HRT - where do we go from here?



John R Lee MD

This article was John Lee’s last, written especially for NPIS.

The recent Lancet publication of the Million Women Study1 (MWS) removes any lingering doubt that there’s something wrong with conventional HRT. Why would supplemental oestrogen and a little progestagen (other than real progesterone) increase a woman’s risk of breast cancer by 30% or more? Other studies found that these same HRT hormones increase one’s risk of heart disease and blood clots (strokes)2-4, and do nothing for preventing Alzheimer’s disease5,6. When you pass through puberty and your sex hormones surge, they don’t make you sick - they cause your body to mature into adulthood and be healthy. But, the hormones used in conventional HRT are somehow not right – they are killing women.

The question is - where do we go from here? My answer is – we go back to the basics and find out where our mistake is. I have some ideas on that.

Over the years I have adopted a simple set of three rules covering hormone supplementation. When these rules are followed, women have a decreased risk of breast cancer, heart attacks or strokes. They are much less likely to get fat, or have poor sleep, or short-term memory loss, fibrocystic breasts, mood disorders or libido problems. And the rules are not complicated.

Rule 1. Give hormones only to those who are truly deficient in them.

The first rule is common sense. We don’t give insulin to someone unless we have good evidence that they need it. The same is true of thyroid, cortisol, and all our hormones. Yet, conventional physicians routinely prescribe oestrogen or other sex hormones without ever testing for hormone deficiency. Conventional medicine assumes that women after menopause are oestrogen deficient. This assumption is false. Twenty-five years ago I reviewed the literature on hormone levels before and after menopause, and all authorities agreed that over two-thirds (66%) of women up to age 80 continue to make all the oestrogen they need. Since then, the evidence has become stronger7. Even with ovaries removed, women make oestrogen, primarily by an aromatase enzyme in body fat and breasts that converts an adrenal hormone, androstenedione, into estrone. Women with plenty of body fat can make more oestrogen after menopause than skinny women make before menopause. Breast cancer specialists are so concerned about all the oestrogen women make after menopause that they now use drugs to block the aromatase enzyme. Consider the irony: some conventional physicians are prescribing oestrogens to treat a presumed hormone deficiency in postmenopausal women, while other colleagues are prescribing drugs that block oestrogen production in postmenopausal women.  

How does one determine if oestrogen deficiency exists? Any woman still having monthly periods has plenty of oestrogen. Vaginal dryness and vaginal mucosal atrophy, on the other hand, are clear signs of oestrogen deficiency. Lacking these signs, the best test is the saliva hormone assay. With new and better technology, saliva hormone testing has become accurate and reliable. As might be expected, we have learned that hormone levels differ between individuals; what is normal for one person is not necessarily normal for another.  Further, one must be aware that hormones work within a complex network of other hormones and metabolic mediators, something like different musicians in an orchestra. To interpret a hormone’s level, one must consider not only its absolute level but also its relative ratios with other hormones that include not only oestradiol, progesterone, and testosterone, but also cortisol and thyroid as well.

For example, in healthy women without breast cancer, we find that the saliva progesterone level is routinely 200-300 times greater than the saliva oestradiol level. In women with breast cancer, the saliva progesterone/oestradiol ratio is considerably less than 200 to 1. As more investigators become more familiar with saliva hormone tests, I believe these various ratios will become more and more useful in monitoring hormone supplements.

Serum or plasma blood tests for steroid hormones should be abandoned – the results so obtained are essentially irrelevant7. Steroid hormones are extremely lipophilic (fat-loving) and are not soluble in serum. Steroid hormones carry their message to cells by leaving the blood flow at capillaries to enter cells where they bond with specific hormone receptors in order to convey their message to the cells. These are called “free” hormones. When eventually they circulate through the liver, they become protein-bound (enveloped by specific globulins or albumin), a process that not only seriously impedes their bio-availability but also makes them water soluble, thus facilitating their excretion in urine. Measuring the concentration of these non-bio-available forms in urine or serum is irrelevant since it provides no clue as to the concentration of the more clinically significant “free” (bio-available) hormone in the blood stream.

When circulating through saliva glands, the “free” non-protein-bound steroid hormone diffuses easily from blood capillaries into the saliva gland and then into saliva. Protein-bound, non-bio-available hormones do not pass into or through the saliva gland. Thus, saliva testing is far superior to blood or urine testing in measuring bio-available hormone levels.    

Serum testing is fine for glucose and proteins but not for measuring "free" steroid hormones. Fifty years of “blood” tests have led to the great confusion that now befuddles conventional medicine in regard to steroid hormone supplementation.

Rule 2. Use bio-identical hormones rather than synthetic hormones.

The second rule is also just common sense. The message of steroid hormones to target tissue cells requires bonding of the hormone with specific unique receptors in the cells. The bonding of a hormone to its receptor is determined by its molecular configuration, like a key is for a lock. Synthetic hormones molecules differ in molecular configuration from endogenous (made in the body) hormones.  From studies of petrochemical xeno-hormones, we learn that substitute synthetic hormones differ in their activity at the receptor level. In some cases, they will activate the receptor in a manner similar to the natural hormone, but in other cases the synthetic hormone will have no effect or will block the receptor completely. Thus, no synthetic hormone provides the same total physiologic activity as the natural hormone it is intended to replace, and all synthetic hormones will provoke undesirable side effects not found with the human hormone. Human insulin, for example, is preferable to pig insulin. Sex hormones identical to human (bio-identical) hormones have been available for over 50 years.

