The more we know, the more we realize we don’t know…if we are honest with ourselves.



Know your number?  Know you numbers?  That is how the marketing goes for Testosterone.  As if the Testosterone number is all there is to know.   The same could be applied to women.  Instead of the low T marketing campaigns, we could all be bombarded with low P commercials instead.  The same logic would apply— women struggle with “low P” the same time men start to struggle with “low T”.  So why no “low P” campaigns?  We learned years ago that focusing on the “low P” loses the forest for the trees.  With men, medicine is repeating the same mistakes that it made with women decades ago.  


The more appropriate question is— is the individual healthy?  Instead of the question what is your number, the better questions would be— what is your hormone balance, what are your hormone receptors, and what is your hormone metabolism.  Know what your body is doing with the hormones that are produced endogenously or given as replacement exogenously.  The key moment for evaluation would be prior to the initiation of hormone therapy.  The same questions could and should be applied to all hormones. I have previously applied these questions to Testosterone metabolism and Cortisol metabolism.  This post, I will apply the questions to Progesterone and Progesterone metabolism.



Dr John Lee was the first to bring Progesterone to the forefront of our collective hormone consciousness.   Thank goodness for Dr Lee.  His writings and contributions can not be underestimated.  Others, such as Dr Zava are equally important.  As it was presented, Progesterone was the answer to all hormone imbalances in women.  In fact, a declining Progesterone is the first significant hormone problem for a women in the peri-menopause years.  For some women, this decline in Progesterone occurs much earlier in PMS and PCOS.   Just give Progesterone, balance Estradiol, and all things were right with the world—at least that is the way it was presented.  Then there is the “Progesterone steal” effect and adrenal fatigue advocated and presented by Dr Wilson.  That is what was and is still presented to the general public today.  The problem is that we now know better.  These presentations are just a part of the Progesterone story.


A recent interview on FoxNews highlights this topic well.  The host of the show, Carol Alt, interviewed the author of a book discussing Hormones in women.  The author of this book was correct in many of her assertions, but many were not up to date.  Progesterone was presented as the means to a women’s quest for Health end.    Again, this is a simplified and out of date view on Progesterone, but also on hormones in general.


Progesterone metabolites.


For years, hormones were presented simply as hormones and hormone metabolismHormones were active and metabolism was simply the means to eliminate the hormones once used.  The elimination of the hormones was via the hormone metabolitesHormone metabolites were the inactive counterparts to the active hormones themselves.  Funny thing that happens along the way to truth—it has been discovered that many of these once thought inactive metabolites actually have significant biologic activity.   Now, we began to look at these hormone metabolites in a little different light.  At least the scientific literature says we should.  Unfortunately, the average medical provider does not.  Remember, a 2001 Institute of Medicine report found that the average physician practices medicine 17 years behind the current science.


Progesterone metabolites are as they are described.  Progesterone metabolites are the products of Progesterone metabolism.  Metabolism is often limited to the discussion of weight gain/weight loss.  However, metabolism is the process by which the body must undergo every second of every day to heal, regenerate, fight disease, and survive.  For hormones, hormone metabolism is the process by which hormones are altered step by step along the metabolic pathway to elimination.




                                                                                                                                                                                                              figure 1


What the body does with hormones is almost as important as the hormone deficiency or the hormone imbalance itself.   Progesterone has several paths that it may take along the pathway of metabolism.  Figure 1 above highlights 2 such pathways and their diverse physiologic effects.  Five enzymes play primary roles in Progesterone metabolism:


  • 5alpha-reductase
  • 3alpha-hydroxysteroid oxidoreductase (3HSO)
  • 3beta-hydroxysteroid oxidoreductase
  • 20alpha-hdyroxysteroid oxidoreductase (20HSO)
  • 6alpha-hydroxylase.


These enzymes determine the pathway of Progesterone metabolism and the resultant Progesterone metabolites.  Remember, for many years Progesterone has been claimed to be anti-inflammatory, anti-tumor, and even protective against breast cancer in comparison to synthetic progestins.  That statement is in its entirety is true, but incomplete.  Progesterone metabolites tell the rest of the story.  Progesterone metabolites may not equate themselves to a 30 second marketing sound bite, but they help to complete the hormone picture—a picture provided through scientific truth.


