Download PDF
Semin Reprod Med 2022; 40(01/02): 053-068
DOI: 10.1055/s-0042-1744495
Review Article

The Interaction of Obesity and Reproductive Function in Adolescents

Victoria Elliott   *
1   Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
,
Stephanie W. Waldrop   *
2   Department of Pediatrics, Section of Nutrition, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado
,
Pattara Wiromrat
3   Division of Endocrinology, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
,
Anne-Marie Carreau
4   Endocrinologue, Centre de Recherche du CHU de Québec-Université Laval, Québec, Canada
5   Endocrinologie–Néphrologie, Québec-Université Laval, Québec, Canada
,
Melanie Cree Green 
2   Department of Pediatrics, Section of Nutrition, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado
6   Center for Women's Health Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado
› Author Affiliations Funding None.
› Further Information
    Permissions and Reprints

Abstract

Obesity is increasing worldwide, including in pediatrics. Adequate nutrition is required for initiation of menses, and there is a clear secular trend toward earlier pubertal onset and menarche in females in countries around the globe. Similar findings of earlier pubertal start are suggested in males. However, as individuals and populations have crossed into over-nutritional states including overweight and obesity, the effect of excess weight on disrupting reproductive function has become apparent. Hypothalamic hypogonadism and polycystic ovary syndrome are two conditions where reproductive function appears to directly relate to excess weight. Clinical findings in individuals with certain polygenic and monogenic obesity syndromes, which also have reproductive disruptions, have helped elucidate neurologic pathways that are common to both. Clinical endocrinopathies such as hypothyroidism or panhypopituitarism also aide in the understanding of the role of the endocrine system in weight gain. Understanding the intersection of obesity and reproductive function may lead to future therapies which can treat both conditions.

Keywords

obesity - adolescence - reproductive disturbances

Disclosures

M.C-G. has served on a pediatric obesity advisory board for Novo Nordisk.


* Joint first authors.




Publication History

Article published online:
13 May 2022

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Di Cesare M, Sorić M, Bovet P. et al. The epidemiological burden of obesity in childhood: a worldwide epidemic requiring urgent action. BMC Med 2019; 17 (01) 212
    CrossrefPubMedGoogle Scholar
  • 2 World Health Organization. Overweight and Obesity - Fact Sheet. Published April 2020. Accessed February 15, 2022 at: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
    PubMedGoogle Scholar
  • 3 Wang Y, Lim H. The global childhood obesity epidemic and the association between socio-economic status and childhood obesity. Int Rev Psychiatry 2012; 24 (03) 176-188
    CrossrefPubMedGoogle Scholar
  • 4 Sarafoglou K, Hoffmann GF, Roth KS. Pediatric Endocrinology and Inborn Errors of Metabolism. 2nd ed.. New York: McGraw-Hill Education; 2017
    Google Scholar
  • 5 Thomas F, Renaud F, Benefice E, de Meeüs T, Guegan JF. International variability of ages at menarche and menopause: patterns and main determinants. Hum Biol 2001; 73 (02) 271-290
    CrossrefPubMedGoogle Scholar
  • 6 Chumlea WC, Schubert CM, Roche AF. et al. Age at menarche and racial comparisons in US girls. Pediatrics 2003; 111 (01) 110-113
    CrossrefPubMedGoogle Scholar
  • 7 Seppä S, Kuiri-Hänninen T, Holopainen E, Voutilainen R. Management of endocrine disease: diagnosis and management of primary amenorrhea and female delayed puberty. Eur J Endocrinol 2021; 184 (06) R225-R242
    CrossrefPubMedGoogle Scholar
  • 8 Rosenfield RL. The diagnosis of polycystic ovary syndrome in adolescents. Pediatrics 2015; 136 (06) 1154-1165
    CrossrefPubMedGoogle Scholar
  • 9 Rosenfield RL. Clinical review: adolescent anovulation: maturational mechanisms and implications. J Clin Endocrinol Metab 2013; 98 (09) 3572-3583
    CrossrefPubMedGoogle Scholar
  • 10 Juul A, Teilmann G, Scheike T. et al. Pubertal development in Danish children: comparison of recent European and US data. Int J Androl 2006; 29 (01) 247-255 , discussion 286–290
    CrossrefPubMedGoogle Scholar
  • 11 Herman-Giddens ME, Steffes J, Harris D. et al. Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network. Pediatrics 2012; 130 (05) e1058-e1068
    CrossrefPubMedGoogle Scholar
  • 12 Biro FM, Lucky AW, Huster GA, Morrison JA. Pubertal staging in boys. J Pediatr 1995; 127 (01) 100-102
