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By Sarah L. Berga, MD
For years, it was taught and widely believed that all estrogen products were comparable and, therefore, what should drive choice was cost and convenience. Emerging evidence suggests that this clinical dictum is not true. If it is not true, by what criteria, then, does one chose an estrogen preparation? To address this issue, we need to understand what an estrogen is and what gates estrogen action.
First, what is an estrogen? The liberal answer is that an estrogen is any substance whose binding to an estrogen receptor initiates postreceptor activity. A more conventional answer is that it is an 18-carbon, 4-ring structure derived from a cholesterol backbone. Selective estrogen receptor modulators, SERMs, bind to estrogen receptors, are not derived from a cholesterol backbone, and either block or do not initiate full physiological postreceptor responses. Phytoestrogens are closer to conventional estrogens in chemical structure, but do not bind as avidly to estrogen receptors. In the same manner as SERMs, they may act as partial agonists or antagonists, depending on the prevailing intracellular hormone soup. Thus, they may antagonize full estrogen action in eumenorrheic women while eliciting partial estrogen action in postmenopausal women. The so-called "cognate" or physiological estrogens (barring pregnancy) are estradiol and estrone. During an ovulatory menstrual cycle, estradiol (E2) ranges from a low of ~30 pg/mL to a high of ~350 pg/mL, with an average of ~110 pg/mL. The ratio of estradiol to estrone (E1) is ~1:1. Common pharmacological estrogen preparations include:
1. those with a saturated B ring (eg, equilin, a constituent of conjugated equine estrogens);
2. conjugated estrogens, the major constituent of which is estrogen sulfate;
3. derivatives such as ethinyl estradiol, which has a ethinyl group added to carbon 17;
4. micronized estradiol, which is designed to be given orally because the micronization process protects the estradiol from being degraded by gastric secretions, and;
5. transdermal estradiol, which diffuses across the skin into the venous circulation and circulates primarily as estradiol.
The most obvious difference between oral from transdermal estradiol administration is the ratio of estradiol:estrone achieved in the circulation. Because of the first-pass hepatic metabolism that accompanies oral administration, the ratio of estradiol:estrone in the circulation is ~3:1. With transdermal or vaginal administration, the ratio of estradiol:estrone is ~1:1, and thus these latter routes of administration lead to more physiological patterns in the circulation. Also with oral administration of estradiol, the level of estrone sulfate is ~10-fold higher than with transdermal administration.1 There is also a myriad of other differences between oral and transdermal estradiol owing to the hepatic first-pass effect, including increased coagulation and altered metabolism of other substances such as alcohol. Since there are no long-term data comparing clinical outcomes with oral vs. transdermal estradiol, we must depend on biochemical evidence. The biochemical evidence suggests that not all estrogens are the same.
Second, what gates estrogen action? The following is a short list of key determinants:
1. the density of steroid receptors in a given tissue;
2. ratio of occupation of ERa and ERb, which is in turn determined by the mix of estrogens in the circulation impinging upon a given tissue;
3. sulfatase activity in the target tissue (makes sulfated estrogens available to the cell by cleaving off the sulfate group);
4. other enzymatic activities in a given tissue that might convert precursors to estrogens;
5. tissue-specific coregulators, often called tissues-specific chaperones, that guide the dimerized estrogen receptors to key areas in the DNA called estrogen response elements (EREs), and;
6. the other steroids interacting with the cellular machinery.
It is interesting to note that one of the key chaperones, referred to as AP-1, interacts with other steroid-receptor complexes, including that of cortisol. The presence of intracellular cortisol makes AP-1 relatively unavailable to estrogen receptor complexes and, thus, high cortisol levels have the potential to dampen or block estrogen action. There are membrane receptors for estrogen as well, and these seem to be splice variants of classical ERa and ERb. In some cell systems, ERa functions to retard ERb action or availability. Thus, it is critical to balance ERa and ERb occupation to preserve physiological balance in the operation of cellular machinery. What I find fascinating is that ER expression has been reported to be much lower in nonreproductive tissues, thus any estrogenic substance is likely to have a greater effect on reproductive tissues than on nonreproductive tissues.2 I suspect that this finding indicates that it is unlikely that we will find a SERM that is devoid of estrogen action in the uterus and brain while still eliciting estrogen action in other tissues such as brain and urogenital tract.
So what, you may ask. How might this information alter prescribing practices? Emerging data in endocrinology suggest that physiological replacement engenders better results. This appears to be true for replacement regimens with hypothyroidism and for Addison’s disease.3,4 Available evidence indicates that this may hold for the treatment of menopause as well. The main question that remains in my mind is whether our goal should be to aim for estradiol levels in the physiological range or whether the level should be subphysiological, in the range of 50-70 pg/mL. There are no epidemiological data to guide us in answering this question. At the present, my treatment hypothesis is that subphysiological HRT begun at the time of menopause potentiates the benefits of a healthy lifestyle to retard the onset of age-related deficits. The only reason I can find to not replicate subphysiology is convenience. However, with transdermal estradiol patches, replicating ovarian estradiol secretion is easy. When fertility is not the goal, I am not as sure how much benefit derives from replicating the luteal phase pattern of progesterone. Since a progesterone patch is not available, our choices here are more limited. In the absence of much data, I lean toward progestin via patch (in combination with estradiol), oral or topical micronized progesterone, or the progestin intrauterine device, Mirena.
There has been a lot of confusion recently regarding the risks and benefits of HRT. I would like to point out that the majority of the studies reporting risks involved women who took an oral estrogen. In particular, the Women’s Health Initiative, for all of its virtues, is a study of one estrogen, Premarin. All women who were randomized to receive Premarin got the same dose. Some were overdosed and others underdosed. We do not know if those who suffered ill effects were overdosed because the study was not designed to measure levels achieved. Further, many subjects were postmenopausal for many years prior to enrollment. The initiation of Premarin may have had profound effects on coagulation, but this also was not measured. Contrary to popular opinion, Premarin is not a weak estrogen and since it is sulfated, the tissues that may have received the highest exposure were the breast and the endometrium, because those tissues have high levels of the enzyme sulfatase.5 I suspect that the increased risks of deep venous thrombosis (DVT) and myocardial infarction (MI) were attributable to the acute effects of oral estrogen upon hepatic stimulation and a subsequent increase in coagulation. Some women may have had pre-exisiting conditions that posed excess risk for DVT or MI. Thus, epidemiological trials in which the main estrogen taken was Premarin do not adequately test the hypothesis that subphysiological estradiol replacement begun at the time of menopause enhances health. I worry that we have oversimplified the art and science of HRT and, in so doing, we have misled our patients and ourselves. Given these considerations, I continue to recommend subphysiological HRT as an adjunct to a healthy lifestyle. I doubt, however, that any estrogen regimen can undo the harm of a lifetime of bad health habits or reverse established disease.
1. Slater CC, et al. Menopause. 2001;8:200-203.
2. Manolagas S, Kousteni S. Endocrinology. 2001;142:
3. Bunevicius R, et al. N Engl J Med. 1999;340:424-429.
4. Arlt W, et al. N Engl J Med. 1999;341:1013-1020.
5. Slater CC, et al. Menopause. 2001;8:200-203.