Journal of Endocrinological Investigation

, Volume 42, Issue 9, pp 1001–1010 | Cite as

Functional hypothalamic and drug-induced amenorrhea: an overview

  • A. Lania
  • L. Gianotti
  • I. Gagliardi
  • M. Bondanelli
  • W. VenaEmail author
  • M. R. Ambrosio
Short Review



Functional hypothalamic amenorrhea (FHA) is a form of chronic anovulation not due to identifiable organic causes and with adverse health consequences. The identification of women with this disorder or the precocious identification of women at risk is based on the knowledge of lifestyle risk factors or behaviors such as stress, weight loss, and excessive physical exercise that are known to negatively impact gonadal axis activity.


In this overview, we described the most common forms of FHA, in particular stress-induced amenorrhea and overtraining-induced amenorrhea. In addition, although its mechanisms can differ from those involved in FHA, we reviewed the available literature on drug-induced amenorrhea, highlighting the clear connection between this condition and psychoactive drugs such as antipsychotics, antidepressants and anti-epilectics thus raising concern about the role that the abuse of substances such as opioids or alcohol can possibly have on the growing unexplained infertility of the female population.


Functional amenorrhea Hypothalamic amenorrhea Drug-induced amenorrhea Hypoestrogenism Opiates Alcohol 



The authors acknowledge Mrs. Racca Anna ( for her contribution to this paper.


None of the authors received funding for the realization of this paper.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This is a review paper, therefore, no ethical approval was necessary.

Informed consent

This is a review paper, therefore, no informed consent was necessary.


