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0021-972x196/$03.0010 Vol. 81, No. 2 Journal of Clinical and Printed in U.S.A. Copyright Q 1996 by The Endocrine Society

Are the Differences Between and Other , 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 , 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 , , , , 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 numerouschemical compounds and biological materials that characterizes estradiol. that have been labeled as estrogens becausethey 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, , equi- synthesis. These modifications do not alter each bi- lin, 17-ethynylestradiol, stilbesterol, (DDT etc), ological property of the estrogens in the same quan- (), clinically-useful extracts of tiative manner. Chemical modification may produce (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 differencesin biological activities that un- 6. After entry into the blood stream, either by doubtedly exist among these materials, cannot help but cause from an or by artificial administration unnecessaryconfusion. In a subjectas complex asreproductive by iu (or im, po, or sq), the compound is me- endocrinology this lack of concernfor the dissimilaritiesamong tabolized in the or elsewhereby 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 statementsconcentrate, in a simplistic way, upon the 7. Estradiol effectuates its estrogenic activity in a char- knowledge that is needed to addressthe question posedin 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 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 in some ) ventricle of the brain, incubation studies with isolated into sexually immature or castrated , preparations, or in vitro binding to receptors or cause cornification of epithelial cells of the . to the plasma binding ) are of uncertain value 2. Estradiol, the estrogenic in , 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 doesnot 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 . 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,,, is con- the point of view advanced in this commentary. The impor- verted to estriol by the of the . 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 , 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 or its , 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, 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 . 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 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 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) 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 . triumph of science over nature, but do these materials imitate To point out that some chemicals, natural () or the natural hormone in all respects? Moreover, does one synthetic (17-ethynyl estradiol) can mimic the biological activ- nonestradiol estrogen mimic in all regards another nonestra- ities of hormones, even though these chemicals themselves are diol estrogen? not classified as hormones, is trite. In no way is the clinical Many published studies may have lost some of their value usefulness of such chemicals diminished by not classifying because of the failure to recognize the complexities that the them as hormones. But then, when is an estrogen an estrogen? word estrogen entails. Certainly it is difficult to make compar- When is it not?’ Is satisfying the definition given in Proposition isons between studies in which the chemical nature of the es- 1 all that matters? The important issue is not to preserve the trogen is not a constant element in the experimental designs. sanctity of the -made designation. The important issue is to This issue may be one reason why no standardized regimen for describe reality as accurately as our methods permit and to use estrogen replacement therapy has yet been established. descriptive language that is in accord with that perceived re- Many relevant examples can be used to illustrate this argu- ality. This includes using names that identify uniquely. When ment. One is particularly troubling for it concerns estriol, an- we use designations that embody classes of substances, espe- other naturally occurring estrogen. It may be useful to repeat cially when the various members of the class do not have here some thoughts expressed a decade ago. Estriol is the most identical properties, we tend to forstall the recognition that real abundant estrogen found in human urine, particularly that of and important differences may exist between the natural es- pregnant women. Soon after its discovery in 1930, it was shown trogen, estradiol, and other estrogens. to be a catabolite of estradiol. It also tests positively, although The argument expressed in this comment may also be weakly, in the above mentioned bioassay. Although there is relevant for other classes of biologically active chemicals, eg something peculiar about its response in this test these facts, , progestins, , etc. The use of im- together with the notion that it “looks like estradiol”, have precise language does not make the formidable task of es- resulted in estriol being labeled an estrogen, albeit a weak one. tablishing a fact less difficult. To this day this characterization prevails even though, in 1966, it was found that 90% of the estriol excreted in the urine of pregnant women is not a catabolite of estradiol. Estriol, pro- ’ With the express permission of my friend, Dr. Nicholas I’. Christy, duced during pregnancy, is biosynthesized through a process I have used this construction to paraphrase relevant questions he once posed, “When is a gland a gland, and when is a gland not a gland?” independent of estradiol. The current belief is that the proximal Christy NT’. 1979 Diseases of the . In: Beeson PB, precursor of most of the estriol produced during pregnancy is McDermott W, Wyngaarden JB, eds. Cecil Textbook of , 15th lba-hydroxy dehydroepiandrosterone or its sulfate, which are ed. Philadelphia; WB Saunders: 206.