Pharmaceutical companies, however, prefer synthetic hormones. Synthetic hormones (not found in nature) can be patented, whereas real (natural, bio-identical) hormones are not. Patented drugs are more profitable than non-patented drugs. Sex hormones prescription sales make more money for pharmaceutical companies than any other prescription drug. Women’s health is sacrificed for commercial profit.

Rule 3. Use only in dosages that provide normal physiologic tissue levels.

The third rule a bit more complicated. Everyone would agree, I think, that dosages of hormone supplements should restore normal physiologic levels. The question is – how do you define normal physiologic levels? Hormones do not work just by floating around in circulating blood; they work by slipping out of blood capillaries to enter cells that have the proper receptors in them. As explained above, protein-bound hormones are unable to leave blood vessels and bond with intracellular receptors. They are non-bioavailable. But they are water-soluble and, thus, found in serum, whereas the “free” bioavailable hormone is lipophilic and not water soluble, thus not likely to be found in serum. Serum tests do not help you measure the “free”, bio-available form of the hormone. The answer is saliva testing.

It is quite simple to measure saliva oestradiol, or progesterone, or testosterone levels of healthy people and compare those results with saliva levels of women with breast cancer, for example. In this manner, saliva testing can be used easily to measure the change of saliva hormone levels when hormone supplementation is given. If more physicians did that, they would find that their usual oestrogen dosages are 8-10 times greater than found in normal healthy people, or that progesterone levels are not raised by giving supplements of synthetic progestagen such as medroxyprogesterone acetate (MPA).

Further, saliva levels (and not serum levels) of progesterone will clearly demonstrate excellent absorption of progesterone from transdermal creams. Transdermal progesterone enters the blood stream fully bioavailable (i.e., without being protein bound). The progesterone increase is readily apparent in saliva testing, whereas serum will show little or no change8. In fact, any rise of serum progesterone after transdermal progesterone dosing is most often a sign of excessive progesterone dosage. Saliva testing helps determine optimal dosages of supplemented steroid hormones, something that serum testing cannot do.

It is important to note that conventional HRT violates all three of these rules for rational use of supplemental steroid hormones.

A 10-year French study of HRT using low-dose oestradiol patch, plus oral progesterone, shows no increased risk of breast cancer, strokes, or heart attacks9. Hormone replacement therapy is a laudable goal, but it must be done correctly. HRT based on correcting hormone deficiency and restoring proper physiologic balanced tissue levels, is proposed as a more sane, successful, and safe technique.

Other Factors

Hormone imbalance is not the only cause of breast cancer, strokes, and heart attacks. Other risk factors of importance include the following:

1. Poor diet (excess sugar and refined starches, trans-fatty acids, lack of needed nutrients such as omega-3 fats, full range of essential amino acids, vitamins, minerals, etc.)

2. Environmental (toxic) xeno-oestrogens and hormones not removed by water treatment plants.

3. Insulin resistance

4. Stress

5. Life style problems such as excess light at night (poor sleep, melatonin deficiency), alcohol, cadmium (cigarette smoking), and birth control pills during early teens.

Men share these risks equally with women. Hormone imbalance and exposure to these risk factors in men leads to earlier heart attacks, lower sperm counts, and higher prostate cancer risk. 


Conventional hormone replacement therapy (HRT) composed of either estrone or oestradiol, with or without progestagens (excluding progesterone) carries an unacceptable risk of breast cancer, heart attacks, and strokes. A more rational HRT using bio-identical hormones in dosages based on true needs as determined by saliva testing is proposed. In addition to proper hormone balancing, other important risk factors are described, all of which are potentially correctable. Combining hormone balancing with correction of other environmental and life style factors is our best hope for reducing the present risks of breast cancer, strokes, and heart attacks.

A much broader discussion of all these factors can be found in my book, What Your Doctor May Not Tell You About Breast Cancer10.  

John R. Lee, MD


1.Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study.  Lancet 2003; 362: 419-27.

2.Scarabin, P-Y, Oger E, Plu-Bureau G. Differential association of oral and transdermal ooestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003; 362: 428-32.

3.Chen C-L, Weiss NS, Newcomb P, Barlow W, White E. Hormone replacement therapy in relation to breast cancer. JAMA 2002; 287: 734-41.

4.Writing Group for the WHI Investigators. Risks and Benefits of oestrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-33.

5.Yaffe K, Lui-Y, Grady D, Cauley J, et al. Cognitive decline in women in relation to non-protein-bound oestradiol concentrations. Lancet 2000; 708-12.

6.Mulnard RA, Cotman CW, Kawas C, van Dyck CH, et al. Oestrogen replacement therapy for treatment of mild to moderate Alzheimer disases. JAMA 2000; 283: 1007-15.

7.Cummings SR, Browner WS, Bauer D, Stone K, et al. Endogenous hormones and the risk of hip and vertebral fracture among women. NEJM 1998; 339: 733-38. 

8.Waddell BJ, O’Leary PC. Distribution and metabolism of topically applied progesterone in a rat model. J Steroid Biochemistry & Molecular Biology 2000; 80: 449-55. Lignieres B, de Vathaire F, Fournier S, Urbinelli R, et al. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric 2002; 5: 332-40. 

10.What Your Doctor May Not Tell You About Breast Cancer, by John R. Lee, MD, David Zava, PhD, and Virginia Hopkins, MA. Published by Warner Books 2002, New York, NY. Also published in England by Thorsons, London.