Medical Grand Rounds USE OF ESTROGENS AFTER THE MENOPAUSE 10 July 1980 Jean D. Wilson Outline I. GENERAL REVIEWS II. ENDOCRINOLOGY OF MENOPAUSE A. Origin of estrogen before or after the menopause B. Effect of weight on estrogen formation in peripheral tissues Ill. ESTROGENS AVAILABLE FOR REPLACEMENT THERAPY IV. EFFECTS OF ESTROGENS IN THE AGING WOMAN A. Vasomotor Instability B. Urogenital Epethelium and Skin C. Atherosclerosis, Myocardial Infarction and Stroke D. Hypertension E. Thromboembolic Disease F. Gallbladder Disease G. Benign and Malignant Breast Tumors H. Endometrial Carcinoma I. Osteoporosis V. CONCLUSIONS -I- I. GENERAL REVIEWS I. Lauritzen, C.H. The female climacteric syndrome: significance, problems, treatment. Acta Obstet. Gynecol. Scand. ~:47-61, 1976. 2. Campbell, S., Ed. The fv1anagement of the Menopause and Post­ Menopausal Years. University Park Press, Baltimore, 1976. 3. VanKeep, P.A., R.B. Greenblatt, and M. Albeaux-Ferret. Consensus on menopausal research. University Park Press, Baltimore, 1976. 4. Gambrell, R.D., Jr. Postmenopausal bleeding. Clin. Obstet. Gynecol. ~:129-143, 1977. 5. Studd, J., S. Chakravarti, and D. Oram. The climacteric. Clin. Obstet. Gynecol. :t:3-29, 1977. 6. Shoemaker, E.S., J.P. Forney, and P.C. MacDonald. Estrogen treatment of postmenopausal women, benefits and risks. J. Amer. Med. Assoc. 138:1524, 1977. 7. Utian, W.H. Current status of menopause and postmenopausal estrogen therapy. Obstet. Gynecol. Surv. 32:193-204, 1977. 8. Greenblatt, R.B. Geriatric Endocrinology, Vol. 5, Raven Press, New York, 1978. 9. Lauritzen, C., and P.A. VanKeep. Frontiers of Hormone Research. S. Karger, Basel, Vol. 5, 1978. 10. Silverberg, S.G., and F.J. Major. Estrogens and Cancer. John Wiley and Sons, New York, 1978. II. Quigley, M.M., and C.B. Hammond. Estrogen-replacement therapy - help or hazard? N. Engl. J. Med. 301:646-648, 1979. 12. Landau, R.L. What you should know about estrogens. JAMA 241:47-51, 1979. 13. Ryan, K.J. Estrogen after the menopause: risk vs. benefits. Consultant _!:218-221, April, 1980. Following the introduction of estrogens into clinical medicine in the late 1930's their use in menopausal women become more and more widespread as the result of several interlocking phenomena. Within medicine, powerful advocates argued that needless suffering of millions of women could be prevented by adequate estrogen replacement therapy (14, 15). -2- FrG.l. Woman showing some of the stigmata of "Xature's defeminization! ' The general Hifine==5 of muscles and lig::Lments , the "dowager's hump" and the "negativistic" expres­ sion are part of a picture usually attributed to age alone. Some of these "·omen exhibit signs and symptoms similar to those in the early stages of Parkinson's di seuse. They exjst ro.ther than live. (14) 14. Wilson, R.A., and T.A. Wilson. The fate of the nontreated postmeno­ pausal woman: a plea for the maintenance of adequate estrogen from puberty to the grave. J. Am. Geriatr. Soc. !!:347-362, 1963. 15. Jern, H.Z. Hormone therapy of the menopause and aging. Charles C. Thomas, Springfield, IL, 1973. (Dedicated to millions of women suffering needlessly.) This viewpoint was promoted aggressively by the pharmaceutical industry. -3- ~ ..... - . , ~ :;- I' Fig. 2 Jn ansu·uing adt'ertiumeniJ p/tnJe mtmion JOURNAl. OF CLINICAL ENDOCRINOLOGY AND METABOLISM The use of estrogen was made scientifically respectable by Fuller Albright who advanced the thesis that osteoporosis is the result of the menopausal state, that premature menopause is associated with worsening of osteoporosis, and that osteroporosis can be prevented by estrogen administration. 16. Albright, F., P.H. Smith, and A.M. Richardson. Postmenopausal osteoporosis. J. Amer. Med. Assoc . .!.!..§_:2465-2474, 1941. -4- After the long term results of such treatment from Albright's clinic were published by Henneman and Wallach (17) it became generally accepted that osteoporosis was a preventable disease. 0 1.0 HEIGHT LOSS 2.0 IN INCH£$ 3.0 4.0 s.o 50 2$ 20 1$ 10 II $ 10 15 20 25 PRE Pa ESTROGEN THERAPY YEARS Figure 3. Loss of height in osteoporotic women treated wi th estrogen and untreated. [From Henneman and Wallach(l7),Arch Intern Med 100:71 5. copyright 1957 Ameri­ can Medical Association.] 17. Henneman, P.H., and S. Wallach. The use of androgens and estrogens and their metabolic effects. Arch. Int. Med. 100:715-723, 1957. Simultaneously, the public at large was propagandized by advertisements, magazine articles, and books (such as Feminine Forever by Robert A. Wilson, M.D., published in 1966) to the belief that a perpetual Spring could be induced in the aging womm by the routine use of estrogens. By the mid 1960's it .was acceptable, indeed standard practice in many areas, including the Endocrine Clinic of Parkland Memorial Hospital, to prescribe estrogens routinely for women undergoing natural or surgically induced menopause. By 1973 51% of menopausal women in Seattle, Washington, used estrogen for a median period of 10 years (18). By 1975 the use of estrogens in this country approached the status of a several hundred million dollar industry, involving some 30 million prescriptions per year. 5- Fig.