RISK FACTORS: Increasing age, Pelvic surgery, Sex chromosome abnormalities (eg, Turner syndrome)
Gonadotropin secretion increases dramatically after menopause. FSH levels are higher than LH levels, and both rise to even higher levels than in the surge during the menstrual cycle. The FSH rise precedes that of LH. The large cyclical variation of estradiol and estrone observed during the menstrual years ceases, and fluctuation in levels is small and inconsequential, with the mean being very much lower. The levels of circulating estradiol have very different ranges before and after menopause, and these levels are obviously much lower in menopause. Smears of the vaginal epithelium provide a composite picture of endogenous and exogenous estrogen stimulation over time; the more estrogen, the greater the number of superficial cells. No specific changes related to menopause have been found in thyroid function.
Endometrial biopsy can show a range of endometrial appearances, from mildly proliferate to atrophic. No secretory changes are observed after menopause because no ovulation occurs, and therefore no corpus luteum forms to produce progesterone. Endometrial hyperplasia is a sign of hyperstimulation by estrogen from either endogenous sources or replacement therapy and may be a precursor of endometrial cancer. Endometrial hyperplasia can also be suggested by ultrasonography (an endometrial thickness of >5 mm), which is useful in trying to exclude hyperplasia and cancer of the endometrium in postmenopausal women.
GENERAL MEASURES
• To retard development of osteoporosis: adequate calcium intake; exercise; avoid smoking, avoid excessive
alcohol or caffeine intake
• HRT for prophylaxis against osteoporosis, relief of vasomotor symptoms and urogenital atrophy. Exceptions
are women with contraindications to therapy and obese women (who usually have sufficient endogenous estrogens produced by peripheral conversion of androgens by adipose tissue).
• HRT has a favorable effect on lipoproteins; elevates HDL and may retard progression of Alzheimer disease
(no proof for prevention).
REPLACEMENT THERAPY :
The main reason to treat symptoms of estrogen level fluctuation prior to actual menopause are to provide relief of vasomotor symptoms, reduce the risk of unwanted pregnancy, avoid the irregularity of menstrual cycles, and preserve bone.
The time to begin therapy depends on the patient's current illness or illnesses, if any, and medical history. Whether a woman is perimenopausal or postmenopausal helps in choosing the most suitable type of therapy. Each patient should make a choice after receiving counseling on all the facts and an explanation of the options. For example, the perimenopausal woman may be started on HRT if either she or her spouse has undergone a sterilization procedure, whereas the same woman may need an OCP if she still needs birth control. Many factors, including personal history, family history, smoking, peer and commercial influences, culture, ethnicity, and economics, also play roles in the final decision, and all must be carefully weighed by the doctor and patient together.
Adverse effects of replacement therapy may include bloating, mastodynia, vaginal bleeding, and headaches. Unexplained adverse effects are often the reason for discontinuation of therapy, and reassuring counseling as well as options and dose combinations should be tried before therapy is stopped.
HRT can be administered systemically through the oral, transdermal, or topical routes or locally via the vaginal route using cream, ring, or tablet. Topical preparations are used solely to treat vaginal symptoms.
Contraindications to estrogen therapy are undiagnosed vaginal bleeding, severe liver disease, pregnancy, venous thrombosis, and personal history of breast cancer. Well-differentiated and early endometrial cancer, once treatment for the malignancy is complete, is no longer an absolute contraindication. Progestins alone may relieve symptoms if the patient is unable to tolerate estrogens.
Alternative products, ranging from herbal preparations to dietary supplements that contain various phytoestrogens, are reputed to ease the transition from perimenopause to postmenopause and are widely available. However, these agents have not undergone the same scrutiny in randomized controlled trials as the pharmaceutical products. Over-the-counter herbal products and phytoestrogens, including soy, are assumed to act the same as their pharmaceutical counterparts, but the herbal and vitamin industry is currently unregulated by the FDA. In women who cannot (due to a history of breast cancer) or choose not to take ERT/HRT and suffer from hot flashes or flushes, the SSRIs (in particular, venlaxifine) have been shown to alleviate vasomotor symptoms.
DRUG(S) OF CHOICE
. Estrogens: commonly oral estrogen, conjugated (Premarin) or estradiol
. For retarding osteoporosis 0.625 mg qd. Doses as low as 0.3 mg, used in conjunction with medroxyprogesterone and adequate calcium and vitamin D supplementation, is also effective.
. If vasomotor symptoms persist at 0.625 mg, increase to 0.9 mg or 1.25 mg, however, optimal cardioprotective
effect is 0.625 mg
. Progestogen: commonly medroxyprogesterone (Provera, Depo-Provera)
. Because estrogens are carcinogenic to the endometrium, a progestogen should be added for its protective
effect against endometrial cancer. (If the uterus has been removed, a progestogen is not needed.)
