Cerrahi olarak menopoz oluşturulmuş sıçanlarda melatonin tedavisinin östrojen, progesteron ve vitamin D’nin serum düzeylerine etkisi

Esra Bihter Gürler; Berrak Çağlayan Yeğen

doi:10.19161/etd.699035

Araştırma Makalesi

Cerrahi olarak menopoz oluşturulmuş sıçanlarda melatonin tedavisinin östrojen, progesteron ve vitamin D’nin serum düzeylerine etkisi

Yıl 2020, Cilt: 59 Sayı: 1, 7 - 13, 13.03.2020

Esra Bihter Gürler Berrak Çağlayan Yeğen

https://doi.org/10.19161/etd.699035

Cited By: 1

Öz

Amaç: Bifosfonatlar menopoz sonrası osteoporozda kemik kütlesinin korunması amacıyla sıklıkla kullanılmaktadır. Melatonin kemik metabolizmasında da düzenleyici rolü olduğu düşünülen bir antioksidan hormondur. Ancak seks hormonları ve Vitamin D düzeylerine etkisi daha önce çalışılmamıştır.

Gereç ve Yöntem: Anestezi altında, Sprague-Dawley sıçanlara (n=40) bilateral overektomi (OVT) ve taklit cerrahi (n=8) uygulanmıştır. Cerrahiden dört hafta sonra OVT’li sıçanlar serum fizyolojik (1 ml/kg/gün), melatonin (25 mg/kg/gün), alendronat (70 μg/kg/hafta) veya melatonin + alendronat ile sekiz hafta tedavi edilmişlerdir. Sıçanlar dördüncü (n=8) ve 12. haftanın (n=12) sonunda kalpten kan alınarak sakrifiye edilmiştir.

Bulgular: Overektomiden sonraki dördüncü ve 12. haftalarda serum östrojen seviyelerindeki düşüş (p<0,05) melatoninle kontrol düzeyine dönmüştür (p<0,001). Ancak melatonin+alendronatla tedavi edilen gruplarda bir değişiklik görülmemiştir. Öte yandan, 12. haftanın sonunda OVT grubunda progesteron düzeylerinde bir değişiklik görülmezken, melatonin, alendronat veya kombine tedavi yapılan gruplarda anlamlı bir artış saptanmıştır (p<0,05-0,001). Seks hormon bağlayıcı globülin düzeylerinde OVT gruplarının hiçbirinde farklılık oluşmamış, fakat melatonin grubunda anlamlı olmayan bir yükseliş eğilimi gözlenmiştir. Benzer olarak, yalnızca melatonin tedavili grupta Vitamin D düzeylerinde anlamlı bir artış bulunmuştur. (p<0,01-0,001).

Sonuç: Bulgularımız melatoninin over-dışı seks hormonlarının ve Vitamin D’nin sentezinde bir rolü olduğunu düşündürmektedir. Melatoninin hormon replasman tedavisinde yeni bir terapötik ajan olarak kullanılabilmesi için klinik araştırmalara gereksinim vardır.

Anahtar Kelimeler

Menopoz, alendronat, melatonin, östrojen, hormon replasman tedavisi.

