Skip to main content

Advertisement

SpringerLink
Log in

Functional hypothalamic and drug-induced amenorrhea: an overview

  • Short Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  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):1413–1439

    Article  PubMed  Google Scholar 

  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):252–260

    Google Scholar 

  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):876–885

    Article  CAS  PubMed  Google Scholar 

  4. Genazzani AD, Chierchia E, Santagni S et al (2010) Hypothalamic amenorrhea: from diagnosis to therapeutical approach. Ann Endocrinol 71:163–169

    Article  CAS  Google Scholar 

  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 17:2147

    Article  PubMed Central  CAS  Google Scholar 

  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):41–48

    Article  PubMed  Google Scholar 

  7. Pentz I, Nakić Radoš S (2017) Functional hypothalamic amenorrhea and its psychological correlates: a controlled comparison. J Reprod Infant Psychol 35(2):137–149

    Article  PubMed  Google Scholar 

  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 39:67–73

    Article  PubMed  PubMed Central  Google Scholar 

  9. Caronia LM, Martin C, Welt CK et al (2011) A Genetic basis for functional hypothalamic amenorrhea. N Engl J Med 364(3):215–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schneiderman Ironson G, Siegel SD (2005) Stress and health: psychological, behavioral, and biological determinants. Annu Rev Clin Psychol 1:607–628

    Article  PubMed  PubMed Central  Google Scholar 

  11. Meczekalski B, Katulski K, Czyzyk A et al (2014) Functional hypothalamic amenorrhea and its influence on women’s health. J Endocrinol Invest 37:1049–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):2103–2110

    Article  CAS  PubMed  Google Scholar 

  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):245–252

    Article  CAS  PubMed  Google Scholar 

  14. Wahab F, Atika B, Ullah F et al (2018) Metabolic impact on the hypothalamic kisspeptin-kiss1r signaling pathway. Front Endocrinol 9:123

    Article  Google Scholar 

  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):133–140

    Article  PubMed  Google Scholar 

  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):11324–11329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):222–226

    Article  CAS  PubMed  Google Scholar 

  18. Cannavo S, Curtò L, Trimarchi F (2001) Exercise-related female reproductive dysfunction. J Endocrinol Invest 24:823–832

    Article  CAS  PubMed  Google Scholar 

  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.e1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):976–981

    Article  PubMed  Google Scholar 

  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 36:812–815

    CAS  PubMed  Google Scholar 

  22. Böttcher B, Seeber B, Leyendecker G, Wildt L (2017) Impact of the opioid system on the reproductive axis. Fertil Steril 108(2):207–213

    Article  PubMed  CAS  Google Scholar 

  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 12:1720

    Article  CAS  PubMed  Google Scholar 

  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):963–967

    Article  CAS  PubMed  Google Scholar 

  25. Mircea CN, Lujan ME, Pierson RA (2007) Metabolic fuel and clinical implications for female reproduction. J Obstet Gynaecol Can 29(11):887–902

    Article  PubMed  Google Scholar 

  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 48:37–49

    Article  CAS  PubMed  Google Scholar 

  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):1–8

    Google Scholar 

  28. Mastorakos G, Pavlatou M, Diamanti-Kandarakis E, Chrousos GP (2005) Exercise and the stress system. Hormones 4(2):73–89

    PubMed  Google Scholar 

  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):433–448

    Article  PubMed  Google Scholar 

  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 99:4037–4050

    Article  PubMed  CAS  Google Scholar 

  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 88:297–311

    Article  CAS  PubMed  Google Scholar 

  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):74–85

    Article  CAS  PubMed  Google Scholar 

  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):987–997

    Article  CAS  PubMed  Google Scholar 

  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 48:289

    Article  PubMed  Google Scholar 

  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):491–497

    Article  PubMed  Google Scholar 

  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 124:413–419

    Article  CAS  PubMed  Google Scholar 

  37. Haddad PM, Wieck A (2004) Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 64(20):2291–2314

    Article  CAS  PubMed  Google Scholar 

  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):42–51

    Article  PubMed  CAS  Google Scholar 

  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):361–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Smith SM (2008) The impact of hyperprolactinaemia on sexual function in patients with psychosis. J Psychopharmacol 22(2 Suppl):63–69

    Article  PubMed  Google Scholar 

  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):383–386

    Article  PubMed  Google Scholar 

  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 45:25–34

    Article  CAS  PubMed  Google Scholar 

  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):3279–3297

    Article  CAS  PubMed  Google Scholar 

  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):193–200

    Article  PubMed  Google Scholar 

  45. Arya DK (1994) Extrapyramidal symptoms with selective serotonin reuptake inhibitors. Br J Psychiatry 165(6):728–733

    Article  CAS  PubMed  Google Scholar 

  46. Nicholas L, Dawkins K, Golden RN (1998) Psychoneuroendocrinology of depression: prolactin. Psychiatr Clin North Am 21(2):341–358

