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Progesterone Side Effects: Understanding the Research


Progesterone side effects, and hormone replacement in general, are subjects surrounded by controversy and confusion.  Many women want to know if there are natural progesterone cream side effects. While I cannot begin to cover the subject completely, I have tried to give you statements from doctors and others on both sides of the issue.  


I have tried to avoid the extremes on both sides of the argument about progesterone side effects:  statements concluding that there are no risks or progesterone side effects with the use of bioidentical progesterone, and statements concluding that there are no studies proving safety or effectiveness of bioidentical progesterone.  


The truth seems to lie somewhere in the middle, and I hope I have given you enough information to explore the issue further on your own, if need be, or at least be a more informed patient or consumer regarding progesterone side effects.


It may help to keep in mind the following statement from Kent Holtorf, M.D.  In referring to a study published in JAMA and the New England Journal of Medicine, Holtorf (2011) says, “It takes on average 17 years for a new proven concept to get accepted in mainstream medicine.”


Unfortunately there are no easy answers to the questions of bioidentical progesterone side effects or increased risks with any other hormone.  


In the case of traditional HRT, some doctors feel it is okay to increase a risk for one nasty disease in order to reduce a risk for another.  To me, this sounds ridiculous.  What kind of a choice is that??


Part of the problem is that we are not investigating other less risky alternatives, like nutrition, with the same enthusiasm, mostly because of money.  The profit motive just isn't there.  


It's also our own fault, in a way.  How many of you would rather change your diet or start exercising than take a pill?  The pill is easy, the lifestyle changes take commitment.


Defining Terms for Progesterone Side Effects: Progesterone, or Progestin?  Progestin or Progesterone?  Natural or Synthetic?

While there are two main types of man-made (yes, they are all man-made) progesterone, it can be difficult, and sometimes impossible, to tell which type someone might be talking about.  


Even research websites participate in the confusion, calling either type progestins or progesterone, as if the bioidentical version and the non-bioidentical version are one and the same.  They are not.  


However, when you are researching progesterone side effects, you will always need to ask which of these progesterone types the writer is referring to.  This is no small task, as, due to power and politics, each “side” claims a descriptive term for their own.


For example, proponents of bioidentical progesterone also call it natural progesterone.  But critics of bioidentical progesterone claim that non-bioidentical progesterone is as natural as bioidentical progesterone, so it could also be called natural.


Same with synthetic.  Critics of bioidenticals point out that these hormones are also made in a lab, just like non-bioidentical progesterone.  


The Free Dictionary (“Progestin,” n.d.) has this definition for progestin:  “A natural or synthetic progestational substance that mimics some or all of the actions of progesterone.”


And here is their definition of progesterone ("Progesterone," n.d.):  

“1. A steroid hormone, C21H30O2, secreted by the corpus luteum of the ovary and by the placenta, that acts to prepare the uterus for implantation of the fertilized ovum, to maintain pregnancy, and to promote development of the mammary glands.  2. A drug prepared from natural or synthetic progesterone, used in the prevention of miscarriage, in the treatment of menstrual disorders, and as a constituent of some oral contraceptives.”


The only term that is not claimed by both sides is bioidentical.  If you see this term used, you can be sure of what the writer is talking about.  


If you see progesterone, progestogen, progestin, natural or synthetic, you will not necessarily know which type of hormone is being written about, although “natural” is still used by many people to refer to “bioidentical,” and “synthetic,” usually describes the non-bioidentical form of the hormone.


Despite what critics of bioidentical hormones say, each substance acts differently in your body.  


In fact, whether you take your hormone by mouth or through the skin also effects the actions on your body, which will determine progesterone side effects.


Should You Take Bioidentical Progesterone?

According to Nan Kathryn Fuchs (2009), a nutritionist, it is always best to start with diet and other lifestyle changes.  You can also try herbal solutions, such as maca root, or vitex.


If, after making these changes, your risk for heart disease and breast cancer is still high, you may want to consider taking progesterone.  


Fuchs (2009) says, “Progesterone cream can help prevent breast cancer in women with estrogen dominance (high levels of estrogen).  In these cases, there are studies that support the careful use of low dose bioidentical progesterone.  Some found it protects against breast cancer.”


Progesterone Side Effects and Your Liver

Taking any kind of hormones sets you up for the possibility of having more than you need.  Excess hormones can affect liver and pituitary function.


Poor liver function can lead to high cholesterol, immune function problems and inflammation.  


Chronic inflammation is associated with heart disease, Alzheimer's disease, asthma, ulcerative colitis, Crohn's disease, and some types of cancer.


