Neuroendocrine features of the pathogenesis of polycystic ovary syndrome (literature review)

Polycystic ovary syndrome (PCOS) is one of the most pressing problems in endocrine gynecology. The main signs of the disease are hyperandrogenism, menstrual and/or ovulatory dysfunction, and polycystic ovarian structure according to ultrasound. Women with PCOS are at risk for developing metabolic syndrome, type 2 diabetes, cardiovascular disease, and endometrial cancer. In this connection, the pathogenetic mechanisms of the occurrence of this syndrome are continuously studied and new methods of treatment are being sought. PCOS is characterized by a wide range of various disorders of the neuroendocrine regulation of the reproductive system. The main focus of the review is aimed at summarizing information about the etiological role of neuropeptides and neurotransmitters, such as phoenixin, galanins, orexins, GABA, in the pathophysiology of PCOS and about the possibility of their use for diagnostic and therapeutic purposes. In recent decades, the interest of scientists has been focused on the study of KNDy neurons, because it is the kisspeptin synthesized by them that is one of the main regulators of the hypothalamic-pituitary-ovarian axis. This article discusses data on the significance of KNDy neurons in the pathogenesis of the syndrome. Information is provided on the effect of elevated levels of androgens and anti-Müllerian hormone on GnRH neurons. Also analyzed are studies on functional and structural disorders in the hypothalamus in PCOS. Literature search was carried out in national (eLibrary, CyberLeninka.ru) and international (PubMed, Cochrane Library) databases in Russian and English. The priority was free access to the full text of articles. The choice of sources was prioritized for the period from 2018 to 2023.However, taking into account the insufficient knowledge of the chosen topic, the choice of sources dates back to 1998.

1. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364-379. doi: https://doi.org/10.1016/j.fertnstert.2018.05.004

2. Rossiiskoe obshchestvo akusherov-ginekologov, Rossiiskaia assotsiatsiia endokrinologov. Klinicheskie rekomendatsii. Sindrom polikistoznykh iaichnikov. Moscow: Ministerstvo zdravookhraneniia RF; 2021. (In Russ.).

3. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270-284. doi: https://doi.org/10.1038/nrendo.2018.24

4. Phylactou M, Clarke SA, Patel B, et al. Clinical and biochemical discriminants between functional hypothalamic amenorrhoea (FHA) and polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf). 2021;95(2):239-252. doi: https://doi.org/10.1111/cen.14402

5. Zeydabadi Nejad S, Ramezani Tehrani F, Zadeh-Vakili A. The role of kisspeptin in female reproduction. Int J Endocrinol Metab. 2017;15(3):e44337. doi: https://doi.org/10.5812/ijem.44337

6. Szeliga A, Rudnicka E, Maciejewska-Jeske M, et al. Neuroendocrine Determinants of Polycystic Ovary Syndrome. Int J Environ Res Public Health. 2022;19(5):3089. doi: https://doi.org/10.3390/ijerph19053089

7. Chang WY, Knochenhauer ES, Bartolucci AA, Azziz R. Phenotypic spectrum of polycystic ovary syndrome: clinical and biochemical characterization of the three major clinical subgroups. Fertil Steril. 2005;83(6):1717-1723. doi: https://doi.org/10.1016/j.fertnstert.2005.01.096

8. Salinas I, Sinha N, Sen A. Androgen-induced epigenetic modulations in the ovary. J Endocrinol. 2021;249(3):R53-R64. doi: https://doi.org/10.1530/JOE-20-0578

9. Sullivan SD, Moenter SM. GABAergic integration of progesterone and androgen feedback to gonadotropin-releasing hormone neurons. Biol Reprod. 2005;72(1):33-41. doi: https://doi.org/10.1095/biolreprod.104.033126

10. Cheng XB, Jimenez M, Desai R, et al. Characterizing the neuroendocrine and ovarian defects of androgen receptor-knockout female mice. Am J Physiol Endocrinol Metab. 2013;305(6):E717-E726. doi: https://doi.org/10.1152/ajpendo.00263.2013

11. Liao B, Qiao J, Pang Y. Central regulation of PCOS: Abnormal neuronal-reproductive-metabolic circuits in PCOS pathophysiology. Front Endocrinol (Lausanne). 2021;(12):667422. doi: https://doi.org/10.3389/fendo.2021.667422

