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Estriol: Emerging Clinical Benefits

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Estriol: Emerging Clinical Benefits Menopause: 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 Estriol: 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 estrogen 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, osteoporosis, 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 estrogens and estradiol 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 estrone (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 hormone therapy 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. Menopause, Vol. 24, No. 9, 2017 1081 Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. ALI ET AL PHYSIOLOGY AND PHARMACOLOGY OF ESTRIOL production of interleukin (IL)-10 and inhibit tumor necrosis Estrogens are produced from testosterone, dehydroepian- factor (TNF)-alpha secretion by T cells, decrease T-cell drosterone (DHEA), or androstenedione. 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 Vaginal estrogen 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 gastrointestinal tract, 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,
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