  1. 1.
    Gordon CM, Ackerman KE, Berga SL et al (2017) Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 102(5):1413–1439PubMedCrossRefGoogle Scholar
  2. 2.
    Sowińska-Przepiera E, Andrysiak-Mamos E, Jarząbek-Bielecka G et al (2014) Functional hypothalamic amenorrhoea—diagnostic challenges, monitoring, and treatment. Endokrynol Polska 66(5):252–260Google Scholar
  3. 3.
    Bomba M, Gambera A, Bonini L et al (2007) Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents. Fertil Steril 87(4):876–885PubMedCrossRefGoogle Scholar
  4. 4.
    Genazzani AD, Chierchia E, Santagni S et al (2010) Hypothalamic amenorrhea: from diagnosis to therapeutical approach. Ann Endocrinol 71:163–169CrossRefGoogle Scholar
  5. 5.
    Prokai D, Berga S (2016) Neuroprotection via reduction in stress: altered menstrual patterns as a marker for stress and implications for long-term neurologic health in women. Int J Mol Sci 17:2147PubMedCentralCrossRefGoogle Scholar
  6. 6.
    Bomba M, Corbetta F, Bonini L et al (2014) Psychopathological traits of adolescents with functional hypothalamic amenorrhea: a comparison with anorexia nervosa. Eat Weight Disord 19(1):41–48PubMedCrossRefGoogle Scholar
  7. 7.
    Pentz I, Nakić Radoš S (2017) Functional hypothalamic amenorrhea and its psychological correlates: a controlled comparison. J Reprod Infant Psychol 35(2):137–149PubMedCrossRefGoogle Scholar
  8. 8.
    Rafique N, Al-Sheikh MA (2018) Prevalence of menstrual problems and their association with psychological stress in young female students studying health sciences. Saudi Med J 39:67–73PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Caronia LM, Martin C, Welt CK et al (2011) A Genetic basis for functional hypothalamic amenorrhea. N Engl J Med 364(3):215–225PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Schneiderman Ironson G, Siegel SD (2005) Stress and health: psychological, behavioral, and biological determinants. Annu Rev Clin Psychol 1:607–628PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Meczekalski B, Katulski K, Czyzyk A et al (2014) Functional hypothalamic amenorrhea and its influence on women’s health. J Endocrinol Invest 37:1049–1056PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Petraglia F, Porro C, Facchinetti F et al (1986) Opioid control of LH secretion in humans: menstrual cycle, menopause and aging reduce effect of naloxone but not of morphine. Life Sci 38(23):2103–2110PubMedCrossRefGoogle Scholar
  13. 13.
    Rossmanith WG, Wirth U, Sterzik K, Yen SS (1989) The effects of prolonged opioidergic blockade on LH pulsatile secretion during the menstrual cycle. J Endocrinol Invest 12(4):245–252PubMedCrossRefGoogle Scholar
  14. 14.
    Wahab F, Atika B, Ullah F et al (2018) Metabolic impact on the hypothalamic kisspeptin-kiss1r signaling pathway. Front Endocrinol 9:123CrossRefGoogle Scholar
  15. 15.
    Iwasa T, Matsuzaki T, Yano K et al (2018) The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders. Endocr J 65(2):133–140PubMedCrossRefGoogle Scholar
  16. 16.
    Kirby ED, Geraghty AC, Ubuka T et al (2009) Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats. Proc Natl Acad Sci U S A 106(27):11324–11329PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Genazzani AD, Petraglia F, Fabbri G et al (1990) Evidence of luteinizing hormone secretion in hypothalamic amenorrhea associated with weight loss. Fertil Steril 54(2):222–226PubMedCrossRefGoogle Scholar
  18. 18.
    Cannavo S, Curtò L, Trimarchi F (2001) Exercise-related female reproductive dysfunction. J Endocrinol Invest 24:823–832PubMedCrossRefGoogle Scholar
  19. 19.
    Michopoulos V, Mancini F, Loucks TL, Berga SL (2013) Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial. Fertil Steril 99(7):2084–2091.e1PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Berga SL, Marcus MD, Loucks TL et al (2003) Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy. Fertil Steril 80(4):976–981PubMedCrossRefGoogle Scholar
  21. 21.
