Synthetic Progesterone May Increase Breast Cancer Risk
Again - Science is Saying Natural Progesterone is Safer

by Dr Gail Valentine

More evidence is out on natural progesterone as a safer alternative to synthetic progesterone, more commonly referred to as a progestin. The most widely prescribed progestin for women is Provera®. For hormone replacement therapy (HRT), Provera has been the standard prescription along with its estrogen counterpart, Premarin®. Premarin is a conjugated estrogen derived from horse urine. Neither of these hormones are "natural" to the body, meaning they have similar, but not identical, molecular makeup compared with their corresponding human hormones. Natural progesterone, however, is identical to the human progesterone molecule produced by the body.

In a recent report in the Annals of Internal Medicinefrom the ongoing Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, researchers found that HRT, and particularly those using equine (horse) estrogen and progestin regimens, significantly increased mammographic density in the first year of use.1 The concern, according to the investigators, is increased breast density that can elevate the risk for breast cancer.

Following more than 300 women enrolled in the PEPI Trial over a three-year period, Dr Elizabeth Barrett-Connor, of the University of California San Diego, and a multi-center team examined the effects of different hormone replacement therapy regimens on changes in mammographic density of the breasts.

Over the course of three years, the women followed one of four hormone replacement regimens or placebo:

    1. Estrogen: conjugated equine estrogens (CEE), used alone. This would be essentially equivalent to taking Premarin alone, a synthetic estrogen. [Note: It is well established that women taking estrogen alone, without progesterone (natural or synthetic), are at higher risk for uterine cancer.2]

    2. Estrogen plus progestin: CEE and synthetic cyclic medroxyprogesterone acetate (MPA), used cyclically. This would be essentially equivalent to taking Premarin plus Provera, whereby Provera is taken on a cyclic basis. Most physicians  recommend cycling  three weeks on and one week off. The study cycled this progestin by having the women use it for 12 days per month.

    3. Estrogen plus progestin: CEE and MPA, used daily. This would be essentially equivalent to taking Premarin and Provera daily.

    4. Estrogen plus natural progesterone: CEE and micronized progesterone (MP), used cyclically. This would be the essential equivalent of taking Premarin and natural progesterone, whereby natural progesterone was taken on a cyclic basis, not daily. Natural progesterone is also referred to as micronized progesterone.

All the women had no history of taking estrogen for at least five years prior to the study. Initially, all were given a baseline mammogram and at least one 12-month follow-up mammogram, according to a report in a recent issue of Annals of Internal Medicine.

Breast Density Increases
When the results were analyzed, women on an HRT program using estrogen exclusively had a mammographic density increase of approximately 8% compared to their initial baseline mammographies. Those who used an HRT program with combined estrogen-progestin had a 19-24% increase in  mammographic density,  most often within the first year. More specifically, those taking a progestin on a daily basis had the 19% increase, and those taking the progestin cyclically (12 days during the month) had the increases of 24%. Women who were taking the estrogen-natural progesterone regimen (on a cyclic basis) resulted with increased densities of 16%. No studies were performed for daily estrogen-natural progesterone usage. By contrast, increases in mammographic density were "rare" among women in the placebo group.

Progestin: Higher Risk for Breast Cancer
The findings indicated that estrogen-progestin regimens were 7 to 13 times more likely than estrogen alone to cause increases in mammographic density. What is clear is that estrogen-natural progesterone users had less breast density increases than estrogen-progestin users regardless of whether the progestin intake was daily or cyclic. It is probable, since daily progestin usage resulted in less density than for cyclic progestin users, that the same would hold true for natural progesterone use too. Meaning, if the researchers would have tested for a regimen of daily estrogen-natural progesterone intake (not just a cyclic regimen), then in all probability, breast density results would be much lower than 16%, and even perhaps approach the values of using estrogen alone. Bottom line: natural progesterone is a better option. And progestins appear to offer no advantage, but in fact, may offer a higher risk for breast cancer.

