|
By Richard M. Foxx, M.D.
Few subjects in medicine have been able to engender the heated debate that surrounds hormone replacement therapy. It's a subject that impacts all of us, but even after all this time it is bedeviled by disagreement and misunderstanding, even among those who have made this their life's work.
When hormone levels drop, the impact on the quality of our lives can be devastating. And the levels almost always drop. Many authorities state that some hormone levels may drop from one to two percent a year starting at age 35.
For many people, the word "hormone" has come to equal the hormones of reproduction. The truth is that the term encompasses so much more, and includes thyroid hormone from the thyroid gland, insulin from the pancreas, and even melatonin from the pineal gland. This initial discussion, however, will be limited to the hormones of reproduction in women. Subsequent articles will expand on this topic.
When hormones become low enough to cause symptoms, replacement should be considered. While this is accepted in cases of hypothyroidism, and the standard of care for diabetes, the picture becomes somewhat less clear when dealing with hormones of reproduction.
Estrogen and testosterone are the only true sex hormones. They are the primary hormones responsible for the development of what is called secondary sex characteristics such breasts in women. Along with progesterone, they help to regulate the menstrual cycle, govern mood and cognition, and determine well-being.
There are three components of what is commonly known as "estrogen", identified as E1, or estrone, E2, or estradiol, and E3, or estriol. As estrone is synthesized in adipose tissue, and as it continues to be synthesized after menopause, estrone is not usually supplemented.
Estradiol is the most potent of the three, and the hormone most often replaced. During reproductive life, estradiol is predominantly synthesized in the developing ovum as well as the adrenal gland. When ovulation stops, levels of estradiol fall 70 to 80 percent.
Estriol is produced by the metabolism of estrone and estradiol and found mainly in extraovarian tissue. Although less potent than estradiol, it is equally important to replace. Some new data, in fact, seem to suggest that estriol not only potentiates estradiol, it also is associated with a lower risk of breast cancer.
Progesterone is only manufactured in two places, the placenta, and the area on the ovary that is left after ovulation occurs. Known as the corpus luteum, this area is present for two weeks, from the time the egg is released to the time that menses begins. During the reproductive years progesterone acts as a balance to estrogen, maturing the lining of the uterus and determining the time of menses. When ovulation stops, the progesterone level falls to zero.
Once in the blood stream, hormones are regulated by enzymes that neutralize the hormones when their job is finished. There is a specific enzyme for each hormone.
When it was determined that lowered levels of the "estrogen" hormones were associated with hot flashes during menopause, the idea of replacing estrogen to relieve these symptoms became accepted. But because naturally-occurring hormones cannot be patented, pharmaceutical companies looked for ways to develop synthetic alternatives. One such substitute for estrogen was Premarin, known by its generic name as conjugated equine estrogen, or CEE. Developed in the mid 1950's, Premarin was derived from the hormone-rich urine of pregnant mares, thus the name: PREgnant MARe serum gonadotropIN.
Premarin contains up to 40 percent equalin, or horse-specific estrogen, Horse-specific estrogen cannot be neutralized by the enzymes found in humans.
When Premarin was first released, it was hailed as the savior of postmenopausal women. Books such as FEMININE FOREVER, were written. Premarin was administered by itself for years, until it was noted that there was a high incidence of thickening of the lining of the uterus, known as endometrial hyperplasia, in women who were taking what was called "unopposed estrogen", i.e., the estrogen was unopposed by progesterone.
A fair number of women who developed endometrial hyperplasia developed atypical hyperplasia, and some of these women went on to develop frank carcinoma of the uterus.
Progesterone, the hormone that acts to counter endometrial development in menstruating women, was seen as the antidote to the effects of unopposed estrogen. Progesterone had the desired effect: on the rate of endometrial hyperplasia and when it was used with estrogen, uterine carcinoma fell to the pre-unopposed estrogen levels.
But as with estrogen, progesterone could not be patented, so the pharmaceutical industry formulated a synthetic substitute, medroxyprogesterone acetate, MDPA, known more familiarly as Provera. Provera, it must be pointed out, is not progesterone and, in fact, belongs to a class of drugs known as progestins. Progestins are progesterone-like products, but they're not progesterone. What was originally called "hormone replacement therapy," had become, in fact, the replacement of hormones by synthetic products.
