Research: Bioidentical (Natural) Progesterone vs. Synthetic Progestins

Overview

Differences between Natural, Bioidentical Progesterone and Synthetic Progestins

Confusion exists, even among leading experts in the field of hormone research, between the terms progesterone, progestin, and progestogen. Although these terms are often used interchangeably, they are not synonymous. Until an authoritative definition is formally adopted, the following reflects the current culture of the usage of these terms, and clarifies how they are used by Women in Balance: “progesterone” refers to the hormone produced in the body, or produced from a plant source but still chemically and structurally identical to human progesterone, and it is therefore referred to as “bioidentical” or “natural”. In contrast, “progestin” refers to a hormone that is synthetically produced and differs in structure from progesterone. There are numerous synthetic progestins used in hormone therapy, in contrast to only one molecule referred to as progesterone. “Progestogen” (sometimes spelled “progestagen”) is a general term for hormones that act like progesterone in the uterus, and therefore includes progestins.

There is increasing evidence that, by virtue of their different chemical structures, synthetic progestins do not always act as progesterone would at the same target tissues. This has long been understood with respect to treatment of pregnancy and fertility issues, when progesterone is effectively prescribed, yet synthetic progestins are contraindicated. While synthetic progestins may mimic some of progesterone’s effects, progestins may react differently with progesterone receptors in the body.

A significant consequence of the additional side effects seen with synthetic progestins has been the recent observation that natural progesterone in hormone therapy regimens does not affect the risk of developing breast cancer, while the use of synthetic progestins increases this risk (see Fournier, below). Clinical trials such as the Women’s Health Initiative, in which more breast cancer was seen in the group taking progestins, did not study natural progesterone.

Research

Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol 2005; 96(2):95-108.
The authors discuss the non-progesterone-like effects of synthetic progestins, which can contribute to the increased risk of breast cancer when these are used as part of a combined hormone therapy regimen. In contrast, bioidentical progesterone does not increase the risk of breast cancer, consistent with experimental in vivo data that shows progesterone has no adverse effect on breast tissue.
Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer 2005; 114(3):448-54.
Combined HRT with estrogen (either oral or transdermal) and synthetic progestins was found to carry a significantly increased risk of breast cancer compared with estrogens plus oral micronized progesterone. In fact, no increase in breast cancer risk was seen in the estrogen plus oral micronized progesterone group compared with estrogen alone. This large multicenter study therefore suggests that there is a dramatic difference between the effects of bioidentical progesterone versus synthetic progestins on breast cancer risk.
Leonetti HB, Landes J, Steinberg D, Anasti JN. Topical progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med 2005; 11(6):36-38.
This study evaluated the endometrial effects and determined patients’ acceptance of transdermal progesterone cream (PC) compared to standard hormone therapy. Healthy menopausal women were recruited and received a pretreatment endometrial biopsy (EMB). They were randomized to 0.625 mg conjugated equine estrogen (CEE) daily and 2.5 mg medroxyprogesterone acetate (MPA) Prempro^TM or daily 0.625 mg CEE and twice daily 20 mg transdermal PC (Pro-gest®). At the end of 6 months, a repeat EMB was obtained, and the women were crossed over to other treatment. A final EMB was performed after the final 6 months. Twenty-six women completed both arms of the study. Seventy-seven percent of women preferred the CEE/PC to the CEE/MPA (P<.001). Of the 52 post-treatment endometrial biopsies: 40 revealed atrophic endometrium and 12 proliferative endometrium (7 in the oral progestin group and 5 in the PC group). There was no evidence of endometrial hyperplasia in any of the specimens. The incidence of vaginal spotting was similar in both groups. Conclusion: Patients preferred transdermal PC over oral MPA. These preliminary data indicate that CEE/PC has a similar effect on the endometrium as standard (CEE/MPA) oral HT over a 6-month period.
Stanczyk FZ. All progestins are not created equal. Steroids 2003; 68:879-90.
This paper describes the molecular and pharmacokinetic differences between various progestins and progesterone. Orally administered progestins require relatively high doses for therapeutic use because of extensive first pass metabolism in the liver. Also, the various molecules show profound differences in progestational activity between human and animal tissues, particularly with respect to androgenicity, which has led to erroneous conclusions being drawn from animal studies regarding androgenicity in humans. The author classifies the various molecules by chemical structure and concludes that they differ widely in metabolism, pharmacokinetics, and potency.

Greendale GA, Reboussin BA, Slone S, Wasilauskas C, Pike MC, Ursin G. Postmenopausal hormone therapy and change in mammographic density. J Natl Cancer Inst 2003 Jan 1;95(1):30-7.
Breast cancer risk independently increases with mammographic density. Use of hormone replacement therapy (HRT) postmenopausally is associated with an increase in mammographic density, but the extent of the density increase is unknown. This study evaluated mammograms from 571 of the 875 women enrolled in the PEPI trial at baseline and after 12 months HRT. The women had been randomized to receive placebo, conjugated equine estrogens (CEE) + medroxyprogesterone acetate (MPA) in a continuous or cyclic fashion, or CEE + micronized progesterone (MP). Mammograms were analyzed digitally and a linear regression analysis was utilized to quantify breast density change in all four treatment arms. The adjusted absolute mean changes in mammographic percent density over 12 months were 4.76% (95% confidence interval [CI] = 3.29% to 6.23%), 4.58% (95% CI = 3.19% to 5.97%), and 3.08% (95% CI = 1.65% to 4.51%) for women in the CEE+MPA-cyclic, CEE+MPA-continuous, and CEE-MP groups, respectively. Each of those absolute mean changes was statistically significantly different from the adjusted absolute mean change in mammographic percent density for women in the placebo group, which was -0.07% (95% CI = -1.50% to 1.38%). Greater mammographic density was associated with the use of estrogen/progestin combination therapy, although the micronized progesterone containing arm appeared to induce a smaller increase that that with MPA.

Ferrero S, Gerbaldo D, Fulcheri E, Cristoforoni P. Vaginal micronized progesterone in continuous hormone replacement therapy. A prospective randomized study. Minerva Ginecol 2002; 54(6):519-30.
Transvaginal micronized progesterone (100 mg/day for 12 days/month) effectively promoted a functional, secretory endometrium, while cyclic oral medroxyprogesterone acetate or transdermal norethisterone acetate more often produced endometrial atrophy, in women receiving continuous transdermal estradiol.

Bagis T, Gokcel A, Zeyneloglu HB, Tarim E, Kilicdag EB, Haydardedeoglu B. The effects of short-term medroxyprogesterone acetate and micronized progesterone on glucose metabolism and lipid profiles in patients with polycystic ovary syndrome: a prospective randomized study. J Clin Endocrinol Metab 2002 Oct;87(10):4536-40.
This randomized prospective study evaluated and compared the effects of 10 days’ treatment with oral and vaginal micronized progesterone (MP) and medroxyprogesterone acetate (MPA) on glucose metabolism, lipid profiles, and hormonal parameters in 28 patients with polycystic ovary syndrome (PCOS). Oral MPA and oral MP decreased LH (P = 0.028, P = 0.009, respectively) and total testosterone (P = 0.013, P = 0.037, respectively) levels. There was no change in hormonal parameters with vaginal MP. Basal insulin decreased (P = 0.021) and insulin sensitivity increased significantly in the oral MPA group. Low density lipoprotein cholesterol (LDL) and lipoprotein (a) levels decreased only in the MPA group. This study concluded that MPA and oral MP may reduce insulin sensitivity in patients with PCOS. Vaginal MP had no effect on glucose metabolism and lipid profiles.
De Lignieres B. Effects of progestogens on the postmenopausal breast. Climacteric 2002; 5(3):229-35.
In this review, the author highlights the differences between progesterone and synthetic progestins in the breast and cautions that progestogens not be “all put in the same bag” with respect to safety. A strong case is made for the protective effect of progesterone on the breast.
Sitruk-Ware R. Progestogens in hormonal replacement therapy: new molecules, risks, and benefits. Menopause 2002;9(1):6-15.
The classifications of various progestogens (natural and synthetic) are reviewed in terms of their risks and benefits. This review clearly elucidates the differences in the mode of action of various synthetic progestins as well as progesterone.
Montplaisir J, Lorrain J, Denesle R, Petit D. Sleep in menopause: differential effects of two forms of hormone replacement therapy. Menopause 2001; 8(1):10-16.
This randomized clinical trial compared the effects of conjugated equine estrogen (CEE) and medroxyprogesterone acetate to CEE and oral micronized progesterone. Twenty-one postmenopausal women were studied in a sleep lab, with results demonstrating an improvement in subjective measures of menopausal symptoms and sleep in both groups. The group receiving natural progesterone had significantly improved sleep efficiency, whereas the medroxyprogesterone acetate group did not, suggesting that the former might better improve sleep in postmenopausal women.
Otsuki M, Saito H, Xu X, Sumitani S, Kouhara H, Kishimoto T, Kasayama S. Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Arterioscler Thromb Vasc Biol 2001 Feb;21(2):243-8.
This study utilizing human umbilical vein endothelial cells (HUVEC’s) demonstrated that progesterone, but not medroxyprogesterone acetate (MPA) inhibited expression of vascular cell adhesion molecule-1 (VCAM-1), demonstrating a role for progesterone in the prevention of atherosclerosis. The differing effects of progesterone and MPA are clinically important, as MPA is widely used in hormone replacement therapy, when, as this research suggests, progesterone might be a more appropriate option.
Ryan N, Rosner A. Quality of life (QOL) and costs associated with micronized progesterone and medroxyprogesterone acetate in hormone replacement therapy for non-hysterectomized, postmenopausal women. Clin Ther 2001 Jul;23(7):1099-115.

This prospective, multicenter, randomized, parallel-group study enrolled 182 postmenopausal women 45 to 65 years of age and evaluated the quality of life (QOL) and menopausal symptoms associated with the use of medroxyprogesterone acetate vs oral micronized progesterone when used as a part of a regular hormone replacement therapy. Menopausal symptoms improved in both groups from baseline to 9 months, as did QOL measures. In addition, patients using micronized progesterone had specific improvements in the areas of cognition and menstrual problems whereas the patients using MPA did not. Micronized progesterone was seen as an effective, cost-comparable alternative to MPA as well as being better tolerated.
Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol 2000 Dec;36(7):2154-9
Eighteen postmenopausal women were randomized to receive 17-beta estradiol with a synthetic progestin (medroxyprogesterone acetate) or a progesterone vaginal gel for 4 weeks, then crossed over to the alternate treatment. Researchers found through treadmill testing that estrogen plus progesterone significantly increased exercise time before myocardial ischemia, when compared to estradiol plus synthetic progestin. In addition, 2 patients on the synthetic progestin arm had to discontinue due to unstable angina. This research suggests that women at risk for cardiovascular disease need to consider progesterone as a safer alternative to synthetic progestins as a part of their hormone replacement therapy regime.
Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000 Oct-Nov;65(10-11):651-8.
This article reviews the effects of various synthetic progestins and progesterone on cardiovascular health. Many synthetic progestins, especially 19-nortestosterone and some 17-hyroxyprogesterones, have negative effects on cardiovascular risk factors, whereas natural progesterone does not. Further studies utilizing natural and other steroids should be considered.
Fitzpatrick LA, Pace C, Wiita B. Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey. J Women Health Gend Based Med 2000 May;9(4):381-7.
A cross-sectional survey was conducted to examine quality of life (QOL) related to physiological, somatic, and vasomotor effects of switching progestogen treatment from medroxyprogesterone acetate (MPA) to micronized progesterone in postmenopausal women already using hormone replacement therapy (HRT). One hundred seventy-six women who were currently using hormone replacement therapy (HRT) containing micronized progesterone for 1-6 months and had previously received HRT containing MPA were surveyed to assess QOL. Women using micronized progesterone-containing HRT experienced significant improvement in vasomotor symptoms, anxiety, somatic complaints and depressive symptoms. Women reported improved control of menopausal symptoms and perceptions of their vaginal bleeding patterns while on the micronized progesterone-containing regimen. Approximately 80% of women reported satisfaction with the progesterone-containing therapy. A micronized progesterone-containing HRT therapy offers the potential for improved QOL with respect to menopausal symptoms.
De Lignieres B. Oral micronized progesterone. Clin Ther 1999; 21(1):41-60.
This review article examines the rationale for selecting oral micronized progesterone over synthetic progestins. It reviews research regarding efficacy and safety and concludes that oral micronized progesterone has fewer side effects than synthetic progestins and is a convenient way to deliver natural progesterone.
Lobo RA. Progestogen metabolism. J Reprod Med 1999 Feb;44(2 Suppl):148-52.
This review clearly elucidates what’s known about the differences in metabolism of various progestins as compared with endogenous or natural progesterone. Not only are there different pathways for metabolism, but the route of administration also has a significant effect. The physiologic and pathologic state of the patient further influences the metabolism, and there are measurable variations between patients. The authors also review the differences expressed by various tissues in metabolizing progestogens as well as the different biologic potencies of the various progestogens. Most importantly, the authors state the lack of knowledge about the synthetic progestins as compared to natural progesterone, which has a much better understood effect in the body.
Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nature Medicine 1997;3(3): 324-327.
Ovariectomized rhesus monkeys were treated with physiological levels of 17-beta estradiol in combination with either medroxyprogesterone or progesterone (oral micronized) for four weeks. Following pathophysiological stimulation without injury to induce coronary vasospasm, it was shown that progesterone plus estradiol was protective against vasospasm, whereas estradiol plus medroxyprogesterone allowed vasospasm, concluding that medroxyprogesterone increases risk of coronary vasospasm, while progesterone does not.
Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 1995; 273(3):199-208.
Bioidentical progesterone (an oral micronized preparation) was used in one group in the PEPI study in place of medroxyprogesterone acetate (MPA). Results showed that the progesterone group had significantly higher HDL cholesterol levels than the MPA group, indicating a different pharmacological effect than the synthetic progestin with a more favorable effect on blood lipids.
Ojasoo T. Multivariate preclinical evaluation of progestins. Menopause: The Journal of the North American Menopause Society 1995; 2(2): 97-107.

