: The Journal of The North American Menopause Society Vol. 24, No. 9, pp. 1081-1085 DOI: 10.1097/GME.0000000000000855 ß 2017 by The North American Menopause Society

REVIEW ARTICLE : emerging clinical benefits

Emad S. Ali, MD,1 Cheyenne Mangold, MSIII,2 and Alan N. Peiris, MD, PhD, FRCP(London)3

Abstract Objective: Estriol is the main in pregnancy, but has received less attention outside gestation. It is well known that pregnancy has an immunosuppressive effect on many autoimmune diseases such as multiple sclerosis, psoriasis, thyroiditis, uveitis, and rheumatoid arthritis. Emerging evidence indicates that estriol has potential immunomodulatory benefits for many disease states including autoimmune, inflammatory, and neurodegenerative conditions. In this review, we discuss emerging roles for estriol in the treatment of menopausal symptoms, , cancer, hyperlipidemia, vascular disease, and multiple sclerosis. Estriol appears to offer a potentially cost-effective approach to a variety of conditions and may offer a wide range of health benefits. Methods: We reviewed the English language MEDLINE literature with estriol in the title with emphasis on publications including nonpregnant females between January 1974 and August 2016. Approximately 393 such articles were considered and 72 articles have been referenced in this review. Results: Estriol offers considerable benefits for postmenopausal women with reduced risks that are normally associated with traditional hormone therapies. These benefits include improved control of menopausal symptoms and better urogenital health. Moreover, the immunomodulatory role of estriol in reducing proinflam- matory cytokines may be an important new therapeutic option for chronic autoimmune and neurodegenerative illnesses. Since it is a relatively weak estrogen, there is potential for use in men for conditions such as multiple sclerosis. Conclusions: We conclude transvaginal estriol potentially offers a suitable physiologic delivery and cost- effective alternative to currently available estrogen regimens in selected patients. Additional studies on mode of delivery, safety, and efficacy merit further investigation. Key Words: Estriol – Menopause – Multiple sclerosis.

hile conjugated equine and prior hysterectomy seems to reduce breast cancer incidence 3 (E2) continue to be used widely for hormone and breast cancer mortality. W therapy, less attention about potential use in The most potent estrogen, 17-beta E2 is the major estrogen clinical practice has been given to estriol. The Women’s secreted by the ovaries in premenopausal women; secondary Health Initiative (WHI) study initially indicated increased estrogens include (E1) and estriol (E3). Estriol is the risk of coronary artery disease and breast cancer with hor- main estrogen of pregnancy.4 Whereas the role of estriol has mone therapy.1 However, reanalysis of the WHI data with age been examined in pregnancy, its role in the nonpregnant stratification now shows consistent reduction in coronary female has received less attention. There is increasing evi- artery disease and mortality when is initiated dence that estriol may have an important modulating role in soon after menopause.2 Similarly, the data on breast cancer several diseases including promising results in the treatment risk with hormone therapy have come under further scrutiny. of multiple sclerosis (MS).5 In an animal model of antigen The sole use of estrogen in postmenopausal women with a provoked antibody production, estriol has been demonstrated to have distinctly different modulatory actions on the immune 6 system than E2. Moreover, in 1-chloro-2, 4-dinitrobenzene Received June 22, 2016; revised and accepted January 4, 2017. (DNCB)-induced contact dermatitis, estriol had the strongest From the 1Department of Internal Medicine, 2School of Medicine, and suppressive effect when compared with estrone and E .7 3 2 Section of Endocrinology, Texas Tech University Health Science In this article, we discuss the emerging clinical significance Center, Lubbock, TX. Funding/support: None reported. and potential roles for estriol in clinical practice. We reviewed Financial disclosure/conflicts of interest: None reported. the English language MEDLINE literature with estriol in the Address correspondence to: Alan N. Peiris, MD, PhD, FRCP(London), title, with emphasis on English-language publications includ- TTUHSC/Department of Internal Medicine, 3601 4th street, STOP 9410, ing nonpregnant females between January 1974 and August Lubbock, TX 79430, E-mail: [email protected] or Emad S. Ali, MD, TTUHSC/Department of Family Medicine, 3601 4th street, STOP 2016. Approximately 393 such articles were considered and 8143, Lubbock, TX 79430, E-mail: [email protected] 72 articles were referenced in this review.

