Research: Bioidentical Estrogens (Estradiol, Estriol)

Overview

Estrogen therapy is still widely recommended for short-term treatment of troublesome menopausal symptoms such as hot flashes and vaginal atrophy, although non-estrogenic vaginal lubricants can also be effective for vaginal symptoms.

Estrogen therapy is no longer advised for long-term protection against cardiovascular disease because of the negative outcome of the Women’s Health Initiative study. However, some researchers suggest that much lower doses of estrogen given to women very soon after the onset of menopause could help protect against later cardiovascular disease, and this is being tested in clinical trials such as the Kronos Early Estrogen Prevention Study (KEEPS). This trial is currently enrolling 720 women early in menopause for the evaluation of lower estrogen doses (0.45 mg/day oral conjugated equine estrogens or 0.05 mg/day transdermal estradiol) in combination with cyclic oral micronized progesterone (Prometrium®, 200 mg/day for 12 days per month) compared with placebo. The researchers are looking at measures of cardiovascular health. Completion of the study is expected in 2010. Also, the Early Versus Late Intervention Trial With Estradiol (ELITE) is enrolling 504 women either less than 6 years or 10 years or more after menopause. They will be randomized to receive either 1 mg/day oral estradiol or placebo (with 4% vaginal progesterone gel or placebo respectively for 10 days each month in women with a uterus) and cardiovascular outcomes measured.

Estrogens have also been prescribed for the prevention of bone loss because of the known effect of estrogen in inhibiting bone resorption. Again, the long-term adverse effects with estrogen therapy seen in clinical trials have led to recommendations for a lower estrogen dosage.

Bioidentical estrogens given transdermally (patches or creams) can be used in much lower doses than oral estrogens. This is because they avoid the “first-pass metabolism” by the liver when drugs are given orally. The recent study by Ho and colleagues below also demonstrates a cardiovascular protective effect of transdermal bioidentical estradiol without the damaging inflammatory effects of oral conjugated estrogens. Atherosclerotic vascular disease is now widely thought to be a result of inflammation.

Research

• Ho JY, Chen MJ, Sheu WH, Yi YC, Tsai AC, Guu HF, Ho ES.  Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women.  Hum Reprod 2006; 21(10):2715-20. 

  In this comparison of 0.625 mg/day oral conjugated equine estrogen (CEE) versus 0.6 mg/day 17β-estradiol transdermal gel for 6 months or no treatment, the oral CEE group showed significantly increased levels of C-reactive protein (CRP), a marker of inflammation, while the transdermal and control groups showed no increase in CRP.  The transdermal estradiol group showed a similar beneficial effect on flow-mediated vasodilation in the brachial artery to the CEE group, indicating a comparative therapeutic benefit but without increasing the risk of atherosclerosis. 

• Ouyang P, Michos ED, Karas RH.  Hormone replacement therapy and the cardiovascular system: lessons learned and unanswered questions.  J Am Coll Cardiol 2006; 49(9):1741-53. 

  This review discusses the lack of benefit of estrogen therapy in older women for the prevention of cardiovascular problems.

• Friel PN, Hinchcliffe C, Wright JV. Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone. Altern Med Rev. 2005 Mar;10(1):36-41.
• Barrett-Connor E, Grady D, Stefanik ML.  The rise and fall of menopausal hormone therapy.  Ann Rev Public Health 2005; 26:115-40. 

  This important review by leading epidemiologists looks at the results of major clinical trials of hormone therapy and suggests that any long term benefits of estrogen therapy for the prevention of fractures could be achieved with much lower doses of estrogen.

• Ettinger B.  Rationale for use of lower estrogen doses for post-menopausal hormone therapy.  Business Briefing: Women’s Healthcare 2004; 1-6.   http://www.touchbriefings.com/pdf/992/Ettinger_pap.pdf [accessed 6/27/06].
• Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M.  Ultralow-dose micronized 17β-estradiol and bone density and bone metabolism in older women: a randomized controlled trial.  JAMA 2003; 290(8):1042-1048. 

  This study of 0.25 mg/day oral estradiol versus placebo for 3 years in women over 65 years old (with 100 mg/day oral micronized progesterone in women with a uterus in both groups) found an increase in bone density in the estradiol group compared with placebo.

• Archer DF; EstroGel Study Group. Percutaneous 17beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause. 2003 Nov-Dec; 10(6):516-21.
   