    Shen ZQ, Xu JJ, Lin JF (2013) Resumption of menstruation and pituitary response to gonadotropin-releasing hormone in functional hypothalamic amenorrhea subjects undertaking estrogen replacement therapy. J Endocrinol Invest 36:812–815PubMedGoogle Scholar
  22. 22.
    Böttcher B, Seeber B, Leyendecker G, Wildt L (2017) Impact of the opioid system on the reproductive axis. Fertil Steril 108(2):207–213PubMedCrossRefGoogle Scholar
  23. 23.
    Roozenburg BJ, van Dessel HJ, Evers JL, Bots RS (1997) Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment. Hum Reprod 12:1720PubMedCrossRefGoogle Scholar
  24. 24.
    Genazzani AD, Despini G, Czyzyk A et al (2017) Modulatory effects of l-carnitine plus l- acetyl-carnitine on neuroendocrine control of hypothalamic functions in functional hypothalamic amenorrhea (FHA). Gynecol Endocrinol 33(12):963–967PubMedCrossRefGoogle Scholar
  25. 25.
    Mircea CN, Lujan ME, Pierson RA (2007) Metabolic fuel and clinical implications for female reproduction. J Obstet Gynaecol Can 29(11):887–902PubMedCrossRefGoogle Scholar
  26. 26.
    Manfredi-Lozano M, Roa J, Tena-Sempere M (2018) Connecting metabolism and gonadal function: novel central neuropeptide pathways involved in the metabolic control of puberty and fertility. Front Neuroendocrinol 48:37–49PubMedCrossRefGoogle Scholar
  27. 27.
    Ruegsegger GN, Booth FW (2017) Running from disease: molecular mechanisms associating dopamine and leptin signaling in the brain with physical inactivity, obesity, and type 2 diabetes. Front Endocrinol 8(109):1–8Google Scholar
  28. 28.
    Mastorakos G, Pavlatou M, Diamanti-Kandarakis E, Chrousos GP (2005) Exercise and the stress system. Hormones 4(2):73–89PubMedGoogle Scholar
  29. 29.
    De Souza MJ, Williams NI (2004) Physiological aspects and clinical sequelae of energy deficiency and hypoestrogenism in exercising women. Hum Reprod Update 10(5):433–448PubMedCrossRefGoogle Scholar
  30. 30.
    Maïmoun L, Georgopoulos NA, Sultan C (2014) Endocrine disorders in adolescent and young female athletes: impact on growth, menstrual cycles, and bone mass acquisition. J Clin Endocrinol Metab 99:4037–4050PubMedCrossRefGoogle Scholar
  31. 31.
    Loucks AB, Thuma JR (2003) Luteinizing hormone pulsatility is disrupted at threshold availability of energy availability in regularly menstruating women. J Clin Endocrinol Metab 88:297–311PubMedCrossRefGoogle Scholar
  32. 32.
    Chan JL (2005) Mantzoros CS Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet 366(9479):74–85PubMedCrossRefGoogle Scholar
  33. 33.
    Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS (2004) Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 351(10):987–997PubMedCrossRefGoogle Scholar
  34. 34.
    De Souza MJ, Nattiv A, Joy E, Misra M, Williams NI, Mallinson RJ, Gibbs JC, Olmsted M, Goolsby M, Matheson G, Expert Panel (2014) Female athlete triad coalition consensus statement on treatment and return to play of the female athlete triad. Br J Sports Med 48:289PubMedCrossRefGoogle Scholar
  35. 35.
    Mountjoy M, Sundgot-Borgen J, Burke L, Carter S, Constantini N, Lebrun C, Meyer N, Sherman R, Steffen K, Budgett R, Ljungqvist A (2014) The IOC consensus statement: beyond the female athlete triad-relative energy deficiency in sport (RED-S). Br J Sports Med 48(7):491–497PubMedCrossRefGoogle Scholar
  36. 36.
    Beumont PJ, Gelder MG, Friesen GH, Harris GW, MacKinnon PC, Mandelbrote BM, Wiles DH (1974) The effects of phenothiazines on endocrine function: I: patients with inappropriate lactation and amenorrhoea. Br J Psychiatry 124:413–419PubMedCrossRefGoogle Scholar
  37. 37.
    Haddad PM, Wieck A (2004) Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 64(20):2291–2314PubMedCrossRefGoogle Scholar
  38. 38.
    Cookson J, Hodgson R, Wildgust HJ (2012) Prolactin, hyperprolactinaemia and antipsychotic treatment: a review and lessons for treatment of early psychosis. J Psychopharmacol 26(5 Suppl):42–51PubMedCrossRefGoogle Scholar
  39. 39.
    Howes OD, Wheeler MJ, Pilowsky LS, Landau S, Murray RM, Smith S (2007) Sexual function and gonadal hormones in patients taking antipsychotic treatment for schizophrenia or schizoaffective disorder. J Clin Psychiatry 68(3):361–367PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Smith SM (2008) The impact of hyperprolactinaemia on sexual function in patients with psychosis. J Psychopharmacol 22(2 Suppl):63–69PubMedCrossRefGoogle Scholar
  41. 41.
    Takahashi T, Uchida H, John M, Hirano J, Watanabe K, Mimura M, Correll CU, Kishimoto T (2013) The impact of prolactin-raising antipsychotics on bone mineral density in patients with schizophrenia: findings from a longitudinal observational cohort. Schizophr Res 147(2–3):383–386PubMedCrossRefGoogle Scholar
  42. 42.
    Montejo ÁL, Arango C, Bernardo M, Carrasco JL, Crespo-Facorro B, Cruz JJ, Del Pino-Montes J, García-Escudero MA, García-Rizo C, González-Pinto A, Hernández AI, Martín-Carrasco M, Mayoral-Cleries F, Mayoral-van Son J, Mories MT, Pachiarotti I, Pérez J, Ros S, Vieta E (2017) Multidisciplinary consensus on the therapeutic recommendations for iatrogenic hyperprolactinemia secondary to antipsychotics. Front Neuroendocrinol 45:25–34PubMedCrossRefGoogle Scholar
  43. 43.
    Grigg J, Worsley R, Thew C, Gurvich C, Thomas N, Kulkarni J (2017) Antipsychotic-induced hyperprolactinemia: synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research. Psychopharmacology 234(22):3279–3297PubMedCrossRefGoogle Scholar
  44. 44.
    Mars B, Heron J, Kessler D, Davies NM, Martin RM, Thomas KH, Gunnell D (2017) Influences on antidepressant prescribing trends in the UK: 1995–2011. Soc Psychiatry Psychiatr Epidemiol 52(2):193–200PubMedCrossRefGoogle Scholar
  45. 45.
    Arya DK (1994) Extrapyramidal symptoms with selective serotonin reuptake inhibitors. Br J Psychiatry 165(6):728–733PubMedCrossRefGoogle Scholar
  46. 46.
    Nicholas L, Dawkins K, Golden RN (1998) Psychoneuroendocrinology of depression: prolactin. Psychiatr Clin North Am 21(2):341–358PubMedCrossRefGoogle Scholar
  47. 47.
    Cam B, Karldere T (2014) Amenorrhea associated with duloxetine: two case reports. J Clin Psychopharmacol 34(4):522–523PubMedCrossRefGoogle Scholar
  48. 48.
    Anand VS (1985) Clomipramine–induced galactorrhoea and amenorrhoea. Br J Psychiatry 147:87–88PubMedCrossRefGoogle Scholar
  49. 49.
    International Narcotics Control Board (INCB). Narcotic drugs technical report: Estimates world requirements for 2018—statistics for 2016. Accessed 29 August 2018
  50. 50.
    Berterame S, Erthal J, Thomas J, Fellner S, Vosse B, Clare P, Hao W, Johnson DT, Mohar A, Pavadia J, Samak AK, Sipp W, Sumyai V, Suryawati S, Toufiq J, Yans R, Mattick RP (2016) Use of and barriers to access to opioid analgesics: a worldwide, regional, and national study. Lancet 387(10028):1644–1656PubMedCrossRefGoogle Scholar
  51. 51.
    Helmerhorst GT, Teunis T, Janssen SJ, Ring D (2017) An epidemic of the use, misuse and overdose of opioids and deaths due to overdose, in the United States and Canada: is Europe next? Bone Joint J 99(7):856–864PubMedCrossRefGoogle Scholar
  52. 52.
    European Drug Report 2017: trends and developments; EMCDDA, Lisbon, June 2017. Accessed 29 August 2018
  53. 53.
    Smith HS, Elliott JA (2012) Opioid-induced androgen deficiency (OPIAD). Pain Physician 15(3 Suppl):ES145–ES156PubMedGoogle Scholar
  54. 54.
    O’Rourke TK Jr, Wosnitzer MS (2016) Opioid-induced androgen deficiency (OPIAD): diagnosis, management, and literature review. Curr Urol Rep 17(10):76PubMedCrossRefGoogle Scholar
  55. 55.
    Orstead KM, Spies HG (1987) Inhibition of hypothalamic gonadotropin-releasing hormone release by endogenous opioid peptides in the female rabbit. Neuroendocrinology 46(1):14–23PubMedCrossRefGoogle Scholar
  56. 56.
    Gabriel SM, Simpkins JW, Kalra SP (1983) Modulation of endogenous opioid influence on luteinizing hormone secretion by progesterone and estrogen. Endocrinology 113(5):1806–1811PubMedCrossRefGoogle Scholar
  57. 57.
    Abs R, Verhelst J, Maeyaert J, Van Buyten JP, Opsomer F, Adriaensen H, Verlooy J, Van Havenbergh T, Smet M, Van Acker K (2000) Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 85(6):2215–2222PubMedCrossRefGoogle Scholar
  58. 58.