12. Barrett ES, Hoeger KM, Sathyanarayana S, et al. Anogenital distance in newborn daughters of women with polycystic ovary syndrome indicates fetal testosterone exposure. J Dev Orig Health Dis. 2018;9(3):307-314. doi: https://doi.org/10.1017/S2040174417001118

13. Palomba S, Marotta R, Di Cello A, et al. Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Clin Endocrinol (Oxf). 2012;77(6):898-904. doi: https://doi.org/10.1111/j.1365-2265.2012.04443.x

14. Tata B, Mimouni NEH, Barbotin AL, et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat Med. 2018;24(6):834-846. doi: https://doi.org/10.1038/s41591-018-0035-5

15. Moore AM. Impaired steroid hormone feedback in polycystic ovary syndrome: Evidence from preclinical models for abnormalities within central circuits controlling fertility. Clin Endocrinol (Oxf). 2022;97(2):199-207. doi: https://doi.org/10.1111/cen.14711

16. Sacha CR, Chavarro JE, Williams PL, et al. Follicular fluid anti-Müllerian hormone (AMH) concentrations and outcomes of in vitro fertilization cycles with fresh embryo transfer among women at a fertility center. J Assist Reprod Genet. 2020;37(11):2757-2766. doi: https://doi.org/10.1007/s10815-020-01956-7

17. Cimino I, Casoni F, Liu X, et al. Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion. Nat Commun. 2016;7(1):10055. doi: https://doi.org/10.1038/ncomms10055

18. Tata B, Mimouni NEH, Barbotin AL, et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat Med. 2018;24(6):834-846. doi: https://doi.org/10.1038/s41591-018-0035-5

19. Barbotin A-L, Mimouni NEH, Kuchcinski G, et al. Hypothalamic neuroglial plasticity is regulated by anti-Müllerian hormone and disrupted in polycystic ovary syndrome. EBioMedicine. 2023;90(1):104535. doi: https://doi.org/10.1016/j.ebiom.2023.104535

20. Jankowska-Kulawy A, Klimaszewska-Łata J, Gul-Hinc S, et al. Metabolic and cellular compartments of Acetyl-CoA in the healthy and diseased brain. Int J Mol Sci. 2022;23(17):10073. doi: https://doi.org/10.3390/ijms231710073

21. Prinz P, Scharner S, Friedrich T, et al. Central and peripheral expression sites of phoenixin-14 immunoreactivity in rats. Biochem Biophys Res Commun. 2017;493(1):195-201. doi: https://doi.org/10.1016/j.bbrc.2017.09.048

22. Yosten GL, Lyu RM, Hsueh AJ, et al. A novel reproductive peptide, phoenixin. J Neuroendocrinol. 2013;25(2):206-215. doi: https://doi.org/10.1111/j.1365-2826.2012.02381.x

23. Kalamon N, Błaszczyk K, Szlaga A, et al. Levels of the neuropeptide phoenixin-14 and its receptor GRP173 in the hypothalamus, ovary and periovarian adipose tissue in rat model of polycystic ovary syndrome. Biochem Biophys Res Commun. 2020;528(4):628-635. doi: https://doi.org/10.1016/j.bbrc.2020.05.101

24. Mills EG, Izzi-Engbeaya C, Abbara A, et al. Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour. Nat Rev Endocrinol. 2021;17(2):97-113. doi: https://doi.org/10.1038/s41574-020-00438-1

25. Azin F, Khazali H. Neuropeptide galanin and its effects on metabolic and reproductive disturbances in female rats with estradiol valerate (EV) - Induced polycystic ovary syndrome (PCOS). Neuropeptides. 2020;80(1):102026. doi: https://doi.org/10.1016/j.npep.2020.102026

26. Altinkaya SO. Galanin and glypican-4 levels depending on metabolic and cardiovascular risk factors in patients with polycystic ovary syndrome. Arch Endocrinol Metab. 2021;65(4):479-487. doi: https://doi.org/10.20945/2359-3997000000340

27. Santic R, Fenninger K, Graf K, et al. Gangliocytes in neuroblastic tumors express alarin, a novel peptide derived by differential splicing of the galanin-like peptide gene. J Mol Neurosci. 2006;29(2):145-152. doi: https://doi.org/10.1385/JMN:29:2:145

