California Proposition 65 (Prop 65) and Progesterone Cream Warnings
Amy Kosowski, M.S., LDN
Prop 65: What is it?
Proposition 65, the Safe Drinking Water and Toxic Enforcement Act of 1986 , was enacted as a ballot initiative in the state of California in November of 1986. The Proposition was intended by its authors to protect California citizens and the State's drinking water sources from chemicals known to cause cancer, birth defects or other reproductive harm, and to inform citizens about exposures to such chemicals 1.
Proposition 65 requires the Governor to publish, at least annually, a list of chemicals "known to the state to cause cancer or reproductive toxicity" . Progesterone, as well as other human hormones, appear on this list 1. Set forth below is the information that formed the bases for the addition of progesterone to the Prop 65 list by the California Office of Environmental Health Hazard Assessment ("OEHHA").
Prop 65 and Progesterone - Perspective
In August of 2004, OEHHA published a document stating the rationale for the addition of Progesterone to the Prop 65 list 2. This document is a review of human, animal, and in vitro studies that used progesterone, synthetic progestins, and other progestagens (progesterone-like compounds). Experimental data from the use of all of these compounds were mixed together, along with data from studies using other steroid hormone derivatives (mainly synthetic estrogens) and many different methods of administration.
Although this review covered the existing scientific literature on progesterone and its many derivative compounds, there are many problems with the type of data analysis that was employed.
First, progesterone is endogenous to humans and necessary for bone and reproductive health while progestins and other synthetic progestagens are not. Progestins and progestagens are similar in molecular structure to progesterone, but when they bind to progesterone receptors, their effects are usually much stronger and more likely to cause abnormal physiologic responses 3, 4. Furthermore, the majority of the studies concerning the health effects of these progesterone derivatives involved combinations with synthetic estrogens 2-4.
There were very few studies mentioned in the 2004 document that used exclusively bio-identical progesterone (the kind found normally produced by humans as well as that used in progesterone creams), and those studies that did were at supra-physiologic doses (very high). The doses of progesterone ranged from 10-1000 times the dose usually recommended by manufacturers of progesterone creams 2, although in a few cases, the doses were closer to the recommended dosages.
The route of administration of progesterone is also at issue. All of the studies cited in the OEHHA document used either oral, injected, or suppository forms of hormones; none was conducted using transdermal creams. This is an important consideration because hormones absorbed through the skin are metabolized differently than hormones that are administered via other routes 5, 6.
Putting it Together
While the OEHHA Prop 65 reference document on progesterone 2 is a broad survey of the published scientific literature examining the potential effects of the pharmaceutical use of progesterone and its synthetic derivatives, it is not clear at all that these effects would be seen with the use of low-dose progesterone creams.
The OEHHA Prop 65 progesterone document evaluates a broad range of information regarding progesterone and synthetic materials that are not natural progesterone. The conclusion reached was not challenged, and it is on that basis that progesterone creams now carry the Prop 65 warning.
1 California OEHHA Web Site: http://www.oehha.ca.gov/prop65/p65faq.html .
2 Reproductive and Cancer Hazard Assessment Section, Office of Environmental Health Hazard Assessment, California Environmental Protection Agency (2004) Evidence on the developmental and Reproductive Toxicity of Progesterone.
3 Campagnoli C, Abba C, Ambroggio S, Peris C (2005) Pregnancy, progesterone and progestin in relation to breast cancer risk. J Steroid Biochem Mol Biol 97(5):441-450.
4Campagnoli C , Clavel-Chapelon F , Kaaks R , Peris C , Berrino F (2005) Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. Steroid Biochem Mol Biol 2005 96(2):95-108.
5 de Lignieres B, Dennerstein L, Backstrom T (1995) Influence of route of administration on progesterone metabolism. Maturitas 21:251-257.
6 Gompel A, et al. (2000) Progestins were also proapoptotic in normal as well as in hormone-dependent breast cancer cells. Steroids 65(10-11):593-598.
7 Bu SZ ( 1997) Progesterone induces apoptosis and up-regulation of p53 expression in human ovarian carcinoma cell lines. Cancer 79(10):1944-50.