Safe Use of Hormones: the Hard Evidence

by Etsuko Ueda, August 2011

"Is it safe? " is the big question on many people's mind when it comes to hormone supplementation today. I believe that question has been settled. In What Your Doctor May Not Tell You About Breast Cancer, estrogen is aptly called as "angel of life and angel of death". It's angel of life because it promotes cell growth and proliferation, the most noticeable for women being the monthly cycle of uterine lining buildup in preparation for pregnancy. It is angel of death because when it is not under progesterone's control, it can run amuck, creating and aiding the generation and growth of cancerous cells, blood clots, and coronary vascular spasm to list just a few. Don't confuse this protective role of progesterone with the destructive nature of progesterone substitutes (aka progestine or progestogen, there are several), which has been clearly demonstrated by WHI Clinical Trials in the U.S. and other studies that used fake progesterone.

It is very important to note that the only large scale long term study that compared real progesterone with fake progesterone so far is the French E3N cohort study series. They produced three reports so far, and all of them (breast cancer risk, blood clot risk, asthma onset risk) show a combination of transdermal estradiol + real progesterone is as safe as not using any hormone, while any other estrogen + progesterone substitute combination or estrogen only therapy shows increased risks.
The E3N studies show estrogen + progesterone is safer than estrogen alone supplementation. The same thing happens with your own hormones when progesterone and estrogen goes out of balance . This is known as estrogen dominance, and it is the primary reason why so many women develop various health problems during the decade leading up to menopause (see Estrogen dominance: it's not just a theory).
Actually, it is not just estrogen, but other hormones (DHEA, androstenedione, testosterone: probably because they easily convert to estrogen in various tissues) can become health hazard also, when progesterone is low. It was demonstrated with breast cancer, both for premenopause women and for postmenopausal women.
It isn't just breast cancer, blood clot, and asthma onset, that progesterone is known to protect you from. In his 1993 edition of "Progesterone in Orthomolecular Medicine", Ray Peat, a biologist listed a wide range of progesterone's protective role from embryo to old age, based on his studies and others' available back then:
  • Prevents acute poisoning of many kinds
  • Reduces the incidence of birth defects
  • Reduces the incidence of cancer of uterus, breast, and kidney
  • Reduces the incidence of epilepsy, habitual miscarriages, auto-immune diseases
  • Regulates heart and vascular smooth muscle, prevent spasm
  • Neutralize excessive estrogen and cortisol
  • Improve metabolic efficiency
  • Resolve hypoxia
  • Reduces edema
  • normalize fluid pressure in bursitis, glaucoma, swollen cartilage, etc.
  • Influence the brain development and intelligence of the baby
  • Promote magnesium uptake and blocks calcium uptake (this has a profound implication in blood clotting, blood sugar stability, diuretic kidney function, histamine release control, phagocytosis and other immune functions, Glucagon, insulin, vascular spasm, vascular tone, nerve stabilization (against over excitation, seizure, epilepsy, sleep apnea) , and protection against toxic or excitotoxic cell death)
Today, there are endless variety of thousands of studies that back up Ray Peat's conclusion, demonstrating how bio-identical natural hormones protect women's health or men's. Below are only a small fraction of the studies out there on the protective role of hormones in the field of neuroscience alone. Although the public is still kept in dark, the evidence is overwhelming. Only the clinical studies designed to show it in women are few and far between. Of course, those lucky enough to have learned of transdermal natural progesterone (sold as skin cream in the U.S.) aren't waiting for their doctors to catch up.

The wasted large scale clinical trials

The WHI Clinical Trials was supposed to give us enough data to answer many questions surrounding menopausal hormone therapy. Instead, they exposed an entire generation of menopausal women to dangerous drugs, scared and confused consumers and doctors alike, and sent researchers chasing dead-end false leads. All because it used a wrong form of hormone therapy (Premarin + Provera), the adverse effects of which have been known for quite some time, and yet, the pharmaceutical industry and medical establishment have chosen to ignore, if not hide (see The Hormone War is Heating Up).

The only safe and effective form of HRT is transdermal Estradiol+ real Progesterone continuous Regimens as the E3N Cohort Studies above and others have clearly shown. However, even when real estrogen and progesterone is used, it is not uncommon to see studies (or prescriptions for that matter) that use more than 10 times of the optimal ranges (around 0.03 ~ 0.05mg of estradiol + 10 ~ 20 mg of progesterone per day, both transdermal. See Hormones: Dos and Don'ts and Hormone overdose: How can you tell?) .
In the French E3N cohort study, the natural progesterone used was primarily oral (paired with 0.05mg transdermal estradiol, 100mg per day progesterone in capsule has been the most common form of natural progesterone prescription). The E3N studies so far has not reported any adverse health hazard associated with natural oral progesterone use, however, progesterone is known to have biphasic action on water retention: at a lower dose it works as diuretic by blocking mineralcorticoid, but at a higher dose causes water retention by increasing mineralcorticoid (100 mg is enough to show this effect: see Hormone overdose: How can you tell?). There are many people who cannot tolerate 100mg per day oral progesterone, including myself, because of the swelling and/or sluggish/tiredness it induces (progesterone and its metabolites act as tranquilizer through GABAa receptors, and given a large enough dose, induce sluggish and tiredness, while the same mechanism prevents over excitation of neurons and make your brain feel calm in optimal dose).
Therefore, many of the existing study results with oral progesterone are of only a limited use from a practical point of view.