• Cohen, L, Soares, C, Poitras, J, Prouty, J, Alexander, A, Shifren, J. Short-term use of estradiol for depression in perimenopausal and postmenopausal women: a preliminary report. Am J Psychiatry. 2003 Aug;160(8):1519-22.

  Twenty-two peri- or post-menopausal women with median age of 50 years experiencing moderate severity depression (DSM-IV major depression, minor depression, or dysthymia) were enrolled in a 4 week open-label clinical trial of 100 micrograms of transdermal 17B estradiol. Results showed decreased score on Montgomery-Asberg Depression Rating Scale (20 to 11.50) and Beck Depression Inventory. Greene-Climacteric Scale scores showed measured improvement during the 4 week study. Changes in depression scales and climacteric scales were not significantly correlated. Perimenopausal (6) women showed greater improvement in depression scales than postmenopausal women (2). Authors suggested this study supports previous results showing that the effect of estrogen therapy on mood may be independent of antidepressant effects mediated by alleviation of vasomotor symptoms and that estrogen therapy may be of benefit to perimenopausal women experiencing moderately severe depression.

• Jarupanich T, Lamlertkittikul S, Chandeying V. Efficacy, safety and acceptability of a seven-day, transdermal estradiol patch for estrogen replacement therapy. J Med Assoc Thai . 2003 Sep;86(9):836-45. 
• Wren BG, Day RO, McLachlan AJ, Williams KM. Pharmacokinetics of estradiol, progesterone, testosterone and dehydroepiandrosterone after transbuccal administration to postmenopausal women. Climacteric. 2003 Jun;6(2):104-11.
• Collette J, Viethel P, Dethor M, Chevallier T, Micheletti MC, Foidart JM, Reginster JY. [Comparison of changes in biochemical markers of bone turnover after 6 months of hormone replacement therapy with either transdermal 17 beta-estradiol or conjugated equine estrogen plus nomegestrol acetate] Gynecol Obstet Fertil. 2003 May;31(5):434-41.
• Zegura B, Keber I, Sebestjen M, Koenig W. Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis. Atherosclerosis. 2003 May;168(1):123-9.
• Zegura B, Keber I, Sebestjen M, Borko E. Orally and transdermally replaced estradiol improves endothelial function equally in middle-aged women after surgical menopause. American Journal of Obstetrics and Gynecology. 2003 May;188(5):1291-6.

  Forty-three surgically induced (6 weeks postop) menopausal women were randomly assigned in a double-blind study to 28 weeks of 2.0mg oral or 50mg transdermal estradiol. Looking at blood flow through the brachial artery, flow-mediated dilation (ultrasound) in the oral group increased 6.0 to 13.2% and in the transdermal group increased 7.0 to 14.9% Results indicate that both oral and transdermal administration had equal effect on arterial endothelium independent of lipid profiles and increased vasodilation.

• Arrenbrecht S, Boermans AJ. Effects of transdermal estradiol delivered by a matrix patch on bone density in hysterectomized, postmenopausal women: a 2-year placebo-controlled trial. Osteoporos Int 2002;13(2):176-83.
• Granberg S, Eurenius K, Lindgren R, Wilhelmsson L. The effects of oral estriol on the endometrium in postmenopausal women. Maturitas 2002 Jun 25;42(2):149-56.

  This study conducted endometrial evaluation using both transvaginal ultrasound (TVS) and histologic biopsy by Pipelle in postmenopausal women taking a low-dose oral estriol (1 or 2 mg daily) for a mean duration of 4.3 years. Mean endothelial thickness in the study group after one year was 3.0mm and in the control group was 2.4mm. There was a noted increase in atrophic vaginal epithelium in the control group. There was a noted increased incidence of endometrial polyps in the study group (14.1%) compared to the control group (2.9%) although this was not determined to be clinically significant.

• Yoshimura T, Okamura H. Short term oral estriol treatment restores normal premenopausal vaginal flora to elderly women. Maturitas 2001 Sep 28;39(3):253-7.

  This study looked at short term (14 days) oral estriol (2.0mg/day) treatment for atrophic vaginitis in 59 postmenopausal women aged 50-75 years. The results showed that in the majority of women in the study group the oral estriol restored normal vaginal flora by the end of the treatment period.

