Skip to main content
SpringerLink
Log in

Physiopathology, Diagnosis, and Treatment of Functional Pituitary Dysfunction

  • Living reference work entry
  • First Online:
Hypothalamic-Pituitary Diseases

Part of the book series: Endocrinology ((ENDOCR))

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

ACTH:

Adrenocorticotropic hormone

AgRP:

Agouti-related-peptide

aMSH:

Alpha-melanocyte-stimulating hormone

AN:

Anorexia nervosa

ATP:

Adenosine tri-phosphate

AVP:

Arginine vasopressin

BMD:

Bone mineral density

BMI:

Body mass index

CFS:

Chronic fatigue syndrome

CRH:

Corticotropin-releasing hormone

CS:

Cushing’s syndrome

DM:

Diabetes mellitus

E2:

Estradiol

FFA:

Free fatty acids

FGF-21:

Fibroblast growth factor-21

FHA:

Functional hypothalamic amenorrhea

FM:

Fibromyalgia

FSH:

Follicle-stimulating hormone

fT3:

Free tri-iodothyronine

fT4:

Free thyroxine

GC:

Glucocorticoid

GH:

Growth hormone

GHD:

Growth hormone deficiency

GHRH:

Growth hormone releasing hormone

GnRH:

Gonadotropin-releasing hormone

GR:

Glucocorticoid receptors

HPA:

Hypothalamo-pituitary-adrenal axis

HPG:

Hypothalamo-pituitary-gonadal axis

HPO:

Hypothalamo-pituitary-ovary

HPT:

Hypothalamo-pituitary-thyroid

ICU:

Intensive care unit

IGF-1:

Insulin-like growth factor 1

IGFBP:

Insulin-like growth hormone binding protein

IHH:

Idiopathic hypogonadotropic hypogonadism

IL:

Interleukin

ITT:

Insulin tolerance test

LH:

Luteinizing hormone

MCH:

Melanine-concentrating hormone

MR:

Mineralocorticoid receptors

MRI:

Magnetic resonance imaging

NEFA:

Non-esterified fatty acids

NPY:

Neuropeptide Y

NTIS:

Non-thyroidal illness syndrome

OSAS:

Obstructive sleep apnea syndrome

PCOS:

Polycystic ovary syndrome

PCS:

Pseudo- Cushing`s syndrome

PRL:

Prolactin

PTSD:

Posttraumatic stress disorder

RAI:

Relative adrenal insufficiency

rT3:

Reverse tri-iodothyronine

SHBG:

Sex hormone binding globulin

T3 :

Tri-iodothyronine

T4:

Thyroxine

TNFa:

Tumor necrosis factor alpha

TRH:

Thyrotropin-releasing hormone

TSH:

Thyroid-stimulating hormone

UFC:

Urinary free cortisol

References

  • 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.

    Article  CAS  Google Scholar 

  • American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5. DSM-5. Washington, DC: APA; 2013.

    Book  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Berthoud HR. Metabolic and hedonic drives in the neural control of appetite: who is the boss? Curr Opin Neurobiol. 2011;21:888–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Besemer F, Pereira AM, Smit JWA. Alcohol-induced Cushing syndrome: Hypercortisolism caused by alcohol abuse. Neth J Med. 2011;69:318–23.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Chambers TJ, Richard RA. The impact of obesity on male fertility. Hormones (Athens). 2015;14(4):563–8.

    Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • De Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol. 2015;225(3):R67–81.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Economidou F, Douka E, Tzanela M, Nanas S, Kotanidou A. Thyroid function during critical illness. Hormones (Athens). 2011;10(2):117–24.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farwell AP. Nonthyroidal illness syndrome. Curr Opin Endocrinol Diabetes Obes. 2013;20(5):478–84.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fazeli PK, Klibanski A. Determinants of GH resistance in malnutrition. J Endocrinol. 2014;220:R57–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fourman LT, Fazelli PK. Neuroendocrine causes of amenorrhea – an update. J Clin Endocrinol Metab. 2015;100:812–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian J Androl. 2014;16(2):223–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Gold PW. The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry. 2015;20:32–47.

    Article  CAS  PubMed  Google Scholar 

  • Gordon CM. Clinical practice.Functional hypothalamic amenorrhea. N Engl J Med. 2010;363:365–71.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Inui A. Eating behavior in anorexia nervosa$an excess of both orexigenic and anorexigenic signalling? Mol Psychiatry. 2001;6:620–4.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jungheim ES, Travieso JL, Carson KR, Moley KH. Obesity and reproductive function. Obstet Gynecol Clin N Am. 2012;39(4):479–93.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Kokkoris P, Pi-Sunyer FX. Obesity and endocrine disease. Endocrinol Metab Clin N Am. 2003;32(4):895–914.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Kopelman PG. Physiopathology of prolactin secretion in obesity. Int J Obes Relat Metab Disord. 2000;24(Suppl 2):S104–8.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Lambrinoudaki I, Papadimitriou D. Pathophysiology of bone loss in the female athlete. Ann N Y Acad Sci. 2010;1205:45–50.

