The Central Mechanism of Endocrine Disorder Induced by Androgen in PCOS Patients

doi:10.12280/gjfckx.20200795

Abstract

Abstract:

Characterized by excess androgen and insulin resistance, polycystic ovary syndrome (PCOS) is a common endocrine disorder with follicular atresia and stasis. Though the etiology and pathogenesis of PCOS remains unclear, androgen is now thought to play an important role in the onset of PCOS. Early in embryonic development, neuroendocrine dysfunction induced by excess androgen affects the hypothalamic-pituitary-ovary axis owing to defects of steroid hormone negative feedback pathway and abnormal activity of gonadotropin releasing hormone neurons, resulting in the downstream consequence in target organs. The key mechanism probably is the abnormal steroid hormone feedback and the increased activity of gonadotropin-releasing hormone neurons. This review discusses the major evidence and conceivable mechanisms by which neuroendocrine dysfunction induced by excess androgen at early developmental points originates PCOS, and prospects the potential clinical applications for preventing and intervening PCOS.

Key words: Polycystic ovary syndrome, Androgens, Receptors, androgen, Gonadal steroid hormones, Feedback, Nervous system

XU Qian, LIU Bin, WANG Dao-juan, WANG Yong. The Central Mechanism of Endocrine Disorder Induced by Androgen in PCOS Patients[J]. Journal of International Obstetrics and Gynecology, 2021, 48(2): 203-208.