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PHYSIOLOGY AND PHARMACOLOGY OF ESTRIOL production of interleukin (IL)-10 and inhibit tumor necrosis Estrogens are produced from , dehydroepian- factor (TNF)-alpha secretion by T cells, decrease T-cell drosterone (DHEA), or . Radiolabeled stud- transmigration, and change the cytokine profile of T cell into 8 24,25 ies indicate that most estriol is formed from estrone. E2 is the the Th2 phenotype. These mechanisms may contribute to predominant estrogen produced by the ovaries in premeno- estriol benefits seen in MS. 26 pausal women. E2 is reversibly oxidized to estrone. Both E2 Sicotte et al showed that treatment of MS with 8 mg of and estrone can be irreversibly converted to estriol in the estriol daily for 6 months demonstrated significant improve- liver.9 Androstenedione can also contribute to estriol for- ment in total enhancing lesions in terms of volume (decreased mation especially in postmenopausal women.10 by 79%) and in terms of numbers (decreased by 82%) in the delivery has local and regional benefits to first 3 months, but this improvement was only limited to the lower urogenital tract.11 Intravaginal estriol (0.5-1 mg) is patients with relapsing remitting MS and not to the secondary well-absorbed and may have detectable effects on gonado- progressive MS group. Oral estriol significantly increases tropins and be equivalent to oral doses of 8 to 12 mg estriol.12 IL-5 due to increases in CD4(þ) and CD8(þ), IL-10, and Estriol is readily absorbed through the , CD64(þ), and decreases in TNF-alpha; these changes in skin, and mucus membranes, and oral estriol delivery may be cytokines correlate with reduction in enhancing lesions on associated with entero-hepatic recirculation and thus prolong magnetic resonance imaging in relapsing remitting MS.27 The exposure due to recycling.13 Estriol, like other estrogens, are immunomodulatory role in reducing proinflammatory cyto- eliminated in urine and feces.13,14 Estriol circulates in low but kines may also benefit men, especially since it is a weak relatively steady levels in the blood, and the possibility of estrogen and it may provide a therapeutic option for MS in some women having ovarian secretion, especially in the luteal men.28 phase, cannot be ruled out.13 Estriol likely contributes little to In addition to the effects of estriol on T cells, estriol may the overall estrogenic activity in nonpregnant, premenopausal have antiapoptotic effects and neurotoxicity protective effects women because of the low circulating value.15 via generation of tolerogenic dendritic cells, and thus may The binding of estriol to sex hormone-binding globulin is protect against inflammatory autoimmune diathesis.29,30 In less potent (lower affinity) than that of E2, and as such a many MS patients, there are cognitive defects related to greater amount is bioavailable, but it has weaker estrogenic defects in hippocampal learning. Estriol treatment can prevent 13,16 activity than E2. Estriol may have both agonistic and decreases in excitatory synaptic transmission and retard neu- 17 5 antagonistic actions, especially in relation to E2. When ropathological changes in the hippocampus. Additional given alone, it seems to have an estrogenic effect, the mag- mechanisms of actions for estriol might be its direct effect nitude of which depends on the dosage. However, when given on neuronal tissue, and this can be either from reduction in 18 31 with E2, it may exert antagonistic effects. In vitro studies microglial activation or protection from neuronal apoptosis. have reported estriol competing with E2–binding, thereby Recently, estriol has been linked to reduction in immune cells offering a mechanism for the antagonistic effects.17 trafficking by down-regulation of the transcription factor Nuclear Factor-kappa beta that subsequently leads to inhi- CLINICAL USES bition of matrix metalloproteinase-9. This protein has an Multiple sclerosis important role in T-cell migration and has elevated levels Conventional remedies for MS have limitations in prevent- in acute MS lesions.32 Collectively, these data support the ing disability. Estrogens have an emerging neuromodulatory hypothesis that estriol may have a strong immunomodulatory and neuroprotective role in MS.19 Since estriol is made by the role that could be beneficial in the management of MS.33 fetal placental unit, progressive increase of levels throughout More recently, estriol in use with glatiramer in a randomized pregnancy, with a peak during the third trimester, occurs. placebo-controlled trial demonstrated reduced relapse rates in Improvement in relapsing remitting MS (RRMS) is most MS, and was well-tolerated over 24 months.34 profound in the third trimester. As estriol levels drop in the postpartum period, MS relapse rate rebounds. Therefore, Menopause increased estriol levels during third trimester may have a Menopause is associated with atrophic changes in the direct protective association with RRMS.20 vagina and lower urinary tract, resulting in an increase in A greater potency for estriol-induced immunomodulation vaginal infections and urinary tract infections (UTIs). About has been shown in both animal and human studies.21,22 In 40% to 45% of postmenopausal women develop symptoms vitro studies of T cells and in vivo experimental studies of related to vaginal atrophy.11 A role for estriol in the treatment autoimmune disease showed that cells cultured with preg- of menopause is not new.35 In a study using 8 mg oral estriol, a nancy levels of estriol diverted their cytokines from Th1 to reduction in vasomotor instability and improved vaginal Th2 profile.23 As such, this may explain the linkage between maturation without side-effects such as endometrial prolifer- estriol and amelioration of autoimmune disease via shift of ation and/or suppression of gonadotrophins were noted.11 In cytokine profile.24 Estriol treatment has been shown to reduce Japanese postmenopausal women, daily oral estriol (2 mg) the severity of experimental autoimmune encephalomyelitis. reduced hot flashes, night sweats, and insomnia, and Possible mechanisms include its ability to up-regulate also lowered gonadotrophins.36 Endometrial histology and

