"March 14, 2013 -- Hormone replacement therapy is the most effective treatment for symptoms like hot flashes, and the benefits are likely to outweigh the risks, major medical societies say.
The statement was published in the April issue "...
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secrets 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions.These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone,and both can be converted to estriol,which is the major urinary metabolite.Estrogens also undergo enterohepatic recircu-lation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates,especially estrone sulfate, which serves as a circulating reservoir for the formulation of more active estrogens.
Estradiol,estrone,and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
Women's Health Initiative Studies.
The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases.The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studies.A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below:
Table 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY
|Eventc||Relative Risk CE/MPA vs place boat 5.2 Years (95% CI*)||Placebo n=8102||CE/MPA n=8506|
|Absolute Risk per 10,000 Person-years|
|CHD events||1.29 (1.02-1.63)||30||37|
|Non-fatal MI||1.32 (1.02-1.72)||23||30|
|CHD death||1.18 (0.70-1.97)||6||7|
|Invasive breast cancerb||1.26 (1.00-1.59)||30||38|
|Pulmonary embolism||2.13 (1.39-3.25)||8||16|
|Colorectal cancer||0.63 (0.43-0.92)||16||10|
|Endometrial cancer||0.83 (0.47-1.47)||6||5|
|Hip fracture||0.66 (0.45-0.98)||15||10|
|Death due to causes other than the events above||0.92 (0.74-1.14)||40||37|
|Global Indexc||1.15 (1.03-1.28)||151||170|
|Deep vein thrombosisd||2.07 (1.49-2.87)||13||26|
|Vertebral fracturesd||0.66 (0.44-0.98)||15||9|
|Other osteoporotic fracturesd||0.77 (0.69-0.86)||170||131|
|aadapted from JAMA,2002; 288:321-333
b includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c a subset of the events was combined in a "global index",defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes
d not included in Global Index
* nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the "global index," absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers,while absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.The absolute excess risk of events included in the "global index"was 19 per 10,000 women-years.There was no difference between the groups in terms of all-cause mortality.(See BOXED WARNING, WARNINGS, and PRECAUTIONS.)
Women's Health Initiative Memory Study
The Women's Health Initiative Memory Study (WHIMS), a sub-study of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years,and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia.The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment.It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia.)
Last reviewed on RxList: 10/28/2008
This monograph has been modified to include the generic and brand name in many instances.
Additional Menest Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.