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A decade in female reproduction: an endocrine view of the past and into the future

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Abstract

Over the last decade, huge achievements have been made in the fields of neurophysiology, molecular endocrinology, and biochemistry, as well as in the successful translation of clinical research into diseases into clinical practice. As regards female reproduction, most of the advances made in this area were achieved in gonadal axis regulation, regulation of behavior through sex steroids, reproductive genetics, preservation of ovarian reproductive function, steroid profiling, and metabolic and overall reproductive outcomes. The coming years are expected to bring further understanding of the relationships between nutrition, energy metabolism, and reproductive function and to succeed in identifying new genetic markers linked to adverse metabolic and unfavorable cardiovascular outcomes in women. From our perspective, future research in the field of female reproduction should be directed toward doing research into genetic reproductive abnormalities and neuroendocrine diseases, pathophysiology, long-term health outcomes for oligo/amenorrhea, hyperandrogenism, and ovulatory dysfunction. It is additionally expected that a better understanding will be gained of the endocrinology of the placenta and of pregnancy, the role of the microbiome in female reproduction, the role of insulin sensitizers, anti-obesity and anti-diabetic drugs, and various advances in the prevention of ovarian damage caused by various oncology therapies, while new therapeutic options for the treatment of infertility, including kisspeptin, will be developed.

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References

  1. Simpson E, Santen RJ (2015) Celebrating 75 years of oestradiol. J Mol Endocrinol 55:T1–T20

  2. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M (2012) Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev 92:1235–1316

  3. Pedersen-White JR, Chorich LP, Bick DP, Sherins RJ, Layman LC (2008) The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Mol Hum Reprod 14:367–370

  4. Rance NE (2009) Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 30:111–122

  5. Oakley AE, Clifton DK, Steiner RA (2009) Kisspeptin signaling in the brain. Endocr Rev 30:713–743

  6. Skorupskaite K, George JT, Anderson RA (2014) The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update 20:485–500

  7. Topaloglu AK, Reimann F, Guclu M et al (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet 41:354–358

  8. Young J, George JT, Tello JA et al (2013) Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology 97:193–202

  9. Jayasena CN, Nijher GM, Abbara A et al (2010) Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clin Pharmacol Ther 88:840–847

  10. Abbara A, Jayasena C, Comninos A, et al, 2014 Kisspeptin: a novel physiological trigger for oocyte maturation in in-vitro fertilisation treatment. Lancet 383: S17

  11. Dandona P, Dhindsa S, Chaudhuri A et al (2008) Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome. Curr Mol Med 8:816–828

  12. Manfredi-Lozano M, Roa J, Ruiz-Pino F et al (2016) Defining a novel leptin-melanocortin-kisspeptin pathway involved in the metabolic control of puberty. Mol Metab 5:844–857

  13. Manfredi-Lozano M, Roa J, Tena-Sempere M (2017) Connecting metabolism and gonadal function: novel central neuropeptide pathways involved in the metabolic control of puberty and fertility. Front Neuroendocrinol 48:37–49.

  14. Galea LA, Uban KA, Epp JR et al (2008) Endocrine regulation of cognition and neuroplasticity: our pursuit to unveil the complex interaction between hormones, the brain, and behaviour. Can J Exp Psychol 62:247–260

  15. Li R, Cui J, Shen Y (2014) Brain sex matters: estrogen in cognition and Alzheimer’s disease. Mol Cell Endocrinol 389:13–21

  16. Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E (2015) Perimenopause as a neurological transition state. Nat Rev Endocrinol 11:393–405

  17. Maguire J, Ferando I, Simonsen C, Mody I (2009) Excitability changes related to GABAA receptor plasticity during pregnancy. J Neurosci 29:9592–9601

  18. Deligiannidis KM, Sikoglu EM, Shaffer SA et al (2013) GABAergic neuroactive steroids and resting-state functional connectivity in postpartum depression: a preliminary study. J Psychiatr Res 47:816–828

  19. Sun D, Wang T, Heianza Y et al (2018) Birthweight and cardiometabolic risk patterns in multiracial children. Int J Obes 42:20–27

  20. Reynolds RM (2013) Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis--2012 Curt Richter award winner. Psychoneuroendocrinology 38:1–11

  21. Damjanović S, Stojić R, Lalić N et al (2009) Relationship between basal metabolic rate and cortisol secretion throughout pregnancy. Endocrine 35:262–268

  22. Goedhart G, Vrijkotte TG, Roseboom TJ et al (2010) Maternal cortisol and offspring birthweight: results from a large prospective cohort study. Psychoneuroendocrinology 35:644–652

  23. Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI (2006) Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab 91:2100–2104

  24. Chen ZJ, Zhao H, He L et al (2011) Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 43:55–59

  25. Shi Y, Zhao H, Shi Y et al (2012) Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet 44:1020–1025

  26. Lee H, Oh JY, Sung YA et al (2015) Genome-wide association study identified new susceptibility loci for polycystic ovary syndrome. Hum Reprod 30:723–731