Bottom line is, if you can avoid hormone treatment, you may be better off.  If you need it, most health professionals now recommend taking as little as possible for the shortest amount of time. This will minimize any potential progesterone side effects.


My Experience - No Progesterone Side Effects


I had an extremely difficult menopausal transition.  I used over the counter progesterone cream for a couple of years in perimenopause, and it helped me sleep (very important for many health reasons), evened out my moods, and seemed to eliminate my headaches.  


Then I stopped, and for about five years, I took no hormones.  About three years post-menopause, I was feeling worse and worse (no energy, plenty of brain fog, and joint stiffness and pain), I began taking compounded bioidentical estradiol, testosterone, and progesterone by prescription.


These products helped me through a very difficult time.  After a year and a half, I found a doctor using functional endocrinology to help with my autoimmune thyroid disease, and with the help of supplements and dietary changes, I stopped using the bioidenticals and I am now, once again, hormone-free.  


I did not even have the dreaded withdrawal symptoms!  I feel much better than expected, although I do still have hot flashes.  I have never found anything to eliminate them, but they don't bother me much anymore.


While there are those who will say that bioidentical progesterone is untested and not proven to be safe and effective, a review of some of the studies begins to paint a different picture.


Bioidentical Progesterone Side Effects

There are some things to keep in mind when using bioidentical progesterone.


Fuchs (2009), notes, “While natural progesterone has been used to reverse vaginal atrophy-common in postmenopausal women-when you take progesterone without having sufficient estrogen, it can actually contribute to vaginal atrophy.”


According to drugs.com (“Progesterone Side Effects,” n.d.), these are common side effects of progesterone.  “Bloating; breast tenderness; diarrhea; dizziness; drowsiness; dry mouth; fluid retention; headache; heartburn; irritability; muscle pain; nausea; stomach pain or cramping; tiredness; vomiting.”


According to the late Dr. John Lee (Lee & Hopkins, 1996), “Some women report estrogen dominance symptoms for a week or so after starting progesterone, but this is caused by a sensitization of estrogen receptors and generally disappears within a few weeks.  If you're still having periods and you take progesterone out of phase with your cycle, it may change the timing of your periods or cause some spotting.”


Some of the symptoms of estrogen dominance are bloating, swollen/tender breasts, headaches, and mood swings.  For more about this, see symptoms of too much estrogen.


Decreased Risk for Heart Disease and Breast Cancer

Kent Holtorf, M.D.,(n.d.), discusses a statement from the American Heart Association: “Based on the results from the PEPI Trial and other studies, the President of the American Heart Association stated that, just based on this difference in the effects on HDL, a woman who changes her medication from MPA to natural progesterone would significantly lower her risk for heart disease.”


Adriane Fugh-Berman, M.D., and Jenna Bythrow, MS candidate (2007), make a more conservative statement about progesterone side effects: 


“Little information is available about long-term effects of micronized progesterone.  There is preliminary evidence from E3N-EPIC, a large French cohort study of 98,997 women followed up for a mean of 5.8 years, that hormone regimens incorporating micronized progesterone rather than other progestogens may be safer in terms of breast cancer risk.  However, this is an observational study, not an RCT [randomized controlled trial], that included hormones rarely used in other countries.”


Deborah Moskowitz, N.D. (a naturopathic doctor), (2006) talks about a reduced risk for ateriosclerosis: “One study comparing MPA to progesterone demonstrated progesterone  reduced the risk for arteriosclerosis by inhibiting vascular cell adhesion molecule-1 (VCAM-1), whereas MPA [medroxyprogesterone acetate, a form of non-bioidentical progesterone] did not.”


Oral progesterone (Bioidentical)

Moskowitz (2006) reviews studies finding extra side effects from using oral progesterone: “Oral progesterone administration resulted in higher levels of progesterone metabolites (deoxycorticosterone, deoxycorticosterone sulfate and 5-alpha and beta pregnenalone) when compared to vaginal administration...progesterone and its metabolites have differing effects in the brain, uterus, smooth muscle, and oocyte...

Given the increase in metabolites seen with OMP [oral micronized progesterone], vaginal or topical delivery systems may reduce expression of side effects attributed to these effects.”


Natural Progesterone Cream Side Effects

If you are going to use natural progesterone cream (bioidentical), then you need to find a doctor that will prescribe an FDA-approved version, or one who uses compounding pharmacies.  If you cannot do this, there are creams available over the counter.  See bioidentical progesterone for more information.


Progesterone Side Effects If You are Taking Estrogen

The thinking is that if you are taking estrogen in any form, it can lead to a higher risk of endometrial cancer.  To counteract that, some form of progesterone is given, however, natural progesterone cream (bioidentical) may not provide the same protection as other forms of progesterone.


