As a result of dramatically increased life expectancies in industrialized countries, healthy women today expect to spend nearly 40% of their lives after menopause. For these postmenopausal women, lack of estrogen may contribute to long-term adverse effects, including cardiovascular disease and osteoporosis. Many postmenopausal women might benefit from hormone replacement therapy (HRT) with estrogens and progestins; however, a number of recent studies in the USA and Europe suggest that the potential risks of hormonal replacement therapy may sometime exceed the expected benefits. Thus, many treaters now avoid the use of hormone replacement therapy in peri- and postmenopausal women.

Conjugated equine estrogen (found in Premarin and Prempro) has been the estrogen preparation most widely used in hormone replacement therapy in postmenopausal women. More recently, synthetic estradiols have been available in Europe and the U.S. and have been used both in both oral and transdermal (patch) preparations. Orally administered estrogen preparations, in contrast to estradiol administered transdermally, are subject to hepatic metabolism and typically result in 4 to 5 times greater estradiol concentrations.

Progestogens (progesterone or a synthetic form of progesterone) are typically used in combination with estrogens to protect the uterus and to prevent the risk of the endometrial and ovarian cancer. Progesterone analogues, known as progestins, are now widely used in HRT. These are synthetic compounds with progesterone-like effects on the uterus, but their chemical structures differ from natural progesterone. The oral route of administration is preferred for all compounds. Progesterone, but not the synthetic progestins, have been found to have protective cardiovascular effects, while also down-regulating the breast tissue estradiol receptors in normal and cancerous cells.

All estrogen formulations and modes of administration have similar beneficial effects on vasomotor and urogenital menopause symptoms and on bone structure. However, experimental studies and clinical trials indicate that the adverse effects of hormone replacement therapy may depend on the estrogen/progesterone formulation, dosage, mode of the administration, and the duration of the treatment. A woman’s age and comorbid medical illnesses may also be important factors.

Moreover, estrogens may exert different effects on certain tissues, depending on the type of estrogen and its mode of administration. For example, oral estrogens influence carbohydrate metabolism and may lead to insulin resistance, an effect not observed with transdermal estradiol. Interestingly, when compared with the transdermal formulation, oral estrogens induce greater lipid oxidation, and may increase body mass index (BMI). Oral and transdermal estrogens both increase HDL (“good”) cholesterol, while decreasing the LDL (“bad”) cholesterol. Oral, but not transdermal, estrogens, raise circulating levels of the coagulation factors and increase C-reactive protein, a marker of cardiovascular morbidity. Both oral and transdermal estrogen preparations are shown to elevate the risk of uterine and ovarian cancer. Cardiovascular, thromboembolic and invasive breast cancer risks appear to be higher in women taking oral estrogen than in those using transdermal estradiol. Risks are also higher in those women taking estrogen in combination with progestin compounds (as opposed to those using oral micronized progesterone).

Based on these finding, it appears that for postmenopausal women who do need HRT, a combination of transdermal estradiol and micronized progesterone would be the best choice. Studies are under way, comparing the effects of transdermal versus oral estrogen in younger postmenopausal women (KEEPS: Kronos Early Estrogen Prevention Study, Dr. Michael Harman et al., Kronos Longevity Research Institute; ELITE: Early versus Late Intervention Trial with Estradiol, Dr. Howard Hodis et al., Keck School of Medicine, University of Southern California).

Snezana Milanovic, MD MSc


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Ho KK, O’Sullivan AJ, Wolthers T, Leung KC. Metabolic effects of oestrogens: impact of the route of administration. Ann Endocrinol (Paris). 2003 Apr;64(2):170-7. Review.

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