  27. Hayes MG, Urbanek M, Ehrmann DA et al (2015) Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 6:7502

  28. Day FR, Hinds DA, Tung JY et al (2015) Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun 6:464

  29. Brower MA, Jones MR, Rotter JI et al (2015) Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals. J Clin Endocrinol Metab 100:E182–E186

  30. Louwers YV, Stolk L, Uitterlinden AG, Laven JS (2013) Cross-ethnic meta-analysis of genetic variants for polycystic ovary syndrome. J Clin Endocrinol Metab 98:E2006–E2012

  31. He C, Kraft P, Chen C et al (2009) Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet 41:724–728

  32. Saxena R, Bjonnes AC, Georgopoulos NA et al (2015) Gene variants associated with age at menopause are also associated with polycystic ovary syndrome, gonadotrophins and ovarian volume. Hum Reprod 30:1697–1703

  33. Keevil BG (2016) LC-MS/MS analysis of steroids in the clinical laboratory. Clin Biochem 49:989–997

  34. van den Ouweland JM, Kema IP (2012) The role of liquid chromatography-tandem mass spectrometry in the clinical laboratory. J Chromatogr B Analyt Technol Biomed Life Sci 883-884:18–32

  35. Keefe CC, Goldman MM, Zhang K et al (2014) Simultaneous measurement of thirteen steroid hormones in women with polycystic ovary syndrome and control women using liquid chromatography-tandem mass spectrometry. PLoS One 9:e93805

  36. Tosi F, Fiers T, Kaufman JM et al (2016) Implications of androgen assay accuracy in the phenotyping of women with polycystic ovary syndrome. J Clin Endocrinol Metab 101:610–618

  37. Haring R, Hannemann A, John U et al (2012) Age-specific reference ranges for serum testosterone and androstenedione concentrations in women measured by liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 97:408–415

  38. Fanelli F, Gambineri A, Belluomo I et al (2013) Androgen profiling by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in healthy normal-weight ovulatory and anovulatory late adolescent and young women. J Clin Endocrinol Metab 98:3058–3067

  39. O'Reilly MW, Taylor AE, Crabtree NJ et al (2014) Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione. J Clin Endocrinol Metab 99:1027–1036

  40. Mezzullo M, Fazzini A, Gambineri A et al (2017) Parallel diurnal fluctuation of testosterone, androstenedione, dehydroepiandrosterone and 17OHprogesterone as assessed in serum and saliva: validation of a novel liquid chromatography-tandem mass spectrometry method for salivary steroid profiling. Clin Chem Lab Med 55:1315–1323.

  41. Bronstein J, Tawdekar S, Liu Y et al (2011) Age of onset of polycystic ovarian syndrome in girls may be earlier than previously thought. J Pediatr Adolesc Gynecol 24:15–20

  42. Khan U (2007) Polycystic ovary syndrome in adolescents. J Pediatr Adolesc Gynecol 20:101–104

  43. Lashen H, Dunger DB, Ness A, Ong KK (2013) Peripubertal changes in circulating antimullerian hormone levels in girls. Fertil Steril 99:2071–2075

  44. Piouka A, Farmakiotis D, Katsikis I et al (2009) Anti-Mullerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels. Am J Physiol Endocrinol Metab 296:E238–E243

  45. Iliodromiti S, Kelsey TW, Anderson RA, Nelson SM (2013) Can anti-Mullerian hormone predict the diagnosis of polycystic ovary syndrome? A systematic review and meta-analysis of extracted data. J Clin Endocrinol Metab 98:3332–3340

  46. Quinn MM, Kao CN, Ahmad AK et al (2017) Age-stratified thresholds of anti-Mullerian hormone improve prediction of polycystic ovary syndrome over a population-based threshold. Clin Endocrinol 87:733–740

  47. Lunding SA, Aksglaede L, Anderson RA et al (2015) AMH as predictor of premature ovarian insufficiency: a longitudinal study of 120 turner syndrome patients. J Clin Endocrinol Metab 100:E1030–E1038

  48. Merhi Z, Doswell A, Krebs K, Cipolla M (2014) Vitamin D alters genes involved in follicular development and steroidogenesis in human cumulus granulosa cells. J Clin Endocrinol Metab 99:E1137–E1145

  49. Ozkan S, Jindal S, Greenseid K et al (2010) Replete vitamin D stores predict reproductive success following in vitro fertilization. Fertil Steril 94:1314–1319

  50. Anifandis GM, Dafopoulos K, Messini CI et al (2010) Prognostic value of follicular fluid 25-OH vitamin D and glucose levels in the IVF outcome. Reprod Biol Endocrinol 8:91

  51. Miyashita M, Koga K, Izumi G et al (2016) Effects of 1,25-Dihydroxy vitamin D3 on endometriosis. J Clin Endocrinol Metab 101:2371–2379

  52. Nikolić M, Macut D, Djordjevic A et al (2015) Possible involvement of glucocorticoids in 5alpha-dihydrotestosterone-induced PCOS-like metabolic disturbances in the rat visceral adipose tissue. Mol Cell Endocrinol 399:22–31