This is noted by Fugh-Berman & Bythrow (2007): “...it is unclear whether topical progesterone can effectively mitigate estrogen-induced endometrial stimulation...” 


Non-bioidentical Progesterone Side Effects: Increased Risk for Heart Disease and Breast Cancer

Holtorf (n.d.) finds evidence of increased risk with use of progestins: “The Nurses Health Study followed 58,000 postmenopausal women for 16 years (725,000 person-years).  The study found that, compared with women who never used hormones, use of unopposed estrogen from ages 50 to 60 years increased the risk of breast cancer to age 70 by 23%.  The addition of a progestin to the estrogen replacement resulted in a tripling of the risk of breast cancer to a 67% increase in the risk of breast cancer.”


In another article, non-bioidentical progesterone is found to have negative effects on glucose metabolism and more:  Panay & Fenton  (2010) state, “The synthetic analogs of progesterone, i.e. progestins/progestogens...in addition to binding to the progesterone receptor, many of these compounds also bind to the glucocorticoid, mineralocorticoid, and androgen receptors.  This binding can lead to unwanted side effects such as unfavorable glucose metabolism, fluid retention, acne and weight gain.”


Kotz (2009), mentions another study related to a higher risk for breast cancer with non-bioidentical progesterone than with bioidentical progesterone:  “A European study of more than 80,000 postmenopausal women published last year in the journal Breast Cancer Research Treatment found that those who took progestins along with estrogen for an average of eight years had about a 70 percent higher risk of breast cancer than those who took bioidentical progesterone or who didn't use hormones at all.”


Another finding about non-bioidentical progesterone is it's effect on the liver:  Moskowitz (2006) says, “Normal liver function is essential for lipid metabolism.  Synthetic progestins retain undesirable effects on liver metabolism, even when administered through the skin.”


Progestins Increase Insulin Resistance

Holtorf (n.d.) notes, “MPA and synthetic progestins are also shown to significantly increase, even double, the amount of insulin resistance (Type II diabetes) when compared to estrogen alone or estrogen and progesterone.”


For the Future

Panay & Fenton (2010) tell us, “New randomized trials such as KEEPS and ELITE have been designed to study bioidentical hormones in the expectation that there will be a more favorable effect on cardiovascular risk markers.”


Whether or not you decide to use bioidentical progesterone or other bioidentical hormones, it's a good idea to keep up with the latest research so that you can make an informed decision about your health.


References

Fuchs, N.K. (2009).  I warned you about this hormone for nearly 30 years – now I can recommend it.  Women's Health Letter.  Vol. 15(7).  Retrieved December 28, 2011 from http://www.thefreelibrary.com/I+warned+you+about+this+hormone+for+nearly+30+years--now+I+can...-a0203532320 

Fugh-Berman, A. & Bythrow, J. (2007).  Bioidentical hormones for menopausal hormone therapy: Variation on a theme.  Journal of General Internal Medicine, 22, 1030-1034.  doi: 10.1007/s11606-007-0141-4 

Holtorf, K. (2011, August 17).  Emerging concepts in the diagnosis and treatment of hypothyroidism, part one.  [Webinar].  Retrieved January 3, 2012, from http://www.bioidenticalhormoneinitiative.org/hypothyroidism-part-one  

Holtorf, K. (n.d.).  Natural (bio-identical) vs. synthetic HRT: Literature review.  Retrieved December 29, 2011 from http://www.holtorfmed.com/handouts.html 

Kotz, D. (2009).  Bioidentical hormones: Safer for hot flashes than HRT?  U.S. News and World Report.  Retrieved December 27, 2011 from http://health.usnews.com/health-news/family-health/articles/2009/03/25/bioidentical-hormones-safer-for-hot-flashes-than-hrt 

Lee, J.R. & Hopkins, V. (1996)j.  What your doctor may not tell you about menopause.  New York, NY:Warner Books, Inc.

Moskowitz, D. (2006).  A comprehensive review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risks.  Alternative Medicine Review, 11(3), 208-223.  Retrieved from EBSCOHost.

Panay, N. & Fenton, A. (2010).  Bioidentical hormones: what is the hype all about? Climacteric, 13, 1-3.  doi: 10.3/09/3697/30903550250

Progesterone. (n.d.) In The Free Dictionary.  Retrieved January 3, 2012, from http://www.thefreedictionary.com/progesterone 

Progesterone Side Effects (n.d.).  In drugs.com  Retrieved January 3, 2012, from http://www.drugs.com/sfx/progesterone-side-effects.html 

Progestin. (n.d.) In The Free Dictionary.  Retrieved January 3, 2012, from http://www.thefreedictionary.com/progestin







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