Are the Differences Between Estradiol and Other Estrogens, Naturally

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Are the Differences Between Estradiol and Other Estrogens, Naturally 0021-972x196/$03.0010 Vol. 81, No. 2 Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright Q 1996 by The Endocrine Society Are the Differences Between Estradiol and Other Estrogens, Naturally Occurring or Synthetic, Merely Semantical? SEYMOUR LIEBERMAN The Women’s Health Center, Department of Obstetrics and Gynecology, St. Luke’s - Roosevelt Institute for Health Sciences, New York, ?VY 10019 Downloaded from https://academic.oup.com/jcem/article/81/2/850/2649606 by guest on 03 October 2021 n 1923, Allen and Doisy’ described a bioassay that de- 3. Estradiol, like other steroids, is a chemical that may I tected estrogenic activity in extracts of biological mate- exhibit a multitude of biological activities; eg. estra- rials.This test also enabled the determination of relative es- diol has effect on bones, skin, arteries, brain, etc. as trogenic potencies of many compounds and of well as on reproductive tissues and processes.It may inhomogeneous materials of natural origin. During the in- also be carcinogenic. tervening 70 years this bioassay, or modifications of it, has 4. Nonestradiol estrogens are also chemicals that may been used to identify and characterize synthetic estrogens and exhibit many biologic activities in addition to estro- those obtained from natural sources,e.g. mammalian tissues, genicity. The profiles of these activities need not re- excreta, and plants, and from chemical syntheses. semble, qualitatively or quantitatively, the profile The numerous chemical compounds and biological materials that characterizes estradiol. that have been labeled as estrogens because they responded 5. The various biological activities of chemicals classi- positively in the above bioassay differ enormously from each fied as estrogens are altered by chemical modifica- other with respect to their chemical structures. The following tions resulting from metabolic processes or chemical abbreviated list will illustrate the point: estradiol, estriol, equi- synthesis. These modifications do not alter each bi- lin, 17-ethynylestradiol, stilbesterol, xenoestrogens (DDT etc), ological property of the estrogens in the same quan- phytoestrogens (coumestrol), clinically-useful extracts of horse tiative manner. Chemical modification may produce urine (premarin), etc. Thus under one rubric a potpourri of a chemical that is both more estrogenic in the Allen- chemical entities have been designated estrogens. Frequently Doisy assay and more carcinogenic than estradiol. In investigators give no recognition to the differences that un- contrast, a chemical modification may also produce a doubtedly exist among membersof the class.Focusing on only chemical that is less estrogenic but more carcinogenic this one characteristic, i.e. a positive responsein a bioassayand than estradiol. neglecting the many differences in biological activities that un- 6. After entry into the blood stream, either by secretion doubtedly exist among these materials, cannot help but cause from an endocrine gland or by artificial administration unnecessaryconfusion. In a subjectas complex asreproductive by iu injection (or im, po, or sq), the compound is me- endocrinology this lack of concern for the dissimilaritiesamong tabolized in the liver or elsewhere by chemical reactions various estrogens promotes neither understanding nor progress. to catabolites, conjugates, etc., which do not possess To provide a common starting point for the view presented profiles of biological activities identical with that of its in this comment several propositions are presented below. progenitor. These statements concentrate, in a simplistic way, upon the 7. Estradiol effectuates its estrogenic activity in a char- knowledge that is needed to addressthe question posed in the acteristically biochemical manner. This action need title. Ordinarily thesetheorems are taught early in the education not be the same as that used to trigger each of its of reproductive biologists but, as evidenced by many flawed other biologic activities. publications, their reiteration here may have value. 8. Experiments done under artificial in vitro conditions 1. A definition: estrogens are materials that, when admin- (injection of chemicals into muscles or into the third istered (usually by injection im as solutions in some oil) ventricle of the brain, incubation studies with isolated into sexually immature or castrated female rodents, tissue preparations, or in vitro binding to receptors or cause cornification of epithelial cells of the vagina. to the plasma binding proteins) are of uncertain value 2. Estradiol, the estrogenic hormone in mammals, is a for they do not always mimic quantitatively (or even member of this class of biologically active chemicals. qualitatively) the behavior of estradiol in the natural in situ situation. This does not mean that such unnatural Received November 1, 1995. Accepted November 1, 1995. studies do not advance science.They often do. But there Address all correspondence and reprint requests to: Seymour is no certainty that the results obtained by them reflect Lieberman, The Women’s Health Center, Department of Obstetrics and Gynecology, St. Luke’s-Roosevelt Institute for Health Sciences, 432 West nature accurately. 