The responsibility of the people who design large scale studies with serious implications
Perhaps the people most disturbed by the WHI results were estrogen researchers themselves. Estrogen looked so promising as the ultimate fountain of youth. At least that was what they were trying to sell. From my vantage point, there is no excuse for not knowing the detrimental effects of the particular estrogen (Premarin) and fake progesterone (Provera=medroxyprogesterone acetate) used in the studies before hand. There has been enough research indicating the risks, even before the clinical trial was launched in 1991 (actual recruitment 1993-1998). They knew the danger as early as 1961 (see Estrogens, progestogens and thrombosis, F . R. Rosendaal, at. al. 2003). By 1967 a study was conducted (Records Unit and Research Advisory Service of the Royal College of General Practitioners. Oral contraception and thromboembolic disease. J R Coll General Pract 1967;). Medroxyprogesterone acetate (the progesterone substitute used in the WHI clinical trials) has been used as contraceptive for many years with a long list of adverse side effects. By 1984 the superiority of bio-identical (natural) progesterone was demonstrated (Oral progesterone and estrogen/progestogen therapy. Effects of natural and synthetic hormones on subfractions of HDL cholesterol and liver proteins. U B Ottosson 1984).

Large scale long term clinical studies: Are they really necessary to determine the effects?
Risks and benefits can be evaluated much earlier, long before the actual diagnosable symptoms appear as clinical end points. In other words, you don't have to wait to see if people get sick to see the effects of the treatments. There are various indicators and markers that can tell what biological processes are activated or suppressed that are critical to the disease development. For example, bone breakdown and formation processes can be monitored by their chemical byproducts for osteoporosis development and reversal. So are blood clots and plaque formation risks in a form of reactive C-protein, fibrinogens, cholesterols, etc. Infrared camera breast exam can detect abnormal pattern of blood vessel development long before the cancerous lumps. It is about time to rethink the barbaric practice of clinical trials that is designed to see if a certain treatment would cure the illness or end up killing the patients.


  1. I don't know if my last question went through as I got an error so I will try again. Are there any transdermal creams that have safe levels of both estradiol and progesterone?

  2. Dear Pal, the safe level of estradiol is extremely low (25 to 50 micro gram per day) to mix into cream, and to supply a fraction of that amount at a steady rate through out the day is even more difficult. I am not an expert of drug delivery system, so, if you find anything other than estradiol patch to achieve that effect, let me know.

  3. Is there a way for doctors to find out what dosage of hormones we actually need? I just got an etonogestrel implant 68mg and trying to do find what exactly it does to my body. Is etonogestrel a bio-identical hormone...what is it exactly? How does birth control cause infertility?

    1. Please read "Hormone overdose: How can you tell?" page for your first question. etonogestrel is a fake progesterone and nobody needs fake progesterone. It prevents pregnancy by blocking your own progesterone. I wonder why you thought a birth control hormone can be a bio-identical hormone.

  4. Etsuko - For the past 5 yrs I have been through hormone replacement hell. It begain in 2010, when I saw an Oprah show about menopause. I was still having my period but I wasn't sleeping well and had been in peri for years. Very sad. So I made an appointment with the doctor on that show and a few months later was in Santa Monica to see the doctor. At first I felt better - taking one or 2 clicks of a 2 mg dispenser of estrodial. I was told with the dispenser that you divided by 4 so that ws really .5 mg. Within a week or two I was instructed to start using progesterone and testosterone. I was also given natural thyroid grain. At fist I felt better. Began sleeping, etc. But when I added in the testosterone and progesterone, I started feeling bad. I would call the doctor's office and they would tell me to add another click of estrodial. The doctor even called to tell me to sleep witht the estrodial under my pillow and add a click when I awoke in the night. I switched doctors after around 6 months to start up with a doctor that left the doctor's practice to start his own. Within a year or so he had me on 28 mg morning and night of estrodial. I had a high libido, and was in terrible shape. I could not think at all to work. But I was all pumped up on estrodial. Fast forward to 5 yrs later - I am feeling terrible and on just 1 click of a 2 mg estrodial cream. I have joint issues and developed breast cancer - for which I had surgery over the summer. Yesterday, I googled stiff neck, as that is my most dibilitating symptom other than total inability to concentrate - and depression. I found your blog an immediately added a click of progesterone last night. Today, I feel the same terrible feeling. My doctor told me several times to eliminate the progesterone - that I didn't need it since I am now on such a low dose of estrodial. I feel like these hormones gave me breast cancer and that I will never feel good again. What do you suggest?