Kaynakça

Lofbonehealth.org [homepage on internet]. Nyos: International Osteoporosis Foundation Online Resources [updated 20 November 2018; cited 20 December 2018]. Available from: www.iofbonehealth.org/what-is-osteoporosis.
Marcucci G, Brandi ML. Rare causes of osteoporosis. Clin Cases Miner Bone Metab 2015; 12 (2): 151-6.
Lafleur J, Rillamas-Sun E, Colón-Emeric CS et al. Fracture Rates and Bone Density Among Postmenopausal Veteran and Non-Veteran Women from the Women’s Health. Initiative The Gerontologist 2016; 56 (Suppl 1): 78-90.
Follin SL, Hansen LB. Current approaches to the prevention and treatment of postmenopausal osteoporosis. Am J Health Syst Pharm 2003; 60 (9): 883-901.
Miller PD. Bisphosphonates: Pharmacology and use in the treatment of osteoporosis. In: Marcus R, Feldman D, Nelson DA. Rosen CJ (Eds). Osteoporosis. 3.Ed, San Diego: Elsevier American Pres; 2008: 1725 – 41.
Eriksen EF, Halse J, Halse M, Haase M. New developments in the treatment of osteoporosis. Acta Obstetricia et Gynecologica Scandinavica 2013; 92 (6): 620- 36.
Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90 (3): 1294-301.
Riggs BL, Khosla S, Melton LJ 3rd. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998; 13 (5): 763-73.
Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21 (2): 115-37.
Seifert-Klauss V, Prior JC. Progesterone and bone: actions promoting bone health in women. J Osteoporosis 2010: 845180.
Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB, De Luca HF. Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients: effect of age and dietary calcium. J Clin Invest 1979; 64 (3): 729-36.
Sørensen OH, Lumholtz B, Lund B, Lund B et al. Acute Effects of Parathyroid Hormone on Vitamin D Metabolism in Patients with the Bone Loss of Aging. The Journal of Clinical Endocrinology & Metabolism 1982; 54 (6): 1258–61.
Lawoyin S, Zerwekh JE, Glass K, Pak CY. Ability of 25-hydroxyvitamin D3 therapy to augment serum 1,25- and 24, 25-dihydroxyvitamin D in postmenopausal osteoporosis. J Clin Endocrinol Metab 1980; 50 (3): 593-6.
Cummings SR, Browner WS, Bauer D, et al. Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1998; 339 (11): 733–8.
Alexandre C. Androgens and bone metabolism. Joint Bone Spine 2005; 72 (3): 383–7.
Khosla, S. Role of Hormonal Changes in the Pathogenesis of Osteoporosis in Men. Calcif Tissue Int 2004; 75 (2): 110.
Hoppé E, Bouvard B, Royer M, Audran M, Legrand E. Sex hormone-binding globulin in osteoporosis, Joint Bone Spine 2010; 77 (4): 306-12.
Melton LJ, Riggs BL Jr. Further characterization of the heterogeneity of the osteoporotic syndromes. In: Kleerekoper M, Krane SM (Eds). Proceedings of the International Symposium on Clinical Disorders of Bone and Mineral Metabolism. New York: Mary Ann Liebert, Inc 1989; 145–52.
Roth JA, Kim BG, Lin WL et al. Melatonin Promotes Osteoblast Differentiation and Bone Formation. Journal of Biological Chemistry 1999; 274 (31): 22041–7.
Cardinali DP, Pévet P. Basic aspects of melatonin action. Sleep Med Rev 1998 Aug; 2 (3): 175-90.
Reiter RJ, Tan DX, Allegra M. Melatonin: reducing molecular pathology and dysfunction due to free radicals and associated reactants. Neuro Endocrinol Lett 2002; 23 (Suppl 1): 3-8.
Ladizesky MG, Boggio V, Albornoz LE et al. Journal of Pineal Research Melatonin increases oestradiol-induced bone formation in ovariectomized rats.2003; 34 (2): 143–51.
Ladizesky MG, Boggio V, Cutrera R et al. Melatonin effect on bone metabolism in rats treated with methylprednisolone. Journal of Pineal Research 2006: 40 (4): 297–304.
Maria S, Witt-Enderby PA. Melatonin effects on bone: potential use for the prevention and treatment for osteopenia, osteoporosis, and periodontal disease and for use in bone-grafting procedures. Journal of Pineal Research 2014; 56 (2): 115–25.
Nakao S, Minamide A, Kawakami M, Boden SD, Yoshido M. The Influence of Alendronate on Spine Fusion in an Osteoporotic Animal Model Spine. 2011; 36 (18): 1446–52.
