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By David M. Odom, MD

Bio-Identical Estrogens and Progesterone

Estrogens are vital hormones of growth and development in humans, but particularly in women between menarche and menopause. The term, “estrogen” is generic for a variety of related steroids. There are 3 estrogens found in humans: estrone, estradiol and estriol, also known as E1, E2 and E3 respectively.
Estradiol (E2) is the most potent estrogen in humans, and it is vital for procreation. If instituted early after menopause, administered E2 provides health benefit [1]. Estradiol importantly prevents bone loss [2,3], protects the heart from arteriosclerotic disease [4], and prevents Alzheimers. Drops in the levels of Estradiol is the notable cause of hot flashes during the peri-menopausal years. However, as you just read, supplementation of bio-identical estrogen after menopause, and after menopausal symptoms subside continue to provide heath benefit.
As an example: Those women, who are particularly, genetically susceptible to damage after E2 levels drop at the time of menopause (average age 51 years) may develop “early Alzheimers” at age 57 or 58 [5,6,7,8]. The same issue is true regarding osteoporosis and heart disease.
Remember, 70% of deaths in women after menopause is due to heart disease that commences after menopause. Menopause is a risk factor for cardiovascular disease because Estradiol withdrawal has a detrimental effect on cardiovascular function and metabolism [9]. When Estradiol production ceases in menopausal women, the risk of coronary heart disease increases [10].
When you hear about “estrogen dominance”, what is really meant is Estradiol unopposed by its necessary complement, Progesterone. It is the monthly rises and falls of these two hormones that regulate the menstrual cycles. The adequate balance of Progesterone modifies the stimulatory effects of Estradiol.
Estradiol, the most feminizing of the estrogens, causes growth of tissue, as in uterus and baby during gestation, and growth of the breasts. As well, Estradiol can cause growth of abnormal tissue, such as cancer, if not opposed by Progesterone. Progesterone has a general cancer preventive effect.
There is no proof that Estradiol (or estrogens in general) cause cancer, only that the more potent estrogens, such as Estradiol, can stimulate a pre-existing cancer.
Although heart disease is the cause of death of most women, cancer is the most frightening affliction facing women. Measures that can be taken to prevent cancer include the addition of Progesterone, as well as the supplementation of “vitamin” D3 (Cholecalciferol) and iodine. Other supplements known to prevent cancer are discussed in a separate article.
I do not prescribe Estradiol without the concomitant use of Progesterone. I often prescribe Progesterone without Estradiol in women prior to the time of menopause. More about Progesterone further in this article.
Estriol (E3) is always found in women of childbearing years but rises too much greater heights during pregnancy. Estriol attaches to the same receptor sites as Estradiol, but the effects are much less powerful. Estriol is reputed to either prevent cancer or not to allow cancer to grow.
For this reason, doctors who prescribe bio-identical (natural) estrogens often prescribe a product that is a combination of Estradiol (E2) and Estriol (D3). Such a combination product allows a lower dose of Estradiol to obtain the same beneficial result as a product containing only Estradiol.
Estradiol and Estriol help prevent wrinkling of skin after menopause. And that is an attention-getter for most women!
But let’s talk about mortality. As stated earlier, most women die of heart disease! And E2 therapy started at menopause cuts heart disease in half! Women taking E2 therapy from the time of menopause have a 40% lower mortality from all causes!

Pharmaceutical companies do not produce combination Estradiol-Estriol products, thus they must be obtained from compounding pharmacies that produce these products in house.

Compounding is the practice of creating personalized medications based on a doctor’s prescription in which individual ingredients are mixed together in the exact dosage form required by the patient. Compounding pharmacies are regulated by state pharmacy boards, and national standards have been created by the Pharmacy Compounding Accreditation Board (PCAB). As you might imagine, compounding is actively opposed by pharmaceutical companies who compete with them. Compounding allows the formulation of a wide variety of natural hormone products that otherwise would not exist.

As well, compounding pharmacies produce various Progesterone products, whereas pharmaceutical companies produce only one Progesterone product, which has been found not to produce adequate blood levels of Progesterone in most women.

Estrone, or E1, is a metabolic breakdown product of Estradiol, but the conversion can go either way. In women during childbearing years, the levels of Estrone typically rise and fall proportionally with Estradiol. After menopause, the levels of Estrone usually increase. Estrone is not as potent as Estradiol, but is still considered to have an effect to stimulate the growth of a pre-existing cancer. Estrone is the major estrogen in Premarin® which is a product of “conjugated equine estrogens” (or CEE) found in the pregnant mare. Besides a small amount of Estradiol in Premarin®, the remainder of estrogens found in the horse are the various super-potent equilins.

Yes, you read correctly, Premarin® as well as the CEE in PremPro® is obtained from urine drained from the bladders of catheterized pregnant horses.

However, the use of CEE alone has not been found to increase risk of cancer. Breast cancer risk was elevated in women using a combination of CEE & Provera®. Provera®, is a drug, not found in nature, but attaches itself to the Progesterone receptor sites throughout the body.

Provera® does not have the general cancer preventive effects of real Progesterone. Many doctors mistakenly refer to Provera® as Progesterone. But, don’t you be fooled!

The huge Women’s Health Initiative (WHI) study which commenced in 1991, and still has components continuing as of 2016, studied 3 groups of post-menopausal women: Those not taking any hormone product, those taking Premarin® alone, and those taking a combination of horse estrogens and Provera®.

The addition of Provera® to Estradiol therapy increases the rate of breast cancer. The use of natural Progesterone in combination with Estradiol decreases the risk of breast cancer!