    CrossrefPubMedGoogle Scholar
  • 13 Lee JM, Wasserman R, Kaciroti N. et al. Timing of puberty in overweight versus obese boys. Pediatrics 2016; 137 (02) e20150164
    CrossrefPubMedGoogle Scholar
  • 14 Ohlsson C, Bygdell M, Celind J. et al. Secular trends in pubertal growth acceleration in Swedish boys born from 1947 to 1996. JAMA Pediatr 2019; 173 (09) 860-865
    CrossrefPubMedGoogle Scholar
  • 15 Cousminer DL, Widén E, Palmert MR. The genetics of pubertal timing in the general population: recent advances and evidence for sex-specificity. Curr Opin Endocrinol Diabetes Obes 2016; 23 (01) 57-65
    CrossrefPubMedGoogle Scholar
  • 16 Aksglaede L, Sørensen K, Petersen JH, Skakkebaek NE, Juul A. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics 2009; 123 (05) e932-e939
    CrossrefPubMedGoogle Scholar
  • 17 De Leonibus C, Marcovecchio ML, Chiavaroli V, de Giorgis T, Chiarelli F, Mohn A. Timing of puberty and physical growth in obese children: a longitudinal study in boys and girls. Pediatr Obes 2014; 9 (04) 292-299
    CrossrefPubMedGoogle Scholar
  • 18 Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics 2001; 108 (02) 347-353
    CrossrefPubMedGoogle Scholar
  • 19 Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index. Pediatrics 2009; 123 (01) 84-88
    CrossrefPubMedGoogle Scholar
  • 20 Lian Q, Mao Y, Luo S. et al. Puberty timing associated with obesity and central obesity in Chinese Han girls. BMC Pediatr 2019; 19 (01) 1
    CrossrefPubMedGoogle Scholar
  • 21 Barcellos Gemelli IF, Farias EDS, Souza OF. Age at menarche and its association with excess weight and body fat percentage in girls in the southwestern region of the Brazilian Amazon. J Pediatr Adolesc Gynecol 2016; 29 (05) 482-488
    CrossrefPubMedGoogle Scholar
  • 22 Eckert-Lind C, Busch AS, Petersen JH. et al. Worldwide secular trends in age at pubertal onset assessed by breast development among girls: a systematic review and meta-analysis. JAMA Pediatr 2020; 174 (04) e195881
    CrossrefPubMedGoogle Scholar
  • 23 Freedman DS, Khan LK, Serdula MK, Dietz WH, Srinivasan SR, Berenson GS. Relation of age at menarche to race, time period, and anthropometric dimensions: the Bogalusa Heart Study. Pediatrics 2002; 110 (04) e43
    CrossrefPubMedGoogle Scholar
  • 24 Pereira A, Busch AS, Solares F, Baier I, Corvalan C, Mericq V. Total and central adiposity are associated with age at gonadarche and incidence of precocious gonadarche in boys. J Clin Endocrinol Metab 2021; 106 (05) 1352-1361
    CrossrefPubMedGoogle Scholar
  • 25 Juul A, Magnusdottir S, Scheike T, Prytz S, Skakkebaek NE. Age at voice break in Danish boys: effects of pre-pubertal body mass index and secular trend. Int J Androl 2007; 30 (06) 537-542
    CrossrefPubMedGoogle Scholar
  • 26 Monteilh C, Kieszak S, Flanders WD. et al. Timing of maturation and predictors of Tanner stage transitions in boys enrolled in a contemporary British cohort. Paediatr Perinat Epidemiol 2011; 25 (01) 75-87
    CrossrefPubMedGoogle Scholar
  • 27 Ong KK, Bann D, Wills AK. et al; National Survey of Health and Development Scientific and Data Collection Team. Timing of voice breaking in males associated with growth and weight gain across the life course. J Clin Endocrinol Metab 2012; 97 (08) 2844-2852
    CrossrefPubMedGoogle Scholar
  • 28 Wang Y. Is obesity associated with early sexual maturation? A comparison of the association in American boys versus girls. Pediatrics 2002; 110 (05) 903-910
    CrossrefPubMedGoogle Scholar
  • 29 Roa J, Herbison AE. Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology 2012; 153 (11) 5587-5599
    CrossrefPubMedGoogle Scholar
  • 30 Vollbach H, Brandt S, Lahr G. et al. Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort. Int J Obes 2017; 41 (01) 13-22
    CrossrefPubMedGoogle Scholar
  • 31 Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty?. Lancet Child Adolesc Health 2019; 3 (01) 44-54
    CrossrefPubMedGoogle Scholar
  • 32 Risselada AJ, Mulder H, Heerdink ER, Egberts TC. Pharmacogenetic testing to predict antipsychotic-induced weight gain: a systematic review. Pharmacogenomics 2011; 12 (08) 1213-1227
    CrossrefPubMedGoogle Scholar
  • 33 Han JC, Lawlor DA, Kimm SY. Childhood obesity. Lancet 2010; 375 (9727): 1737-1748
    CrossrefPubMedGoogle Scholar
  • 34 Bell CG, Walley AJ, Froguel P. The genetics of human obesity. Nat Rev Genet 2005; 6 (03) 221-234
    CrossrefPubMedGoogle Scholar
  • 35 Rak A, Mellouk N, Froment P, Dupont J. Adiponectin and resistin: potential metabolic signals affecting hypothalamo-pituitary gonadal axis in females and males of different species. Reproduction 2017; 153 (06) R215-R226
