Helen Pensanti, M.D.

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Why Natural Progesterone is better than Synthetic

by Jim Paoletti RPh

I am often asked about the statement “she doesn’t need progesterone if she doesn’t have a uterus.” It’s hard to conceive that medical schools are still teaching the idea that a woman without a uterus does not need progesterone. It’s also hard to believe that large number of practitioners consider this statement true, since it is not supported by physiology, biochemistry or science.

Synthetic progestins do not have the same actions as progesterone outside of the uterus. In fact, medroxyprogesterone acetate (MPA), the most frequently prescribed synthetic progestin in the U.S., produces the exact opposite effects of endogenous progesterone in almost all, if not all, organs or systems outside of the uterus. The drug first given to us to mimic the effects of natural progesterone works only like progesterone in one organ and everywhere else produces the exact opposite effect of progesterone!

This misguided philosophy results in practitioners not giving progesterone or progestins to patients who have had a hysterectomy, and therefore practitioners never see a direct comparison of the effects of the two different agents on the rest of the body. The above statement helps to keep practitioners from comparing the known proven effects of progesterone on many body systems to the results caused by administration of the “progesterone-mimicking” synthetic progestins. If practitioners would look at the lack of science behind the statement, and the body of evidence supporting overall health benefits of progesterone itself, synthetic progestin use would most likely plummet.

Limiting the use of progesterone to women who have a uterus ignores the science that progesterone has beneficial effects outside of the uterus. Progesterone receptors have been identified in almost every cell in the body; therefore, progesterone has functions throughout the entire body. A quick look at the evidence shows many favorable effects of progesterone, whereas MPA produces unwanted side effects or risks which are the exact opposite of the actions of progesterone.

Breast cancer risk is a chief concern for the majority of women considering hormone replacement therapy. Evidence overwhelmingly shows that any synthetic progestin use, even for a limited time, increases the risk of breast cancer. The longer the use of progestin, or the more testosterone-like the synthetic progestin, the greater the risk becomes. The studies may disagree on how high the risk increase is, but they all agree that synthetic progestins significantly increase the risk of breast cancer. The mechanisms have been identified for the most part, and they are opposite to the mechanisms of endogenous progesterone in breast tissue.

In opposition to the increased risk of synthetic progestins, bioidentical progesterone has been shown to possess anti-proliferative and anti-cancer properties. A low level of endogenous progesterone is associated with an increased risk of breast cancer. Clinical studies suggest progesterone therapy protects against breast cancer. Some studies have even shown a decreased risk of breast cancer when natural progestin is added to estrogen therapy.

Speroff’s textbook, Clinical Gynecologic Endocrinology and Infertility, states that the proliferative action of estrogens and the progesterone actions of differentiation and apoptosis are the same in the breast tissue as in the uterus. Therefore, progesterone, and only progesterone, can protect the breast tissue from cancer by the same mechanism that any progestin protects the uterus. Looking at the science, the above statement needs to be modified to “she doesn’t need progesterone if she doesn’t have a uterus or breasts.”

The number one killer of women over the age of 50 is cardiovascular-related events. MPA has been shown to completely negate the favorable effects of estrogen on the maintenance of a healthy lipid profile and the cardiovascular benefits of estrogen, and significantly increase cardiovascular risks. In contrast, progesterone works synergistically with estrogen to increase lipid maintenance and cardiovascular health. Based on the difference between MPA and progesterone, the writers of the largest hormone study at its time, the 1995 PEPI study, concluded that “we should be giving woman natural progesterone” (this conclusion has still to be incorporated into mainstream medicine). Based on the evidence, the statement needs to be modified to “she doesn’t need progesterone if she doesn’t have a uterus, breasts or a cardiovascular system.”

Other major health concerns for the aging female patient are the development of osteoporosis and dementia. Progesterone works synergistically with estrogen to provide better bone remodeling through stimulation of bone growth, while progestins do not. While progesterone provides neuroprotective benefits for the nervous system, side effects of synthetic progestins are the opposite. Now we need to correctly state, “she doesn’t need progesterone if she doesn’t have a uterus, breasts, a cardiovascular system, bones, or a brain!”

Additional evidence continues to demonstrate the opposite effects of progesterone vs. the synthetic substitutes. MPA is proliferative and inflammatory; progesterone has been demonstrated to be neutral or slightly anti-inflammatory and anti-proliferative in its actions. Progesterone is the drug of choice for protection from further damage in traumatic brain injuries, and in at least two small studies progesterone has been shown to help reverse the debilitating effects of brain injury. MPA causes degenerative changes in the liver, while progesterone does not. Physiologic levels of progesterone augment the release of insulin from the pancreas, while synthetics increase insulin resistance.

The evidence clearly indicates that bioidentical progesterone provides a number of protective benefits not offered by synthetic progestins. Synthetic progestins instead increase risks associated with loss of these protective benefits. Therefore, I would recommend that our health professional educators examine the evidence and teach what the scientific evidence demonstrates: a woman does not need a progestin if she does not have a uterus, but she requires progesterone when it becomes deficient in perimenopause to continue to provide protection of her breasts, heart, blood vessels, bones, nervous system muscles, liver, skin, and perhaps much more yet to be discovered.


Helen Pensanti M.D.

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