Amazingly, in the WHI, the most complex, extensive, and expensive publicly funded study of female hormones in the U.S. to date, there was no study of real Progesterone, only the entirely synthetic Provera®!

​Progesterone is a “feel good” hormone according the vast majority of patients using it. It aids the growth of bone and protects the heart. Most importantly, although totally ignored in the WHI, Progesterone’s cancer preventive effects are proven in other scientific studies.

Bi-Estrogen, meaning a combination of 2 estrogens, usually in a combination of 80% Estriol & 20% Estradiol, is usually used as a sublingual rapid dissolve tablet taken in the morning. Some women feel better using Bi-Est twice daily, thus using a lower single dose to maintain more even blood levels. The dose varies from person to person and usually can be lowered with distance from the time of menopause, as menopausal symptoms, such hot flashes, subside.

Sublingual Progesterone is more popular with women prior to menopause who are having menstrual problems during the week before period. The reason for this is the rapid onset of action of the hormone when used under the tongue gives relief of symptoms.

All untoward premenstrual symptoms are caused by an imbalance of Progesterone to Estradiol. This is due to inadequate production of Progesterone after ovulation, or because of a lack of ovulation during the monthly cycle. Some women produce huge amounts of Estradiol, also causing an imbalance. The invariable answer to either problem is supplementing Progesterone to effect.

Most women notice cessation of premenstrual bloat, food cravings, cramps, irritability, and water retention after using 100 to 400 mg per day of sublingual Progesterone during the week to 2 weeks prior to starting menses. A few women notice benefit only after using as much as 600 to 800 mg per day. The important issue is to use as much Progesterone as needed to obtain the desired effect, that is, cessation of PMS.

Women who come to see me after menopause typically want to swallow the slow release Progesterone capsules near bedtime. Many women tell me that such a dose form is a wonderful sleep aid.

Some women rather like the idea of using creams applied to skin for B-HRT. Testosterone given this way results in easily recognized rises in blood levels, but not so from Estradiol and Progesterone. Saliva testing is the best way to measure changes derived from transdermal application of Estradiol & Progesterone. Patients preferring creams tell me that they notice salutary effects of the hormones, regardless of blood levels not changing. Still, major hormone studies correlating hormone benefit to dose type all use blood studies. For that reason, I prescribe only Testosterone for transdermal application in women unless the patient specifically requests creams for her other hormones.

As I mentioned before, most women love the way they feel using Progesterone. It is commonly referred to as a “feel good hormone.” However, a small minority of women do not like the way they feel on Progesterone, declaring that it makes them feel “icky”. This is a dose related effect, but I have found a few women who note these negative feelings with Progesterone, regardless of dose reduction.

I think that the bottom line regarding all this is that “one size does not fit all.”

This is why many B-HRT practitioners, including myself, refer to their practice as the “art of hormone balancing”, not “hormone replacement.”

If a woman starts the use of Estradiol and Progesterone at the time of menopause, when should she stop using them? This question arises because other medical practitioners comprehend the use of bio-identical estrogens and Progesterone as useful only to allay the symptoms of menopause. They are not understanding the benefits regarding prevention of heart disease, osteoporosis, and other physiological decline extending far past the decade of the 50's. This is a source of confusion to patients who are encouraged by these conventional thinkers to stop hormone supplementation after a few years.

​My advice: stop using them when you are ready to stop living. And that is no joke.

Bibliography:● Neal Rouzier, MD. How to Achieve Healthy Aging, Worldlink Medical Publishing (2007)● Nakamura T, et al. Estrogen Prevents Bone Loss via Estrogen Receptor a and Induction of Fas Ligand in Osteoclasts. Cell. 2007 Sep 7;130(5).:811-23. http://www.ncbi.nlm.nih.gov/pubmed/17803905● Harold N. Rosen, MD. Patient information: Osteoporosis prevention and treatment. http://www.uptodate.com/contents/osteoporosis-prevention-and-treatment-beyond-the-basics● Rosano GM & Panina G. Oestrogens and the heart. Therapie. 1999 May-Jun;54(3):381-5. http://www.ncbi.nlm.nih.gov/pubmed/10500455● Zhao L & Diaz-Brinton R. Select estrogens within the complex formulation of conjugated equine estrogens (Premarin®) are protective against neurodegenerative insults: implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer's disease. BMC● Neurosci. 2006; 7: 24. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421415/● Steenhuysen J. Hormone therapy may cut Alzheimer's risk in menopausal women. http://www.reuters.com/article/us-hormones-alzheimers-idUSBRE89N1S020121024● Goldman B. Accelerated biological aging evident in women with Alzheimer's risk factor, but inhibited by hormone therapy, researchers say. Stanford● Medicine News Center. https://med.stanford.edu/news/all-news/2013/02/accelerated-biological-aging-evident-in-women-with-alzheimers-risk-factor-but-inhibited-by-hormone-therapy-researchers-say.html● Slooter Arjen JC, et al. Estrogen use and early onset Alzheimer’s disease: a population-based study. J Neurol Neurosurg Psychiatry 1999;67:779–781. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1736655/pdf/v067p00779.pdf● Rosano GM. Menopause and cardiovascular disease: the evidence. Climacteric. 2007 Feb;10 Suppl 1:19-24. http://www.ncbi.nlm.nih.gov/pubmed/17364594● Bulliyya G. Risk of coronary heart disease in women after menopause. J Indian Med Assoc. 2001 Sep;99(9):478-80, 482.