Physiopathology, Diagnosis, and Treatment of Functional Pituitary Dysfunction

  • Dragana Miljic
  • Sandra Pekic
  • Marko Stojanovic
  • Vera Popovic
Reference work entry
Part of the Endocrinology book series (ENDOCR)


Neuroendocrine signals are integrated by the hypothalamus. Both hypothalamic and peripheral hormone signals are executed in the pituitary. Functional hypothalamic-pituitary changes may develop as a result of chronic stress, energy imbalance (both positive-obesity and negative-anorexia nervosa), and critical illness. Abnormalities of the endocrine system include increased activity of hypothalamic-pituitary-adrenal axis (HPA), impaired growth hormone axis, gonadal and thyroid dysfunction, and alteration in prolactin secretion. These hormonal alterations may also contribute to the development of underlying condition. A skillful use of dynamic tests together with careful clinical evaluation and follow-up are necessary to establish the correct diagnosis. Some of these changes are viewed as adaptive, and improvement in pituitary dysfunctions is expected with reversal of causation.


Obesity Amenorrhea Eating disorders Thyroid Pseudo-Cushing’s 

List of Abbreviations


Adrenocorticotropic hormone




Alpha-melanocyte-stimulating hormone


Anorexia nervosa


Adenosine tri-phosphate


Arginine vasopressin


Bone mineral density


Body mass index


Chronic fatigue syndrome


Corticotropin-releasing hormone


Cushing’s syndrome


Diabetes mellitus




Free fatty acids


Fibroblast growth factor-21


Functional hypothalamic amenorrhea




Follicle-stimulating hormone


Free tri-iodothyronine


Free thyroxine




Growth hormone


Growth hormone deficiency


Growth hormone releasing hormone


Gonadotropin-releasing hormone


Glucocorticoid receptors


Hypothalamo-pituitary-adrenal axis


Hypothalamo-pituitary-gonadal axis






Intensive care unit


Insulin-like growth factor 1


Insulin-like growth hormone binding protein


Idiopathic hypogonadotropic hypogonadism




Insulin tolerance test


Luteinizing hormone


Melanine-concentrating hormone


Mineralocorticoid receptors


Magnetic resonance imaging


Non-esterified fatty acids


Neuropeptide Y


Non-thyroidal illness syndrome


Obstructive sleep apnea syndrome


Polycystic ovary syndrome


Pseudo- Cushing`s syndrome




Posttraumatic stress disorder


Relative adrenal insufficiency


Reverse tri-iodothyronine


Sex hormone binding globulin






Tumor necrosis factor alpha


Thyrotropin-releasing hormone


Thyroid-stimulating hormone


Urinary free cortisol



This work was supported by the Serbian Ministry of Science (project number 17503).