    CrossrefPubMedGoogle Scholar
  • 36 Roth CL, Enriori PJ, Harz K, Woelfle J, Cowley MA, Reinehr T. Peptide YY is a regulator of energy homeostasis in obese children before and after weight loss. J Clin Endocrinol Metab 2005; 90 (12) 6386-6391
    CrossrefPubMedGoogle Scholar
  • 37 Álvarez-Castro P, Pena L, Cordido F. Ghrelin in obesity, physiological and pharmacological considerations. Mini Rev Med Chem 2013; 13 (04) 541-552
    CrossrefPubMedGoogle Scholar
  • 38 Elias CF. Leptin action in pubertal development: recent advances and unanswered questions. Trends Endocrinol Metab 2012; 23 (01) 9-15
    CrossrefPubMedGoogle Scholar
  • 39 Vazquez MJ, Velasco I, Tena-Sempere M. Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition. J Endocrinol 2019; 242 (02) R51-R65
    CrossrefPubMedGoogle Scholar
  • 40 Hill JW, Elias CF. Neuroanatomical framework of the metabolic control of reproduction. Physiol Rev 2018; 98 (04) 2349-2380
    CrossrefPubMedGoogle Scholar
  • 41 Manfredi-Lozano M, Roa J, Ruiz-Pino F. et al. Defining a novel leptin-melanocortin-kisspeptin pathway involved in the metabolic control of puberty. Mol Metab 2016; 5 (10) 844-857
    CrossrefPubMedGoogle Scholar
  • 42 Pinhas-Hamiel O, Singer S, Pilpel N. et al. Adiponectin levels in adolescent girls with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2009; 71 (06) 823-827
    CrossrefPubMedGoogle Scholar
  • 43 Rao PM, Kelly DM, Jones TH. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nat Rev Endocrinol 2013; 9 (08) 479-493
    CrossrefPubMedGoogle Scholar
  • 44 Rosenfield RL, Bordini B. Evidence that obesity and androgens have independent and opposing effects on gonadotropin production from puberty to maturity. Brain Res 2010; 1364: 186-197
    CrossrefPubMedGoogle Scholar
  • 45 Silvestris E, de Pergola G, Rosania R, Loverro G. Obesity as disruptor of the female fertility. Reprod Biol Endocrinol 2018; 16 (01) 22
    CrossrefPubMedGoogle Scholar
  • 46 Sarchielli E, Comeglio P, Squecco R. et al. Tumor necrosis factor-α impairs kisspeptin signaling in human gonadotropin-releasing hormone primary neurons. J Clin Endocrinol Metab 2017; 102 (01) 46-56
    PubMedGoogle Scholar
  • 47 Morelli A, Sarchielli E, Comeglio P. et al. Metabolic syndrome induces inflammation and impairs gonadotropin-releasing hormone neurons in the preoptic area of the hypothalamus in rabbits. Mol Cell Endocrinol 2014; 382 (01) 107-119
    CrossrefPubMedGoogle Scholar
  • 48 Gesink Law DC, Maclehose RF, Longnecker MP. Obesity and time to pregnancy. Hum Reprod 2007; 22 (02) 414-420
    CrossrefPubMedGoogle Scholar
  • 49 Kelsey MM, Braffett BH, Geffner ME. et al; TODAY Study Group. Menstrual dysfunction in girls from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study. J Clin Endocrinol Metab 2018; 103 (06) 2309-2318
    CrossrefPubMedGoogle Scholar
  • 50 Broughton DE, Moley KH. Obesity and female infertility: potential mediators of obesity's impact. Fertil Steril 2017; 107 (04) 840-847
    CrossrefPubMedGoogle Scholar
  • 51 Wu RX, Dong YY, Yang PW. et al. CD36- and obesity-associated granulosa cells dysfunction. Reprod Fertil Dev 2019; 31 (05) 993-1001
    CrossrefPubMedGoogle Scholar
  • 52 Dhindsa S, Ghanim H, Batra M, Dandona P. Hypogonadotropic hypogonadism in men with diabesity. Diabetes Care 2018; 41 (07) 1516-1525
    CrossrefPubMedGoogle Scholar
  • 53 Cohen J, Nassau DE, Patel P, Ramasamy R. Low testosterone in adolescents & young adults. Front Endocrinol (Lausanne) 2020; 10: 916
    CrossrefPubMedGoogle Scholar
  • 54 Fernandez CJ, Chacko EC, Pappachan JM. Male obesity-related secondary hypogonadism - pathophysiology, clinical implications and management. Eur Endocrinol 2019; 15 (02) 83-90
    CrossrefPubMedGoogle Scholar
  • 55 Nokoff N, Thurston J, Hilkin A. et al. Sex differences in effects of obesity on reproductive hormones and glucose metabolism in early puberty. J Clin Endocrinol Metab 2019; 104 (10) 4390-4397
    CrossrefPubMedGoogle Scholar
  • 56 Sopher AB, Jean AM, Zwany SK. et al. Bone age advancement in prepubertal children with obesity and premature adrenarche: possible potentiating factors. Obesity (Silver Spring) 2011; 19 (06) 1259-1264
    CrossrefPubMedGoogle Scholar
  • 57 Clark AM, Ledger W, Galletly C. et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 1995; 10 (10) 2705-2712
    CrossrefPubMedGoogle Scholar
  • 58 Corona G, Rastrelli G, Monami M. et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol 2013; 168 (06) 829-843
    CrossrefPubMedGoogle Scholar