38th Street, New York, New York 10019. ’ Allen E, Doisy EA. 1923 An ovarian hormone: preliminary report on For the argument advanced in this essay to be valuable it its localization, extraction and partial purification, and action in test is not necessary that all the propositions given above be animals. JAMA. 81: 819. totally without flaw. Exceptions to those generalities may 850 COMMENTS exist, but these flaws will probably not invalidate completely secreted by the adrenals of the fetus. This C,,, steroid is con- the point of view advanced in this commentary. The impor- verted to estriol by the aromatase of the placenta. The relation- tant point is: for a chemical to act as a physiologically im- ship between estradiol and estriol is unclear. Although estriol portant hormone in situ, it must reach a target (a specific production is not a good index of the outcome of the pregnancy, receptor or some other specific structure) as a chemical spe- it seems reasonable to assume that estriol or its precursors, cies possessing the capacity to trigger the same response as 16cY-hydroxy dehydroepiandrosterone or its sulfate, or all three the natural hormone itself. Whether the physiological con- play some physiologic role. At present this role is unknown, but sequence of estradiol is on calcium metabolism, cholesterol when it is established, will this role be related to estrogenicity? metabolism, or reproduction, estradiol, in situ, has a natural It may be argued that our understanding of the true function affinity for whatever specific target is being activated. On the of these substances in the pregnant state has been delayed other hand, under these conditions, the target in question has because the endocrine community during the last 30 years has a natural affinity for estradiol. That the target can bind or been content to let the matter rest. Generally estriol is consid- react with chemical entities other than estradiol is clearly ered to be not very important because it is derogated as only a Downloaded from https://academic.oup.com/jcem/article/81/2/850/2649606 by guest on 03 October 2021 apparent from the evidence, but whether each of the systems weak estrogen. activated by estradiol will react quantitatively with other Seventy years ago it may not have been difficult to propose chemicals (synthetic estrogens, phytoestrogens, xenoestro- an all-inclusive definition of a hormone. Nowadays it is daunt- gens) quantitatively through the same mechanism as estra- ing. Traditionally a hormone is considered as a chemical se- diol is dubious. Data collected decades ago showed that creted by a specialized mammalian organ, an endocrine gland, synthetic steroids frequently do not behave in the same way into the blood stream, by means of which it is transported to a as a natural hormone toward all the various biological ac- specific target where the chemical initiates a cascade of re- tivities. Whatever the mechanism for this lack of parallelism, sponses, ending in a physiological or biochemical event we this long known phenomenon (expressed in Proposition 4, recognize as the characteristic consequence of the secretion of above) proves the point: a positive test in the immature the hormone. Many chemicals serve as messengers, although female rodent assay is not predictive of all the physiological relatively few satisfy all the criteria of this definition of a hor- or pharmacological properties of a test material. For most mone. In fact, many chemicals now designated as hormones endocrinologists this conclusion is obvious and even plati- also do not satisfy all the parts of the definition. To give only tudinous, but then how can one take seriously so many two examples: a) estradiol can be made in what are ordinarily published studies in which estrogens are tacitly assumed to not considered to be endocrine glands, the brain and adipose mimic the natural hormone in all respects? That materials tissue; and b) testosterone may serve as a paracrine stimulator: labeled estrogens have important clinical uses is undeniable. it augments the FSH-activation of the aromatase present in the Many synthetic modifications are considered to represent a granulosa cells of the ovary. triumph of science over nature, but do these materials imitate To point out that some chemicals, natural
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