Skip to main content

Pharmacological and Integrative Treatment of Stress-Induced Hypothalamic Amenorrhea

  • Chapter
  • First Online:
Book cover Frontiers in Gynecological Endocrinology

Part of the book series: ISGE Series ((ISGE))

Abstract

Among secondary amenorrheas, hypothalamic amenorrhea (HA) is the one with no evidence of endocrine/systemic causal factors. HA is mainly related to various stressors affecting neuroendocrine control of the reproductive axis. In clinical practice, HA is mainly associated with metabolic, physical, or psychological stress. Stress is the adaptive response of our body through all its homeostatic systems, to external and/or internal stimuli that activate specific and nonspecific physiological pathways. HA occurs generally after severe stressed conditions/situations such as dieting, heavy training, or intense emotional events, all situations that can induce amenorrhea with or without body weight loss and HA is a secondary amenorrhea with a diagnosis of exclusion. In fact, the diagnosis is essentially based on a good anamnestic investigation. It has to be investigated using the clinical history of the patient: occurrence of menarche, menstrual cyclicity, time and modality of amenorrhea, and it has to be excluded any endocrine disease or any metabolic (i.e., diabetes) and systemic disorders. It is necessary to identify any stressed situation induced by loss, family or working problems, weight loss or eating disorders, or physical training or agonist activity. Peculiar, though not specific, endocrine investigations might be proposed but no absolute parameter can be proposed since HA is greatly dependent from individual response to stressors and/or the adaptive response to stress. This chapter aims to give insights into diagnosis and putative therapeutic strategies.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Batrinos ML, Panitsa-Faflia C, Courcoutsakis N, Chatzipavlou V (1990) Incidence, type, and etiology of menstrual disorders in the age group 12–19 years. Adolesc Pediatr Gynecol 3:149–153

    Article  Google Scholar 

  2. Fourman LT, Fazeli PK (2015) Neuroendocrine causes of amenorrhea – an update. J Clin Endocrinol Metab 100:812–824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Frisch RE, McArthur JW (1974) Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 185:949–951

    Article  CAS  PubMed  Google Scholar 

  4. Veldhuis JD, Evans WS, Demers LM, Thorner MO, Wakat D, Rogol AD (1985) Altered neuroendocrine regulation of gonadotropin secretion in women distance runners. J Clin Endocrinol Metab 61:557–562

    Article  CAS  PubMed  Google Scholar 

  5. Cameron JL, Helmreich DL, Schreihofer DA (1993) Modulation of reproductive hormone secretion by nutritional intake: stress signals versus metabolic signals. Hum Reprod 8:162–167

    Article  CAS  PubMed  Google Scholar 

  6. Facchinetti F, Fava M, Fioroni L, Genazzani AD, Genazzani AR (1993) Stressful life events and affective disorders inhibit pulsatile LH secretion in hypothalamic amenorrhea. Psychoneuroendocrinology 18:397–404

    Article  CAS  PubMed  Google Scholar 

  7. Rivier C, Rivier V, Vale W (1986) Stress-induced inhibition of reproductive functions: role of endogenous corticotropin- releasing factor. Science 231:607–609

    Article  CAS  PubMed  Google Scholar 

  8. Petraglia F, Sutton S, Vale W, Plotsky P (1987) Corticotropin-releasing factor decreases plasma luteinizing hormone levels in female rats by inhibiting gonadotropin- releasing-hormone release into hypophyseal-portal circulation. Endocrinology 120:1083–1088

    Article  CAS  PubMed  Google Scholar 

  9. Genazzani AD, Petraglia F, Gastaldi M, Volpogni C, D’Ambrogio G, Facchinetti F, Genazzani AR (1993) FSH secretory pattern and degree of concordance with LH in amenorrheic, fertile and postmenopausal women. Am J Physiol 264:E776–E781

    CAS  PubMed  Google Scholar 

  10. Petraglia F, Vale W, Rivier C (1986) Opioids act centrally to modulate stress-induced decrease in luteinizing hormone in the rat. Endocrinology 119:2445–2450