Progesterone metabolites can be divided broadly into 2 categories: 5alpha-pregnanes and 4alpha-pregnanes (see figure 2).  The primary 5alpha-pregnane hormone metabolite is 5alpha-hydroProgesterone, which is the product of the enzyme 5alpha-reductase.  In contrast, the primary 4alpha-pregnane hormone metabolites are 3alpha-hydroProgesterone and 20alpha-hydroProgesterone, which are products of the enzymes 3alphaHSO and 20alphaHSO respectively.  Understand that these are not the only Progesterone metabolites identified.  They just provide the current understanding of Progesterone metabolites and their effects on breast tumors, which is where the majority of the research on Progesterone metabolites has been done.  With time, our understanding can and will change.




                                                                                                                                                                                                   figure 2


What is evident currently is that the 4alpha-pregnane Progesterone metabolites decrease inflammation and tumor growth potential, whereas the 5alpha-pregnane Progesterone metabolites increase inflammation and tumor growth potential (see figure 1 above).  In fact, the balance of the 2 categories of Progesterone metabolites can be used to estimate tumor potential.  Think of that, the ability to determine the tumor potential of a hormone, Progesterone in this case, prior to the initiation of therapy.  Breast tumors produce more 5alpha-pregnanes.  In contrast, healthy breast tissue produce more 4alpha-pregnanes.  The balance of these 2 metabolic pathways provide insight into the disease potential of breast tissue.  An elevated 5alpha-preganane:4alpha-pregnane ratio is associated with an increase tumor potential.  This disease potential is not from the Progesterone “number”, but from the movement of Progesterone metabolism and the resultant production of metabolites.  This almost leaves the “number” irrelevant.


The balance of 4alpha-pregnanes and 5alpha-pregnanes provides insight into the disease potential.  What about the individual Progesterone metabolites themselves?  The 4alpha-pregnanes, via 3HSO enzyme activity, have been shown to increase apoptosis (programmed cell death), decrease cell proliferation (growth), and decrease cell attachment (important in metastasis of cancer).  In contrast, the 5alpha-pregnanes have been shown to increase cell proliferation, decrease cell apoptosis and increase cell attachment.  In tumor potential, cell proliferation or inhibition of cell proliferation is self-explanatory.  Apoptosis is a key step the body can use to protect itself.  Apoptosis is programmed cell death.  If the cell detects abnormal function, such as compromised energy production or abnormal growth, the body can tell that cell to destroy itself.  Metastasis requires the ability of cancer cells to break free from the primary tumor and reattach to tissue in a remote location.  This could be considered a rate-limiting step in metastasis.  If the cancer cells ability to detach from the primary tumor is decreased and the ability of the cancer to reattach to a foreign site is decreased, then a key step in the metastatic potential of a tumor is lost.  In contrast, if a cancer cell has an increased capacity to detach from the primary tumor and increased capacity to attach to a foreign site, then the metastatic potential is increased significantly.  John P. Weibe  summarizes it well through the statement: “the enzyme activity and expression studies strongly suggest that 5alpha-reductase stimulation and 3alpha- and 20alphaHSO suppression are associated with transition from normalcy to cancer of the breast”.  This points to the evidence that Progesterone metabolism plays a crucial role in the transition to cancer.


These Progesterone metabolites are very much biologically active and significantly involved in health versus disease potential in the breast.  Let’s take this one step further, Progesterone metabolites can even regulate each other.  This is very similar and reminiscent to the regulation that Estrogen receptor beta (ER-beta) has on Estrogen receptor alpha (ER-alpha), which I discuss in my bookMan Boob Nation”.  A quick review of estrogen receptors:  ER-alpha promotes inflammation and proliferation in breast and prostate tumors, whereas ER-beta inhibits inflammation, proliferation, and inhibits ER-alpha expression.  The loss of ER-beta expression in the prostate is critical to the initiation and progression of cancer.  Likewise, the 4alpha-pregnane, 3alpha-hydroProgesterone, decreases the stimulatory effects of the 5alpha-pregnane, 5alpha hydroProgesterone.  In cell culture studies by Weibe et al., this inhibition of 5alpha-hydroProgesterone by 3alpha-hydroProgesterone occurs when applied at the same time (see figure 3).  It is one thing to counter the pro-tumor potential when applied at the same time and no tumor exists.  However, studies have shown that 3alpha-hydroProgesterone can decrease tumor growth even once 5alpha-hydroProgesterone stimulated tumor growth has occurred.  You may not be a biochemistry junky like me, but that is just cool!



                                                                                                                                                                                                                figure 3

The next point about Progesterone metabolites, brings into the light the serious problems with the “women are just estrogen” approach to Hormone Replacement Therapy (HRT) that dominates today.  Above, I reviewed the scientific literature of how the different Progesterone metabolites can either increase tumor potential or decrease tumor potential.  What about EstrogenEstradiol is the most potent Estrogen and is the primary mode of HRT for women today.  Estradiol has been shown to increase the production and expression of the receptors for 5alpha-hydroProgesterone.  Remember, this is the Progesterone metabolite that inhibits apoptosis, increases proliferation, increases reattachment (increased metastatic potential), all of which increase disease potential.  Contrast this with the Progesterone metabolites 3alpha-dihydroProgesterone and 20alpha-dihydroProgesterone, which have been shown to decrease the production and expression of 5alpha-dihydroProgesterone receptor production and expression.


The story just continues.  Progesterone metabolites can effect the expression of the Estrogen Receptors (see above).  The Progesterone metabolite 5alpha-dihydroProgesterone increases ER-alpha expression.  In contrast, the Progesterone metabolite 3alpha-dihydroProgesterone increases ER-beta expression.  Tumor potential is increased with ER-alpha expression and decreased with ER-beta expression.


This really brings to light the questionable way that we use HRT in women today.  The standard practice HRT for women is Estradiol in those women after a hysterectomy.  Heck, even those with a uterus are still given this unopposed Estradiol therapy.  According to the study above, Estradiol will increase the expression of the Progesterone metabolite receptors that promote disease potential.  Add to that, now Testosterone is becoming a prominent addition to HRT in women—especially in the supra-physiologic pellet therapies.  Testosterone can be a primary source of Estradiol production in women post-menopause, which further increases the stimulation for production and expression of 5apha-dihydroProgesterone receptor expression—all this without the opposition of Progesterone.  If  Progesterone is metabolized down the 3alphaHSO and 20alphaHSO pathways to produce the 4alpha-pregnanes, then decreased 5alpha-dihydroProgesterone expression occurs, increased ER-beta expression occurs, increased apoptosis results, decrease proliferation results, and decreased attachment results—all of which reduce tumor potential.  In contrast, If Progesterone is metabolized down the 5alpha-reductase pathway to produce 5alpha-dihydroProgesterone, then increased tumor potential occurs through increased 5alpha-dihydroProgesterone receptor expression, decreased apoptosis, increase proliferation, and increased attachment (metastatic potential), and increased ER-alpha expression.


If only the story ended here.   This discussion has dealt just with Progesterone metabolites and cancer, particularly breast cancer risk.  The vast majority of research on Progesterone metabolites has been done in the area of breast cancer research. Progesterone metabolites have been shown to play a healing role in Traumatic Brain Injuries (TBI).  The  production of Progesterone and its metabolite Allopregnanolone has been shown to increase in the presence of TBI and appear to play an important role in inflammation reduction and the promotion of healing post TBI.  The metabolite 5alpha-dihydroProgesterone (5alpha-pregnane) has been shown to play a role in the healing effects of the brain post TBI as well.  This makes sense when you remember that the 5alpha-pregnanes increases proliferation.  A pro-proliferative signal would be critical in the recovery phases of TBI–how else could the brain heal, repair, and regenerate?  But, this doesn’t make sense when you consider that 5alpha-pregnanes promote a pro-inflammatory response in breast tumors–but maybe that is just in breast tumors?  I never said we had everything worked out.


Complex?  Yes, it is.  But, complexity that can be evaluated prior to the initiation of HRT and during HRT to prevent untoward sided effects and complications from needed hormone therapy.



Know your number?  Know your numbers—whether it is Testosterone or Progesterone?  Hardly a sufficient step to provide Health and Wellness.


I will close with a great quote from a recent journal publication:


“steroid hormones are known to be converted to many other steroids occupying different receptors and thereby exerting various different effects…”

Johannes Huber


Know your Hormone metabolites.