  • 59 Jensterle M, Podbregar A, Goricar K, Gregoric N, Janez A. Effects of liraglutide on obesity-associated functional hypogonadism in men. Endocr Connect 2019; 8 (03) 195-202
    CrossrefPubMedGoogle Scholar
  • 60 Mushannen T, Cortez P, Stanford FC, Singhal V. Obesity and hypogonadism - a narrative review highlighting the need for high-quality data in adolescents. Children (Basel) 2019; 6 (05) E63
    PubMedGoogle Scholar
  • 61 Teede HJ, Misso ML, Costello MF. et al; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018; 110 (03) 364-379
    CrossrefPubMedGoogle Scholar
  • 62 Mu L, Zhao Y, Li R, Lai Y, Chang HM, Qiao J. Prevalence of polycystic ovary syndrome in a metabolically healthy obese population. Int J Gynaecol Obstet 2019; 146 (02) 164-169
    CrossrefPubMedGoogle Scholar
  • 63 Teede HJ, Joham AE, Paul E. et al. Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women. Obesity (Silver Spring) 2013; 21 (08) 1526-1532
    CrossrefPubMedGoogle Scholar
  • 64 Ollila MM, Piltonen T, Puukka K. et al. Weight gain and dyslipidemia in early adulthood associate with polycystic ovary syndrome: prospective cohort study. J Clin Endocrinol Metab 2016; 101 (02) 739-747
    CrossrefPubMedGoogle Scholar
  • 65 Coutinho EA, Kauffman AS. The role of the brain in the pathogenesis and physiology of polycystic ovary syndrome (PCOS). Med Sci (Basel) 2019; 7 (08) E84
    PubMedGoogle Scholar
  • 66 Cree-Green M, Bergman BC, Coe GV. et al. Hepatic steatosis is common in adolescents with obesity and PCOS and relates to de novo lipogenesis but not insulin resistance. Obesity (Silver Spring) 2016; 24 (11) 2399-2406
    CrossrefPubMedGoogle Scholar
  • 67 Cree-Green M, Rahat H, Newcomer BR. et al. Insulin resistance, hyperinsulinemia, and mitochondria dysfunction in nonobese girls with polycystic ovarian syndrome. J Endocr Soc 2017; 1 (07) 931-944
    CrossrefPubMedGoogle Scholar
  • 68 Dunaif A. Insulin resistance in polycystic ovarian syndrome. Ann N Y Acad Sci 1993; 687: 60-64
    CrossrefPubMedGoogle Scholar
  • 69 Fox JH, Licholai T, Green G, Dunaif A. Differential effects of oral glucose-mediated versus intravenous hyperinsulinemia on circulating androgen levels in women. Fertil Steril 1993; 60 (06) 994-1000
    CrossrefPubMedGoogle Scholar
  • 70 Rosenbaum D, Haber RS, Dunaif A. Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 1993; 264 (2, Pt 1): E197-E202
    PubMedGoogle Scholar
  • 71 Glintborg D, Andersen M, Hagen C. et al. Evaluation of metabolic risk markers in polycystic ovary syndrome (PCOS). Adiponectin, ghrelin, leptin and body composition in hirsute PCOS patients and controls. Eur J Endocrinol 2006; 155 (02) 337-345
    CrossrefPubMedGoogle Scholar
  • 72 Shorakae S, Abell SK, Hiam DS. et al. High-molecular-weight adiponectin is inversely associated with sympathetic activity in polycystic ovary syndrome. Fertil Steril 2018; 109 (03) 532-539
    CrossrefPubMedGoogle Scholar
  • 73 Arusoglu G, Koksal G, Cinar N, Tapan S, Aksoy DY, Yildiz BO. Basal and meal-stimulated ghrelin, PYY, CCK levels and satiety in lean women with polycystic ovary syndrome: effect of low-dose oral contraceptive. J Clin Endocrinol Metab 2013; 98 (11) 4475-4482
    CrossrefPubMedGoogle Scholar
  • 74 Hirschberg AL, Naessen S, Stridsberg M, Bystrom B, Holtet J. Impaired cholecystokinin secretion and disturbed appetite regulation in women with polycystic ovary syndrome. Gynecol Endocrinol 2004; 19 (02) 79-87
    CrossrefPubMedGoogle Scholar
  • 75 Kim JY, Tfayli H, Michaliszyn SF, Lee S, Arslanian S. Distinguishing characteristics of metabolically healthy versus metabolically unhealthy obese adolescent girls with polycystic ovary syndrome. Fertil Steril 2016; 105 (06) 1603-1611
    CrossrefPubMedGoogle Scholar
  • 76 George JT, Kakkar R, Marshall J. et al. Neurokinin B receptor antagonism in women with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 2016; 101 (11) 4313-4321
    CrossrefPubMedGoogle Scholar
  • 77 Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998; 83 (06) 2001-2005
    PubMedGoogle Scholar
  • 78 Abdolahian S, Tehrani FR, Amiri M. et al. Effect of lifestyle modifications on anthropometric, clinical, and biochemical parameters in adolescent girls with polycystic ovary syndrome: a systematic review and meta-analysis. BMC Endocr Disord 2020; 20 (01) 71
    CrossrefPubMedGoogle Scholar
  • 79 Moran LJ, Brown WJ, McNaughton SA, Joham AE, Teede HJ. Weight management practices associated with PCOS and their relationships with diet and physical activity. Hum Reprod 2017; 32 (03) 669-678
    PubMedGoogle Scholar