    1. I watched the Oprah show featuring Suzanne Somers. It was sad in that Suzanne seemed have bought in to the premise and disregarded what her body was telling her. As far as I could tell, she went through the same hormone hell as you have, cancer and all while on the hormones. May be she thought it was a trade-off to keep a youthful body, but she looked pudgy but not healthy, a typical hormone overdose symptoms. Research shows nobody need estradiol beyond 0.05mg (50 micro gram) per day and progesterone 40 mg per day for controlling menopause. If you need testosterone, use DHEA 5 to 10 mg per day rather than straight testosterone.
      Please read "Hormone overdose: How can you tell?" and "Hormones: Dos and Don'ts" among other articles on this blog site.

    2. Also, I strongly recommend to use estradiol patch such as Vivelle-Dot and Estradot from Novartis and over-the-counter progesterone cream from well establish company such as UNICITY and Emerita, rather than compounded ones. They are not paying me to say these thing. This is based on my experience.

      You may also want to read my article "Safe & Effective Natural HRT = natural progesterone cream + DHEA + low dose estradiol patch" at http://fly.hiwaay.net/~eueda/health/hormone.htm

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    1. For estradiol, patch is the best delivery method because you need a very minute amount, however, for progesterone, the larger required dose cannot be delivered by patch. Therefore the best method is cream. For estradiol, the place you put the patch makes a big difference. Place it close to the base of your legs. Avoid putting it on your upper body such as arms. I tried it once, and my brain felt like seized up, even with 0.025 mg patch. It felt like all the estradiol went straight up to my brain.
      Always listen to your body, and reduce the dosage (and take a few days off) if you suspect it is causing a problem. Never increase the dose when a problem arises.

  6. Etsuko - I ran out today and purchase Emerita progesterone cream and came home to continue reading some of your postings. You referenced an ABC article on brain fog - this mentions something about as we get older that estrogen replacement may actually become less effective - that it shoul be used mostly in the early phases of peri and not some much in the later years. What are your thougths about that? I am now 58 yrs old. I do not want to continue with brain fog.

    1. "Menopausal Symptoms And Underlying Mechanism" is my research into that subject. The research in this field are so poorly designed that we cannot determine what really happens at this point. My conclusion at this point is that hormones are beneficial at any age when they are used sensibly in terms of the dosage and the balance.

  7. I have been told by my doctor (and other women in the menopause community) that transdermal Progesterone such as Emerita's Pro-Gest, is not strong enough to counteract the proliferating effects of a low-mud dose estradiol patch (0.0375 or 0.05). Hence why many women will use the 100mg Prometrium micronized progesterone.

    You are implying that OTC progesterone cream is enough. Is this accurate info?

    1. I am not aware of any credible study that demonstrated what your doctor is telling you. On the other hand, I have see at least three studies demonstrating that transdermal progesterone as little as 10mg per day is enough to control Endometrium thickening. One demonstrated 30mg /day Emerita's Pro-Gest is enough to control Endometrium thickening against premarin 0.625mg/day (Leonetti et al. 2003), and two others demonstrated that vaginal ring progesterone 10mg/day was enough to control Endometrium thickening against vaginal ring estradiol 160 microg/day (Hamada et at. 2003, and Ben-Chetrit et al. 2005). Please see "Hormones: Dos and Don'ts" page in this blog site for detail.
      Besides, Endometrium thickening can be easily checked by sonogram, you can try the OTC progesterone cream for a few months and see if you can get the benefit also, in case it does not work for you for some season. As to the OTC progesterone, late Dr. John R. Lee who wrote the "What Your Doctor May Not Tell You about" series, did independent lab tests of the OTC progesterone potency (he tested over 30 brands).

    2. You might also want to read "Natural Hormones: Why are doctors clueless?" and "The Hormone War is Heating Up" on this site if you want to learn about the "funny" business that has been going on in the medical world.

  8. My gyn also told me progesterone cream is not strong enough. However I notice I get the same progesterone side effects with comparable doses of the cream and a compounded oral progesterone pill, leading me to believe the docs are wrong in this instance.

    1. Thank you for doing the experiment and sharing it here.


Before you post your HRT questions, please try what I think safe and effective for at least 3 months: estradiol 0.025~0.050mg/day patch, with 20~40mg/day progesterone cream (about 1000mg progesterone in 2oz cream). You can also add DHEA 5~10mg /day.
That is the only recommendation you will get from me.