Definitions of Bioidentical hormones have a chemical structure identical to human hormones but are chemically synthesized, such as progesterone, estriol, and estradiol. Non-bioidentical hormones are not structurally identical to human hormones and may either be chemically synthesized, such as MPA, or derived from a nonhuman source, such as CEE.
Databases and Keywords Literature searches were conducted for HRT formularies, focusing on those that either are or have been used in the United States. Published papers identified for review by PubMed/MEDLINE, Google Scholar, and Cochrane database searches included the keywords: “bioidentical hormones,” “synthetic hormones,” “progestin,” “menopausal hormone replacement,” “hormone replacement therapy,” “HRT,” “estriol,” “progesterone,” “natural hormones,” “conjugated equine estrogens,” “medroxyprogesterone acetate,” “breast cancer,” and “cardiovascular disease.”
Published papers that focused on 3 key areas were identified: 1) clinical efficacy, 2) physiologic actions on breast tissue, and 3) risks for breast cancer and cardiovascular disease. Papers included human clinical studies that compared bioidentical and non-bioidentical hormones, animal studies based on similar comparisons, and in vitro experimental work that focused on physiological or biochemical aspects of the hormones.
Results 1) Symptomatic Efficacy of Synthetic Progestins versus Progesterone
Four studies of patients using HRT, including either progesterone or MPA, compared efficacy, patient satisfaction, and quality of life. Women in all 4 studies reported greater satisfaction, fewer side effects, and improved quality of life when they were switched from synthetic progestins to progesterone replacement. In a cross-sectional survey, Fitzpatrick et al compared patient satisfaction and quality of life, as well as other somatic and psychological symptoms (ie, anxiety, depression, sleep problems, menstrual bleeding, vasomotor symptoms, cognitive difficulties, attraction, and sexual functioning) in 176 menopausal women on HRT with MPA versus HRT with progesterone.2 Significant differences were seen for all somatic, vasomotor, and psychological symptoms, except for attraction, when bioidentical progesterone was used rather than MPA .
The effect of progesterone compared with MPA included a 30% reduction in sleep problems, a 50% reduction in anxiety, a 60% reduction in depression, a 30% reduction in somatic symptoms, a 25% reduction in menstrual bleeding, a 40% reduction in cognitive difficulties, and a 30% improvement in sexual function. Overall, 65% of women felt that HRT combined with progesterone was better than the HRT combined with MPA.2
In a randomized study comparing HRT with MPA or progesterone in 23 postmenopausal women with no mood disorders such as depression or anxiety, Cummings and Brizendine found significantly more negative somatic effects but no differences in mood assessment with synthetic hormones. These negative effects included increased vaginal bleeding and increased breast tenderness, with a trend for increased hot flashes with the use of MPA compared with progesterone.3 In the 3-year, double-blind, placebo-controlled Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, 875 menopausal women received either placebo, CEE with MPA (cyclic or continuous), or progesterone (cyclic). Those taking progesterone had fewer episodes of excessive bleeding than those on MPA (either continuous or cyclic), but no differences were noted in symptomatic relief.
2) Differing Physiological Effects of Bioidentical Progesterone and Synthetic Progestins
Progesterone and synthetic progestins generally have indistinguishable effects on endometrial tissue, which are not the focus of this review. Studies that compared the physiological differences in breast tissue of those on progesterone, with those on other progestins, have the potential to predict differing risks of breast cancer. While variations in methodology and study design are considerable, most of the literature demonstrates physiological differences between progestins and progesterone and their effects on breast tissue. Synthetic progestins have potential anti-apoptotic effects and may significantly increase estrogen-stimulated breast cell mitotic activity and proliferation.
In contrast, progesterone inhibits estrogen-stimulated breast epithelial cells. Progesterone also down-regulates estrogen receptor-1 (ER-1) in the breast, induces breast cancer cell apoptosis, diminishes breast cell mitotic activity, and arrests human breast cancer cells in the G1 phase by upregulating cyclin-dependent kinase inhibitors and down-regulating cyclin D1.23,32 Synthetic progestins, in contrast, up-regulate cyclin D121 and increase breast cell proliferation.
Progesterone consistently demonstrates antiestrogenic activity in breast tissue. This result is generally in contrast to that for synthetic progestins, especially the 19-nortestosteronederived progestins, which bind to estrogen receptors in breast tissue (but not in endometrial tissue) and display significant intrinsic estrogenic properties in breast but not endometrial tissue. Synthetic progestins may also increase the conversion of weaker endogenous estrogens into more potent estrogens, potentially contributing to their carcinogenic effects, which are not apparent with progesterone.
Synthetic progestins may promote the formation of the genotoxic estrogen metabolite 16-hydroxyestrone. Synthetic progestins, especially MPA, stimulate the conversion of inactive estrone sulfate into active estrone by stimulating sulfatase, as well as increasing 17-beta-hydroxysteroid reductase activity, which in turn increases the intracellular formation of more potent estrogens and potentially increases breast cancer risk.
Progesterone has an opposite effect, stimulating the oxidative isoform of 17-beta-hydroxysteroid dehydrogenase, which increases the intracellular conversion of potent estrogens to their less potent counterparts. At least 3 subclasses of progesterone receptors (PR) have been identified: PRA, PRB, and PRC, each with different cellular activities. In normal human breast tissue, the ratio of PRA:PRB is approximately 1:1. This ratio is altered in a large percentage of breast cancer cells and is a risk for breast cancer.
In contrast to progesterone, synthetic progestins alter the normal PRA:PRB ratio, which may be a mechanism by which synthetic progestins increase the risk for breast cancer. Synthetic progestins and progesterone have a number of differences in their molecular and pharmacological effects on breast tissue, as some of the pro-carcinogenic effects of synthetic progestins contrast with the anticarcinogenic properties of progesterone.
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