  • 80 Lie Fong S, Douma A, Verhaeghe J. Implementing the international evidence-based guideline of assessment and management of polycystic ovary syndrome (PCOS): how to achieve weight loss in overweight and obese women with PCOS?. J Gynecol Obstet Hum Reprod 2021; 50 (06) 101894
    CrossrefPubMedGoogle Scholar
  • 81 Woodward A, Broom D, Harrop D. et al. The effects of physical exercise on cardiometabolic outcomes in women with polycystic ovary syndrome not taking the oral contraceptive pill: a systematic review and meta-analysis. J Diabetes Metab Disord 2019; 18 (02) 597-612
    CrossrefPubMedGoogle Scholar
  • 82 Aktaş HŞ, Uzun YE, Kutlu O. et al. The effects of high intensity-interval training on vaspin, adiponectin and leptin levels in women with polycystic ovary syndrome. Arch Physiol Biochem 2022; 128: 37-42
    CrossrefPubMedGoogle Scholar
  • 83 Porchia LM, Hernandez-Garcia SC, Gonzalez-Mejia ME, López-Bayghen E. Diets with lower carbohydrate concentrations improve insulin sensitivity in women with polycystic ovary syndrome: a meta-analysis. Eur J Obstet Gynecol Reprod Biol 2020; 248: 110-117
    CrossrefPubMedGoogle Scholar
  • 84 Kazemi M, Hadi A, Pierson RA, Lujan ME, Zello GA, Chilibeck PD. Effects of Dietary glycemic index and glycemic load on cardiometabolic and reproductive profiles in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Adv Nutr 2021; 12 (01) 161-178
    CrossrefPubMedGoogle Scholar
  • 85 Yheulon CG, Millard AJ, Balla FM. et al. Laparoscopic sleeve gastrectomy outcomes in patients with polycystic ovary syndrome. Am Surg 2019; 85 (03) 252-255
    CrossrefPubMedGoogle Scholar
  • 86 Teede H, Tassone EC, Piltonen T. et al. Effect of the combined oral contraceptive pill and/or metformin in the management of polycystic ovary syndrome: a systematic review with meta-analyses. Clin Endocrinol (Oxf) 2019; 91 (04) 479-489
    CrossrefPubMedGoogle Scholar
  • 87 Teede HJ, Meyer C, Hutchison SK, Zoungas S, McGrath BP, Moran LJ. Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy. Fertil Steril 2010; 93 (01) 184-191
    CrossrefPubMedGoogle Scholar
  • 88 Manzoor S, Ganie MA, Amin S. et al. Oral contraceptive use increases risk of inflammatory and coagulatory disorders in women with polycystic ovarian syndrome: an observational study. Sci Rep 2019; 9 (01) 10182
    CrossrefPubMedGoogle Scholar
  • 89 Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org, Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril 2017; 108 (03) 426-441
    CrossrefPubMedGoogle Scholar
  • 90 Majuri A, Santaniemi M, Rautio K. et al. Rosiglitazone treatment increases plasma levels of adiponectin and decreases levels of resistin in overweight women with PCOS: a randomized placebo-controlled study. Eur J Endocrinol 2007; 156 (02) 263-269
    CrossrefPubMedGoogle Scholar
  • 91 Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93 (07) 2670-2678
    CrossrefPubMedGoogle Scholar
  • 92 Frøssing S, Nylander M, Chabanova E. et al. Effect of liraglutide on ectopic fat in polycystic ovary syndrome: a randomized clinical trial. Diabetes Obes Metab 2018; 20 (01) 215-218
    CrossrefPubMedGoogle Scholar
  • 93 Jensterle M, Goricar K, Janez A. Metformin as an initial adjunct to low-dose liraglutide enhances the weight-decreasing potential of liraglutide in obese polycystic ovary syndrome: randomized control study. Exp Ther Med 2016; 11 (04) 1194-1200
    CrossrefPubMedGoogle Scholar
  • 94 Jensterle M, Kravos NA, Goričar K, Janez A. Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: randomized trial. BMC Endocr Disord 2017; 17 (01) 5
    CrossrefPubMedGoogle Scholar
  • 95 Jensterle M, Kravos NA, Pfeifer M, Kocjan T, Janez A. A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome. Hormones (Athens) 2015; 14 (01) 81-90
    CrossrefPubMedGoogle Scholar
  • 96 Güngör NK. Overweight and obesity in children and adolescents. J Clin Res Pediatr Endocrinol 2014; 6 (03) 129-143
    CrossrefPubMedGoogle Scholar
  • 97 Mason K, Page L, Balikcioglu PG. Screening for hormonal, monogenic, and syndromic disorders in obese infants and children. Pediatr Ann 2014; 43 (09) e218-e224
    CrossrefPubMedGoogle Scholar
  • 98 Malhotra S. Genetic and syndromic obesity. Paper presented at: Harvard Medical School and Massachusetts General Hospital 2019 Blackburn Course in Obesity Medicine. 2019. Boston, MA:
    Google Scholar
  • 99 Hammoud AO, Gibson M, Peterson CM, Hamilton BD, Carrell DT. Obesity and male reproductive potential. J Androl 2006; 27 (05) 619-626
    CrossrefPubMedGoogle Scholar
  • 100 McFarlane KJaS. Secondary cause of obesity. Therapy 2007; 4 (05) 641-650
    CrossrefPubMedGoogle Scholar
