Hormone Replacement Therapy in Women

Role of Periodic Progestogen

In medical school doctors are taught that menopause announces the liberation of women from the tyrannical hormonal rule that subjugated them during the reproductive phase of their lives.

Their onerous burden of constantly varying biochemistry was over - they were free! Nothing could be further from the truth however--women are not free, for beyond menopause, hormones still remain very much in charge of female health and well-being. Instead of cyclic surges of ovarian estrogen (and progesterone) dominating their daily existence, follicle-stimulating hormone (FSH) now becomes a woman's new ruler.

With depletion of ovarian estrogen, pituitary FSH--now unchecked--progressively rises. The excessive elevation of this substance is the cause of menopausal night sweats, hot flashes and emotional liability.

The burden of this new ruler is now constant and slowly progressive as FSH levels rise; to truly astronomical levels in some women. True some women, perhaps as many as 25%, breeze through menopause with no more than a sigh of relief, or perhaps regret, but for the majority their only change has been the replacement of one despotic king by another.


Throughout the reproductive phase of a woman's life, any semblance of hormonal (and physiological) stability is prevented by the constant monthly interplay of pituitary and ovarian hormones. Once triggered by the onset of puberty this cyclic two-step is governed by what is called a feedback loop.

If the pituitary "master gland" senses insufficient estrogen output, it will secrete FSH--a whip, if you will, to stimulate the ovaries to increase their monthly estrogen output. Estrogen, of course, prepares the uterine lining for reception of a fertilized egg, seeking a comfortable and nutritious site for implantation & development. The rising estrogen level suppresses the FSH level in this 30-year jousting match for dominance. This is nothing but a chemical balancing act which achieves, at best, a sort of equilibrium between the opposing hormonal forces.

First estrogen dominates, then FSH, in a never-ending biological skirmish...so much for any possibility of hormonal or physiological stability during a woman's reproductive years. There can be no such thing in a functioning woman--hence my choice of the phrase "tyrannical hormonal rule." Once the woman has reached menopause however, gonadal exhaustion occurs and her ovaries are physiologically unable to respond to their "master's" whip. After this point her FSH rises and for many if not most, the disagreeable consequences of menopause begin. What then; what recourse is there?

Estrogen Replacement:

As doctors soon learned that when treatment to control menopausal symptoms became necessary, estrogen was the drug of choice. By bringing FSH down to lesser levels, flushes and sweats vanished. It seemed medical science had triumphed. And they are not getting into hormonally uncharted waters by giving supplemental estrogen to these women--they were only bringing these unfortunate victims into line with their more fortunate peers.

Other asymptomatic menopausal women have endogenous estrogen reserves of adrenal origin sufficient to keep their "master's" FSH at bay. In this respect they are somewhat like the happy, smiling endogenous Beta-endorphin producers among us. One might refer to them as "estrogenic do-it-yourselfers" with menopausal passage a breeze.

However, it soon became evident that estrogen (with its natural proclivity to stimulate endometrial cell growth and division), almost inevitably had to enhance any underlying tendency for endometrial hyperplasia and cancer. Naturally, doctors tended towards smaller & smaller doses of estrogen, and sought ways to minimize this proliferatory role of estrogen without sacrificing its effectiveness in FSH suppression.

Progestogen supplementation:

In recent decades Progestogen, which could be made synthetically, began to be added to the estrogen therapy in what is now known as hormone replacement therapy (HRT). Natural progesterone has the very important role of causing the proliferative endometrial lining to slough off as menstrual flow in the usual monthly cycle, when fertilization of the egg does not occur, and the luxuriant cellular lining of the uterus no longer is required.

Seemingly, Progestogen--created by the pharmaceutical industry as a substitute for natural progesterone--was a perfect additive to estrogen therapy to counter excessive endometrial buildup. Doctors began to explore the safest and most effective protocols for the use of Progestogen. This is a curious class of chemicals, similar in their action to natural progesterone but synthetic--and therefore, profitably patentable by the pharmaceutical industry.