~. The numbers of estrogen pnoscriptiono rose dramatically during the period when use of the synthetic hormones peaked, and then fell off sharply after studies showing an increase In the risk of endometrial concer _, publicized. I.Jlgging somewhot behind Wll 1 concomitant rise ond fill in the Incidence of endometrial concor. 1. Source: N1tlonel Pretcription Audit. 2. Source: Nation•! Cancer lnatttute. 18. Stadel, B.V., and N. Weiss. Characteristics of menopausal women: a survey of King and Prince Counties in Washington, 1973-74. Am. J. Epidemiol. 102:209, 1975. Then, beginning in the mid 1970's a series of papers was published to suggest that an increase had occurred in the prevalence of endometrial cancer in menopausal women in this country (of epidemic proportions) and that this increase was the direct result of estrogen therapy. These claims have provoked a literal avalanche of papers in the past few years, relating both to the question of the purported relation of estrogen odministration to cancer and to the overall question of benefit to risk ratios of estrogen therapy. Coincidental to this new interest in the subject, the role of estrogen therapy in preventing osteoporosis is also undergoing reevaluation. What I propose to do today is to review the endocrine changes that take place at' menopause, the current concepts of the pathophysiology of the menopausal syndrome, the comparative pharmacology of the estrogens now available for replacement therapy, and the effects and side effects of estrogens in the aging woman. II. ENDOCRINOLOGY OF THE MENOPAUSE One of the major developments in steroid hormone physiology during the past 20 years was the demonstration by Drs. MacDonald and Siiteri and their colleagues at this institution that circulating estrogens can be derived both from direct secretion by the ovary and from formation in peripheral tissues from c androgens (19, 20). 19 Androstenedione Testosterone (Adrenal Androgen) l Estrtne ~ 1713-Estradiol ( -6- Prior to the menopause about 60% of estrogen formation is in the form of estradiol secreted into the plasma by the ovaries whereas 40% is estrone formed predominately by peripheral aromati.wtion of androgens. 200 ,.. NORMAL FEMALE-OVULATORY MENSES 0 0 'c 160 .9 0 .g 120 e a.. 80 40 4 6 8 w ~ ~ • ~ w u ~ ~ u Day of Cycle FIC. 5. Sources of estrogen production during a normal ovula­ tory ~menst rual cycle. Total height of bars represents sum of estrone a nd estradiol production; the hatclud portion , that amount derived fro.;, plasma andros tenedione. (Ref . 20) As the result of the menopause, the ovarian component of direct estrogen production is virtually obliterated, but the peripheral aromatase system remains intact so that estrone production remains substantialy unchanged. As a result, there is a switch from estradiol to estrone as the predominant estrogen in the aging woman. 1 BO 10 •• [, ~ ...... · A Ipq 124 ... 70 • PREIOO" ·A I •o .~ 50 ~ 4 0 ~ 30 I ·' 20 10 1- OflR. R. E S R.BI. LF. 0~P. H. ~L .SI. FIC. 6. Estrogen production from circulating androstenedione in normal postmenopausal women. PREI, total estrone production rate; PREI 4 • . A, production rate of estrone from plasma andro· stenedione; and PREl J.l A• -"• amount of estrone derived from androstenedione that enters the plasma as free estrone. As indi~ cated in text, formation and release of estrone sulfate likely ac ~ counts for difference between PRE I•• -• and PRE I' •'·• . (Ref. 20) -7- r The factors that regulate the rate of estrogen formation in peripheral tissues are largely undefined, but ane major determinant is body weight, a relation that is true both for the rate of estrogen formation (20) and for the plasma levels of estrogens in postmenopausal women (4). 12 510 iii e; 8 >z 8 6 .... z ~ 4 0:: w 0.. 2 0 o 40 80 120 160 200 240 280 320 360 BODY WEIGHT (lbs.l FIG. 7. Correlati on of extent of com·crsion of androstenedione tn estronC., ( p ) 1~li 1 , with body weig hl in postwenopausal women. Cc~r ­ rela lion coefficient = 0.7+.(Rei . 20) .. 20 ~ ....ll: , 0 ~ E 10 . •• so 40 ~ ...z 0 E 20 10 _, 0 2S ~ 75 100 EXCESS FAT ( lbsl FIG. 8. Correlation of estradiol and estrone levels with excess fat in postmenopausal patients with endometrial cancer (•) and without endometrial cancer (0 ). Dashed regression line is for all patients, while solid line is for cancer patients only. (Ref . 21) -8- Exactly why peripheral oromotose activity is enhanced in obesity is unclear, presumably due to an increase in the number of odipocytes and pre-odipocytes (23). In some postmenopausal women mean estrogen production may be as high or higher than prior to the menopause - the predominant estrogen being changed and the secretory rate constant rather than intermittent (20).