  1. Ackerman KE, Slusarz K, Guereca G, Pierce L, Slattery M, Mendes N, Herzog DB, Misra M. Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls. Am J Phys Endocrinol Metab. 2012;302:E800–6.CrossRefGoogle Scholar
  2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5. DSM-5. Washington, DC: APA; 2013.CrossRefGoogle Scholar
  3. Bao S, Oiknine R, Fisher SJ. Differentiating nonthyroidal illness syndrome from central hypothyroidism in the acutely ill hospitalized patient. Endocrine. 2012;42(3):758–60.PubMedCrossRefGoogle Scholar
  4. Bensson S, Arck PC, Tan S, Hahn S, Mann K, Rifaie N, Janssen OE, Schedlowski M, Elsenbruch S. Disturbed stress responses in women with polycystic ovary syndrome. Psychoneuroendocrinology. 2009;34(5):727–35.CrossRefGoogle Scholar
  5. Beresford TP, Arciniegas DB, Alfers J, Clapp L, Martin B, Beresford HF, Du Y, Liu D, Shen D, Davatzikos C, Laudenslager ML. Hypercortisolism in alcohol dependence and its relation to hippocampal volume loss. J Stud Alcohol. 2006;67:861–7.PubMedCrossRefGoogle Scholar
  6. Berga SL, Daniels TL, Giles DE. Women with functional hypothalamic amenorrhea but not other forms of anovulation display amplified cortisol concentrations. Fertil Steril. 1997;67:1024–30.PubMedCrossRefGoogle Scholar
  7. Berga SL, Loucks-Daniels TL, Adler LJ, Chrousos GP, Cameron KL, Methews KA, Marcus MD. Cerebrospinal fluid levels of corticotropin-releasing-hormone in women with functional hypothalamic amenorrhea. Am J Obstet Gynecol. 2000;182:776–84.PubMedCrossRefGoogle Scholar
  8. Berga SL, Marcus MD, Loucks TL, Hlastala S, Ringham R, Krohn MA. Recovery of ovarian activity in women with functional hypothalamic amenorrhea (FHA) treated with cognitive behavior therapy (CBT). Fertil Steril. 2003;80:976–81.PubMedCrossRefGoogle Scholar
  9. Berga SL, Mortola JF, Girton L, Suh B, Laughlin G, Pham P, Yen SSC. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1989;68:301–8.PubMedCrossRefGoogle Scholar
  10. Berthoud HR. Metabolic and hedonic drives in the neural control of appetite: who is the boss? Curr Opin Neurobiol. 2011;21:888–96.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Besemer F, Pereira AM, Smit JWA. Alcohol-induced Cushing syndrome: Hypercortisolism caused by alcohol abuse. Neth J Med. 2011;69:318–23.PubMedGoogle Scholar
  12. Biller BMK, Federoff HJ, Koenig JI, Klibanski A. Abnormal cortisol secretion and responses to corticotropin-releasing hormone in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1990;70:311–7.PubMedCrossRefGoogle Scholar
  13. Boelen A, Kwakkel J, Wiersinga WM, Fliers E. Chronic local inflammation in mice results in decreased TRH and type 3 deiodinase mRNA expression in the hypothalamic paraventricular nucleus independently of diminished food intake. J Endocrinol. 2006;191(3):707–14.PubMedCrossRefGoogle Scholar
  14. Boonen E, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE, Vanwijngaerden Y-M, Spriet I, Wouters PJ, Vander Perre S, Langouche L, Vanhorebeek I, Walker BR, Van Den Berghe G. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013;368:1477–88.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Boyar RM, Hellman LD, Roffwarg H, Katz J, Zumoff B, O’Connor J, Bradlow HL, Fukushima DK. Cortisol secretion and metabolism in anorexia nervosa. N Engl J Med. 1997;296:190–3.CrossRefGoogle Scholar
  16. Brundu B, Loucks TL, Adler LJ, Cameron JL, Berga SL. Increased cortisol in the cerebrospinal fluid of women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 2006;91:1561–5.PubMedCrossRefGoogle Scholar
  17. Bunevicius R, Steibliene V, Prange AJ Jr. Thyroid axis function after in-patient treatment of acute psychosis with antipsychotics: a naturalistic study. BMC Psychiatry. 2014;14:279.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Camastra S, Manco M, Frascerra S, Iaconelli A, Mingrone G, Ferrannini E. Daylong pituitary hormones in morbid obesity: effects of bariatric surgery. Int J Obes. 2009;33(1):166–72.CrossRefGoogle Scholar
  19. Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, Avbelj M, Dhruvakumar S, Plummer L, Hughes V, Seminara SB, Boepple PA, Sidis Y, Crowley WF Jr, Martin KA, Hall JE, Pitteloud N. (2011). A genetic basis for functional hypothalamic amenorrhea. N Engl J Med, 364, 215-225.Google Scholar
  20. Casanueva FF, Dieguez C, Popovic V, Peino R, Considine R, Caro J. Serum immunoreactive leptin concentrations in patients with anorexia nervosa before and after partial weight recovery. Biochem Mol Med. 1997;60:116–20.PubMedCrossRefGoogle Scholar