• Perera M, Sattar N, Petrie JR, Hillier C, Small M, Connell JM, Lowe GD, Lumsden MA. The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with Type 2 diabetes: a randomized, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism 2001 Mar;86(3):1140-3.

  This study showed that transdermal estradiol and oral norethisterone reduce plasma triglyceride and total cholesterol levels, factor VII activity and von Willebrand factor antigen levels in women with Type 2 diabetes without a concurrent change in adiposity or glycemic control. The authors suggest that this protocol might be of benefit for women at high risk of cardiovascular disease.

• Manonai J, Theppisai U. Effect of oral estriol on urogenital symptoms, vaginal cytology, and plasma hormone level in postmenopausal women. J Med Assoc Thai 2001 Apr;84(4):539-44.
• Prestwood KM, Kenny AM, Unson C, Kulldorff M. The effect of low dose micronized 17b-estradiol on bone turnover, sex hormone levels, and side effects in older women: a randomized, double blind, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism 2000 Dec;85(12):4462-9.

  This study determined that oral low-dose estrogen (0.25mg/day) had similar beneficial effects on bone health in elderly (mean age 75 years) postmenopausal women without the breast tenderness and bleeding associated with higher doses. Authors recommended the use of serum E2 levels as the guide for therapeutic effect at a range of 10-28 pg/L.

• Davis SR, Walker KZ, Strauss BJ. Effects of estradiol with and without testosterone on body composition and relationships with lipids in postmenopausal women. Menopause 2000 Nov-Dec;7(6):395-401.
• Bruce-Keller AJ, Keeling JL, Keller JN, Huang FF, Camondola S, Mattson MP. Antiinflammatory effects of estrogen on microglial activation. Endocrinology 2000 Oct;141(10):3646-56.

  This study identified new pathways for the estrogenic anti-inflammatory effects on brain function, potentially leading to identification of new methods for improving neurodegenerative disease, specifically involving the microglial cells.

• Itoi H, Minakami H, Iwasaki R, Sato I. Comparison of the long-term effects of oral estriol with the effects of conjugated estrogen on serum lipid profile in early menopausal women. Maturitas 2000 Oct 31;36(3):217-22.

  This was a randomized comparison study with three arms: 2.0mg estriol + 2.5mg medroxyprogesterone (E3), 0.625mg conjugated estrogen + 2.5mg medroxyprogesterone (CE) and a vitamin D and Calcium combination (control), looking at changes in serum lipid profiles in early menopausal women. The sample size was 67 women. After 48 months on the randomized protocol, the serum lipid profiles showed that those in the E3 group decreased total cholesterol and triglycerides (-4.9 and – 6.7) compared to the control of (+5.4 and +6.1) and CE group of (-1.9 and +17.6). The E3 group showed less significant changes in HDL cholesterol and LDL cholesterol when compared to the CE protocol: E3 (+3.8 and -5.2), CE (+10.7 and -11.4), control (-3.6 and +11.8). The results show the improvement of serum lipid profiles in response to estrogen. The authors suggested that in women where bleeding has been a problem response to certain estrogen protocols, the low-dose estriol may be an alternative treatment for those at risk of cardiovascular disease.

• Miller BE, De Souza MJ, Slade K, Luciano AA. Sublingual administration of micronized estradiol and progesterone, with and without micronized testosterone: effect on biochemical markers of bone metabolism and bone mineral density. Menopause 2000 Sep-Oct;7(5):318-26.
• Lose G, Englev E. Oestradiol-releasing vaginal ring versus oestriol vaginal pessaries in the treatment of bothersome lower urinary tract symptoms. BJOG 2000 Aug;107(8):1029-34.
• Takahashi K, Okada M, Ozaki T, Kurioka H, Manabe A, Kanasaki H, Miyazaki K. Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause. Hum Reprod 2000 May;15(5):1028-36.
• de Lignieres B, Silberstein S. Pharmacodynamics of oestrogens and progestogens. Cephalalgia 2000 Apr;20(3):200-7.
• Hayashi T, Ito I, Kano H, Endo H, Iguchi A. Estriol (E3) replacement improves endothelial function and bone mineral density in very elderly women. J Gerontol A Biol Sci Med Sci 2000 Apr;55(4):B183-90; discussion B191-3.
• Takahashi K, Manabe A, Okada M, Kurioka H, Kanasaki H, Miyazaki K. Efficacy and safety of oral estriol for managing postmenopausal symptoms. Maturitas 2000 Feb 15;34(2):169-77.
• Head KA. Estriol: safety and efficacy. Altern Med Rev. 1998 Apr;3(2):101-13.
   
• Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997 Nov;17(11):3071-8.
• Snabes, M, Payne, J, Kopelen, H, Dunn, JK, Young, R, Zoghbi, W. Physiologic estradiol replacement therapy and cardiac structure and function in normal postmenopausal women: a randomized, double-blind, placebo-controlled crossover trial. Obstetrics and Gynecology, 1997;89(3):332-39.

  In a randomized, double-blind, placebo-controlled, crossover clinical trial of 31 postmenopausal women, average age 59.7 years, using 2.0 mg of oral estradiol (E2) daily, the authors investigated the effects of estradiol on cardiac function and structure. This study did not include the use of progestins with estrogen. 12 weeks of E2 therapy showed no change in left ventricular thickness or mass, left atrial size or aortic size. There was a small but significant increase in left ventricular end-diastolic volume but it was not associated with change in end-systolic volume or ejection fraction changes. Heart rate and systolic and diastolic pressures were unchanged after 3 months of treatment. Time-velocity integral of flow and peak flow velocities were unaffected by E2 treatment. Authors concluded that estrogen replacement therapy did not affect cardiac structure or size in normal postmenopausal women (after 12 weeks of treatment).

• Suvanto-Luukkonen E, Sundstrom H, Penttinen J, Laara E, Pramila S, Kauppila A. Percutaneous estradiol gel with an intrauterine levonorgestrel releasing device or natural progesterone in hormone replacement therapy. Maturitas 1997 Apr;26(3):211-7.
• Haines, C, Chung, T, Chang, A, Masarei, J, Tomlinson, B, Wong, E. Effect of oral estradiol on Lp(a) and other lipoproteins in postmenopausal women. A randomized, double-blind, placebo-controlled, crossover study.Arch Intern Med 1996 Apr 22;156(8):866-72.

  In a randomized, double-blind, placebo-controlled, crossover study, 91 surgically postmenopausal women received either 6 months of 2mg daily oral estradiol followed by 6 months of placebo or the opposite regimen. During treatment phase, Group One showed decreased Lipoprotein (a) concentration (10.78 to 6.44 mg/dL) and LDL-C with increase in HDL-C and TG while Group Two showed a less pronounced decrease (12.74 to 10.75). 53 women continued oral estrogen therapy for an additional 12 months. Lipoprotein (a) levels were essentially unchanged from previous measures at the end of the treatment phase after 12 months of additional therapy. Authors suggested that reduced Lipoprotein (a) levels with extended oral estrogen therapy support a cardioprotective effect of HRT in postmenopausal women.

• Lindoff C, Peterson F, Lecander I, Martinsson G, Astedt B. Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease. Maturitas 1996 May;24(1-2):43-50.
• Nozaki M, Hashimoto K, Inoue Y, Sano M, Nakano H. [Usefulness of estriol for the treatment of bone loss in postmenopausal women] Nippon Sanka Fujinka Gakkai Zasshi. 1996 Feb;48(2):83-8.
• Evans SF, Davie MW. Low and conventional dose transdermal oestradiol are equally effective at preventing bone loss in spine and femur at all post-menopausal ages. Clin Endocrinol (Oxf) 1996 Jan;44(1):79-84.
• Koloszar S, Kovacs L. [Treatment of climacteric urogenital disorders with an estriol-containing ointment] Orv Hetil 1995 Feb 12;136(7):343-5.
• Riedel M, Oeltermann A, Mugge A, Creutzig A, Rafflenbeul W, Lichtlen P. Vascular responses to 17 beta-oestradiol in postmenopausal women. Eur J Clin Invest 1995 Jan;25(1):44-7.
• Yang TS, Tsan SH, Chang SP, Ng HT. Efficacy and safety of estriol replacement therapy for climacteric women. Zhonghua Yi Xue Za Zhi ( Taipei ). 1995 May;55(5):386-91.
• Darj E, Axelsson O, Carlstrom K, Nilsson S, von Schoultz B. Liver metabolism during treatment with estradiol and natural progesterone. Gynecol Endocrinol 1993 Jun;7(2):111-4.
• Kainz C, Gitsch G, Stani J, Breitenecker G, Binder M, Schmidt JB. When applied to facial skin, does estrogen ointment have systemic effects? Arch Gynecol Obstet 1993;253(2):71-4.
• Raul, R, Stamm, W. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. The New England Journal of Medicine. 1993;329(11):753-56.