References 35

[1]	Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)[J]. Hum Reprod, 2004,19(1):41-47. doi: 10.1093/humrep/deh098. doi: 10.1093/humrep/deh098 pmid: 14688154
[2]	Escobar-Morreale HF. Polycystic ovary syndrome: definition,aetiology,diagnosis and treatment[J]. Nat Rev Endocrinol, 2018,14(5):270-284. doi: 10.1038/nrendo.2018.24. pmid: 29569621
[3]	Caldwell A, Edwards MC, Desai R, et al. Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome[J]. Proc Natl Acad Sci U S A, 2017,114(16):E3334-E3343. doi: 10.1073/pnas.1616467114. doi: 10.1073/pnas.1616467114 pmid: 28320971
[4]	Walters KA, Bertoldo MJ, Handelsman DJ. Evidence from animal models on the pathogenesis of PCOS[J]. Best Pract Res Clin Endocrinol Metab, 2018,32(3):271-281. doi: 10.1016/j.beem.2018.03.008. doi: 10.1016/j.beem.2018.03.008 pmid: 29779581
[5]	Pignatelli D. Non-classic adrenal hyperplasia due to the deficiency of 21-hydroxylase and its relation to polycystic ovarian syndrome[J]. Front Horm Res, 2013,40:158-170. doi: 10.1159/000342179. doi: 10.1159/000342179 pmid: 24002412
[6]	Escobar-Morreale HF, San Millán JL. Abdominal adiposity and the polycystic ovary syndrome[J]. Trends Endocrinol Metab, 2007,18(7):266-272. doi: 10.1016/j.tem.2007.07.003. doi: 10.1016/j.tem.2007.07.003 pmid: 17693095
[7]	Hakim C, Padmanabhan V, Vyas AK. Gestational Hyperandrogenism in Developmental Programming[J]. Endocrinology, 2017,158(2):199-212. doi: 10.1210/en.2016-1801. doi: 10.1210/en.2016-1801 pmid: 27967205
[8]	Moore AM, Prescott M, Campbell RE. Estradiol negative and positive feedback in a prenatal androgen-induced mouse model of polycystic ovarian syndrome[J]. Endocrinology, 2013,154(2):796-806. doi: 10.1210/en.2012-1954. doi: 10.1210/en.2012-1954
[9]	Walters KA. Androgens in polycystic ovary syndrome: lessons from experimental models[J]. Curr Opin Endocrinol Diabetes Obes, 2016,23(3):257-263. doi: 10.1097/MED.0000000000000245. doi: 10.1097/MED.0000000000000245 pmid: 26866639
[10]	Caldwell AS, Eid S, Kay CR, et al. Haplosufficient genomic androgen receptor signaling is adequate to protect female mice from induction of polycystic ovary syndrome features by prenatal hyperandrogenization[J]. Endocrinology, 2015,156(4):1441-1452. doi: 10.1210/en.2014-1887. pmid: 25643156
[11]	Silva MS, Prescott M, Campbell RE. Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS[J]. JCI Insight, 2018,3(7):e99405. doi: 10.1172/jci.insight.99405. doi: 10.1172/jci.insight.99405
[12]	Kawwass JF, Sanders KM, Loucks TL, et al. Increased cerebrospinal fluid levels of GABA,testosterone and estradiol in women with polycystic ovary syndrome[J]. Hum Reprod, 2017,32(7):1450-1456. doi: 10.1093/humrep/dex086. doi: 10.1093/humrep/dex086 pmid: 28453773
[13]	Cheng XB, Jimenez M, Desai R, et al. Characterizing the neuroendocrine and ovarian defects of androgen receptor-knockout female mice[J]. Am J Physiol Endocrinol Metab, 2013,305(6):E717-E726. doi: 10.1152/ajpendo.00263.2013. doi: 10.1152/ajpendo.00263.2013 pmid: 23880317
[14]	Moore AM, Campbell RE. Polycystic ovary syndrome: Understanding the role of the brain[J]. Front Neuroendocrinol, 2017,46:1-14. doi: 10.1016/j.yfrne.2017.05.002. doi: 10.1016/j.yfrne.2017.05.002 pmid: 28551304
[15]	Herbison AE. Physiology of the gonadotropin-releasing hormone neuronal network[M]//Neill JD. Knobil and Neill′s Physiology of Reproduction. Academic Press, 2006: 1415-1482.
[16]	Moore AM, Campbell RE. The neuroendocrine genesis of polycystic ovary syndrome: A role for arcuate nucleus GABA neurons[J]. J Steroid Biochem Mol Biol, 2016,160:106-117. doi: 10.1016/j.jsbmb.2015.10.002. pmid: 26455490
[17]	Xita N, Tsatsoulis A. Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental,clinical,and genetic association studies[J]. J Clin Endocrinol Metab, 2006,91(5):1660-1666. doi: 10.1210/jc.2005-2757. doi: 10.1210/jc.2005-2757 pmid: 16522691
[18]	Foecking EM, Szabo M, Schwartz NB, et al. Neuroendocrine consequences of prenatal androgen exposure in the female rat: absence of luteinizing hormone surges,suppression of progesterone receptor gene expression,and acceleration of the gonadotropin-releasing hormone pulse generator[J]. Biol Reprod, 2005,72(6):1475-1483. doi: 10.1095/biolreprod.105.039800. pmid: 15744016
[19]	Maliqueo M, Galgani JE, Pérez-Bravo F, et al. Relationship of serum adipocyte-derived proteins with insulin sensitivity and reproductive features in pre-pubertal and pubertal daughters of polycystic ovary syndrome women[J]. Eur J Obstet Gynecol Reprod Biol, 2012,161(1):56-61. doi: 10.1016/j.ejogrb.2011.12.012. doi: 10.1016/j.ejogrb.2011.12.012 pmid: 22277163
[20]	Zuloaga DG, Heck AL, De Guzman RM, et al. Roles for androgens in mediating the sex differences of neuroendocrine and behavioral stress responses[J]. Biol Sex Differ, 2020,11(1):44. doi: 10.1186/s13293-020-00319-2. doi: 10.1186/s13293-020-00319-2 pmid: 32727567
[21]	Wang F, Pan J, Liu Y, et al. Alternative splicing of the androgen receptor in polycystic ovary syndrome[J]. Proc Natl Acad Sci U S A, 2015,112(15):4743-4748. doi: 10.1073/pnas.1418216112. pmid: 25825716
[22]	Penatti CA, Davis MC, Porter DM, et al. Altered GABAA receptor-mediated synaptic transmission disrupts the firing of gonadotropin-releasing hormone neurons in male mice under conditions that mimic steroid abuse[J]. J Neurosci, 2010,30(19):6497-6506. doi: 10.1523/JNEUROSCI.5383-09.2010. pmid: 20463213
[23]	Ruka KA, Burger LL, Moenter SM. Both Estrogen and Androgen Modify the Response to Activation of Neurokinin-3 and κ-Opioid Receptors in Arcuate Kisspeptin Neurons From Male Mice[J]. Endocrinology, 2016,157(2):752-763. doi: 10.1210/en.2015-1688. doi: 10.1210/en.2015-1688 pmid: 26562263
[24]	Walters KA, Edwards MC, Tesic D, et al. The Role of Central Androgen Receptor Actions in Regulating the Hypothalamic-Pituitary-Ovarian Axis[J]. Neuroendocrinology, 2018,106(4):389-400. doi: 10.1159/000487762. doi: 10.1159/000487762 pmid: 29635226
[25]	Amodei R, Gribbin K, He W, et al. Role for Kisspeptin and Neurokinin B in Regulation of Luteinizing Hormone and Testosterone Secretion in the Fetal Sheep[J]. Endocrinology, 2020,161(4):bqaa013. doi: 10.1210/endocr/bqaa013. doi: 10.1210/endocr/bqaa022 pmid: 32052048
[26]	George JT, Kakkar R, Marshall J, et al. Neurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized,Placebo-Controlled Trial[J]. J Clin Endocrinol Metab, 2016,101(11):4313-4321. doi: 10.1210/jc.2016-1202. pmid: 27459523
[27]	Abbott DH. Neuronal androgen receptor: Molecular gateway to polycystic ovary syndrome?[J]. Proc Natl Acad Sci U S A, 2017,114(16):4045-4047. doi: 10.1073/pnas.1703436114. doi: 10.1073/pnas.1703436114 pmid: 28377515
[28]	Kumar D, Candlish M, Periasamy V, et al. Specialized subpopulations of kisspeptin neurons communicate with GnRH neurons in female mice[J]. Endocrinology, 2015,156(1):32-38. doi: 10.1210/en.2014-1671. doi: 10.1210/en.2014-1671 pmid: 25337655
[29]	Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease[J]. Hum Reprod Update, 2014,20(4):485-500. doi: 10.1093/humupd/dmu009. doi: 10.1093/humupd/dmu009 pmid: 24615662
[30]	Clarkson J, Han SY, Piet R, et al. Definition of the hypothalamic GnRH pulse generator in mice[J]. Proc Natl Acad Sci U S A, 2017,114(47):E10216-E10223. doi: 10.1073/pnas.1713897114. pmid: 29109258
[31]	Sullivan SD, Moenter SM. Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder[J]. Proc Natl Acad Sci U S A, 2004,101(18):7129-7134. doi: 10.1073/pnas.0308058101. pmid: 15096602
[32]	Kawwass JF, Sanders KM, Loucks TL, et al. Increased cerebrospinal fluid levels of GABA,testosterone and estradiol in women with polycystic ovary syndrome[J]. Hum Reprod, 2017,32(7):1450-1456. doi: 10.1093/humrep/dex086. doi: 10.1093/humrep/dex086 pmid: 28453773
[33]	Zhang L, Li H, Li S, et al. Reproductive and metabolic abnormalities in women taking valproate for bipolar disorder: a meta-analysis[J]. Eur J Obstet Gynecol Reprod Biol, 2016,202:26-31. doi: 10.1016/j.ejogrb.2016.04.038. pmid: 27160812
[34]	Berg T, Silveira MA, Moenter SM. Prepubertal Development of GABAergic Transmission to Gonadotropin-Releasing Hormone (GnRH) Neurons and Postsynaptic Response Are Altered by Prenatal Androgenization[J]. J Neurosci, 2018,38(9):2283-2293. doi: 10.1523/JNEUROSCI.2304-17.2018. doi: 10.1523/JNEUROSCI.2304-17.2018 pmid: 29374136
[35]	Walters KA, Gilchrist RB, Ledger WL, et al. New Perspectives on the Pathogenesis of PCOS: Neuroendocrine Origins[J]. Trends Endocrinol Metab, 2018,29(12):841-852. doi: 10.1016/j.tem.2018.08.005. doi: 10.1016/j.tem.2018.08.005 pmid: 30195991