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ultrasound of breasts were normal along with blood pressure, Bone bone, and liver parameters after 12 months of therapy. In Whereas climacteric symptoms were improved as per Yang contrast, Punnonen and So¨derstro¨m37 used oral estriol succi- et al,49 a dose of 2 mg estriol daily for 2 years did not improve nate reported proliferative endometrial changes, especially bone density estimated by quantitative computed tomography when given in varying divided daily doses over 4 weeks. (CT) scan after 2 years of treatment. In contrast, Blum,50 in a However, in a prospective study of 911 patients over 5 years, study of 25 postmenopausal women, reported that estriol estriol succinate (2-12 mg) was shown to be safe and an vaginal cream was able to prevent osteoporosis. Similarly, effective treatment for climacteric complaints and atrophic Hayashi et al51 found that using a daily dose of 2 mg estriol genital changes related to estrogen deficiency.38 However, improved bone density by inhibition of bone resorption. In a unlike Punnonen and So¨derstro¨m,37 the authors reported no 2-year study of oral estriol (2 mg) in a Japanese population, endometrial changes. estriol demonstrated similar bone preservation to 0.625 mg of Transvaginal estriol has also been successfully used to conjugated estrogen.52 The reduced bone turnover may have alleviate menopausal symptoms. Bottiglione et al12 reported contributed to bone preservation. Intravaginal estriol 0.5 mg that using transvaginal estriol, either in 0.5 or 1-mg dose, was every other day with nasal salmon calcitonin demonstrated equally effective at improving urogenital symptoms with fewer declines in bone mineral density when assessed by dual- minimal side-effects; the higher dose also had more effect energy X-ray absorptiometry scan and also demonstrated on climacteric complaints. Low-dose estriol (0.03 mg) pessa- reduction in urinary hydroxyproline excretion.53 Moreover, ries were effective in treating vaginal atrophy and decreasing estriol may up-regulate the cellular viability of the osteoblast, the vaginal pH significantly when compared with the and concomitant treatment with estriol and vitamin D may placebo.39 Similarly, in a phase III study of 167 women, a further augment the viability of the osteoblast.54 Overall, the very low dose of 0.005% estriol vaginal gel was shown to be effects of estriol on bone mass have been inconsistent. More safe and effective in the treatment of postmenopausal vaginal favorable results have been obtained in Japanese populations. 40 41 atrophy. Dugal et al found that both E2 vaginal tablets and estriol vagitories were effective in treating vaginal atrophy; Lipids however, transient endometrial thickening was more marked Natural estrogens including estriol did not change plasma 55 in the E2 group (1.1 vs 0.5 mm for estriol). In a meta-analysis lipids in a study by Walter and Jensen. of 12 studies, intravaginal estriol did not result in endometrial Itoi et al compared the long-term effects of oral estriol with proliferation, and raised the interesting option of omitting in regards to serum lipid profile. Estriol, sequential such that there will be no induced unlike conjugated estrogens, did not induce hypertriglyceride- withdrawal bleeding.42 mia.56 Similarly, Kika et al57 found that oral estriol in the dose of 2 mg daily was not associated with triglyceride elevation, Urinary tract infections whereas conjugated estrogens did increase triglycerides. Estrogen deficiency contributes to urogenital atrophy, uri- nary incontinence, and recurrent UTI in postmenopausal Vascular women with vaginal estriol as a viable option to standard In animal models, estriol may reduce atherosclerosis with- hormone therapy.43 Intravaginal estriol cream was shown to out changes in plasma lipids through a nitric oxide-mediated prevent recurrent UTIs through modification of vaginal flora mechanism.58 Estriol may also exert a direct atheroprotective and reduction of vaginal pH.44 Intravaginal estriol significantly effect on vascular smooth muscle cells.59 Additional rheo- improved urogenital atrophy and incontinence documented logical mechanisms by which estriol may benefit the micro- through colposcopy and urethral pressure readings.43,45 In a circulation include improved erythrocyte membrane fluidity, study of 206 postmenopausal women, intravaginal estriol and microviscosity.60 Unlike conventional estrogens, estriol (starting at 1 mg daily) plus pelvic floor rehabilitation was does not seem to be linked to hypertension. Oral estriol effective in ameliorating symptoms of urogenital aging.46 succinate in the dose of 2 mg daily did not influence the Improved colposcopic findings, maximum urethral pressure, renin- axis.61 Endothelial benefits of estriol may urethral closure pressure, and the abdominal pressure trans- also contribute to antiatherosclerotic benefits.51,62 mission ratio to the proximal urethra were noted.46 In contrast, Raz et al47 found that a dose of 0.5 mg estriol pessary used twice Cancer weekly, was able to reduce bacteruria but proved less effective In postmenopausal women treated with 14 days of vaginal than nitrofurantoin 100 mg daily for prevention of bacteriuria in estriol, estrogen and progesterone receptors were enhanced in postmenopausal women. The mechanisms may relate to the the uterine endometrium and myometrium without endo- failure to restore the lactobacilli colonization and reduce metrial proliferation.63 Valdivia and Ortega,64 in a study of vaginal pH. It should be noted, however, the estriol dose used 210 nonobese postmenopausal women with a normal mam- in this study was a relatively low dose and used only twice mogram at baseline, noted increased breast density with E2; weekly. Estriol (0.5 mg every second day) was equally effective no such increase was seen with estriol. Lemon found that as E2 administered via vaginal ring in alleviating urinary tract intermittent implantation of estriol subcutaneously reduced symptoms in postmenopausal women.48 the development of chemically induced breast cancer in rats