    Google Scholar 

  • Laughlin GA, Yen SSC. Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab. 1997;82:318–21.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee S, Farwell AP. Euthyroid sick syndrome. Compr Physiol. 2016;6(2):1071–80.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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): MDText.com, Inc; 2016. 2000-2016 Mar 1.

    Google Scholar 

  • Liu JH. Hypothalamic amenorrhea: Clinical perspectives, pathophysiology, and management. Am J Obstet Gynecol. 1990;163:1732–6.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • Meczekalski B, Podfigurna-Stopa A, Warenk-Szymankiewicz A, Genazzani AR. Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations. Gynecol Endocrinol. 2008;24:4–11.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Misra M, Klibanski A. Anorexia nervosa and its associated endocrinopathy in young people. Horm Res Paediatr. 2016;85:147–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Misra M, Klibanski A. Endocrine consequences of anorexia nervosa. Lancet Diabetes Endocrinol. 2014;2:581–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Misra M. Neuroendocrine mechanisms in athletes. Handb Clin Neurol. 2014;124:373–86.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pantalone KM, Nasr C. Approach to a low TSH level: patience is a virtue. Cleve Clin J Med. 2010;77(11):803–11.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008;31:464–8.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Popovic V, Casanueva FF. Leptin, nutrition and reproduction: new insight. Hormones. 2002;1:204–17.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Popovic V. Approach to testing growth hormone (GH) secretion in obese subjects. J Clin Endocrinol Metab. 2013;98(5):1789–96.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  Google Scholar 

  • Santoro N. Update in hyper- and hypogonadotropic amenorrhea. J Clin Endocrinol Metab. 2011;96:3281–8.

    Article  CAS  PubMed  Google Scholar 

  • Sanyal D, Raychaudhuri M. Hypothyroidism and obesity: an intriguing link. Indian J Endocrinol Metab. 2016;20(4):554–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Seetho IW, Wilding JP. How to approach endocrine assessment in severe obesity? Clin Endocrinol. 2013;79(2):163–7.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Siddiqui A, Madhu SV, Sharma SB, Desai NG. Endocrine stress responses and risk of type 2 diabetes mellitus. Stress. 2015;18(5):498–506.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Silveira LFG, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013;98:1781–8.

    Article  CAS  PubMed  Google Scholar 

  • Singhal V, Misra M, Klibanski A. Endocrinology of anorexia nervosa in young people: recent insights. Curr Opin Endocrinol Diabetes Obes. 2014;21:64–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smalls AG, Kloppenborg PW, Njo KT, Knoben JM, Ruland CM. Alcohol-induced Cushingoid syndrome. Br Med J. 1976;2:1298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Somer L, Matavulj M, Hadzic B. The hypophyseal-adrenal axis in chronic alcoholism. Med Pregl. 1996;49:349–55.

    CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tirabassi G, Boscaro M, Arnaldi G. Harmful effects of functional hypercortisolism: a working hypothesis. Endocrine. 2014;46(3):370–86.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53:865–71.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Vigersky RA, Loriaux D, Andersen AE, Lipsett MR. Anorexia nervosa: behavioral and hypothalamic aspects. Clin Endocrinol Metab. 1976;5:515–35.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol. 2010;205(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  • Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol. 2001;170:3–11.

    Article  CAS  PubMed  Google Scholar 

  • Warren MP. Health issues for women athletes: exercise-induced amenorrhea. J Clin Endocrinol Metab. 1999;84:1892–6.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

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

Author information

Authors and Affiliations

  1. Clinic for Endocrinology, Diabetes and Metabolic Diseases, Neuroendocrine Unit, Clinical Centre of Serbia, Belgrade, Serbia

    Dragana Miljic, Sandra Pekic & Marko Stojanovic

  2. University of Belgrade, School of Medicine, Belgrade, Serbia

    Dragana Miljic, Sandra Pekic, Marko Stojanovic & Vera Popovic

Authors
  1. Dragana Miljic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra Pekic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marko Stojanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vera Popovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vera Popovic .

Editor information

Editors and Affiliations

  1. DepT of Endocrinology and Nutrition, Univ de Santiago de Compostela, Santiago de Compostela, Spain

    Felipe F. Casanueva

  2. Division of Endocrinology, Diabetol, University of Torino, Torino, Torino, Italy

    Ezio Ghigo

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Cite this entry

Miljic, D., Pekic, S., Stojanovic, M., Popovic, V. (2018). Physiopathology, Diagnosis, and Treatment of Functional Pituitary Dysfunction. In: Casanueva, F., Ghigo, E. (eds) Hypothalamic-Pituitary Diseases. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-38681-2_6-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-38681-2_6-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-38681-2

  • Online ISBN: 978-3-319-38681-2

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation