Research: Progesterone Safety
Overview
Historically, progesterone and synthetic progestins have been lumped together with respect to their safety profiles, although they are very different in their molecular structure and effects.
There is no documented evidence in the scientific literature of any cases of cancer as a result of treatment with bioidentical progesterone. Unfortunately, progesterone has been implicated in the development of breast cancer because of the results of large trials in which an increase in the incidence of breast cancer was seen when synthetic progestins were used in combination with estrogens for postmenopausal hormone therapy. These studies, such as the Women’s Health Initiative, DID NOT use bioidentical progesterone. A large European study, on the other hand, found that women using bioidentical progesterone plus estrogen had a lower risk of breast cancer than women using estrogen alone, whereas women using synthetic progestins plus estrogen had a significantly higher risk of breast cancer. See the section on Progesterone and Breast Health for the research on progesterone and breast cancer.
The following studies particularly highlighted the lack of adverse findings with bioidentical progesterone.
Research
General Safety:
- Stephenson K, Price C, Kurdowska A, Neuenschwander P, Stephenson J, Pinson B, Stephenson D, Alfred D, Krupa A, Mahoney D, Zava D, Bevan M. Topical progesterone cream does not increase thrombotic and inflammatory factors in postmenopausal women. Presented at the 46th Annual Meeting of the American Society of Hematology, San Diego, December 4-7, 2004. Blood 2004; 104(11): Abstract 5318.
No change in any of the thrombotic or inflammatory markers studied (total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFα, and IL-6) was observed, despite significant symptomatic improvement compared to placebo, in 30 women receiving 20 mg/day progesterone cream for 4 weeks.
- 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 ten days treatment with oral and vaginal 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. - Shantha S, Brooks-Gunn J, Locke RJ, Warren MP. Natural vaginal progesterone is associated with minimal psychological side effects: a preliminary study. J Women Health Gend Based Med 2001 Dec;10(10):991-7.
This 3 month, multicenter randomized study evaluated the psychological side effects of a vaginally applied progesterone gel in reproductive aged women treated for hypothalamic amenorrhea or premature ovarian failure. No differences were noted in psychometric measures as evaluated by the Hopkins Symptom Checklist. Natural progesterone in a vaginal gel can be an effective treatment for women requiring hormone therapy.
- de Ziegler D, Fanchin R. Progesterone and progestins: applications in gynecology. Steroids 2000 Oct-Nov;65(10-11):671-9.
This paper reviews the use of a transvaginal progesterone gel as a viable option to other routes of application of natural progesterone (intramuscular, oral micronized), and offered it as a viable option to synthetic progestins given the low incidence of side effects noted in existing studies.
- 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, Good A. Micronized progesterone: clinical indications and comparison with current treatments. Fertil Steril 1999 Sep;72(3):389-97.
The literature reviewed in this tutorial indicates a potential use for oral micronized progesterone for the treatment of secondary amenorrhea, dysfunctional uterine bleeding, luteal phase disorders, premenopausal bleeding disorders, and as a component of hormone replacement therapy that may provide a better safety profile than commonly utilized synthetic progestins.
- Darj E, Axelsson O, et al. Liver Metabolism During Treatment with Estradiol and Natural Progesterone. Gynecological Endocrinology June 1993; 7(2):111-4.
Thirty postmenopausal women were treated daily for four months with 2 mg micronized 17 beta-estradiol and micronized progesterone orally in doses of 50, 100 and 200 mg daily. Serum concentrations of sex hormone-binding globulin (SHBG), corticosteroid binding globulin (CBG), ceruloplasmin, lipoprotein A and liver enzymes were measured. Serum SHBG and CBG increased during treatment with a weak association shown between progesterone and serum CBG. Levels of lipoprotein A and liver enzymes did not change, concluding that natural progesterone supplementation in postmenopausal women does not appear to cause any side effects to the liver.
- 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.
