Side Effects of the Progestins – The Drugs Used to Replace Human Progesterone in Conventional HRT

Progestins – used by millions of women as contraceptives & in HRT – increase risk of breast cancer and coronary heart disease

Progestins are prescribed to millions of women as contraceptives as well as HRT – despite the fact that the molecular mechanisms of action of these patented alien-to-nature medicines are very poorly understood.

As noted in a review published in June 2011 the journal Steroids,1 the importance of investigating what progestins do inside the human body, as compared to the actions of bio-identical progesterone, has been underscored by clinical evidence showing that medroxyprogesterone acetate (MPA), a first generation progestin, increases the risk of breast cancer and coronary heart disease in HRT users. Furthermore, the World Health Organization has recently cited birth control pills, which contain progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk.”

The pharmaceutical industry has now created a diverse range of later generations of progestins with varying structures that are FDA “approved” for use, and it is becoming clear that different progestins cause a wide variety of different effects.

It seems only rational that we fully understand what all these progestins are doing inside the millions of women worldwide who regularly take these drugs. In fact, it seems highly irrational that doctors are prescribing, and women are agreeing to take, progestins without a much better understanding of what they do!

Just what are the progestins?

Progestins are a class of man-made, new-to-nature compounds that are structurally different from progesterone and remain active in the body far longer than the natural hormone. The progestin drugs were created around 50 years ago to mimic some of progesterone’s actions and are now used in HRT and as contraceptives.

Progestins in HRT

Progestins were designed to halt proliferation of the lining of the uterus caused by estrogen. They were created to serve this purpose in women taking HRT because unopposed estrogen (especially when it is the super potent estrogens used in HRT, the conjugated equine [horse] estrogens), promotes breast and uterine cancers. For this reason, postmenopausal women on HRT are typically prescribed a combination of conjugated equine [horse] estrogens plus a progestin.

Unfortunately, multiple studies have now demonstrated that this combination (but not conjugated equine [horse] estrogens alone, so it’s the progestins at fault here), results in increased breast cell proliferation and breast density in humans, which is an established risk factor for breast cancer. In addition, these studies highlight the fact that the actions of the progestins are very different from those of the human hormone progesterone, which opposes breast cell proliferation.

What we already know about the progestins

First, it’s important to understand that many progestins have now been created and are being used, and the effects produced by these drugs differ, one from another.

The first progestins created were medroxyprogesterone acetate (MPA) and norethisterone enanthate (NET-EN), shortly followed by its first derivative norethisterone acetate (NET-A). These remain the most widely used female contraceptives; at least 20 million women are currently using MPA worldwide.

Many more synthetic progestins have been developed. We now have second, third and fourth generation progestins. Examples are levonorgestrel (LNG, 2nd generation), gestodene (GES, 3rd generation), and drospirenone (DRSP), dienogest (DNG) and trimegestone (TMG), all fourth generation.

All these drugs produce some progesterone-like effects, but they also produce a wide range of effects that differ greatly from those of natural progesterone. Plus, the progestins differ from one another in the effects each produces.1

The serious adverse side-effects already reported in women using progestins include:

  • Increased risk of breast cancer (MPA and NET)
  • Increased risk of cardiovascular complications in long term HRT users
  • Significant increase in shedding of HIV-1 DNA in humans
  • Decreased bone density
  • Increased blood pressure
  • Adverse effects on immune function
  • Adverse neurological effects

And progestins are also known to cause what the researchers classify as mere “minor effects”:

  • Mood swings
  • Weight gain
  • Hot flashes
  • Loss of libido

What we don’t know about the progestins

At the cellular level, progestins cause their effects by altering which genes get turned on in target cells, mainly by binding to and regulating the activity of the cell receptors for steroids. So, for example, the progestins’ progesterone-like effects have been thought to be the result of the drugs’ binding to the progesterone receptor in female reproductive tissues.

However, as the authors of the recent review in Steriods note, “many of their side-effects are most likely [italics added to emphasize the fact that we don’t know] due to binding to other members of the steroid receptor family in non-reproductive tissues.”1

As explained below, it has now come to light that the progestins not only cause a wide range of serious adverse side-effects, but also that these drugs are doing much more than they were designed to do, which was to bind to the progesterone receptor on cells and mimic a couple of the protective actions of progesterone. We now know that the progestins 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.

What’s the problem with progestins binding to all these steroid receptors?

In human bodies, our natural hormones are expected to bind to these receptors and to activate genes, which then produce thousands of compounds that interact symphonically with one another to create normal, healthy physiology. When the progestins bind, their effects on what genes get activated and the musical notes played in this symphony are truly out there in Star Trek territory: it’s the Vast Unknown. These drugs are literally taking human women where no one has ever gone before.

The scope of what could go wrong is pretty much limitless.

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. 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.)