  21. Castellano JM, Navarro VM, Fernández-Fernández R, Nogueiras R, Tovar S, Roa J, Vazquez MJ, Vigo E, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology. 2005;146:3917–25.PubMedCrossRefGoogle Scholar
  22. Catargi B, Rigalleau V, Poussin A, Ronci-Chaix N, Bex V, Vergnot V, Gin H, Roger P, Tabarin A. Occult Cushing’s syndrome in type-2 diabetes. J Clin Endocrinol Metab. 2003;88(12):5808–13.PubMedCrossRefGoogle Scholar
  23. Chambers TJ, Richard RA. The impact of obesity on male fertility. Hormones (Athens). 2015;14(4):563–8.Google Scholar
  24. Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhea and anorexia nervosa. Lancet. 2005;366:74–85.PubMedCrossRefGoogle Scholar
  25. Chiodini I, Adda G, Scillitani A, Coletti F, Morelli V, Di Lembo S, Epaminonda P, Masserini B, Beck-Peccoz P, Orsi E, Ambrosi B, Arosio M. Cortisol secretion in patients with type 2 diabetes: relationship with chronic complications. Diabetes Care. 2007;30:83–8.PubMedCrossRefGoogle Scholar
  26. Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, Brinkoetter MT, Gong H, Arampatzi K, Mantzoros CS. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A. 2011;108:6585–90.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Christin-Maitre S, de Crecy M, Groupe Francais des popes. GnRH pregnancy outcomes following pulsatile GnRH treatment: results of a large multicenter retrospective study. J Gynecol Obstet Biol Reprod. 2007;36:8–12.CrossRefGoogle Scholar
  28. Dall'Asta C, Paganelli M, Morabito A, Vedani P, Barbieri M, Paolisso G, Folli F, Pontiroli AE. Weight loss through gastric banding: effects on TSH and thyroid hormones in obese subjects with normal thyroid function. Obesity (Silver Spring). 2010;18(4):854–7.CrossRefGoogle Scholar
  29. De Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol. 2015;225(3):R67–81.PubMedCrossRefGoogle Scholar
  30. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock. Crit Care Med. 2013;41(2):580–637.PubMedCrossRefGoogle Scholar
  31. Desbriere R, Vuaroqueaux V, Achard V, Boullu-Ciocca S, Labuhn M, Dutour A, Grino M. 11beta-hydroxysteroid dehydrogenase type 1 mRNA is increased in both visceral and subcutaneous adipose tissue of obese patients. Obesity (Silver Spring). 2006;14:794–8.CrossRefGoogle Scholar
  32. Dostálová I, Kaválková P, Haluzíková D, Lacinová Z, Mráz M, Papezová H, Haluzík M. Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa. J Clin Endocrinol Metab. 2008;93:3627–32.PubMedCrossRefGoogle Scholar
  33. Dumont A, Dewailly D, Plouvier P, Catteau-Jonard S, Robin G. Does polycystic ovarian morphology influence the response to treatment with pulsatile GnRH in functional hypothalamic amenorrhea? Reprod Biol Endocrinol. 2016;14:24–9.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Economidou F, Douka E, Tzanela M, Nanas S, Kotanidou A. Thyroid function during critical illness. Hormones (Athens). 2011;10(2):117–24.CrossRefGoogle Scholar
  35. Faje AT, Karim L, Taylor A, Lee H, Miller KK, Mendes N, Meenaghan E, Goldstein MA, Bouxsein ML, Misra M, Klibanski A. Adolescent girls with anorexia nervosa have impaired cortical and trabecular microarchitecture and lower estimated bone strength at the distal radius. J Clin Endocrinol Metab. 2013;98:1923–9.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Farwell AP. Nonthyroidal illness syndrome. Curr Opin Endocrinol Diabetes Obes. 2013;20(5):478–84.PubMedCrossRefGoogle Scholar
  37. Fazeli PK, Faje AT, Cross EJ, Lee H, Rosen CJ, Bouxsein ML, Klibanski A. Serum FGF-21 levels are associated with worsened radial trabecular bone microarchitecture and decreased radial bone strength in women with anorexia nervosa. Bone. 2015;77:6–11.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Fazeli PK, Klibanski A. Determinants of GH resistance in malnutrition. J Endocrinol. 2014;220:R57–65.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Fourman LT, Fazelli PK. Neuroendocrine causes of amenorrhea – an update. J Clin Endocrinol Metab. 2015;100:812–24.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian J Androl. 2014;16(2):223–31.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Gambineri A, Forlani G, Munarini A, Tomassoni F, Cognigni GE, Ciampaglia W, Pagotto U, Walker BR, Pasquali R. Increased clearance of cortisol by 5 beta-reductase in a subgroup of women with adrenal hyperandrogenism in polycystic ovary syndrome. J Endocrinol Investig. 2009;32(3):210–8.CrossRefGoogle Scholar
