Introduction

Essentials of Diagnosis

 
• Cessation of menses due to aging or to bilateral oophorectomy.  
• Elevation of FSH and LH levels.  
• Hot flushes and night sweats (in 80% of women).  
• Decreased vaginal lubrication; thinned vaginal mucosa with or without dyspareunia.

General Considerations

The term “menopause” denotes the final cessation of menstruation, either as a normal part of aging or as the result of surgical removal of both ovaries. In a broader sense, as the term is commonly used, it denotes a 1- to 3-year period during which a woman adjusts to a diminishing and then absent menstrual flow and the physiologic changes that may be associated - hot flushes, night sweats, and vaginal dryness.

The average age at menopause in Western societies today is 51 years. Premature menopause is defined as ovarian failure and menstrual cessation before age 40; this often has a genetic or autoimmune basis. Surgical menopause due to bilateral oophorectomy is common and can cause more severe symptoms owing to the sudden rapid drop in sex hormone levels.

There is no objective evidence that cessation of ovarian function is associated with severe emotional disturbance or personality changes. However, mood changes toward depression and anxiety can occur at this time. Furthermore, the time of menopause often coincides with other major life changes, such as departure of children from the home, a midlife identity crisis, or divorce. These events, coupled with a sense of the loss of youth, may exacerbate the symptoms of menopause and cause psychologic distress.

Clinical Findings

A. Symptoms and Signs

1. Cessation of menstruation
Menstrual cycles generally become irregular as menopause approaches. Anovular cycles occur more often, with irregular cycle length and occasional menorrhagia. Menstrual flow usually diminishes in amount owing to decreased estrogen secretion, resulting in less abundant endometrial growth. Finally, cycles become longer, with missed periods or episodes of spotting only. When no bleeding has occurred for 1 year, the menopausal transition can be said to have occurred. Any bleeding after this time warrants investigation by endometrial curettage or aspiration to rule out endometrial cancer.

2. Hot flushes
Hot flushes (feelings of intense heat over the trunk and face, with flushing of the skin and sweating) occur in 80% of women as a result of the decrease in ovarian hormones. Hot flushes can begin before the cessation of menses. An increase in pulsatile release of gonadotropin-releasing hormone from the hypothalamus is believed to trigger the hot flushes by affecting the adjacent temperature-regulating area of the brain. Hot flushes are more severe in women who undergo surgical menopause. Flushing is more pronounced late in the day, during hot weather, after ingestion of hot foods or drinks, or during periods of tension. Occurring at night, they often cause sweating and insomnia and result in fatigue on the following day.

3. Vaginal atrophy
With decreased estrogen secretion, thinning of the vaginal mucosa and decreased vaginal lubrication occur and may lead to dyspareunia. The introitus decreases in diameter. Pelvic examination reveals pale, smooth vaginal mucosa and a small cervix and uterus. The ovaries are not normally palpable after the menopause. Continued sexual activity will help prevent tissue shrinkage.

4. Osteoporosis
Osteoporosis may occur as a late sequela of menopause.

B. Laboratory Findings
Serum FSH and LH levels are elevated. Vaginal cytologic examination will show a low estrogen effect with predominantly parabasal cells, indicating lack of epithelial maturation due to hypoestrinism.

Treatment

A. Natural Menopause

Education and support from health providers, midlife discussion groups, and reading material will help most women having difficulty adjusting to the menopause. Physiologic symptoms can be treated as follows.

1. Vasomotor symptoms
Oral conjugated estrogens, 0.3 mg or 0.625 mg, estradiol, 0.5 or 1 mg, or estrone sulfate, 0.625 mg; or estradiol can be given transdermally as skin patches that are changed once or twice weekly and secrete 0.05-0.1 mg of hormone daily. When either form of estrogen is used, add a progestin (medroxyprogesterone acetate) to prevent endometrial hyperplasia or cancer. The hormones can be given in several differing regimens. Give estrogen on days 1-25 of each calendar month, with 5-10 mg of medroxyprogesterone acetate added on days 14-25. Withhold hormones from day 26 until the end of the month, when the endometrium will be shed, producing a light, generally painless monthly period. Alternatively, give the estrogen along with 2.5 mg of medroxyprogesterone acetate daily, without stopping. This regimen causes some initial bleeding or spotting, but within a few months it produces an atrophic endometrium that will not bleed. If the patient has had a hysterectomy, a progestin need not be used.

