imaging Studies

• Hyperprolactinemia or hypopituitarism without obvious cause should prompt pituitary MRI (see Hypopituitarism)

Medications

• Selective serotonin receptor inhibitors (SSRIs)

  • May offer modest relief for women with severe hot flushes who cannot take estrogen

  • Effective within a week

  • Escitalopram (10–20 mg orally daily)

    • Can reduce hot flushes significantly

    • Must not be used by women taking tamoxifen for breast cancer, since it inhibits its metabolism to its active metabolite

• Serotonin-norepinephrine reuptake inhibitor

  • Venlafaxine extended release (75 mg orally daily)

    • May also be effective

    • Does not have a drug interaction with tamoxifen

• Paroxetine (7.5 mg orally daily)

  • FDA-approved for treatment of vasomotor symptoms

  • However, it is not recommended for women taking tamoxifen because it reduces the conversion of tamoxifen to its active metabolite

• Gabapentin, 200–800 mg orally every 8 hours

  • Useful for women with hot flushes who cannot take estrogen

  • Side effects include drowsiness, fatigue, headache, dizziness, and headache; such symptoms are most pronounced during the first 2 weeks of therapy but often improve within 4 weeks

• Black cohosh, an herb, may possibly relieve hot flushes

• Hormone replacement therapy (HRT) recommended for

  • Women with premature ovarian failure (< 40 years of age)

  • Older women on a case-by-case basis

• Estrogens

  • Lower-dose estrogen is favored

  • Transdermal estradiol and vaginal estrogen are favored over oral estrogen

  • Transdermal estradiol: do not apply to the breasts

  • Vaginal estrogen creams, tablets, and rings

    • Relieve vaginal dryness and discomfort, dyspareunia, urinary urgency, and dysuria

    • Can cause endometrial proliferation with prolonged use

• Vaginal progesterone

  • Minimizes dysfunctional uterine bleeding while reducing systemic progesterone exposure

  • Administered twice weekly with daily estrogen, most women experience no endometrial hypertrophy or dysfunctional uterine bleeding

• Progestins

  • Added to conventional-dose estrogen for women with a uterus to avoid endometrial hyperplasia

  • Exposure can be minimized by using lower-dose estrogen or progestin-eluting intrauterine devices (IUDs)

  • Progestin-eluting IUDs

    • Available as levonorgestrel (eg, Norplant); replaced every 5 years

    • Best tolerated by parous women

• Selective estrogen receptor modulators (SERMs)

  • Raloxifene (Evista)

    • In doses of 60 mg/day orally, it inhibits bone loss without stimulating effects on the breasts or endometrium

    • Reduces the risk of invasive breast cancer by about 50%

    • Does not reduce hot flushes, vaginal dryness, skin wrinkling, or breast atrophy; it does not improve cognition

    • Slightly increases the risk of venous thromboembolism (though less so than tamoxifen), so it should not be used by women at prolonged bed rest or otherwise prone to thrombosis

  • Tamoxifen (Soltamox)

    • Dose is 20 mg/day orally daily

    • Reduces the risk of invasive breast cancer

    • Increases the risks of venous thromboembolism, pulmonary emboli, uterine adenocarcinoma and sarcoma, stroke

    • Benefits outweigh risks in women already diagnosed with breast cancer

  • Ospemifene (Osphena)

    • Indicated for the treatment of postmenopausal dyspareunia when other therapies are ineffective

    • Given orally in doses of 60 mg/day, it commonly aggravates hot flushes, but has an estrogenic effect upon bone and slows bone loss in menopause

    • Does not usually cause endometrial hypertrophy

    • Has unknown long-term effects on the breast

  • Bazedoxifene

    • A SERM that is available as a fixed-dose combination medication with conjugated estrogens

    • FDA-approved for the prevention of osteoporosis in postmenopausal women with an intact uterus

    • Unlike raloxifene, it has not been shown to reduce the risk of breast cancer

    • Long-term use may increase risk of thromboembolic disease

  • Tibolone

    • Not available in the United States

    • Its metabolites have mixed estrogenic, progestogenic, and weak androgenic activity

    • Comparable to HRT for the treatment of climacteric-related complaints

    • Does not appear to significantly stimulate proliferation of breast or endometrial tissue

    • Depresses both serum triglycerides and HDL cholesterol

Benefits and risks

• HRT: Benefits

  • Improvement in hot flushes, vaginal moisture, libido, sleep, rheumatic complaints

  • Improved bone density; fewer fractures

  • Improved skin moisture and thickness

  • Improvement in symptoms of overactive bladder

• HRT: Risks

  • Dose-dependent

  • Oral estrogens

    • Increases risk of arterial and venous thrombotic events in dose-dependent manner

    • Increases risk of thromboembolic disease among older women and those with increased stroke proclivity

  • Estrogen replacement appears to increase the risk of seizures in women with epilepsy

  • Estrogen can stimulate the growth of untreated large pituitary prolactinomas

  • Oral estrogen and SERMs also increase the risk of gastroesophageal reflux disease (GERD)

  • Oral HRT can increase the size of hepatic hemangiomas, but significant enlargement is uncommon

• Estrogen replacement without progestin: Benefits

  • Women's Health Initiative (WHI) study reported that postmenopausal women taking unopposed estrogen had a reduction in breast cancer risk

  • However, the California Teachers' Study reported an increase in breast cancer risk among such women

  • Improvement in menopause-related depression

  • Better control of type 2 diabetes mellitus

• Estrogen replacement without progestin: Risks

  • Increased risk of stroke among women taking conjugated equine estrogens

  • Endometrial hyperplasia and dysfunctional uterine bleeding (DUB)

  • Endometrial carcinoma, low absolute risk

  • Mortality from ovarian cancer, low absolute risk

• Estrogen replacement with progestin: Benefits

  • Reduced risk for endometrial carcinoma

• Estrogen replacement with progestin: Risks

  • In the WHI study, women receiving conventional-dose combined oral HRT experienced an increased risk of stroke (31 strokes per 10,000 women/year versus 26 strokes per 10,000 women/year for placebo)

  • Long-term conventional-dose oral combined HRT increases breast density and the risk for abnormal mammograms (9.4% versus 5.4% for placebo)

  • There is also a higher risk of breast cancer (8 cases per 10,000 women/year versus 6.5 cases per 10,000 women/year for placebo

Therapeutic Procedures

• Hot flushes

  • May be reduced with low room temperatures, dressing coolly, and consuming cold beverages

  • Can be ameliorated by slow, deep breathing

  • Avoid known triggers, such as smoking, alcohol, caffeine, and hot spicy foods

• Aerobic training for 50 minutes four times weekly reduced all menopausal symptoms except vaginal dryness in a randomized controlled trial

• Vaginal lubricants can be used daily or 2 hours prior to intercourse

• Postmenopausal women should be evaluated for osteoporosis and treated if appropriate (see Osteoporosis)

Follow-Up

• Hypothalamic amenorrhea

  • Patients typically recover spontaneously

  • However, they should have regular evaluations and a progestin withdrawal test about every 3 months to detect loss of estrogen effect

Prognosis

• Ovarian failure (premature or menopausal) is usually irreversible

Complications

• Menopause

  • Osteoporosis and fractures

  • Increased LDL/HDL cholesterol ratio causes increased risk of atherosclerosis

Prevention

• Diet adequate in protein, calories, calcium, and vitamins; calcium and vitamin D supplements and exercise for those at risk for osteoporosis

• Consider bisphosphonate for osteoporosis

• Mammography recommended yearly for menopausal women receiving HRT

• Tamoxifen and raloxifene offer protection against osteoporosis but aggravate hot flushes