28. Fraley GS, Leathley E, Lundy N, et al. Effects of alarin on food intake, body weight and luteinizing hormone secretion in male mice. Neuropeptides. 2012;46(2):99-104. doi: https://doi.org/10.1016/j.npep.2011.12.003

29. Gül FC, Kobat SG, Çelik F, et al. Plasma and aqueous levels of alarin and adipsin ın patients with and without diabetic retinopathy. BMC Ophthalmol. 2022;22(1):176. doi: https://doi.org/10.1186/s12886-022-02403-0

30. Fraley GS, Leathley E, Nickols A, et al. Alarin 6-25Cys antagonizes alarin-specific effects on food intake and luteinizing hormone secretion. Neuropeptides. 2013;47(1):37-41. doi: https://doi.org/10.1016/j.npep.2012.08.007

31. Bicer M, Alan M, Alarslan P, et al. Alarin: A novel circulating peptide hormone linked to luteinizing hormone and hiperandrogenismin polycystic ovary syndrome. Gratis. 2018;1(1):72-81. doi: https://doi.org/10.18314/cogo.v1i1.1284

32. Gorkem U, Yildirim E. Alarin: A new predictive marker in infertile women with polycystic ovary syndrome: A case-control study. J Obstet Gynaecol Res. 2022;48(4):980-986. doi: https://doi.org/10.1111/jog.15176

33. Li MQ, Li JY, Xie L. Level of circulating Alarin in obese children and its association with insulin resistance. Zhongguo Dang Dai Er Ke Za Zhi. 2019;21(10):983-986. doi: https://doi.org/10.7499/j.issn.1008-8830.2019.10.006

34. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573-585. doi: https://doi.org/10.1016/s0092-8674(00)80949-6

35. de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA. 1998;95(1):322-327. doi: https://doi.org/10.1073/pnas.95.1.322

36. Ebrahim IO, Semra YK, De Lacy S, et al. CSF hypocretin (Orexin) in neurological and psychiatric conditions. J Sleep Res. 2003;12(1):83-84. doi: https://doi.org/10.1046/j.1365-2869.2003.00333.x

37. Dale NC, Hoyer D, Jacobson LH, et al. Orexin signaling: A complex, multifaceted process. Front Cell Neurosci. 2022;16(1):102026. doi: https://doi.org/10.3389/fncel.2022.812359

38. Shainidze KZ, Novikova NS, Korneva EA. Orexin neurons of hypothalamus under stress and some pathologies. Vestnik Sankt-Peterburgskogo universiteta. Meditsina. 2011;(2):182-199. (In Russ.).

39. Silveyra P, Cataldi NI, Lux-Lantos VA, Libertun C. Role of orexins in the hypothalamic-pituitary-ovarian relationships. Acta Physiol (Oxf). 2010;198(3):355-360. doi: https://doi.org/10.1111/j.1748-1716.2009.02049.x

40. Dalal MA, Schuld A, Haack M, et al. Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients [published correction appears in Neurology 2002;58(2):334]. Neurology. 2001;56(12):1749-1751. doi: https://doi.org/10.1212/wnl.56.12.1749

41. Ouedraogo R, Näslund E, Kirchgessner AL. Glucose regulates the release of orexin-a from the endocrine pancreas. Diabetes. 2003;52(1):111-117. doi: https://doi.org/10.2337/diabetes.52.1.111

42. Skrzypski M, T Le T, Kaczmarek P, et al. Orexin A stimulates glucose uptake, lipid accumulation and adiponectin secretion from 3T3-L1 adipocytes and isolated primary rat adipocytes. Diabetologia. 2011;54(7):1841-1852. doi: https://doi.org/10.1007/s00125-011-2152-2

43. Celik O, Celik N, Hascalik S, et al. An appraisal of serum preptin levels in PCOS. Fertil Steril. 2011;95(1):314-316. doi: https://doi.org/10.1016/j.fertnstert.2010.08.058

44. Yilmaz E, Celik O, Celik N, et al. Serum orexin-A (OXA) level decreases in polycystic ovarian syndrome. Gynecol Endocrinol. 2013;29(4):388-390. doi: https://doi.org/10.3109/09513590.2012.754874