26. Raghavendra V, Shrinivas K, Kulkarni A. Melatonin reversal of DOI-induced hypophagia in rats; possible mechanism by suppressing 5-HT2A receptor-mediated activation of HPA axis, Brain Research 2000; 860 (1-2): 112-8.
Kenealy BP, Kapoor A, Guerriero KA et al. Neuroestradiol in the hypothalamus contributes to the regulation of gonadotropin releasing hormone release. J Neurosci 2013; 33 (49): 19051-9.
Ogle TF, Kitay JI. Effects of melatonin and an aqueous pineal extract on adrenal secretion of reduced steroid metabolites in female rats, Neuroendocrinology 1977; 23 (2): 113-20.
Malendowicz LK, Majchrzak M, Nowak M. Estradiol and melatonin effects on adrenal cortex of ovariectomized and pinealectomized rats. Exp Clin Endocrinol 1985 Jun; 85 (3): 276-82.
Maganhin CC, Simões RS, Fuchs LP Sasso GRS et al. Melatonin influences on steroidogenic gene expression in the ovary of pinealectomized rats, Fertility and Sterility 2014; 102 (1): 291-8.
Chottanapund S, Van Duursen MBM, Navasumrit P et al. Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts, Toxicology in Vitro 2014; 28 (7): 1215-21.
Bondi CD, Alonso-Gonzalez C, Clafschenkel WP et al. The effect of estradiol, progesterone, and melatonin on estrous cycling and ovarian aromatase expression in intact female mice. European Journal of Obstetrics Gynecology and Reproductive Biology 2014; 174: 80–5.
Alvarez-García V, González A, Martínez-Campa C, Alonso-González C, Cos S. Melatonin modulates aromatase activity and expression in endothelial cells. Oncol Rep 2013; 29 (5): 2058-64.
Webley GE, Leidenberger F.The circadian pattern of melatonin and its positive relationship with progesterone in women. J Clin Endocrinol Metab 1986 Aug; 63 (2): 323-8.
Prior JC. Progesterone for Symptomatic Perimenopause Treatment - Progesterone politics, physiology and potential for perimenopause. Facts Views Vis Obgyn. 2011; 3 (2): 109-20.
Norman AW ve Litwack G. Hormones. Orlando: Academic press. 1987. Norman AW ve Litwack G. Hormones (2nd Ed.). Academic Press USA, 1997; 361-384.
Balfour WE, Comline RS, Short RT. Secretion of Progesterone by the Adrenal Gland. Nature 1957; 180:1480-1.
Fajer AB, Holzbauer M ve Newport H. The contribution of the adrenal gland to the total amount of progesterone produced in the female rat. J. Physiol 1971 214 (1): 115-26.
Taketani T, Tamura H, Takasaki A et al. Protective role of melatonin in progesterone production by human luteal cells. J Pineal Res 2011; 51 (2): 207-13.
Wang SJ, Liu WJ, Wu CJ et al. Melatonin suppresses apoptosis and stimulates progesterone production by bovine granulosa cells via its receptors (MT1 and MT2). Theriogenology 2012; 78 (7): 1517-26.
Schlaghecke R, Beuscher D, Kley HK, Juli E. Age-related changes in 11 beta hydroxy androstenedione concentration in normal and osteoporotic women. J Steroid Biochem Mol Biol 1991; 40 (4-6): 731-3.
Varsavsky M, Reyes-García R, García-Martín A, Ramírez RG, Avilés-Perez MD, Muñoz-Torres M. SHBG levels are associated with bone loss and vertebral fractures in patients with prostate cancer. Osteoporosis International 2013; 24 (2): 713–9.
Pardridge WM. Serum bioavailability of sex steroid hormones. Clin Endocrinol Metab. 1986; 15 (2): 259-78.
Lund B. Sorensen OH, Lund B, Agner E. Serum 1,25 (OH) 2D in normal subjects and in patients with postmenopausal osteopenia. Influence of age, renal function and estrogen therapy, Horm Met Res 1982; 14 (5): 271-4.
Stock JL, James A, Coderre E, Lawrence E, Malette E. Effects of a Short Course of Estrogen on Mineral Metabolism in Postmenopausal Women, The Journal of Clinical Endocrinology & Metabolism 1985; 61 (4): 595-600.
Golan D, Staun-Ram E, Glass-Marmor L et al. The influence of vitamin D supplementation on melatonin status in patients with multiple sclerosis, Brain, Behavior, and Immunity 2013; 32: 180-5.

