Front. Hormone Res., vol. 5, pp. 126-144 (Karger, Basel 1978) Endometrial Response to Different Estrogens E.MYHRE Institute of Pathology, Rikshospitalet, University of Oslo, Oslo Introduction Estrogenic hormones are often referred to simply as 'estrogens' as if they were all of the same type having the same effects. This phraseology occurs in official reports as well as in articles in scientific journals. It is, therefore, difficult, if not impossible in many instances, to evaluate the ef­ fect of a particular estrogenic hormone. For the sake of clarity the literally hundreds of different estrogenic substances ought to be divided into three separate main groups: (1) the naturally occurring human estrogens; (2) the conjugated estrogens, which are mixtures of the sodium salts of the sulphate esters of estrone and equine estrogens, and (3) the synthetic estrogens, which may be alkyl-substituted estrogenic steroids or of non-steroidal origin. Particularly where adverse consequences of treatment with estrogens are concerned, each specific estrogen should be dealt with separately due to their different effects on various parameters, including proliferation of the endometrium. However, reports on specific estrogenic compounds are relatively few compared with the numerous publications dealing solely with 'estrogens'. Different Estrogens Synthetic Estrogens Differences in uterine response to various estrogens have been dem­ onstrated in rats [BRIGGS and BROTHERTON, 1970] (table I) and clinically Downloaded by: Université de Paris 193.51.85.197 - 1/14/2020 5:16:16 AM Endometrial Response to Different Estrogens 127 Table I. Rank estrogenic potencies by the uterine weight method (after BRIGGS and BROTIlERTON, 1970) Diethylstilbestrol dipropionate 14.37 Estradiol 17-cypionate 11.09 Estradiol benzoate 10.75 Estradiol dipropionate 10.00 Ethinyl estradiol 9.72 Benzestrol 9.28 Diethylstilbestrol 8.76 Estrone 8.59 Estradiol 8.02 Dienestrol 7.73 Promestrol dipropionate 6.83 Diethylstilbestrol dipalmitate 6.60 Sodium estrone sulphate 4.00 Monomestrol 3.26 Hexestrol 2.48 Estriol 2.26 Control 1.00 Table ll. Daily substitution doses of oral estrogens in climacteric women and proliferation doses within 14 days (after LAURITZEN, 1975) Daily substitution Proliferation dose Estrogens doses, mg within 14 days, mg Conjugated estrogens 0.6-1.25 (-3.75) 60-80 Estradiol valerate 1.0-2.0 60-80 Estriol 1.0-5.0 Estriol succinate 2.0-6.0 (-8.0) Ethinyl estradiol 0.02-0.04 2.0 Ethinyl estradiol-cyclopcntylether (Quinestrol) 0.025-0.05 2.5 Stilbestrol 0.5-2.0 20 Dienestrol 0.5-4.0 30 [LAURITZEN, 1975] (table II). One observes that synthetic estrogens like ethinyl estradiol have a much stronger effect than natural human estrogens. DELFORGE and FERIN [1970] showed that the proliferative effect of ethinyl estradiol proved to be 50 0/0 stronger that its methyl ether, mestranol, in the human endometrium when 100 {lg of each substance was used in a sequential regime, but GOLDZIEHER et al. [1975], who gave the same sub· stances in doses ranging from 50 to 100 ,ug/day for two consecutive 21-day Downloaded by: Université de Paris 193.51.85.197 - 1/14/2020 5:16:16 AM MYHRE 128 cycles, detected no difference between doses or between drugs, indicating that a plateau in endometrial response was reached. A similar plateau was obtained with 50 flg ethinyl estradiol and mestranol in young women with an absence of ovarian function. Mitotic index was lower than during nor­ mal menstrual cycles [BROSENS and PIJNENBORG, 1976]. Development of adenocarcinoma of the endometrium has been re­ ported in 4 young women using a preparation containing ethinyl estradiol and dimethisterone, a synthetic progestagen, as long-term sequential oral contraception [LYON, 1975]. The rapidly increasing literature on the pharmacokinetics of the ethinyl estrogens has recently been summarized by HELTON and GOLDZIEHER [1977]; their conclusion at that time was that knowledge of the pharmaco­ kinetic of these compounds was just beginning to accumulate. Stilbestrol and diethylstilbestrol are non-steroidal estrogenic substances with strong proliferative effects on the endometrium. SIROTA and MARINOFF [1975] reported endometrial carcinoma in a 27-year-old woman with Turner's syndrome who had received approximately 15 g diethylstilbestrol over an 8-year period. From the literature they collected seven previous cases of Turner's syndrome who also developed endometrial carcinoma after treatment with large doses of diethylstilbestrol. Conjugated/Equine Estrogens The conjugated estrogens contain nearly 50 % estrone, while the rest of the preparations contain equine estrogens. To my knowledge little is known about the effects of the equine estrogens on the human endo­ metrium. The effect of estrone is dealt with below. Natural Human Estrogens While estradiol is the naturally occurring estrogenic hormone, estrone is also important, though it has less activity than estradiol, and its activity probably depends upon its metabolic conversion into estradiol [FOTHERBY, 1975]. Estriol is regarded as a weak estrogen with hardly any effect upon the