  This randomized, double blind, placebo-controlled trial looked at the incidence of urinary tract infections (UTI) in 93 postmenopausal women using 0.5 mg estriol vaginal cream once nightly for two weeks followed by twice weekly application or placebo. Results showed significantly lower UTI rates in treatment group (0.5 infections per patient-year vs. 5.9 for placebo group). The mean vaginal pH fell from 5.5+-0.7 to 3.6+-1.0 for treatment group and 5.8+-1/2 to 6.1+-2.0 in placebo group and there was an increase in vaginal colonization with lactobacilli in the treatment group. Authors recommend use of topical vaginal estriol in preventive treatment of women with frequent UTI as possible replacement for long-term use of nitrofurantoin, co-trioxazole, trimethoprim, cehpalexin or fluoroquinolones.

• Ettinger B, Genant HK, Steiger P, Madvig P. Low-dosage micronized 17 beta-estradiol prevents bone loss in postmenopausal women. American Journal of Obstetrics and Gynecology. 1992 Feb;166(2):479-88.

  The authors evaluated the effects of 17 beta-estradiol (E2) in a randomized, double-blind, dose ranging study of 41 postmenopausal women conducted in 2 phases. Phase one included phased E2 doses (0.5mg, 1.0mg, 2.0mg) plus calcium supplementation (to serum value of 1500mg). Phase two included E2 doses plus random cessation of calcium supplementation. Progestins were added during phase two (total study time of 18 months). Results showed very little change in bone density results for placebo group (0.5 – 0.9%) whereas treatment group showed significant increases from baseline bone density. In phase two the treatment groups showed an annual change in bone density of 2.0%. There was a positive correlation between total calcium intake and the change in bone density results. The study showed a continuous dose-response effect on bone density results. Authors concluded that low dose (1.0mg) beta-estradiol and 1000mg of calcium prevented bone loss in postmenopausal women.

• Iosif CS. Effects of protracted administration of estriol on the lower genitourinary tract in postmenopausal women. Arch Gynecol Obstet 1992;251(3):115-20.
• Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Hershman JM, Alkjaersig NK, Fletcher AP, Judd HL. Biologic effects of transdermal estradiol. N Engl J Med 1986 Jun 19;314(25):1615-20.

  Twenty-three postmenopausal women were randomly assigned to use of transdermal estradiol in four increasing doses (25, 50, 100, 100 micrograms per 24 hours) followed by daily oral dose of conjugated equine estrogens in two doses (0.625 mg, 1.25 mg) or to use of oral conjugated equine estrogens followed by transdermal estradiol. Results showed a dose-response relationship between the amount of estradiol delivered and the serum measure of the hormone. Estrone concentrations also rose with transdermal application. At the 50 and 100 microgram transdermal dose levels, results were comparative to the 0.625 and 1.25 mg conjugated equine estrogen results. Non-hepatic markers (serum gonadotropin, vaginal cytologic studies, urinary calcium levels and urinary calcium/creatinine ratios all increased in dose-dependent fashion. Hepatic markers (hepatic protein level, lipid metabolism, clotting factors, renin substrate) were not affected by transdermal doses of estradiol. Transdermal estradiol provided benefit of increased serum hormone levels without hepatic protein effects of oral conjugated equine estrogens.

• Haspels AA, Luisi M, Kicovic PM. Endocrinological and clinical investigations in post-menopausal women following administration of vaginal cream containing oestriol. Maturitas 1981 Dec;3(3-4):321-7.
• Tzingounis VA, Aksu MF, Greenblatt RB. Estriol in the management of the menopause. JAMA 1978 Apr 21;239(16):1638-41.
• Callantine MR, Martin PL, Bolding OT, Warner PO, Greaney MO Jr. Micronized 17 beta-estradiol for oral estrogen therapy in menopausal women. Obstet Gynecol 1975 Jul;46(1):37-41.

Source: www.womeninbalance.org/research/estrogen2.html