  • 101 Hainerová IA, Zamrazilová H, Sedláčková D, Hainer V. Hypogonadotropic hypogonadism in a homozygous MC4R mutation carrier and the effect of sibutramine treatment on body weight and obesity-related health risks. Obes Facts 2011; 4 (04) 324-328
    PubMedGoogle Scholar
  • 102 Aminzadeh M, Kim HG, Layman LC, Cheetham TD. Rarer syndromes characterized by hypogonadotropic hypogonadism. Front Horm Res 2010; 39: 154-167
    CrossrefPubMedGoogle Scholar
  • 103 Napolitano L, Barone B, Morra S. et al. Hypogonadism in Patients with Prader Willi syndrome: a narrative review. Int J Mol Sci 2021; 22 (04) 1993
    CrossrefPubMedGoogle Scholar
  • 104 Gross-Tsur V, Hirsch HJ, Benarroch F, Eldar-Geva T. The FSH-inhibin axis in Prader-Willi syndrome: heterogeneity of gonadal dysfunction. Reprod Biol Endocrinol 2012; 10: 39
    CrossrefPubMedGoogle Scholar
  • 105 Shokrpour M, Foroozanfard F, Afshar Ebrahimi F. et al. Comparison of myo-inositol and metformin on glycemic control, lipid profiles, and gene expression related to insulin and lipid metabolism in women with polycystic ovary syndrome: a randomized controlled clinical trial. Gynecol Endocrinol 2019; 35 (05) 406-411
    CrossrefPubMedGoogle Scholar
  • 106 Rodrigues JM, Fernandes HD, Caruthers C, Braddock SR, Knutsen AP. Cohen syndrome: review of the literature. Cureus 2018; 10 (09) e3330
    PubMedGoogle Scholar
  • 107 Goldstone AP, Beales PL. Genetic obesity syndromes. Front Horm Res 2008; 36: 37-60
    CrossrefPubMedGoogle Scholar
  • 108 Forsythe E, Beales PL. Bardet-Biedl syndrome. Eur J Hum Genet 2013; 21 (01) 8-13
    CrossrefPubMedGoogle Scholar
  • 109 Koscinski I, Mark M, Messaddeq N. et al. Reproduction function in male patients with Bardet Biedl syndrome. J Clin Endocrinol Metab 2020; 105 (12) e4417-e4429
    CrossrefPubMedGoogle Scholar
  • 110 Feuillan PP, Ng D, Han JC. et al. Patients with Bardet-Biedl syndrome have hyperleptinemia suggestive of leptin resistance. J Clin Endocrinol Metab 2011; 96 (03) E528-E535
    CrossrefPubMedGoogle Scholar
  • 111 Zaghloul NA, Katsanis N. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest 2009; 119 (03) 428-437
    CrossrefPubMedGoogle Scholar
  • 112 Stoler JM, Herrin JT, Holmes LB. Genital abnormalities in females with Bardet-Biedl syndrome. Am J Med Genet 1995; 55 (03) 276-278
    CrossrefPubMedGoogle Scholar
  • 113 Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 1999; 36 (06) 437-446
    CrossrefPubMedGoogle Scholar
  • 114 Marion V, Stoetzel C, Schlicht D. et al. Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc Natl Acad Sci U S A 2009; 106 (06) 1820-1825
    CrossrefPubMedGoogle Scholar
  • 115 Starks RD, Beyer AM, Guo DF. et al. Regulation of insulin receptor trafficking by Bardet Biedl syndrome proteins. PLoS Genet 2015; 11 (06) e1005311
    CrossrefPubMedGoogle Scholar
  • 116 Toma HS, Tan PL, McKusick VA, Katsanis N, Adams NA. Bardet-Biedl syndrome in an African-American patient: should the diagnostic criteria be expanded to include hydrometrocolpos?. Ophthalmic Genet 2007; 28 (02) 95-99
    CrossrefPubMedGoogle Scholar
  • 117 Mantovani G, Bastepe M, Monk D. et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement. Nat Rev Endocrinol 2018; 14 (08) 476-500
    CrossrefPubMedGoogle Scholar
  • 118 Weinstein LS, Chen M, Liu J. Gs(alpha) mutations and imprinting defects in human disease. Ann N Y Acad Sci 2002; 968: 173-197
    CrossrefPubMedGoogle Scholar
  • 119 Linglart A, Levine MA, Jüppner H. Pseudohypoparathyroidism. Endocrinol Metab Clin North Am 2018; 47 (04) 865-888
    CrossrefPubMedGoogle Scholar
  • 120 Haldeman-Englert CR, Hurst ACE, Levine MA. Disorders of GNAS inactivation. In: Adam MP, Ardinger HH, Pagon RA. et al., eds. GeneReviews(®). Seattle, WA: University of Washington, Seattle Copyright © 1993–2021, University of Washington, Seattle; 1993
    Google Scholar
  • 121 Shoemaker AH, Jüppner H. Nonclassic features of pseudohypoparathyroidism type 1A. Curr Opin Endocrinol Diabetes Obes 2017; 24 (01) 33-38
    CrossrefPubMedGoogle Scholar
  • 122 Wolfsdorf JI, Rosenfield RL, Fang VS, Kobayashi R, Razdan AK, Kim MH. Partial gonadotrophin-resistance in pseudohypoparathyroidism. Acta Endocrinol (Copenh) 1978; 88 (02) 321-328
    CrossrefPubMedGoogle Scholar
  • 123 Tahani N, Maffei P, Dollfus H. et al. Consensus clinical management guidelines for Alström syndrome. Orphanet J Rare Dis 2020; 15 (01) 253
    CrossrefPubMedGoogle Scholar
  • 124 Paisey RB, Steeds R, Barrett T, Williams D, Geberhiwot T, Gunay-Aygun M. Alström syndrome. In: Adam MP, Ardinger HH, Pagon RA. et al., eds. GeneReviews(®). Seattle, WA: University of Washington, Seattle Copyright © 1993–2021, University of Washington, Seattle; 1993