45. Szeliga A, Rudnicka E, Maciejewska-Jeske M, et al. Neuroendocrine determinants of polycystic ovary syndrome. Int J Environ Res Public Health. 2022;19(5):3089. doi: https://doi.org/10.3390/ijerph19053089

46. Silva MSB, Desroziers E, Hessler S, et al. Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: Implications for polycystic ovary syndrome. EBioMedicine. 2019;(44):582-596. doi: https://doi.org/10.1016/j.ebiom.2019.05.065

47. Kawwass JF, Sanders KM, Loucks TL, et al. Increased cerebrospinal fluid levels of GABA, testosterone and estradiol in women with polycystic ovary syndrome. Hum Reprod. 2017;32(7):1450-1456. doi: https://doi.org/10.1093/humrep/dex086

48. Porter DT, Moore AM, Cobern JA, et al. Prenatal testosterone exposure alters GABAergic synaptic inputs to GnRH and KNDy neurons in a sheep model of polycystic ovarian syndrome. Endocrinology. 2019;160(11):2529-2542. doi: https://doi.org/10.1210/en.2019-00137

49. Moore AM, Prescott M, Marshall CJ, et al. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Natl Acad Sci USA. 2015;112(2):596-601. doi: https://doi.org/10.1073/pnas.1415038112

50. Wang L, Burger LL, Greenwald-Yarnell ML, et al. Glutamatergic transmission to hypothalamic kisspeptin neurons is differentially regulated by estradiol through estrogen receptor α in adult female mice. J Neurosci. 2018;38(5):1061-1072. doi: https://doi.org/10.1523/JNEUROSCI.2428-17.2017

51. Chaudhari N, Dawalbhakta M, Nampoothiri L. GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile. Reprod Biol Endocrinol. 2018;16(1):37. doi: https://doi.org/10.1186/s12958-018-0354-x

52. d’Anglemont de Tassigny X, Ackroyd KJ, et al. Kisspeptin signaling is required for peripheral but not central stimulation of gonadotropin-releasing hormone neurons by NMDA. J Neurosci. 2010;30(25):8581-8590. doi: https://doi.org/10.1523/JNEUROSCI.5486-09.2010

53. Kiałka M, Milewicz T, Spałkowska M, et al. β-endorphins plasma level is higher in lean Polycystic Ovary Syndrome (PCOS) women. Exp Clin Endocrinol Diabetes. 2016;124(1):55-60. doi: https://doi.org/10.1055/s-0035-1564094

54. Linares R, Hernández D, Morán C, et al. Unilateral or bilateral vagotomy induces ovulation in both ovaries of rats with polycystic ovarian syndrome. Reprod Biol Endocrinol. 2013;11(1):68. doi: https://doi.org/10.1186/1477-7827-11-68

55. Linares R, Acuña XN, Rosas G, et al. Participation of the cholinergic system in the development of polycystic ovary syndrome. Molecules. 2021;26(18):5506. doi: https://doi.org/10.3390/molecules26185506

56. Arai Y, Ishii H, Kobayashi M, Ozawa H. Subunit profiling and functional characteristics of acetylcholine receptors in GT1-7 cells. J Physiol Sci. 2017;67(2):313-323. doi: https://doi.org/10.1007/s12576-016-0464-1

57. Zemkova H, Kucka M, Bjelobaba I, et al. Multiple cholinergic signaling pathways in pituitary gonadotrophs. Endocrinology. 2013;154(1):421-433. doi: https://doi.org/10.1210/en.2012-1554

58. Szawka RE, Poletini MO, Leite CM, et al. Release of norepinephrine in the preoptic area activates anteroventral periventricular nucleus neurons and stimulates the surge of luteinizing hormone. Endocrinology. 2013;154(1):363-374. doi: https://doi.org/10.1210/en.2012-1302

59. Spergel DJ. Modulation of Gonadotropin-releasing hormone neuron activity and secretion in mice by non-peptide neurotransmitters, gasotransmitters, and gliotransmitters. Front Endocrinol (Lausanne). 2019;10(1):68. doi: https://doi.org/10.3389/fendo.2019.00329

60. Hernández I, Parra A, Méndez I, et al. Hypothalamic dopaminergic tone and prolactin bioactivity in women with polycystic ovary syndrome. Arch Med Res. 2000;31(2):216-222. doi: https://doi.org/10.1016/s0188-4409(00)00059-x