. Combination: conjugated estrogen-medroxyprogesterone (Prempro) or ethinyl estradiol-norethindrone
(FemHRT) or estradiol-norethindrone (Activella)
. Bisphosphonates: only agents shown to reduce spine and nonspine fractures; commonly:
. Alendronate (Fosamax) 10 mg qd or 70 mg every week
. Risedronate (Actonel) 5 mg qd or 30 mg every week
. Calcium: 1500 mg elemental calcium per day
. Vitamin D: 600 to 800 IU per day
. Administration
. Estrogens and progestogens may be administered continuously (no withdrawal bleeding expected) or
cyclically
. Common regimens: Premarin 0.625 mg + Provera 2.5 mg q day or Premarin 0.625 mg for 25 days per month + Provera 5 mg during the last 14 days of estrogen therapy OR Premarin 0.625 mg daily
+ Provera 5 mg during 14 days of month. Fixed combinations (Prempro, Premphase) may be convenient.
Another option is Premarin and micronized progesterone.
Contraindications:
. Estrogen dependent malignancies
. Unexplained abnormal uterine bleeding
. History of thrombophlebitis
. Active liver disease
. Malignant melanoma
Precautions:
. Continuous combination therapy should not result in uterine bleeding
. Women on cyclic therapy may bleed normally only during those days when no therapy is given. Any other bleeding must be evaluated for the possibility of endometrial cancer.
. Higher doses of estrogen can cause hypercoagulability, breast tenderness, gall bladder disease and hypertension
. Combination estrogen/progestin therapy has been shown to increase risk of invasive breast cancer,coronary
heart disease, stroke and pulmonary embolism after more than 5 years of use
ALTERNATIVE DRUGS
. Other forms of estrogen used:
. Oral: estropipate (Ogen) 0.625 mg, estradiol (Estrace) 1-2 mg
. Transdermal: estradiol (Estraderm, Esclim, Vivelle, Alora, Climara) 0.05-0.1 mg/day applied twice weekly, or 0.05-0.1 mg/day applied weekly (Climara)
. Vaginal: conjugated estrogens (Premarin cream) - best for local therapy of atrophic vaginitis only; blood
levels are unpredictable.
. Intramuscular: not recommended - may not be protective against coronary artery disease without first passing through the liver
. For women who cannot take estrogens - using progestogens (Depo-Provera) 150 mg IM every month is helpful in alleviating hot flashes. This may retard the development of osteoporosis, but is not helpful in preventing coronary artery disease or urogenital atrophy.
. Raloxifene (Evista) 60 mg/day has been shown to increase bone density, decrease vertebral and hip
fractures and decrease risk of breast cancer . Androgens/testosterone can increase libido and protect
bone mass; can decrease triglyceride and HDL levels
. Clonidine (Catapres), oral or transdermal, may be used to treat vasomotor symptoms, but is not effective
against other menopausal occurrences
PATIENT MONITORING
. Annual Pap smear, pelvic and breast exams
. Monthly breast self-examination
. Annual mammography
. Endometrial sampling in patients with abnormal bleeding
PREVENTION/AVOIDANCE Menopause is a physiological process. It cannot be avoided, but the untoward effects can be moderated or eliminated by HRT.
POSSIBLE COMPLICATIONS
. Vasomotor symptoms
. Uncomfortable psychologic symptoms
. Vaginal atrophy
. Skin wrinkles
. Osteoporosis
. Arteriosclerosis
. Urinary tract symptoms
EXPECTED COURSE/PROGNOSIS
. If untreated
. Ultimate disappearance of vasomotor symptoms
- usually takes several years
. Urogenital atrophy
. Osteoporosis - possible fractures especially of the hip, vertebrae and wrists. Mortality associated with hip fractures is 15%.
. Coronary artery disease - increased risk
. If treated
. Minimal effects of estrogen deprivation
. Slower bone loss and reduced incidence of coronary artery disease. Delayed appearance of Alzheimer
disease
MISCELLANEOUS:
• Estrogen replacement therapy is especially important in women having an early menopause, either spontaneous or surgical. Without such therapy, they may be at a significantly increased risk for osteoporosis.
• Following surgical menopause, vasomotor symptoms often appear very rapidly. Estrogen replacement
therapy may be started in the early postoperative period.
• In perimenopausal women bothered by severe vasomotor symptoms, cyclic estrogen and progestogen therapy may be started even though the patient is still having periodic uterine bleeding