Progestin Drugs: More Side Effects & Risks

by Lara Pizzorno, MDiv, MA, LMT

Progestins – what other risks and side effects could they cause besides breast cancer, bone loss, cardiovascular disease and loss of libido?

Progestins were designed to bind to the progesterone receptor on cells and mimic a couple of the protective actions of progesterone. However, we now know that these drugs bind not just to the progesterone receptor, but also to the androgen receptor, glucocorticoid receptor, and mineralocorticoid receptor, and most recently, it has been noted that the estrogen receptor is a progestin target as well.

To give you an idea of what these unintended bindings could do, let’s look at what normally binds to the androgen, glucocorticoid and mineralocorticoid receptors.

DHEA, testosterone, and its metabolite, dihydrotestosterone (DHT) are what our bodies expect to be binding to the androgen receptor.

Just think about what might go awry in a woman’s body if her androgen receptors get abnormally blocked off by progestins. Bye-bye libido, for one thing. Another outcome, already noted in our article on Side Effects of Progestins, is breast cancer.1

Yes, you may be surprised to learn that normal breast metabolism involves a delicate balance between estrogens and androgens. Androgen signaling opposes and balances estrogen signaling.  Estrogen promotes breast cell proliferation. Androgen signaling opposes this and inhibits the growth of breast cancer cells. Progestins upset this balance, allowing unopposed estrogen stimulation and breast cell proliferation – which is just one of the ways progestins promote breast cancer.

So, progestins act as endocrine disruptors, negating the protective effects of androgen signaling in the breast. How else are these drugs acting as endocrine disruptors? Good question. No one knows.

Cortisol is what our bodies expect is going to be binding to the glucocorticoid receptor

Cortisol, the hormone that enables us to deal with stress and impacts virtually every aspect of our immune and inflammatory responses, is what is supposed to be binding to the glucocorticoid receptor. It turns out, however, that the progestins have a higher binding affinity to the glucocorticoid receptor than cortisol. So, if progestins are around (and they remain in the human body for a much longer time than progesterone), they will supplant cortisol.

What might be the repercussions of progestins supplanting cortisol on the body’s ability to deal with stressors, on the immune and inflammatory response? Good question — and one that the purveyors of these drugs and the FDA have not looked into. So far, to quote the research, they’re guessing that progestins’ “negative effects on bone density and immune function are most likely [italics added] mediated by glucocorticoid receptor agonism [an action of progestins, but not progesterone].”2 Will there be even more problems? Another good question.

Aldosterone and progesterone are what are supposed to bind to the mineralocorticoid receptor

Aldosterone and progesterone are what normally bind to the mineralocorticoid receptor. Although aldosterone is mainly recognized for promoting sodium reabsorption in the kidneys, and therefore water retention which can cause high blood pressure, aldosterone also affects the central nervous system, and the functioning of the endothelium (the lining of our blood vessels) and the heart.

When progesterone binds to the mineralocorticoid receptor, it prevents excessive aldosterone binding, prevents water retention and maintains normal, healthy blood pressure. Most of the progestins don’t bind to the mineralocorticoid receptor, so they confer none of these protective effects, and in fact, promote just the opposite.

Only the 4th generation progestins bind to the mineralocorticoid receptor, but they do so much less effectively than progesterone.  Researchers think that “the increased blood pressure, weight gain and risk of cardiovascular disease [caused by the progestins] are most likely [italics added] due to lack of mineralocorticoid receptor antagonism in the colon and kidneys”2 [Real progesterone is a mineralocorticoid antagonist].

On the flip side, because the progestins hang around a lot longer than progesterone, some researchers have suggested that even the progestins’ weak binding may help – or it could cause excessively low blood pressure. Once again, no one knows.

Estrogen is what is supposed to be binding to the estrogen receptor

The progestins are not supposed to do so, but to quote the latest review article on the subject: “However, it is possible that MPA and NET [the two most widely prescribed progestins] do act via the estrogen receptor, although the evidence is contradictory…Both MPA and NET-A have previously been reported to bind estrogen receptors both in vivo (in the rat uterus) and in vitro.”2 What might the effects of this be? You guessed it: no one knows. No one has even thought about it – yet.

In sum, the progestins are a diverse group of new-to-nature molecules that were supposed to just bind to the progesterone receptor and mimic some of progesterone’s protective actions. In fact, these drugs have estrogenic, androgenic, glucocorticoid, and mineralocorticoid activity. And no one knows what the results of these actions will be.

What we do know is that any of these bindings by progestins to any of these receptors can distort normal functioning in a woman’s body. The results? To be determined by what happens to the millions of women taking these drugs.  No kidding! It’s a crapshoot.

A key question for the women taking these drugs – and the men who love them – is: “Are you willing to participate in this experiment?”

For more information on drugs and formulations used in hormone replacement therapy, see our following articles:

Stay Young & Sexy with Bio-Identical Hormone Replacement: The Science Explained

This article summarizes key points presented in-depth in almost 500 pages in Stay Young & Sexy with Bio-Identical Hormone Replacement, the Science Explained by Jonathan V. Wright, MD, and. Lane Lenard, PhD. This book is the definitive resource on Bio-identical Hormone Replacement Therapy and fully explains why BHRT is the best option for women, not only to alleviate the discomforts of menopause, but to prevent the long-term negative health consequences of our aging-related decline in sex hormones.


  1. Birrell SN, Butler LM, Harris JM, et al. Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer. FASEB J. 2007 Aug;21(10):2285-93. Review.
  2. Africander D, Verhoog N, Hapgood JP. Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids. 2011 Jun;76(7):636-52.