  42. Gold PW. The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry. 2015;20:32–47.PubMedCrossRefGoogle Scholar
  43. Gordon CM. Clinical practice.Functional hypothalamic amenorrhea. N Engl J Med. 2010;363:365–71.PubMedCrossRefGoogle Scholar
  44. Gorwood P, Blanchet-Collet C, Chartrel N, Duclos J, Dechelotte P, Hanachi M, Fetissov S, Godart N, Melchior J, Ramoz N, Rovere-Jovene C, Tolle V, Viltart O, Epelbaum J, on behalf of the GIR-AFDAS-TCA Group. (2016). New insights in anorexia nervosa. Front Neurosci, 10, 256.Google Scholar
  45. Gungunes A, Sahin M, Demirci T, Ucan B, Cakir E, Arslan MS, Unsal IO, Karbek B, Caliskan M, Ozbek M, Cakal E, Delibasi T. Cushing’s syndrome in type 2 diabetes patients with poor glycemic control. Endocrine. 2014;47(3):895–900.PubMedCrossRefGoogle Scholar
  46. Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology. 2000;25(1):1–35.PubMedCrossRefGoogle Scholar
  47. Holsen LM, Lawson EA, Blum J, Ko E, Makris N, Fazeli PK, Klibanski A, Goldstein JM. Food motivation circuitry hypo activation related to hedonic and non-hedonic aspects of hunger and in women with active and weight-restored anorexia nervosa. J Psychiatry Neurosci. 2012;37(5):322–32.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hotta M, Ohwada R, Akamizu T, Shibasaki T, Takano K, Kangawa K. Ghrelin increases hunger and food intake in patients with restricting-type anorexia nervosa: a pilot study. Endocr J. 2009;56:1119–28.PubMedCrossRefGoogle Scholar
  49. Howard SR, Guasti L, Ruiz-Babot G, Mancini A, David A, Storr HL, Metherell LA, Sternberg MJE, Cabrera CP, Warren HR, Barnes MR, Quinton R, de Roux N, Young J, Guiochon-Mantel A, Wehkalampi K, Andre V, Gothilf Y, Cariboni A, Dunkel L. IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty. EMBO Mol Med. 2016;8:626–42.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Incollingo Rodriguez AC, Epel ES, White ML, Standen EC, Seckl JR, Tomiyama AJ. Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: a systematic review. Psychoneuroendocrinology. 2015;62:301–18.PubMedCrossRefGoogle Scholar
  51. Inui A. Eating behavior in anorexia nervosa--an excess of both orexigenic and anorexigenic signalling? Mol Psychiatry. 2001;6:620–4.PubMedCrossRefGoogle Scholar
  52. Inviti C, De Martin M, Delitala G, Veldhuis JD, Cavagnini F. Altered morning and night time pulsatile corticotropin and cortisol release in polycystic ovary syndrome. Metabolism. 1998;47(2):143–8.CrossRefGoogle Scholar
  53. Javed A, Kashyap R, Lteif AN. Hyperandrogenism in female athletes with functional hypothalamic amenorrhea: a distinct phenotype. Int J Wom Health. 2015;7:103–11.Google Scholar
  54. Jayasena CN, Abbara A, Veldhuis JD, Comninos AN, Ratnasabapathy R, De Silva A, Nijher GM, Ganiyu-Dada Z, Mehta A, Todd C, Ghatei MA, Bloom SR, Dhillo WS. Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of Kisspeptin-54. J Clin Endocrinol Metab. 2014;99:E953–61.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Jungheim ES, Travieso JL, Carson KR, Moley KH. Obesity and reproductive function. Obstet Gynecol Clin N Am. 2012;39(4):479–93.CrossRefGoogle Scholar
  56. Kaufman BA, Warren MP, Dominguez JE, Wang J, Heymsfield SB, Pierson RN. Bone density and amenorrhea in ballet dancers are related to a decreased resting metabolic rate and lower leptin levels. J Clin Endocrinol Metab. 2002;87:2777–83.PubMedCrossRefGoogle Scholar
  57. Kaye WH, Gwirtsman HE, George DT, Ebert MH, Jimerson DC, Tomai TP, Chrousos GP, Gold PW. Elevated cerebrospinal fluid levels of immunoreactive corticotropin-releasing hormone in anorexia nervosa: relation to state of nutrition, adrenal function, and intensity of depression. J Clin Endocrinol Metab. 1987;64:203–8.PubMedCrossRefGoogle Scholar
  58. Kaye WH, Berrettini WH, Gwirtsman HE, Gold PW, George DT, Jimerson DC, Ebert MH.Contribution of CNS neuropeptide (NPY, CRH, and beta-endorphin) alterations to psychophysiological abnormalities in anorexia nervosa. 1989;25:433–8.Google Scholar
  59. Kokkoris P, Pi-Sunyer FX. Obesity and endocrine disease. Endocrinol Metab Clin N Am. 2003;32(4):895–914.CrossRefGoogle Scholar
  60. Kontula K, Anderson LC, Huttumen M, Pelkonen R. Reduced level of cellular glucocorticoid receptors in patients with anorexia nervosa. Horm Metab Res. 1982;14:619–20.PubMedCrossRefGoogle Scholar