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65-67 by 80% to 90%. Giving 1 to 2 mg oral estriol for 6 months 2. Lobo RA, Pickar JH, Stevenson JC, Mack WJ, Hodis HN. Back to the to postmenopausal women did not result in any clinically future: hormone replacement therapy as part of a prevention strategy for 68 women at the onset of menopause. Atherosclerosis 2016;254:282-290. relevant difference in endometrial histology and thickness. 3. Chlebowski RT, Aragaki AK, Anderson GL. Menopausal hormone However, there were more endometrial polyps (14%) in the therapy influence on breast cancer outcomes in the Women’s Health estriol-treated group compared with placebo (2.9%). In con- Initiative. J Natl Compr Canc Netw 2015;13:917-924. 69 4. Ding J, Zhu BT. Unique dose-dependent effects of the human pregnancy trast, Lippman et al, in studies on human breast cancer cell hormone estriol on the ratio of blood IgM to IgG in female mice. Mol Med lines, concluded that estriol could bind and stimulate breast Rep 2016;13:447-452. cancer in tissue culture. Pratt and Longcope70 concluded that 5. Ziehn MO, Avedisian AA, Dervin SM, O’Dell TJ, Voskuhl RR. Estriol preserves synaptic transmission in the hippocampus during autoimmune physiological levels of estriol were not a significant protector demyelinating disease. Lab Invest 2012;92:1234-1245. in breast cancer. Given the lack of concordance among the 6. Ding J, Zhu BT. Unique effect of the pregnancy hormone estriol on studies, more research is needed to further examine the role of antigen-induced production of specific antibodies in female BALB/c mice. 2008;73:289-298. estriol in cancer. 7. Zhang EY, Zhu BT. Estriol strongly inhibits DNCB-induced contact dermatitis: role of antigen-specific antibodies in pathogenesis. Endocr CONCLUSIONS Connect 2014;3:161-172. 8. Guerami A, MacDonald PC, Casey ML. Variation in the fractional We conclude that estriol may offer considerable potential conversion of plasma estrone to estriol among women and men. J Clin benefits for postmenopausal women with reduced risks nor- Endocrinol Metab 1984;58:1148-1152. mally associated with traditional hormone therapies. This is 9. Lappano R, Rosano C, De Marco P, De Francesco EM, Pezzi V, Maggiolini M. Estriol acts as a GPR30 antagonist in - especially so if the transvaginal delivery route is considered. negative breast cancer cells. Mol Cell Endocrinol 2010;320:162-170. Since compounding pharmacies may have varying bioavail- 10. Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in ability, a standardized estriol formulation for transvaginal postmenopausal women. J Clin Endocrinol Metab 1973;36:207-214. 11. Archer DF. Efficacy and tolerability of local estrogen therapy for delivery is highly desirable. Its lesser potency compared with urogenital atrophy. Menopause 2010;17:194-203. 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