At the end of the first year, the probabilities of continued increases in breast density were calculated. The results paralleled those of the preceding study. In declining order, the results were: estrogen plus cycled progestin at 13.1%; estrogen plus daily progestin at 9.0%; and estrogen plus cycled natural progesterone at 7.2% - compared to estrogen alone. Cyclic progestin was associated with a bigger increase in breast density than daily progestin. Natural progesterone was less yet. In fact, estrogen with natural progesterone was nearly 31% less than cyclic progestin and 45% less than daily progestin.

The investigators were concerned because of the consistent link between greater mammographic density and an increased risk of breast cancer. While the underlying mechanisms of this association are not clear, the relationship is worrisome and "strong." This is not so surprising for those schooled in natural HRT.

Progestin-Induced Heart Attack
Less than two years ago, another study was done using estrogen, either along with progestin or natural progesterone, in menopausally-induced rhesus monkeys.3 The progestin used was medroxyprogesterone acetate (MPA, the same drug as Provera, the most widely prescribed synthetic progesterone in the U.S.). In the short period of four weeks, progestin caused severe coronary artery deterioration, leaving the monkeys susceptible to heart attack and death. When platelet-forming drugs induced heart attack in the monkeys, they had to be treated with emergency rescue medication. Otherwise they would have died. However, those monkeys receiving natural progesterone plus estrogen, or estrogen alone, were found to recover rapidly without the use of emergency drugs. In the judgement of the researchers, MPA or Provera (but not natural progesterone) increases the risk of coronary vasospasm.

Progestin, a synthetic that is similar to human progesterone, appears to be inferior to natural progesterone, which is identical to the hormone naturally produced in the human body. In the words of researcher Kent Hermsmeyer, PhD, "The big surprise is that [Provera] poses such a huge risk. This is really a dangerous drug."4

Progestin: Worse Than No Treatment At All
Another scientist doing work with monkeys at Wake Forrest University is not surprised.5 In an editorial comment in the same issue of Nature Medicine, Dr J. Koudy Williams stated that based on his own research, Provera (synthetic progesterone) can counteract the beneficial effects that estrogen therapy has on heart disease. On the same side are other scientists, who have long suspected the destructive influence of Provera on coronary function.6 At London's National Heart and Lung Institute, a group of scientists have concluded that natural progesterone can actually reduce platelet aggregation (clumping of blood cells which can form harmful clots).7 About Provera, Dr Williams warns, "It's worse than no treatment at all."

Natural Progesterone is Safer
When you take the statements above into consideration, and then review the comments made by Dr Barrett-Conner and her colleagues about their own findings, it is puzzling that the PEPI group does not appear very alarmed about their own results. They themselves indict progestins, and support that natural progesterone is safer. Dr Barrett-Conner and her colleagues were cited as saying " . . . increases in density found in the PEPI Trial may confer some as yet unquantifiable increase in risk. Further study of this potentially important risk stratifier is warranted."

The glacial pace of discoveries generated by the PEPI Trial is creating a growing number of more aware and knowledgeable scientists, physicians, and other health care providers. These professionals have studied natural hormone replacement and understand that natural progesterone is far superior to any synthetic progestin regimen. They understand that natural progesterone can lend increased protection against heart disease, osteoporosis, and probably breast cancer.


  1. Greendale GA, Reboussin BA, Sie A, Singh HR, Olson LK, Gatewood O, Bassett LW, Wasilauskas C, Bush T, Barrett-Connor E. Ann Intern Med16 Feb1999;130:262-269.
  2. Fujimoto J, Hirose R, Sakaguchi H, Tamaya T. Estrogen dependency in uterine endometrial cancers. Oncology1998 Dec;55 Suppl 1:53-59.
  3. Miyagawa K, Rssch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nature Med.1997;3:324-327.
  4. Raloff J. Hormone Therapy: Issues of the Heart. Science News.1997;151;140.
  5. Williams JK, Adams MR. Estrogens, progestins and coronary artery reactivity. Nature Med.1997;3:273-274.
  6. De Ziegler D. Cardiovascular effects of the ovarian hormones. Arch Malad Coeur Vais1996;89(suppl):9-16.
  7. Jiang C, Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P. Progesterone induces endothelium-independent relaxation of rabbit coronary artery in vitro. Eur J Pharmacol.1992;211:163-167.

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