  61. Kopelman PG. Physiopathology of prolactin secretion in obesity. Int J Obes Relat Metab Disord. 2000;24(Suppl 2):S104–8.PubMedCrossRefGoogle Scholar
  62. Kyriakidis M, Caetano L, Anastasiadou N, Karasu T, Lashen H. Functional hypothalamic amenorrhea: leptin treatment, dietary intervention and counseling as alternatives to traditional practice – systematic review. Eur J Obstet Gynecol Reprod Biol. 2016;198:131–7.PubMedCrossRefGoogle Scholar
  63. Lambrinoudaki I, Papadimitriou D. Pathophysiology of bone loss in the female athlete. Ann N Y Acad Sci. 2010;1205:45–50.Google Scholar
  64. Laughlin GA, Yen SSC. Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab. 1997;82:318–21.PubMedCrossRefGoogle Scholar
  65. Laughlin GA, Dominguez CE, Yen SS. Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea. J ClinEndocrinolMetab. 1998;83:25–32.Google Scholar
  66. Lawson EA, Holsen LM, DeSanti R, McKale S, Meenaghan E, Herzog DB, Goldstein JM, Klibanski A. Increased hypothalamic-pituitary-adrenal drive is associated with decreased appetite and hypo activation of food motivation neurocircuitry in anorexia nervosa. Eur J Endocrinol. 2013;169(5):639–47.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Lee J, Yoon J, Kang MJ, Lee YA, Lee SY, Shin CH, Yang SW. Influence of body mass index on the growth hormone response to provocative testing in short children without growth hormone deficiency. J Korean Med Sci. 2013;28(9):1351–5.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Lee S, Farwell AP. Euthyroid sick syndrome. Compr Physiol. 2016;6(2):1071–80.PubMedCrossRefGoogle Scholar
  69. Li C, Liu Y, Lu C, Liu D, Jianq H, Pan F. Long-term effects of early adolescent stress: dysregulation of hypothalamic-pituitary-adrenal axis and central corticotropin releasing factor receptor 1 expression in adult male rats. Behav Brain Res. 2015;288:39–49.PubMedCrossRefGoogle Scholar
  70. Licinio J, Caglayan S, Ozata M, Yildiz BO, Miranda PB, O’Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, AM DP, SM MC, Wong ML. 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;101:4531–6.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Liu JH, Patel B, Collins G. Central causes of amenorrhea. In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, Koch C, Mc Lachlan R, New M, Rebar R, Singer F, Vinik A, Weickert MO, editors. Endotext [Internet]. South Dartmouth (MA):, Inc; 2016. 2000-2016 Mar 1.Google Scholar
  72. Liu JH. Hypothalamic amenorrhea: Clinical perspectives, pathophysiology, and management. Am J Obstet Gynecol. 1990;163:1732–6.PubMedCrossRefGoogle Scholar
  73. Loucks AB, Mortola JF, Girton L, Yen SSC. Alterations in the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes in athletic women. J Clin Endocrinol Metab. 1989;68:402–11.PubMedCrossRefGoogle Scholar
  74. Loucks AB, Verdun M, Heath EM. Low energy availability, not stress or exercise, alters LH pulsatility in exercising women. J Appl Physiol. 1998;84:37–46.PubMedCrossRefGoogle Scholar
  75. Maccario M, Grottoli S, Procopio M, Oleandri SE, Rossetto R, Gauna C, Arvat E, Ghigo E. The GH/IGF-I axis in obesity: influence of neuro-endocrine and metabolic factors. Int J Obes Relat Metab Disord. 2000;24(Suppl 2):S96–9.PubMedCrossRefGoogle Scholar
  76. Manenschijn L, van Kruysbergen RG, de Jong FH, Koper JW, van Rossum EF. Shift work at young age is associated with elevated long-term cortisol levels and body mass index. J Clin Endocrinol Metab. 2011;96:1862–5.CrossRefGoogle Scholar
  77. Martin KA, Hall JE, Adams JM, Crowley Jr WF. (1993). Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metab, 77, 125-129.Google Scholar
  78. Meczakalski B, Katulski K, Czyzyk A, Podfigurna-Stopa A, Maciejewska-Jeske M. Functional hypothalamic amenorrhea and its influence on women′s health. J Endocrinol Investig. 2014;37:1049–56.CrossRefGoogle Scholar
  79. Meczekalski B, Podfigurna-Stopa A, Warenk-Szymankiewicz A, Genazzani AR. Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations. Gynecol Endocrinol. 2008;24:4–11.PubMedCrossRefGoogle Scholar
  80. Melin A, Tornberg AB, Skouby S, Moller SS, Faber J, Sundgot-Borgen J, Sjodin A. Low-energy density and high fiber intake are dietary concerns in female endurance athletes. Scand J Med Sci Sports. 2016;26:1060–71.PubMedCrossRefGoogle Scholar
  81. Michalaki MA, Vagenakis AG, Leonardou AS, Argentou MN, Habeos IG, Makri MG, Psyrogiannis AI, Kalfarentzos FE, Kyriazopoulou VE. Thyroid function in humans with morbid obesity. Thyroid. 2006;16(1):73–8.PubMedCrossRefGoogle Scholar
  82. Michopoulos V, Mancini F, Loucks TL, Berga SL. Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized controlled trial. Fertil Steril. 2013;99:2084–91.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Miller KK, Parulekar MS, Schoenfeld E, Anderson E, Hubbard J, Klibanski A, Grinspoon SK. Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. J Clin Endocrino lMetab. 1998;83:2309–12.Google Scholar
  84. Miljic D, Pekic S, Djurovic M, Doknic M, Milic N, Casanueva FF, Ghatei M, Popovic V. Ghrelin has partial or no effect on appetite, growth hormone, prolactin, and cortisol release in patients with anorexia nervosa. J Clin Endocrinol Metab. 2006;91:1491–5.PubMedCrossRefGoogle Scholar
  85. Milutinovic DV, Macut D, Bozic I, Nestorov J, Damjanovic S, Matic G. Hypothalamic-pituitary-adrenocortical axis hypersensitivity and glucocorticoid receptor expression and function in women with polycystic ovarian syndrome. Exp Clin Endocrinol Diabetes. 2011;119:636–43.PubMedCrossRefGoogle Scholar
  86. Mingrone G, Manco M, Iaconelli A, Gniuli D, Bracaglia R, Leccesi L, Calvani M, Nolfe G, Basu S, Berria R. Prolactin and insulin ultradian secretion and adipose tissue lipoprotein lipase expression in severely obese women after bariatric surgery. Obesity (Silver Spring). 2008;16(8):1831–7.CrossRefGoogle Scholar
  87. Misra M, Klibanski A. Anorexia nervosa and its associated endocrinopathy in young people. Horm Res Paediatr. 2016;85:147–57.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Misra M, Klibanski A. Endocrine consequences of anorexia nervosa. Lancet Diabetes Endocrinol. 2014;2:581–92.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Misra M. Neuroendocrine mechanisms in athletes. Handb Clin Neurol. 2014;124:373–86.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Morgan SA, McCabe EL, Gathercole LL, Hassan-Smith ZK, Larner DP, Bujalska IJ, Stewart PM, Tomlinson JW, Lavery GG. 11beta-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. PNAS. 2014;111:E2482–91.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Morris MC, Compas BE, Garber J. Relations among posttraumatic stress disorder, co morbid major depression, and HPA function: a systematic review and meta-analysis. Clin Psychol Rev. 2012;32(4):301–15.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Moulin de Moraes CM, Mancini MC, de Melo ME, Figueiredo DA, Villares SM, Rascovski A, Zilberstein B, Halpern A. Prevalence of subclinical hypothyroidism in a morbidly obese population and improvement after weight loss induced by Roux-en-Y gastric bypass. Obes Surg. 2005;15(9):1287–91.PubMedCrossRefGoogle Scholar
  93. Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev. 1998;19(5):647–72.PubMedGoogle Scholar
  94. Oltmanns KM, Dodt B, Schultes B, Raspe HH, Schweiger U, Born J, Fehm HL, Peters A. Cortisol correlates with metabolic disturbances in a population study of type 2 diabetic patients. Eur J Endocrinol. 2006;154:325–31.PubMedCrossRefGoogle Scholar
  95. Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD, Gautron L, Kliewer SA, Mangelsdorf DJ. FGF21 contributes to neuroendocrine control of female reproduction. Nat Med. 2013;19:1153–6.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Pan A, Schernhammer ES, Sun Q, Hu FB. Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women. PLoS Med. 2011;8(12):e1001141.PubMedPubMedCentralCrossRefGoogle Scholar
  97. Pantalone KM, Nasr C. Approach to a low TSH level: patience is a virtue. Cleve Clin J Med. 2010;77(11):803–11.PubMedCrossRefGoogle Scholar
  98. Pappa TA, Vagenakis AG, Alevizaki M. The nonthyroidal illness syndrome in the non-critically ill patient. Eur J Clin Investig. 2011;41(2):212–20.CrossRefGoogle Scholar
  99. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008;31:464–8.PubMedCrossRefGoogle Scholar
  100. Pasquali R, Vicennati V, Cacciari M, Pagotto U. The hypothalamic-pituitary-adrenal axis activity in obesity and the metabolic syndrome. Ann N Y Acad Sci. 2006;1083:111–28.PubMedCrossRefGoogle Scholar
  101. Pasquali R, Vicennati V. Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Int J Obes Relat Metab Disord. 2000;24(Suppl 2):S47–9.PubMedCrossRefGoogle Scholar
  102. Pecori Giraldi F, Pivonello R, Ambrogio AG, De Martin MC, Scacchi M, Colao A, Toja PM, Lombardi G, Cavagnini F. The dexamethasone-suppressed corticotropin-releasing hormone stimulation test and the desmopressin test to distinguish Cushing’s syndrome from pseudo-Cushing’s states. Clin Endocrinol. 2007;66:251–7.CrossRefGoogle Scholar
  103. Perkins RB, Hall JE, Martin KA. Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability, and response to neurotransmitter modulation. J Clin Endocrinol Metab. 1999;84:1905–11.Google Scholar
  104. Peters A, Schweiger U, Pellerin L, Hubold C, Oltmanns KM, Conrad M, Schultes B, Born J, Fehm HL. The selfish brain: competition for energy resources. Neurosci Biobehav Rev. 2004;28:143–80.PubMedCrossRefGoogle Scholar
  105. Popovic V, Casanueva FF. Leptin, nutrition and reproduction: new insight. Hormones. 2002;1:204–17.PubMedCrossRefGoogle Scholar
  106. Popovic V, Djurovic M, Cetkovic A, Vojvodic D, Pekic S, Spremovic S, Petakov M, Damjanovic S, Milic N, Dieguez C, Casanueva FF. Inhibin B: a potential marker of gonadal activity in patients with anorexia nervosa during weight recovery. J Clin Endocrinol Metab. 2004;89:1838–43.PubMedCrossRefGoogle Scholar
  107. Popovic V. Approach to testing growth hormone (GH) secretion in obese subjects. J Clin Endocrinol Metab. 2013;98(5):1789–96.PubMedCrossRefGoogle Scholar
  108. Prpić-Križevac I, Canecki-Varžić S, Bilić-Ćurčić I. Hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with type 2 diabetes and relations with insulin resistance and chronic complications. Wien Klin Wochenschr. 2012;124(11-12):403–11.PubMedCrossRefGoogle Scholar
  109. Raff H, Trivedi H. Circadian rhythm of salivary cortisol, plasma cortisol, and plasma ACTH in end-stage renal disease. Endocr Connect. 2012;2(1):23–31.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Ray DC, Macduff A, Drummond GB, Wilkinson E, Adams B, Beckett GJ. Endocrine measurements in survivors and non-survivors from critical illness. Intensive Care Med. 2002;28(9):1301–8.PubMedCrossRefGoogle Scholar
  111. Reame NE, Sauder SE, Case GD, Kelch RP, Marshall JC. Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulation. J Clin Endocrinol Metab. 1985;61:851–8.PubMedCrossRefGoogle Scholar
  112. Ricketts ML, Verhaeg JM, Bujalska I, Howie AJ, Rainey WE, Stewart PM. Immunohistochemical localization of type 1 11betahydroxysteroid dehydrogenase in human tissues. J Clin Endocrinol Metab. 1998;83:1325–35.PubMedGoogle Scholar
  113. Roa J, Tena-Sempere M. Connecting metabolism and reproduction: roles of central energy sensors and key molecular mediators. Mol Cell Endocrinol. 2014;397(1-2):4–14.PubMedCrossRefGoogle Scholar
  114. Romuladi D, Giuliani M, Draisci G, Costantini B, Cristello F, Lanzone A, Guido M. Pioglitezone reduces the adrenal androgen response to corticotropin-releasing factor without changes in ACTH release in hyperinsulinemic women with polycystic ovary syndrome. Fertil Steril. 2007;88(1):131–8.CrossRefGoogle Scholar
  115. Rosen MP, Cedars ML. Female reproductive endocrinology and infertility. In: Gardner D, Shoback D, editors. Greenspan’s basic & clinical endocrinology. 8th ed. USA: McGraw-Hill Comp; 2007. p. 502–61.Google Scholar
  116. Rumińska M, Witkowska-Sędek E, Majcher A, Pyrżak B. Thyroid function in obese children and adolescents and its association with anthropometric and metabolic parameters. Adv Exp Med Biol. 2016;912:33–41.PubMedCrossRefGoogle Scholar
  117. Santoro N. Update in hyper- and hypogonadotropic amenorrhea. J Clin Endocrinol Metab. 2011;96:3281–8.PubMedCrossRefGoogle Scholar
  118. Sanyal D, Raychaudhuri M. Hypothyroidism and obesity: an intriguing link. Indian J Endocrinol Metab. 2016;20(4):554–7.PubMedPubMedCentralCrossRefGoogle Scholar
  119. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW. American Heart Association Councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention: kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention. Hypertension. 2003;42(5):1050–65.PubMedCrossRefGoogle Scholar
  120. Seetho IW, Wilding JP. How to approach endocrine assessment in severe obesity? Clin Endocrinol. 2013;79(2):163–7.CrossRefGoogle Scholar
  121. Sermondade N, Faure C, Fezeu L, Shayeb AG, Bonde JP, Jensen TK, Van Wely M, Cao J, Martini AC, Eskandar M, Chavarro JE, Koloszar S, Twigt JM, Ramlau-Hansen CH, Borges E Jr, Lotti F, Steegers-Theunissen RP, Zorn B, Polotsky AJ, La Vignera S, Eskenazi B, Tremellen K, Magnusdottir EV, Fejes I, Hercberg S, Lévy R, Czernichow S. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum Reprod Update. 2013;19(3):221–31.PubMedCrossRefGoogle Scholar