endometrium. An excellent survey of the hormonal profiles after the menopause is given by CHAKRAVARTI [1976]. Post-menopausal ovaries make no contribution to estrogen production [BARLOW et al. J 1969]. The potencies of the three natural estrogens on the vaginal epithelium and the uterine weight give the relative effect for estradiol/estrone/estriol as 100/10/1 [BRIGGS and BROTHERTON, 1970; LABHART, 1974]. Table III [HASKINS et al. J 1968] summarizes the estrogenicity of the three natural Downloaded by: Université de Paris 193.51.85.197 - 1/14/2020 5:16:16 AM Endometrial Response to Different Estrogens 129 Table III. Estrogenicity relative to estradiol (100 Ufo); (after HASKINS et al., 1968) Investigator and method Estradiol Estrone Estriol SEALEY and SONDERN Immature rat, uterine weight and 100 25 10 vaginal cytology (oil) SZEGO Immature and castrated rats, 100 18 256 uterine weight (oil) HUFFMAN and GROLLMAN Immature rat, opening of vagina 100 10 33 (aqueous) EVANS, VARNEY and KOCH Immature mouse, uterine weight 100 33 12 (oil) estrogens relative to estradiol. It is generally agreed that estriol is less es­ trogenic than estradiol. One author, however, has indicated to the contrary, that estriol is highly estrogenic when compared to estrone and estradiol. The reason for this is not clear; it may be due to the test conditions. Estrone circulates in post-menopausal women in amounts of about 40 pg/ml [RADER et ai., 1973]. It derives from the conversion of andro­ stenedione from the adrenals to estrone in peripheral tissue [MACDoNALD et ai., 1968; MATIINGLY and HUANG, 1969; PROCOPE, 1969; LONGCOPE, 1971; SAEZ et ai., 1972; GRODIN et aI., 1973a, b; PROCOPE and ADLER­ CREUTZ, 1973; SIITERI and MAcDONALD, 1973; SIITERI et at., 1974]. The aromatization of androstenedione takes place in the fat tissue [NIMROD and RYAN, 1975). With advancing age the effectiveness of the conversion from andro­ stenedione to estrone increases up to four times the values in young women [HEMSELL et ai., 1974]. The normal rate of conversion is about 2 0/ 0, but this may increase to 11 % in post-menopausal women giving an amount of 180 flg estrone/day. If more than 40 flg of estrone is synthesized in this way in post-menopausal women, bleeding may occur [GRODIN et ai., 1973a, b]. Levels of estrone amounting to 180 flg/day have been observed in adenomatous hyperplasia and adenocarcinoma uteri [SIITERI, 1975]. From such observations the so-called estrone theory has evolved [MACDONALD and SlITERI, 1974], relating the development of endometrial tumours ex­ clusively to the peripheral estrone production. Another argument for this theory is found in the fact that the constitutional stigmata associated with Downloaded by: Université de Paris 193.51.85.197 - 1/14/2020 5:16:16 AM MYHRE 130 the increased incidence of endometrial tumours are identical to those who give origin to the metabolic mechanism which increases the extra glandular estrone production. The main stigma in this respect is obesity. Prior to the menopause the ovaries are the most important source of estradiol, but they supply only 50 Ofo of the estrone, the remainder coming from the peripheral conversion of androstenedione to estradiol. Andro­ stenedione is secreted by the ovaries and by the adrenals [THIJSSEN, 1976]. After the menopause, practically all estrogenic hormones circulating in the blood derive from the conversion of androgenic hormones into estrogens. The quantity of estrogens resulting from this conversion is greater the higher the body weight of the woman. All sexual steroid levels with the exception of estrone are significantly lower in post-menopausal women than in young women [VERMEULEN, 1976]. Also androstenedione levels are lower, but the transfer constant is about twice as high in post-menopausal than in pre-menopausal women. This suggests a marked increase in the conversion of androstenedione to estrone with age [SOMMERVILLE et al., 1976]. MARSHALL et al. [1976] have confirmed that there is no fall in plasma estrone with age in post-meno­ pausal women. It is generally accepted that the conversion of androstenedione to es­ trone is correlated to body weight [MACDONALD et al., 1963]. Circulating estrogen levels are not significantly different in post-menopausal patients with endometrial cancer than in women of similar age and weight who do not have the tumour [JUDD et al., 1976]. ROME et al. [1977] found that pre-operative estrogen values were higher in post-menopausal women with atypical hyperplasia and adenocarcinoma of the endometrium than in the controls, and further, that the elevated values persisted after oophorectomy. YEN [1977] pointed to the lack of knowledge of the pharmacokinetic aspects by using exogenous estrogens with different molecular structures. He says that it is possible that the use of estrogens today as far as the choice of drugs, the dosage and so on are concerned is unphysiological. He makes particular mention of the use of Premarin, containing estrone and micronised 17,B-estradiol, which leads to a rapid increase in the cir­ culating estrone which reaches a summit after 2-3 h.