    Daniell HW (2008) Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain 9(1):28–36PubMedCrossRefGoogle Scholar
  59. 59.
    Vuong C, Van Uum SH, O’Dell LE, Lutfy K, Friedman TC (2010) The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev 31(1):98–132PubMedCrossRefGoogle Scholar
  60. 60.
    Fraser LA, Morrison D, Morley-Forster P, Paul TL, Tokmakejian S, Larry Nicholson R, Bureau Y, Friedman TC, Van Uum SH (2009) Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes 117(1):38–43PubMedCrossRefGoogle Scholar
  61. 61.
    GBD Alcohol Collaborators (2018) Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 10152:1015–1035Google Scholar
  62. 62.
    Rachdaoui N, Sarkar DK (2013) Effects of alcohol on the endocrine system. Endocrinol Metab Clin N Am 42(3):593–615CrossRefGoogle Scholar
  63. 63.
    Mello NK, Mendelson JH, King NW, Bree MP, Skupny A, Ellingboe J (1988) Alcohol self-administration by female macaque monkeys: a model for study of alcohol dependence, hyperprolactinemia and amenorrhea. J Stud Alcohol 49(6):551–560PubMedCrossRefGoogle Scholar
  64. 64.
    Mendelson JH, Mello NK (1988) Chronic alcohol effects on anterior pituitary and ovarian hormones in healthy women. J Pharmacol Exp Ther 245(2):407–412PubMedGoogle Scholar
  65. 65.
    Oomizu S, Boyadjieva N, Sarkar DK (2003) Ethanol and estradiol modulate alternative splicing of dopamine D2 receptor messenger RNA and abolish the inhibitory action of bromocriptine on prolactin release from the pituitary gland. Alcohol Clin Exp Res 27(6):975–980PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    De A, Boyadjieva N, Oomizu S, Sarkar DK (2002) Ethanol induces hyperprolactinemia by increasing prolactin release and lactotrope growth in female rats. Alcohol Clin Exp Res 26(9):1420–1429PubMedCrossRefGoogle Scholar
  67. 67.
    Lomniczi A, Mastronardi CA, Faletti AG, Seilicovich A, De Laurentiis A, McCann SM, Rettori V (2000) Inhibitory pathways and the inhibition of luteinizing hormone-releasing hormone release by alcohol. Proc Natl Acad Sci U S A. 97(5):2337–2342PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Block GD, Yamamoto ME, Mallick A, Styche A (1993) Effects on pubertal hormones by ethanol abuse in adolescents. Alcohol Clin Exp Res 17:505Google Scholar
  69. 69.
    Dees WL, Srivastava V, Hiney JK (2009) Actions and interactions of alcohol and insulin-like growth factor-1 on female pubertal development. Alcohol Clin Exp Res 33(11):1847–1856PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Li N, Fu S, Zhu F, Deng X, Shi X (2013) Alcohol intake induces diminished ovarian reserve in childbearing age women. J Obstet Gynaecol Res 39(2):516–521PubMedCrossRefGoogle Scholar
  71. 71.
    Jensen TK, Hjollund NH, Henriksen TB, Scheike T, Kolstad H, Giwercman A, Ernst E, Bonde JP, Skakkebaek NE, Olsen J (1998) Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy. BMJ 317(7157):505–510PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Fan D, Liu L, Xia Q, Wang W, Wu S, Tian G, Liu Y, Ni J, Wu S, Guo X, Liu Z (2017) Female alcohol consumption and fecundability: a systematic review and dose-response meta-analysis. Sci Rep 7(1):13815PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Bauer J, Cooper-Mahkorn D (2008) Reproductive dysfunction in women with epilepsy: menstrual cycle abnormalities, fertility, and polycystic ovary syndrome. Int Rev Neurobiol 83:135–155PubMedCrossRefGoogle Scholar
  74. 74.
    Verrotti A, D’Egidio C, Mohn A, Coppola G, Parisi P, Chiarelli F (2011) Antiepileptic drugs, sex hormones, and PCOS. Epilepsia 52(2):199–211PubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  • A. Lania
    • 1
  • L. Gianotti
    • 2
  • I. Gagliardi
    • 3
  • M. Bondanelli
    • 3
  • W. Vena
    • 1
    Email author
  • M. R. Ambrosio
    • 3
  1. 1.Endocrinology Unit, Department of Biomedical SciencesHumanitas University and Humanitas Research HospitalRozzanoItaly
  2. 2.Division of Endocrinology Diabetology and MetabolismS. Croce and Carle HospitalCuneoItaly
  3. 3.University of FerraraFerraraItaly

Personalised recommendations