The effect of melatonin on serum levels of estrogen, progesterone and vitamin D in a rat model of surgically induced menopause

Yıl 2020, Cilt: 59 Sayı: 1, 7 - 13, 13.03.2020

Esra Bihter Gürler Berrak Çağlayan Yeğen

https://doi.org/10.19161/etd.699035

Cited By: 1

Öz

Aim: In order to maintain bone mass in post-menopausal osteoporosis, bisphosphonates (e.g. alendronate) are frequently used, while the antioxidant agent melatonin was also suggested to have a regulatory role in bone physiology. However, their impact on the serum levels of sex hormones and vitamin D was not studied before.

Materials and Methods: Under anesthesia, Sprague-Dawley rats (n=40) underwent bilateral ovariectomy (OVT), while control group had sham surgery (n=8). Four weeks after the surgery, OVT rats were treated with saline (1 ml/kg/day), melatonin (25 mg/kg/day), alendronate (70 μg/kg/week) or melatonin + alendronate for 8 weeks. Rats were euthanized at the end of 4th (n=8) or 12th weeks (n=40).

Results: At the 4th and 12th weeks after OVT, serum levels of estrogen were depressed (p<0.05), while melatonin abolished the reduction in estrogen (p<0.01), but OVT-induced reduction in estrogen levels was still evident in alendronate or melatonin + alendronate-treated groups.

Despite that progesterone levels were not significantly changed by OVT on the 12th week, melatonin, alendronate or their combination elevated progesterone levels (p<0.05-0.001). Sex hormone binding globulin was not altered significantly in none of the OVT groups, while a tendency to increase was observed by melatonin treatment. Similarly, in only melatonin-treated group, serum levels of Vitamin D were elevated significantly (p<0.01-0.001).

Conclusion: The results implicate that melatonin may have an impact on the extraovarian synthesis of sex hormones and vitamin D, suggesting its clinical investigation as a potential therapeutic agent for hormone replacement therapy.