    Google Scholar
  • 125 Marshall JD, Bronson RT, Collin GB. et al. New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 2005; 165 (06) 675-683
    CrossrefPubMedGoogle Scholar
  • 126 Dassie F, Favaretto F, Bettini S. et al. Alström syndrome: an ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity. Endocrine 2021; 71 (03) 618-625
    CrossrefPubMedGoogle Scholar
  • 127 Han JC, Reyes-Capo DP, Liu CY. et al. Comprehensive endocrine-metabolic evaluation of patients with Alström syndrome compared with BMI-matched controls. J Clin Endocrinol Metab 2018; 103 (07) 2707-2719
    CrossrefPubMedGoogle Scholar
  • 128 Aykut A, Özen S, Gökşen D. et al. Melanocortin 4 receptor (MC4R) gene variants in children and adolescents having familial early-onset obesity: genetic and clinical characteristics. Eur J Pediatr 2020; 179 (09) 1445-1452
    CrossrefPubMedGoogle Scholar
  • 129 De Rosa MC, Chesi A, McCormack S. et al. Characterization of rare variants in MC4R in African American and Latino Children with severe early-onset obesity. J Clin Endocrinol Metab 2019; 104 (07) 2961-2970
    CrossrefPubMedGoogle Scholar
  • 130 Lubrano-Berthelier C, Durand E, Dubern B. et al. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 2003; 12 (02) 145-153
    CrossrefPubMedGoogle Scholar
  • 131 Martinelli CE, Keogh JM, Greenfield JR. et al. Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion. J Clin Endocrinol Metab 2011; 96 (01) E181-E188
    CrossrefPubMedGoogle Scholar
  • 132 Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003; 348 (12) 1085-1095
    CrossrefPubMedGoogle Scholar
  • 133 Farooqi IS, Wangensteen T, Collins S. et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007; 356 (03) 237-247
    CrossrefPubMedGoogle Scholar
  • 134 Nunziata A, Funcke JB, Borck G. et al. Functional and phenotypic characteristics of human leptin receptor mutations. J Endocr Soc 2018; 3 (01) 27-41
    CrossrefPubMedGoogle Scholar
  • 135 Paz-Filho G, Mastronardi C, Delibasi T, Wong ML, Licinio J. Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy. Arq Bras Endocrinol Metabol 2010; 54 (08) 690-697
    CrossrefPubMedGoogle Scholar
  • 136 Dubern B, Clement K. Leptin and leptin receptor-related monogenic obesity. Biochimie 2012; 94 (10) 2111-2115
    CrossrefPubMedGoogle Scholar
  • 137 Fischer-Posovszky P, von Schnurbein J, Moepps B. et al. A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness. J Clin Endocrinol Metab 2010; 95 (06) 2836-2840
    CrossrefPubMedGoogle Scholar
  • 138 Israel D, Chua Jr S. Leptin receptor modulation of adiposity and fertility. Trends Endocrinol Metab 2010; 21 (01) 10-16
    CrossrefPubMedGoogle Scholar
  • 139 Farooqi IS, Jebb SA, Langmack G. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341 (12) 879-884
    CrossrefPubMedGoogle Scholar
  • 140 Licinio J, Caglayan S, Ozata M. et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A 2004; 101 (13) 4531-4536
    CrossrefPubMedGoogle Scholar
  • 141 Ratra DV, Elias CF. Chemical identity of hypothalamic neurons engaged by leptin in reproductive control. J Chem Neuroanat 2014; 61-62: 233-238
    CrossrefPubMedGoogle Scholar
  • 142 Stijnen P, Ramos-Molina B, O'Rahilly S, Creemers JW. PCSK1 mutations and human endocrinopathies: from obesity to gastrointestinal disorders. Endocr Rev 2016; 37 (04) 347-371
    CrossrefPubMedGoogle Scholar
  • 143 Pépin L, Colin E, Tessarech M. et al. A new case of PCSK1 pathogenic variant with congenital proprotein convertase 1/3 deficiency and literature review. J Clin Endocrinol Metab 2019; 104 (04) 985-993
    CrossrefPubMedGoogle Scholar
  • 144 Martín MG, Lindberg I, Solorzano-Vargas RS. et al. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology 2013; 145 (01) 138-148
    CrossrefPubMedGoogle Scholar
  • 145 Jonklaas J, Bianco AC, Bauer AJ. et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid 2014; 24 (12) 1670-1751
    CrossrefPubMedGoogle Scholar
  • 146 Pacifico L, Anania C, Ferraro F, Andreoli GM, Chiesa C. Thyroid function in childhood obesity and metabolic comorbidity. Clin Chim Acta 2012; 413 (3-4): 396-405
    CrossrefPubMedGoogle Scholar
  • 147 Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010; 31 (05) 702-755
    CrossrefPubMedGoogle Scholar
  • 148 Saei Ghare Naz M, Rostami Dovom M, Ramezani Tehrani F. The menstrual disturbances in endocrine disorders: a narrative review. Int J Endocrinol Metab 2020; 18 (04) e106694
    CrossrefPubMedGoogle Scholar