Current thinking, it should be pointed out, discourages the use of unopposed estrogen.
The beneficial effects of postmenopausal hormone replacement therapy with estrogen and progesterone are well-known. Estrogen definitely decreases the incidence of Alzheimer's Disease, works to prevent the development of osteoporosis by slowing bone loss, acts as an anti-oxidant in the prevention of cardiovascular disease, decreases the incidence of colon cancer, and has a salutary effect on the skin, preventing the loss of collagen and increasing skin thickness.
Progesterone has many of the same benefits. In some cases progesterone occupies the same hormone receptor sites as does estrogen. Where estrogen slows bone loss, progesterone actually increases bone build-up. It is as beneficial, therefore, to administer it as it is to administer estrogen.
Even if that were not the case, progesterone is required as a balance to estrogen to maintain the body is a physiologic balance.
So widely accepted was the principle of taking estrogen with progesterone that a pill combining both agents, called PremPro, was developed. In an attempt to expand the market for this drug from relief of hot flashes to prevention of heart disease, a major study was undertaken about eight years ago. It was called the Women's Health Initiative, or WHI, and was to be one of the largest studies done with hormones. More than 16,000 women enrolled.
After four years, the study was halted because of a perceived increase in breast cancer, dementia and Alzheimer's Disease. This was in 2002, and in what can best be described as a mass knee-jerk reaction, millions of women were literally cut loose by their gyns and left to their hot flashes. Many sources even suggested that drugs such as Zoloft or one of the other SSRI drugs would be a workable alternative.
Since that time, many of the issues that arose from the WHI study have been laid to rest. The confusion, and the ominous data, arose from two issues: First, the hormone replacement used was the artificial hormone PremPro (a combination of Premarin and Provera), and second, most of the women enrolled in the study were over the age of 65 and had been off hormones (either endogenous or synthetic) for more than 15 years. We have since learned that when off hormones for that long, many of the receptor sites turn off and reintroduced hormones act like foreign proteins.
Many of the women included in the study would most likely have been flagged as high risk for breast cancer, but were not screened for these factors until the study was underway. Many of them had a family history of breast cancer, or other risk factors such as early menarche, late menopause, and obesity.
Many of the patients who developed Alzheimer's Disease (AD) during the WHI study had been enrolled at an average age of 65 and had been off hormones for 15 years or more. The incidence of AD increases beginning at 65 and the bad news is that up to 40% of the damage is done before the diagnosis is made. Once AD starts, it cannot be reversed. The thinking is that many of the women who developed AD on hormones would, in fact have developed that anyway.
Oral hormones must first traverse the liver via the portal circulation before they are released to the body. Once in the liver, oral hormones, specifically estrogen, raise several cardiovascular risk factors including fibrinogen, C-reactive protein, and triglycerides. Oral estrogen has a few other insidious effects in the liver including the increase of sex hormone binding globulin, or SHBG. SHBG binds estrogen and testosterone making these hormones less available to the body. As testosterone contributes to libido in women, this phenomenon explains the lowered libido often found in women on oral estrogen.
Estrogen, progesterone, and testosterone can be chemically replicated to match the body's own molecules. It is possible, therefore, to create bio-identical hormones, atom for atom identical to those that exist in the human body.
The ideal route for the replacement of these bio-identical hormones is transdermal, through the skin. Transdermal therapy is well-documented and well-accepted and used for such drugs as seasick meds. Using this route avoids the problems associated with the oral route, bypasses the liver, and makes flexibility of dose ultimately possible. As recently as several weeks ago, an article in MENOPAUSE concluded that changing to transdermal estradiol may improve triglyceride metabolism in women who developed elevated triglycerides during oral estrogen-progestin therapy.
One of the difficulties associated with bio-identical transdermal therapy, however, is availability. As the hormones cannot be patented, they are not available as traditional drugs from your neighborhood Sav-On. So-called compounding pharmacies must be employed.
Having said that, however, it's worth seeking out a compounding pharmacy when the alternative is experiencing the gamut of menopausal or hormone deficiency symptoms.
This is clearly a complex topic. Individualization of therapy is the key. This is clearly something you don't want to undertake alone. The best recommendation I could make is to seek out an experienced and concerned physician whose interest lies in the area of bio-identical hormone therapy. Be sure the physician performs appropriate laboratory evaluation and commits to regular follow up.
| 