Anahtar Kelimeler

Menopause, alendronate, melatonin, estrogen, hormone replacement therapy

Kaynakça

Lofbonehealth.org [homepage on internet]. Nyos: International Osteoporosis Foundation Online Resources [updated 20 November 2018; cited 20 December 2018]. Available from: www.iofbonehealth.org/what-is-osteoporosis.
Marcucci G, Brandi ML. Rare causes of osteoporosis. Clin Cases Miner Bone Metab 2015; 12 (2): 151-6.
Lafleur J, Rillamas-Sun E, Colón-Emeric CS et al. Fracture Rates and Bone Density Among Postmenopausal Veteran and Non-Veteran Women from the Women’s Health. Initiative The Gerontologist 2016; 56 (Suppl 1): 78-90.
Follin SL, Hansen LB. Current approaches to the prevention and treatment of postmenopausal osteoporosis. Am J Health Syst Pharm 2003; 60 (9): 883-901.
Miller PD. Bisphosphonates: Pharmacology and use in the treatment of osteoporosis. In: Marcus R, Feldman D, Nelson DA. Rosen CJ (Eds). Osteoporosis. 3.Ed, San Diego: Elsevier American Pres; 2008: 1725 – 41.
Eriksen EF, Halse J, Halse M, Haase M. New developments in the treatment of osteoporosis. Acta Obstetricia et Gynecologica Scandinavica 2013; 92 (6): 620- 36.
Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90 (3): 1294-301.
Riggs BL, Khosla S, Melton LJ 3rd. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998; 13 (5): 763-73.
Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21 (2): 115-37.
Seifert-Klauss V, Prior JC. Progesterone and bone: actions promoting bone health in women. J Osteoporosis 2010: 845180.
Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB, De Luca HF. Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients: effect of age and dietary calcium. J Clin Invest 1979; 64 (3): 729-36.
Sørensen OH, Lumholtz B, Lund B, Lund B et al. Acute Effects of Parathyroid Hormone on Vitamin D Metabolism in Patients with the Bone Loss of Aging. The Journal of Clinical Endocrinology & Metabolism 1982; 54 (6): 1258–61.
Lawoyin S, Zerwekh JE, Glass K, Pak CY. Ability of 25-hydroxyvitamin D3 therapy to augment serum 1,25- and 24, 25-dihydroxyvitamin D in postmenopausal osteoporosis. J Clin Endocrinol Metab 1980; 50 (3): 593-6.
Cummings SR, Browner WS, Bauer D, et al. Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1998; 339 (11): 733–8.
Alexandre C. Androgens and bone metabolism. Joint Bone Spine 2005; 72 (3): 383–7.
Khosla, S. Role of Hormonal Changes in the Pathogenesis of Osteoporosis in Men. Calcif Tissue Int 2004; 75 (2): 110.
Hoppé E, Bouvard B, Royer M, Audran M, Legrand E. Sex hormone-binding globulin in osteoporosis, Joint Bone Spine 2010; 77 (4): 306-12.
Melton LJ, Riggs BL Jr. Further characterization of the heterogeneity of the osteoporotic syndromes. In: Kleerekoper M, Krane SM (Eds). Proceedings of the International Symposium on Clinical Disorders of Bone and Mineral Metabolism. New York: Mary Ann Liebert, Inc 1989; 145–52.
Roth JA, Kim BG, Lin WL et al. Melatonin Promotes Osteoblast Differentiation and Bone Formation. Journal of Biological Chemistry 1999; 274 (31): 22041–7.
Cardinali DP, Pévet P. Basic aspects of melatonin action. Sleep Med Rev 1998 Aug; 2 (3): 175-90.
Reiter RJ, Tan DX, Allegra M. Melatonin: reducing molecular pathology and dysfunction due to free radicals and associated reactants. Neuro Endocrinol Lett 2002; 23 (Suppl 1): 3-8.
Ladizesky MG, Boggio V, Albornoz LE et al. Journal of Pineal Research Melatonin increases oestradiol-induced bone formation in ovariectomized rats.2003; 34 (2): 143–51.
Ladizesky MG, Boggio V, Cutrera R et al. Melatonin effect on bone metabolism in rats treated with methylprednisolone. Journal of Pineal Research 2006: 40 (4): 297–304.
Maria S, Witt-Enderby PA. Melatonin effects on bone: potential use for the prevention and treatment for osteopenia, osteoporosis, and periodontal disease and for use in bone-grafting procedures. Journal of Pineal Research 2014; 56 (2): 115–25.
Nakao S, Minamide A, Kawakami M, Boden SD, Yoshido M. The Influence of Alendronate on Spine Fusion in an Osteoporotic Animal Model Spine. 2011; 36 (18): 1446–52.
26. Raghavendra V, Shrinivas K, Kulkarni A. Melatonin reversal of DOI-induced hypophagia in rats; possible mechanism by suppressing 5-HT2A receptor-mediated activation of HPA axis, Brain Research 2000; 860 (1-2): 112-8.