    Article  CAS  PubMed  Google Scholar 

  47. Cam B, Karldere T (2014) Amenorrhea associated with duloxetine: two case reports. J Clin Psychopharmacol 34(4):522–523

    Article  PubMed  Google Scholar 

  48. Anand VS (1985) Clomipramine–induced galactorrhoea and amenorrhoea. Br J Psychiatry 147:87–88

    Article  CAS  PubMed  Google Scholar 

  49. International Narcotics Control Board (INCB). Narcotic drugs technical report: Estimates world requirements for 2018—statistics for 2016. https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2017/Narcotic_drugs_technical_publication_2017.pdf. Accessed 29 August 2018

  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):1644–1656

    Article  PubMed  Google Scholar 

  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):856–864

    Article  PubMed  Google Scholar 

  52. European Drug Report 2017: trends and developments; EMCDDA, Lisbon, June 2017. http://www.emcdda.europa.eu/publications/edr/trends-developments/2017. Accessed 29 August 2018

  53. Smith HS, Elliott JA (2012) Opioid-induced androgen deficiency (OPIAD). Pain Physician 15(3 Suppl):ES145–ES156

    PubMed  Google Scholar 

  54. O’Rourke TK Jr, Wosnitzer MS (2016) Opioid-induced androgen deficiency (OPIAD): diagnosis, management, and literature review. Curr Urol Rep 17(10):76

    Article  PubMed  Google Scholar 

  55. Orstead KM, Spies HG (1987) Inhibition of hypothalamic gonadotropin-releasing hormone release by endogenous opioid peptides in the female rabbit. Neuroendocrinology 46(1):14–23

    Article  CAS  PubMed  Google Scholar 

  56. Gabriel SM, Simpkins JW, Kalra SP (1983) Modulation of endogenous opioid influence on luteinizing hormone secretion by progesterone and estrogen. Endocrinology 113(5):1806–1811

    Article  CAS  PubMed  Google Scholar 

  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):2215–2222

    Article  CAS  PubMed  Google Scholar 

  58. Daniell HW (2008) Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain 9(1):28–36

    Article  CAS  PubMed  Google Scholar 

  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):98–132

    Article  CAS  PubMed  Google Scholar 

  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):38–43

    Article  CAS  PubMed  Google Scholar 

  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 10152:1015–1035

    Google Scholar 

  62. Rachdaoui N, Sarkar DK (2013) Effects of alcohol on the endocrine system. Endocrinol Metab Clin N Am 42(3):593–615

    Article  Google Scholar 

  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):551–560

    Article  CAS  PubMed  Google Scholar 

  64. Mendelson JH, Mello NK (1988) Chronic alcohol effects on anterior pituitary and ovarian hormones in healthy women. J Pharmacol Exp Ther 245(2):407–412

    CAS  PubMed  Google Scholar 

  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):975–980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1420–1429

    Article  CAS  PubMed  Google Scholar 

  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):2337–2342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Block GD, Yamamoto ME, Mallick A, Styche A (1993) Effects on pubertal hormones by ethanol abuse in adolescents. Alcohol Clin Exp Res 17:505

    Google Scholar 

  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):1847–1856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):516–521

    Article  PubMed  CAS  Google Scholar 

  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):505–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):13815

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Bauer J, Cooper-Mahkorn D (2008) Reproductive dysfunction in women with epilepsy: menstrual cycle abnormalities, fertility, and polycystic ovary syndrome. Int Rev Neurobiol 83:135–155

    Article  PubMed  Google Scholar 

  74. Verrotti A, D’Egidio C, Mohn A, Coppola G, Parisi P, Chiarelli F (2011) Antiepileptic drugs, sex hormones, and PCOS. Epilepsia 52(2):199–211

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge Mrs. Racca Anna (annaracca@gmail.com) for her contribution to this paper.

Funding

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

Author information

Authors and Affiliations

  1. Endocrinology Unit, Department of Biomedical Sciences, Humanitas University and Humanitas Research Hospital, Rozzano, Italy

    A. Lania & W. Vena

  2. Division of Endocrinology Diabetology and Metabolism, S. Croce and Carle Hospital, Cuneo, Italy

    L. Gianotti

  3. University of Ferrara, Ferrara, Italy

    I. Gagliardi, M. Bondanelli & M. R. Ambrosio

Authors
  1. A. Lania
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Gianotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Gagliardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Bondanelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W. Vena
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. R. Ambrosio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W. Vena.

Ethics declarations

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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lania, A., Gianotti, L., Gagliardi, I. et al. Functional hypothalamic and drug-induced amenorrhea: an overview. J Endocrinol Invest 42, 1001–1010 (2019). https://doi.org/10.1007/s40618-019-01013-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-019-01013-w

Keywords

Search

Navigation