Recent data from the Women’s Health Initiative (WHI) study suggest that women should not use combination progestin-estrogen therapy for more than 3 or 4 years. In this study, the increased risk of cardiovascular disease, cerebrovascular disease, and breast cancer with this regimen outweighed the benefits. Women who cannot find relief with alternative approaches may wish to consider continuing use of combination therapy after a thorough discussion of the risks and benefits. Alternatives to hormone therapy for vasomotor symptoms include selective serotonin reuptake inhibitors such as paroxetine 12.5 mg or 25 mg/d, venlafaxine 75 mg/d. Gabapentin, an antiseizure medication, is also effective at 900 mg/d. Clonidine given orally or transdermally, 100-150 ug daily, may also reduce the frequency of hot flushes, but its use is limited by side effects, including dry mouth, drowsiness, and hypotension.

2. Vaginal atrophy
This problem can be treated with hormone therapy as outlined above. Alternatively, an estradiol vaginal ring that can be left in place for 3 months and is suitable for long-term use provides effective relief of vaginal atrophy. There is minimal systemic absorption of estradiol with the ring, and progestin therapy to protect the endometrium is unnecessary. Short-term use of estrogen vaginal cream will relieve symptoms of atrophy, but because of variable absorption, therapy with either systemic hormone replacement or the vaginal ring is preferable. Testosterone propionate 1-2%, 0.5-1 g, in a vanishing cream base used in the same manner is also effective if estrogen is contraindicated. A bland lubricant such as unscented cold cream or water-soluble gel can be helpful at the time of coitus.

3. Osteoporosis
Women should ingest at least 800 mg of calcium daily throughout life. Nonfat or low-fat milk products, calcium-fortified orange juice, green leafy vegetables, corn tortillas, and canned sardines or salmon consumed with the bones are good dietary sources. In addition, 1 g of elemental calcium should be taken as a daily supplement at the time of the menopause and thereafter; calcium supplements should be taken with meals to increase their absorption. Vitamin D, 400 units/d from food, sunlight, or supplements, is necessary to enhance calcium absorption. A daily program of energetic walking and exercise to strengthen the arms and upper body helps maintain bone mass.

Women most at risk for osteoporotic fractures should consider bisphosphonates, raloxifene, or hormone replacement therapy. This includes white and Asian women, especially if they have a family history of osteoporosis; are thin, short, cigarette smokers, and physically inactive; or have had a low calcium intake in adult life.

B. Risks of Hormone Therapy

Double-blinded randomized, controlled trials have shown no overall cardiovascular benefit with estrogen-progestin replacement therapy in a group of postmenopausal women with or without established coronary disease. Both in the WHI trial and the Heart and Estrogen/Progestin Replacement Study (HERS), the overall health risks (increased risk of coronary heart events, strokes, thromboembolic disease, breast cancers, gallstones) exceeded the benefits from the use of combination estrogen and progesterone. The trial of unopposed estrogen use in the WHI study is ongoing. Progestins counteract some but not all favorable effects of estrogen. Women who have been receiving long-term estrogen-progestin hormone replacement therapy (HRT), even in the absence of complications should be encouraged to stop, especially if they do not have menopausal symptoms. An ancillary study of the WHI study showed that not only did estrogen-progestin HRT not benefit cognitive function but there was a small increased risk of cognitive decline in that group compared with women in the placebo group. Several other studies have shown an increased risk of breast cancer in women taking estrogen-progestin therapy, while estrogen alone did not increase the risk. Endometrial cancer can occur if adequate progestin is not used. Estrogen may cause the growth of uterine myomas, which otherwise shrink after the menopause.

C. Surgical Menopause

The abrupt hormonal decrease resulting from oophorectomy generally results in severe vasomotor symptoms and rapid onset of dyspareunia and osteoporosis unless treated. Estrogen replacement is generally started immediately after surgery. Conjugated estrogens 1.25 mg, estrone sulfate 1.25 mg, or estradiol 2 mg is given for 25 days of each month. After age 45-50 years, this dose can be tapered to 0.625 mg of conjugated estrogens or equivalent.

Preferences:
Grady D et al: Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49.

Grimes DA et al: Perspectives on the Women’s Health Initiative trial of hormone replacement therapy. Obstet Gynecol 2002;100:1344.

Hulley S et al: Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:58.

Rapp SR et al: Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2663.

Rossouw JE et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321.