Kenealy BP, Kapoor A, Guerriero KA et al. Neuroestradiol in the hypothalamus contributes to the regulation of gonadotropin releasing hormone release. J Neurosci 2013; 33 (49): 19051-9.
Ogle TF, Kitay JI. Effects of melatonin and an aqueous pineal extract on adrenal secretion of reduced steroid metabolites in female rats, Neuroendocrinology 1977; 23 (2): 113-20.
Malendowicz LK, Majchrzak M, Nowak M. Estradiol and melatonin effects on adrenal cortex of ovariectomized and pinealectomized rats. Exp Clin Endocrinol 1985 Jun; 85 (3): 276-82.
Maganhin CC, Simões RS, Fuchs LP Sasso GRS et al. Melatonin influences on steroidogenic gene expression in the ovary of pinealectomized rats, Fertility and Sterility 2014; 102 (1): 291-8.
Chottanapund S, Van Duursen MBM, Navasumrit P et al. Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts, Toxicology in Vitro 2014; 28 (7): 1215-21.
Bondi CD, Alonso-Gonzalez C, Clafschenkel WP et al. The effect of estradiol, progesterone, and melatonin on estrous cycling and ovarian aromatase expression in intact female mice. European Journal of Obstetrics Gynecology and Reproductive Biology 2014; 174: 80–5.
Alvarez-García V, González A, Martínez-Campa C, Alonso-González C, Cos S. Melatonin modulates aromatase activity and expression in endothelial cells. Oncol Rep 2013; 29 (5): 2058-64.
Webley GE, Leidenberger F.The circadian pattern of melatonin and its positive relationship with progesterone in women. J Clin Endocrinol Metab 1986 Aug; 63 (2): 323-8.
Prior JC. Progesterone for Symptomatic Perimenopause Treatment - Progesterone politics, physiology and potential for perimenopause. Facts Views Vis Obgyn. 2011; 3 (2): 109-20.
Norman AW ve Litwack G. Hormones. Orlando: Academic press. 1987. Norman AW ve Litwack G. Hormones (2nd Ed.). Academic Press USA, 1997; 361-384.
Balfour WE, Comline RS, Short RT. Secretion of Progesterone by the Adrenal Gland. Nature 1957; 180:1480-1.
Fajer AB, Holzbauer M ve Newport H. The contribution of the adrenal gland to the total amount of progesterone produced in the female rat. J. Physiol 1971 214 (1): 115-26.
Taketani T, Tamura H, Takasaki A et al. Protective role of melatonin in progesterone production by human luteal cells. J Pineal Res 2011; 51 (2): 207-13.
Wang SJ, Liu WJ, Wu CJ et al. Melatonin suppresses apoptosis and stimulates progesterone production by bovine granulosa cells via its receptors (MT1 and MT2). Theriogenology 2012; 78 (7): 1517-26.
Schlaghecke R, Beuscher D, Kley HK, Juli E. Age-related changes in 11 beta hydroxy androstenedione concentration in normal and osteoporotic women. J Steroid Biochem Mol Biol 1991; 40 (4-6): 731-3.
Varsavsky M, Reyes-García R, García-Martín A, Ramírez RG, Avilés-Perez MD, Muñoz-Torres M. SHBG levels are associated with bone loss and vertebral fractures in patients with prostate cancer. Osteoporosis International 2013; 24 (2): 713–9.
Pardridge WM. Serum bioavailability of sex steroid hormones. Clin Endocrinol Metab. 1986; 15 (2): 259-78.
Lund B. Sorensen OH, Lund B, Agner E. Serum 1,25 (OH) 2D in normal subjects and in patients with postmenopausal osteopenia. Influence of age, renal function and estrogen therapy, Horm Met Res 1982; 14 (5): 271-4.
Stock JL, James A, Coderre E, Lawrence E, Malette E. Effects of a Short Course of Estrogen on Mineral Metabolism in Postmenopausal Women, The Journal of Clinical Endocrinology & Metabolism 1985; 61 (4): 595-600.
Golan D, Staun-Ram E, Glass-Marmor L et al. The influence of vitamin D supplementation on melatonin status in patients with multiple sclerosis, Brain, Behavior, and Immunity 2013; 32: 180-5.

Toplam 46 adet kaynakça vardır.

Ayrıntılar

Birincil Dil	Türkçe
Konular	Sağlık Kurumları Yönetimi
Bölüm	Araştırma Makaleleri
Yazarlar	Esra Bihter Gürler 0000-0001-8259-521X Berrak Çağlayan Yeğen 0000-0003-0791-0165
Yayımlanma Tarihi	13 Mart 2020
Gönderilme Tarihi	20 Aralık 2018
Yayımlandığı Sayı	Yıl 2020Cilt: 59 Sayı: 1

Kaynak Göster

Vancouver	Gürler EB, Çağlayan Yeğen B. Cerrahi olarak menopoz oluşturulmuş sıçanlarda melatonin tedavisinin östrojen, progesteron ve vitamin D’nin serum düzeylerine etkisi. ETD. 2020;59(1):7-13.