Estriol: Safety and Efficacy by Kathleen A. Head, N.D. Abstract While conventional hormone replacement therapy provides certain benefits, it is not without significant risks. Estriol has been found to provide some of the protection without the risks associated with stronger estrogens. Depending upon the situation, estriol may exert either agonistic or antagonistic effects on estrogen. Estriol appears to be effective at controlling symptoms of menopause, including hot flashes, insomnia, vaginal dryness, and frequent urinary tract infections. Results of research on its bone- density-maintaining effects have been contradictory, with the most promising results coming from Japanese studies. Estriol’s effect on cardiac risk factors has also been somewhat equivocal; however, unlike conventional estrogen prescriptions, it does not seem to contribute to hypertension. Although estriol appears to be much safer than estrone or estradiol, its continuous use in high doses may have a stimulatory effect on both breast and endometrial tissue. (Alt Med Rev 1998;3(2):101-113) Introduction A significant problem facing peri- and postmenopausal women, as well as their healthcare practitioners, is determining what approach to take regarding hormone replacement. There are many options, ranging from no intervention at all to conventional hormone replacement therapy (HRT). Approaches which lie somewhere in between involve the use of herbal and nutritional approaches or the use of “friendlier” more gentle hormone replacement regimes than those typically prescribed. One of the hormones which has been virtually ignored by conventional medicine but which shows some promise of effectiveness without as many side-effects is es- triol. Its use is increasing in popularity, prescribed either alone or in the form of triple estrogen (80% estriol, 10% estrone, 10% estradiol). The purpose of this article is to examine the research on this hormone to determine its effectiveness in the treatment of peri- and postmenopausal conditions — hot flashes, osteoporosis, cardiovascular risk; and to determine its safety, particu- larly in regard to cancer risk. Biosynthesis, Metabolism, and Excretion of Estrogens Estrogens are steroids whose immediate precursors are either androstenedione or test- osterone. (See Figure 1.) These precursors are synthesized primarily in the ovaries, adrenals, and testes. Estradiol, produced by androgenic precursors, is the principle estrogen secreted by the ovaries premenopausally. Secreted estradiol is oxidized reversibly to estrone, and both of Kathi Head, N.D.—Technical Advisor, Thorne Research, Inc.; Associate Editor, Alternative Medicine Review. Correspondence address: P.O. Box 25, Dover, ID 83825, e-mail: [email protected] Alternative Medicine Review ◆ Volume 3, Number 2 ◆ 1998 Page 101 Copyright©1998 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Figure 1. Biosynthesis of estrogens O O O H C H C H C 3 3 OH 3 OH H3C 16a - OHase H3C 3b - OH - SDH H3C HO HO O Dehydroepiandrosterone 16α - Hydroxydehydroepiandrosterone 16α - Hydroxyandrostenedione 3b - OH - SDH 17 - OH - SDH, aromatase O O OH H C H C H C 3 3 3 OH aromatase 17 - OH - SDH H C 3 16a - OHase O HO HO Androstenedione Estrone Estriol 16a - OHase Enzyme Abbreviations 17 - OH - SDH 17 - OH - SDH OH OH 3β - OH - SDH H3C H3C 3b-Hydroxysteroid dehydrogenase H C 3 aromatase 17 - OH - SDH 17-Hydroxysteroid dehydrogenase O HO 16α - OHase 16a-Hydroxylase Testosterone Estradiol these estrogens can be converted to estriol. hand, estriol has a much lower affinity for These conversions take place primarily in the binding to SHBG; therefore, a greater percent liver. While there appears to be some level of is available for biological activity.1 enterohepatic recirculation of estriol, it appears In his study on estriol production, to be somewhat less than that for other estro- Longcope found something unexpected. While gens.1 it is commonly believed most estriol results Longcope studied the levels of circu- from conversion of estradiol and estrone, in lating estriol in postmenopausal women, and his study there was evidence of no more than also in premenopausal women during both the 0.4 percent peripheral conversion of either follicular and luteal phases. It appears to be estrone or estradiol. The researchers concluded present at low but fairly steady concentrations either there is a small secretion of estriol di- throughout the day and throughout the men- rectly from the adrenals or ovaries of repro- strual cycle, with a slightly higher level noted ductive-age women, or that other precursors during the luteal phase. The levels that do ex- exist.1 Other researchers have found similar ist are far lower than those for estrone and es- ratios