  122. Siddiqui A, Madhu SV, Sharma SB, Desai NG. Endocrine stress responses and risk of type 2 diabetes mellitus. Stress. 2015;18(5):498–506.PubMedCrossRefGoogle Scholar
  123. Sienkiewicz E, Magkos F, Aronis KN, Brinkoetter M, Chamberland JP, Chou S, Arampatzi KM, Gao C, Koniaris A, Mantzoros CS. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism. 2011;60:1211–21.PubMedCrossRefGoogle Scholar
  124. Silveira LFG, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013;98:1781–8.PubMedCrossRefGoogle Scholar
  125. Singhal V, Misra M, Klibanski A. Endocrinology of anorexia nervosa in young people: recent insights. Curr Opin Endocrinol Diabetes Obes. 2014;21:64–70.PubMedPubMedCentralCrossRefGoogle Scholar
  126. Smalls AG, Kloppenborg PW, Njo KT, Knoben JM, Ruland CM. Alcohol-induced Cushingoid syndrome. Br Med J. 1976;2:1298.PubMedPubMedCentralCrossRefGoogle Scholar
  127. Smith JT, Acohido BV, Clifton DK, Steiner RA. Kiss-1 neurons are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol. 2006;18:298–303.PubMedCrossRefGoogle Scholar
  128. Somer L, Matavulj M, Hadzic B. The hypophyseal-adrenal axis in chronic alcoholism. Med Pregl. 1996;49:349–55.PubMedGoogle Scholar
  129. Steiblienė V, Mickuvienė N, Prange AJ Jr, Bunevičius R. (2012). Concentrations of thyroid axis hormones in psychotic patients on hospital admission: the effects of prior drug use Medicina (Kaunas) 48(5):229-234.Google Scholar
  130. Steyn FJ, Xie TY, Huang L, Ngo ST, Veldhuis JD, Waters MJ, Chen C. Increased adiposity and insulin correlates with the progressive suppression of pulsatile GH secretion during weight gain. J Endocrinol. 2013;218(2):233–44.PubMedCrossRefGoogle Scholar
  131. Stimson IRH, Andrew R, McAvoy NC, Tripathi D, Hayes PC, Walker BR. Increased whole-body and sustained liver cortisol regeneration by 11 beta-hydroxysteroid dehydrogenase type 1 in obese men with type 2 diabetes provides a target for enzyme inhibition. Diabetes. 2011;60:720–5.PubMedPubMedCentralCrossRefGoogle Scholar
  132. Tirabassi G, Boscaro M, Arnaldi G. Harmful effects of functional hypercortisolism: a working hypothesis. Endocrine. 2014;46(3):370–86.PubMedCrossRefGoogle Scholar
  133. Tirabassi G, Faloia F, Papa R, Furlani G, Boscaro M, Arnaldi G. Use of the desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease. J Clin Endocrinol Metab. 2010;95:1115–22.PubMedCrossRefGoogle Scholar
  134. Tirabassi G, Papa R, Faloia E, Boscaro M, Arnaldi G. Corticotrophin-releasing hormone and desmopressin tests in the differential diagnosis between Cushing’s disease and pseudo-Cushing state: a comparative study. Clin Endocrinol. 2011;75:666–72.CrossRefGoogle Scholar
  135. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53:865–71.PubMedCrossRefGoogle Scholar
  136. Valsamakis G, Anwar A, Tomlinson JW, Shackleton CH, McTernan PG, Chetty R, Wood PJ, Banerjee AK, Holder G, Barnett AH, Stewart PM, Kumar S. 11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004;89:4755–61.PubMedCrossRefGoogle Scholar
  137. Vigersky RA, Loriaux D, Andersen AE, Lipsett MR. Anorexia nervosa: behavioral and hypothalamic aspects. Clin Endocrinol Metab. 1976;5:515–35.CrossRefGoogle Scholar
  138. Walker BR, Andrew R. Tissue production of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 and metabolic disease. Ann N Y Acad Sci. 2006;1083:165–84.PubMedCrossRefGoogle Scholar
  139. Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol. 2010;205(1):1–13.PubMedCrossRefGoogle Scholar
  140. Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol. 2001;170:3–11.PubMedCrossRefGoogle Scholar
  141. Warren MP. Health issues for women athletes: exercise-induced amenorrhea. J Clin Endocrinol Metab. 1999;84:1892–6.PubMedGoogle Scholar
  142. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351:987–97.PubMedCrossRefGoogle Scholar
  143. Zhu J, Choa RE, Guo MH, Plummer L, Buck C, Palmert MR, Hirschhorn JN, Seminara SB, Chan YM. A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2015;100:E646–54.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Dragana Miljic
    • 1
    • 2
  • Sandra Pekic
    • 1
    • 2
  • Marko Stojanovic
    • 1
    • 2
  • Vera Popovic
    • 2
  1. 1.Clinic for Endocrinology, Diabetes and Metabolic Diseases, Neuroendocrine UnitClinical Centre of SerbiaBelgradeSerbia
  2. 2.University of Belgrade, School of MedicineBelgradeSerbia

Personalised recommendations