Specificity profiles of numerous progestins were evaluated by multivariate analysis. Twenty steroid hormones, including natural progesterone, were tested for anti-estrogenic activity and for binding to the androgen, progesterone, and glucocorticoid receptors.
Martorano JT, Ahlgrimm M, Meyers D. Differentiating between natural progesterone and synthetic progestogens: clinical implications for PMS management. Comprehensive Therapy 1993; 19(3):96-8.
Clinical observations demonstrate that patients suffering from PMS respond to treatment with natural progesterone, whereas synthetic progestins may exacerbate the condition. The authors review the differences between natural progesterone and synthetic progestins.
Ottosson UB, Johansson BG, et al. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: A comparison between progestogens and natural progesterone. American Journal of Obstetrics and Gynecology 1993 Mar;151(6): 746-50.
Fifty-eight postmenopausal women were followed with respect to subfractions of high-density lipoprotein during 3 cycles of unopposed estrogen. The women received either levonorgestrel, medroxyprogesterone acetate, or natural progesterone during the last ten days of the treatment period. Both progestogens significantly lowered HDL cholesterol, whereas natural progesterone had no effect on HDL levels.
Saarikoski S, Yliskoski M, Penttila I. Sequential use of norethisterone and natural progesterone in pre-menopausal bleeding disorders. Maturitas 1990 Jun;12(2):89-97.
This randomized controlled study evaluated the effects of norethisterone (NET) and micronized progesterone (MP) on bleeding disorders in pre-menopausal women. 80 patients were randomized to the trial and all were found via endometrial morphology to need progestogen therapy. They were subsequently treated with NET or MP. In both treatment groups, hyperplastic changes disappeared during the first three cycles, with the duration of treatment being 6 months. NET decreased follicle-stimulating hormone, luteinizing hormone, estradiol and sex-hormone-binding globulin levels (P < 0.001) whereas no changes were seen during MP treatment. High-density-lipoprotein cholesterol and triglyceride levels were also lowered by NET (P< 0.001-0.02) slightly decreased phospholipids. MP treatment had no effect on lipid profiles suggesting it may be a preferred progestogen for the treatment of bleeding disorders.
Dalton K. The effects of progesterone and progestogens on the foetus. Neuropharmacology 1981; 20:1267-9.
This article looks at the differing effects of progesterone and synthetic progestogens on the fetus. Of note in this article is evidence that progesterone supplementation may reduce episodes of pre-eclampsia. Synthetic progestogen supplementation during pregnancy may produce a variety of side effects. Several references are made to articles documenting cases of masculinization of external genitalia in female babies. There are two known cases of true hermaphroditism and several cases of behavioral problems developing in adolescent girls whose mothers took oral synthetic progestogens during pregnancy. More problematic may be administration of oral estrogen-progestogen preparations. Side effects may include spina bifida, esophageal anomalies, heart defects and limb reduction deformities.