    Article  Google Scholar 

  53. Vojnović Milutinović D, Nikolić M, Veličković N et al (2017) Enhanced inflammation without impairment of insulin signaling in the visceral adipose tissue of 5α-dihydrotestosterone-induced animal model of polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 125:522–529

    Article  Google Scholar 

  54. Tepavčević S, Vojnović Milutinović D, Macut D et al (2015) Cardiac fatty acid uptake and metabolism in the rat model of polycystic ovary syndrome. Endocrine 50:193–201

  55. Tepavčević S, Vojnović Milutinović D, Macut D et al (2014) Dihydrotestosterone deteriorates cardiac insulin signaling and glucose transport in the rat model of polycystic ovary syndrome. J Steroid Biochem Mol Biol 141:71–76

    Article  Google Scholar 

  56. Kauffman AS, Thackray VG, Ryan GE et al (2015) A novel Letrozole model recapitulates both the reproductive and metabolic phenotypes of polycystic ovary syndrome in female mice. Biol Reprod 93:69.

  57. Noordam C, Dhir V, McNelis JC et al (2009) Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med 360:2310–2318.

  58. Conway G, Dewailly D, Diamanti-Kandarakis E et al (2014) The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol 171:P1–P29.

  59. Ruebel M, Shankar K, Gaddy D et al (2016) Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1. Am J Physiol Endocrinol Metab 311:E269–E277.

  60. Diamanti-Kandarakis E, Dunaif A (2012) Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33:981–1030.

  61. Panidis D, Tziomalos K, Misichronis G et al (2012) Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study. Hum Reprod 27:541–549.

  62. Macut D, Simic T, Lissounov A et al (2011) Insulin resistance in non-obese women with polycystic ovary syndrome: relation to byproducts of oxidative stress. Exp Clin Endocrinol Diabetes 119:451–455.

  63. Gambineri A, Patton L, Altieri P et al (2012) Polycystic ovary syndrome is a risk factor for type 2 diabetes: results from a long-term prospective study. Diabetes 61:2369–2374.

  64. Kandaraki EA, Chatzigeorgiou A, Papageorgiou E et al (2018) Advanced glycation end products interfere in luteinizing hormone and follicle stimulating hormone signaling in human granulosa KGN cells. Exp Biol Med (Maywood) 243:29–33.

  65. Legro RS, Dodson WC, Kris-Etherton PM et al (2015) Randomized controlled trial of preconception interventions in infertile women with polycystic ovary syndrome. J Clin Endocrinol Metab 100:4048–4058.

  66. Anderson SA, Barry JA, Hardiman PJ (2014) Risk of coronary heart disease and risk of stroke in women with polycystic ovary syndrome: a systematic review and meta-analysis. Int J Cardiol 176:486–487.

  67. Schmidt J, Landin-Wilhelmsen K, Brannstrom M, Dahlgren E (2011) Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J Clin Endocrinol Metab 96:3794–3803.

  68. Manson JE, Aragaki AK, Rossouw JE et al (2017) Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials. JAMA 318:927–938.

  69. Gore AC, Chappell VA, Fenton SE et al (2015) EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev 36:E1–E150

  70. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC et al (2009) Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev 30:293–342

  71. Bloom MS, Kim D, Vom Saal FS et al (2011) Bisphenol a exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization. Fertil Steril 96:672–677 e672

  72. Franssen D, Gerard A, Hennuy B et al (2016) Delayed neuroendocrine sexual maturation in female rats after a very low dose of bisphenol a through altered GABAergic neurotransmission and opposing effects of a high dose. Endocrinology 157:1740–1750

  73. Lee SH, Kang SM, Choi MH et al (2014) Changes in steroid metabolism among girls with precocious puberty may not be associated with urinary levels of bisphenol A. Reprod Toxicol 44:1–6

  74. Brougham MF, Crofton PM, Johnson EJ et al (2012) Anti-Mullerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study. J Clin Endocrinol Metab 97:2059–2067

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Funding

This work was supported by the Ministry of Education, Science, and Technological Development of the Republic of Serbia, Grants 41009 and 175032.

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Authors and Affiliations

  1. Clinic of Endocrinology, Diabetes and Metabolic Diseases, Faculty of Medicine, University of Belgrade, Dr Subotića 13, Belgrade, 11000, Serbia

    Djuro Macut

  2. Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia

    Danijela Vojnović Milutinović & Jelena Nestorov

  3. Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia

    Aleksandra Rašić-Marković & Olivera Stanojlović

  4. UMC Bežanijska kosa, Faculty of Medicine, University of Belgrade, Belgrade, Serbia

    Jelica Bjekić-Macut

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  1. Djuro Macut
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  2. Danijela Vojnović Milutinović
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  3. Aleksandra Rašić-Marković
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Correspondence to Djuro Macut.

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Macut, D., Milutinović, D.V., Rašić-Marković, A. et al. A decade in female reproduction: an endocrine view of the past and into the future. Hormones 17, 497–505 (2018). https://doi.org/10.1007/s42000-018-0073-x

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