  • 149 Salerno M, Micillo M, Di Maio S. et al. Longitudinal growth, sexual maturation and final height in patients with congenital hypothyroidism detected by neonatal screening. Eur J Endocrinol 2001; 145 (04) 377-383
    CrossrefPubMedGoogle Scholar
  • 150 Nieman LK, Biller BM, Findling JW. et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93 (05) 1526-1540
    Google Scholar
  • 151 Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol 2016; 4 (07) 611-629
    CrossrefPubMedGoogle Scholar
  • 152 Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD. et al. Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab 1998; 83 (09) 3083-3088
    PubMedGoogle Scholar
  • 153 Garne E, Rissmann A, Addor MC. et al. Epidemiology of septo-optic dysplasia with focus on prevalence and maternal age - a EUROCAT study. Eur J Med Genet 2018; 61 (09) 483-488
    CrossrefPubMedGoogle Scholar
  • 154 Patel L, McNally RJ, Harrison E, Lloyd IC, Clayton PE. Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England. J Pediatr 2006; 148 (01) 85-88
    CrossrefPubMedGoogle Scholar
  • 155 Webb EA, Dattani MT. Septo-optic dysplasia. Eur J Hum Genet 2010; 18 (04) 393-397
    CrossrefPubMedGoogle Scholar
  • 156 Kelberman D, Dattani MT. Septo-optic dysplasia - novel insights into the aetiology. Horm Res 2008; 69 (05) 257-265
    PubMedGoogle Scholar
  • 157 Cerbone M, Güemes M, Wade A, Improda N, Dattani M. Endocrine morbidity in midline brain defects: differences between septo-optic dysplasia and related disorders. EClinicalMedicine 2020; 19: 100224
    CrossrefPubMedGoogle Scholar
  • 158 Vedin AM, Garcia-Filion P, Fink C, Borchert M, Geffner ME. Serum prolactin concentrations in relation to hypopituitarism and obesity in children with optic nerve hypoplasia. Horm Res Paediatr 2012; 77 (05) 277-280
    CrossrefPubMedGoogle Scholar
  • 159 Ladjouze A, Soskin S, Garel C. et al. GH deficiency with central precocious puberty: a new rare disorder associated with a developmental defect of the hypothalamic-pituitary area. Eur J Endocrinol 2007; 156 (04) 463-469
    CrossrefPubMedGoogle Scholar
  • 160 Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013-2017. Neuro-oncol 2020; 22 (12, Suppl 2): iv1-iv96
    CrossrefPubMedGoogle Scholar
  • 161 McCrea HJ, George E, Settler A, Schwartz TH, Greenfield JP. Pediatric suprasellar tumors. J Child Neurol 2016; 31 (12) 1367-1376
    CrossrefPubMedGoogle Scholar
  • 162 Abuzzahab MJ, Roth CL, Shoemaker AH. Hypothalamic obesity: prologue and promise. Horm Res Paediatr 2019; 91 (02) 128-136
    CrossrefPubMedGoogle Scholar
  • 163 Haliloglu B, Bereket A. Hypothalamic obesity in children: pathophysiology to clinical management. J Pediatr Endocrinol Metab 2015; 28 (5-6): 503-513
    CrossrefPubMedGoogle Scholar
  • 164 van Iersel L, Brokke KE, Adan RAH, Bulthuis LCM, van den Akker ELT, van Santen HM. Pathophysiology and individualized treatment of hypothalamic obesity following craniopharyngioma and other suprasellar tumors: a systematic review. Endocr Rev 2019; 40 (01) 193-235
    CrossrefPubMedGoogle Scholar
  • 165 Santoro C, Perrotta S, Picariello S. et al. Pretreatment endocrine disorders due to optic pathway gliomas in pediatric neurofibromatosis type 1: multicenter study. J Clin Endocrinol Metab 2020; 105 (06) dgaa138
    CrossrefPubMedGoogle Scholar
  • 166 Chemaitilly W, Merchant TE, Li Z. et al. Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes. Clin Endocrinol (Oxf) 2016; 84 (03) 361-371
    CrossrefPubMedGoogle Scholar
  • 167 ACOG Committee Opinion No. 747. Summary: gynecologic issues in children and adolescent cancer patients and survivors. Obstet Gynecol 2018; 132 (02) 535-536
    CrossrefPubMedGoogle Scholar
  • 168 Swee DS, Quinton R. Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males. Ther Adv Endocrinol Metab 2019; 10: 2042018819826889
    CrossrefPubMedGoogle Scholar
  • 169 Huseyin K, Berk B, Tolga K, Eser O, Ali G, Murat A. Management of ovulation induction and intrauterine insemination in infertile patients with hypogonadotropic hypogonadism. J Gynecol Obstet Hum Reprod 2019; 48 (10) 833-838
    CrossrefPubMedGoogle Scholar
  • 170 El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia. Lancet 2017; 390 (10108): 2194-2210
    CrossrefPubMedGoogle Scholar
  • 171 Papadakis G, Kandaraki EA, Tseniklidi E, Papalou O, Diamanti-Kandarakis E. Polycystic ovary syndrome and NC-CAH: distinct characteristics and common findings. a systematic review. Front Endocrinol (Lausanne) 2019; 10: 388
    CrossrefPubMedGoogle Scholar
  • 172 Speiser PW, Arlt W, Auchus RJ. et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2018; 103 (11) 4043-4088
    CrossrefPubMedGoogle Scholar