Progestogens were delivered in abundance to practicing physicians as a substitute for progesterone. Few physicians realized how different they actually were but at first their use was relatively limited as a cyclic supplement. However about a decade ago the pharmaceutical industry developed and began aggressive promotion of a combination pill for menopausal women known as Prem-Pro.

This product contained estrogen in the form of conjugated estrogen 0.625 mg (commonly known as Premarin), and a Progestogen in the form of medroxyprogesterone acetate, 2.5 mg (commonly known as Provera), to be taken daily. This seemingly innocuous and (no doubt) financially rewarding product seems to have been the start of the present HRT crisis.

For decades Provera was felt by most physicians to be physiologically similar, if not identical to, natural progesterone. The substance of the corpus luteum, progesterone is the necessary ingredient for a successful pregnancy. However the sad truth is that this is not so--whereas natural progesterone has no known side effects, this close cousin Provera, with only a minor departure in its chemical structure, has a long list of warnings, precautions & side effects including but not limited to thrombophlebitis, pulmonary embolism and stroke.

While both Provera and natural progesterone share the cholesterol biochemical structure common to a large number of hormones, that is where the similarity ends--for Provera carries not only an extra methyl group at one critical point in its chemical makeup, but an entire acetate group at another. When one has experienced how major a physiological difference may result from seemingly minor manipulation of the parent molecule, it becomes easy to comprehend the negative side effect profile of Provera when compared with natural progesterone. In fact, some have stated that the difference between the two is even greater than the minor changes of the same cholesterol parent molecule that gives us testosterone rather than estrogen; the very basis of our sexual differentiation.

Knowing this, it is not difficult to understand the announcement by the National Institutes of Health (July, 2002) regarding a major clinical trial on the risks & benefits of Prem-Pro in menopausal women. This trial was halted after only 5.2 of a planned 8-year study period, when preliminary results indicated an alarming incidence of unacceptable side effects. For not only thrombophlebitis, pulmonary embolism and stroke--but also breast cancer and heart disease, were found to be significantly more likely on Prem-Pro takers than their peers not taking this medicine. Suddenly the world of the menopausal woman was in an uproar!

Premarin, the conjugated estrogen used for decades to help suppress FSH levels and secondary menopausal symptoms, was not to blame. The culprit was the Progestogen Provera, and it's method of use. This physiologically alien chemical, trying for years to masquerade as natural progesterone, was finally unmasked for all to see.
Abruptly we learned that Provera is associated with unacceptable side effects when used daily as in the combination pill, Prem-Pro.

Many doctors, in frustration and fearing litigation, have thrown up their hands in surrender and advised their patients to stop HRT completely. But meanwhile the problem of severe and distracting menopausal symptoms remain for many women; tempered now by fear and frustration within the medical establishment. What recourse do these women have? What recourse do the doctors have?

First we should remember that the current dilemma was based entirely on this Woman's Health Initiative (WHI) study using Provera combined with Premarin (in the form of Prem-Pro), administered on a daily basis. If anything is more unnatural than the chemical Provera, it is the administration of this substance daily to menopausal women. These women ordinarily have relatively small amounts of natural progesterone and, of course, no Provera in the natural state.

Not only have menopausal symptoms been controlled by keeping FSH levels in check, but there are other important benefits anticipated from Premarin therapy in menopausal women. Heart attack risk reduction, relative freedom from depression, maintenance of more youthful skin & mucus membranes and last, but certainly not least, assistance in absorption of ingested calcium (vital for the prevention & treatment of osteoporosis), are all possible benefits which bear further study.

A closing word about Natural Progesterone - Natural progesterone, long available in an over-the-counter topical cream, has recently been approved by the FDA for use in an oral form. Whether taken orally or used transdermally, clearly this product has the potential to assume completely its rightful role in HRT. Several drug companies now produce this OTC transdermal cream with a fixed concentration of progesterone--thus greatly enhancing reliability. All that is needed at the time of this writing are the results of proper studies of both the oral and transdermal forms to define usage protocols. When these studies are completed, natural progesterone could replace Provera and other forms of Progestogen in HRT protocols.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor


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