of radio-labeled estrone and urinary es- tradiol. Most estradiol, however, is bound to triol, indicating most of the estriol had come sex-hormone binding globulin (SHBG), so from estrone.2 Longcope noted others have re- only a portion of the circulating estradiol is ported direct conversion of androstenedione available for entry into cells. On the other to estriol without passing through the blood pool of estrone.1 Page 102 Alternative Medicine Review ◆ Volume 3, Number 2 ◆ 1998 Copyright©1998 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Estriol In men and in postmenopausal women Estriol appears to have both estrogeni- the principle site of estrogen secretion is adi- cally antagonistic and agonistic effects. When pose tissue, where estrone is formed from given alone, it generally exerts an estrogenic dehydroepiandrosterone (DHEA), which is effect, the strength of which depends on the secreted by the adrenal cortex. In addition to dosage. When given in conjunction with es- circulating estrogens secreted by the ovaries, tradiol, it appears to exert antagonistic effects.4 estrogens may be produced locally and may Researchers have also found estriol to be an play a causal role in certain disease states such estrogen antagonist when given as a short- as breast cancer. All three estrogens are ex- burst bolus.5 Others have found estriol to be a creted in the urine.1 short-acting agonist when administered in a single dose. In addition, in vitro studies have Pharmacokinetics of Estriol found estriol competes with estradiol binding, Pharmacokinetic studies of estriol and offering a mechanism for its antagonistic ef- its effect on target tissues have been contra- fects.6 dictory, with dosage and routes of administra- tion appearing to be key factors. The effects Estriol for the Management of of oral and vaginal administration of Menopausal Symptoms unconjugated estriol were studied. One mg Because of concern with conventional intravaginal estriol resulted in serum levels hormone replacement protocols regarding the equivalent to 10 mg of the orally administered increased risk of certain cancers—particularly hormone. Vaginal application circumvents the breast and endometrial—as well as other con- first pass through the liver, where a large por- ditions such as liver and gall bladder disease, tion of estriol is immediately conjugated, an thromboemboli, and hypertension, clinicians action believed to contribute to the short du- and patients are continually searching for a less ration of action of the orally-administered hor- toxic approach to menopausal hormone re- mone. On the other hand, entero-hepatic re- placement. A review of the literature is pro- circulation, which is enhanced by periodic fat- vided below to help determine the effective- rich meals, results in prolonged elevation of ness and dosage requirements of estriol. plasma estriol levels, thus enhancing the po- Tzingounis et al studied the use of tency of estriol.3 These same researchers found estriol on 52 postmenopausal women to the administration of activated charcoal re- determine its effect at varying dosages on sulted in binding of estriol in the colon and vasomotor instability (as determined by hot subsequent excretion via the feces, stopping flashes), vaginal cytology, vaginal mucus, and the recirculation process and leading to a rapid endometrial proliferation. Serum levels of decline in plasma estriol levels. FSH, LH, estrone, and estradiol were taken Estriol levels spike for about 3-4 hours before, during and after this six-month trial. after a daytime oral dose; a meal after four Mammograms were also administered when hours results in a second spike. The dietary indicated. Subjects were divided into four effects on vaginal administration, due to the dosage groups: 20 received 2 mg/day, 16 diminished importance of entero-hepatic cir- received 4 mg/day, and two groups of eight culation, are negligible. Therefore, some re- received either 6 or 8 mg/day. All patients searchers report vaginal administration offers selected for this study had severe menopausal a more standardized regime; whereas, oral symptoms. In all patients menopausal administration is affected by many variables.3 symptoms were decreased, the degree of Alternative Medicine Review ◆ Volume 3, Number 2 ◆ 1998 Page 103 Copyright©1998 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Figure 2. Kupperman index for subjective assessment of menopausal symptoms Symptoms Assessed women. The Kupperman in- dex was used to measure sub- *vasomotor instability (hot flashes) * insomnia 0 = absent jective complaints. The aver- * headache 1 = slightly present age score prior to therapy was *excessive sweating 2 = moderate 34, but it decreased consider-