    Article  CAS  PubMed  Google Scholar 

  11. Ringstrom SJ, Suter D, D’Agostino J, Hoestler JP, Scwartz NB (1991) Effects of glucocorticoids on the hypothalamic-pituitary- gonadal axis. In: Genazzani AR, Nappi G, Petraglia F, Martignoni E (eds) Stress and related disorders from adaptation to dysfunction. Parthenon Publ, Carnforth, pp 297–305

    Google Scholar 

  12. Kamel F, Kubajak CL (1987) Modulation of gonadotropic secretion by corticosterone interaction with gonadal steroids and mechanism of action. Endocrinology 121:561–568

    Article  CAS  PubMed  Google Scholar 

  13. Gala RR (1990) The physiology and mechanisms of the stress- induced changes in prolactin secretion in rat. Life Sci 46:1407–1410

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  15. American Psychiatric Association (1995) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC

    Google Scholar 

  16. Genazzani AD, Petraglia F, Fabbri G, Monzani A, Montanini V, Genazzani AR (1990) Evidence of luteinizing hormone secretion in hypothalamic amenorrhea associated with weight loss. Fertil Steril 54:222–226

    Article  CAS  PubMed  Google Scholar 

  17. Vigersky RA, Andersen AE, Thompson RH, Lauriaux DL (1977) Hypothalamic dysfunction in secondary amenorrhea associated with simple weight loss. N Engl J Med 297:1141–1146

    Article  CAS  PubMed  Google Scholar 

  18. Berga SL, Mortola SF, Girton L, Suh B, Laughlin G, Pham P, Yen SSC (1989) Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 68:301–308

    Article  CAS  PubMed  Google Scholar 

  19. Genazzani AD, Petraglia F, Benatti R, Montanini V, Algeri I, Volpe A, Genazzani AR (1991) Luteinizing hormone (LH) secretory burst duration is independent from LH, prolactin, or gonadal steroid plasma levels in amenorrheic women. J Clin Endocrinol Metab 72:1220–1225

    Article  CAS  PubMed  Google Scholar 

  20. Genazzani AD, Petraglia F, Gastaldi M, Volpogni C, Surico N, Genazzani AR (1994) Episodic release of prolactin in women with weight loss-related amenorrhea. Gynecol Endocrinol 8:95–100

    Article  CAS  PubMed  Google Scholar 

  21. Fioroni L, Fava M, Genazzani AD, Facchinetti F, Genazzani AR (1994) Life events impact in patients with secondary amenorrhea. J Psychosom Res 6:617–622

    Article  Google Scholar 

  22. Quigley ME, Sheehan KL, Casper RF, Yen SSC (1980) Evidence for increased dopaminergic and opioid activity in patients with hypothalamic hypogonadotropic amenorrhea. J Clin Endocrinol Metab 50:949–954

    Article  CAS  PubMed  Google Scholar 

  23. Petraglia F, Panerai AE, Rivier C, Cocchi D, Genazzani AR (1988) Opioid control of gonadotropin secretion. In: Genazzani AR, Montemagno U, Nappi C, Petraglia F (eds) Brain and female reproductive function. The Parthenon Publishing Group, Carnforth, pp 65–72

    Google Scholar 

  24. Khoury SA, Reame NE, Kelch RP, Marschall JC (1987) Diurnal patterns of pulsatile luteinizing hormone secretion in hypothalamic amenorrhea: reproducibility and responses to opiate blockade and an a2-adrenergic agonist. J Clin Endocrinol Metab 64:755–762

    Article  CAS  PubMed  Google Scholar 

  25. Petraglia F, D’Ambrogio G, Comitini G, Facchinetti F, Volpe A, Genazzani AR (1985) Impairment of opioid control of luteinizing hormone secretion in menstrual disorders. Fertil Steril 43:535–540

    Article  Google Scholar 

  26. Quigley ME, Yen SSC (1980) The role of endogenous opiates on LH secretion during the menstrual cycle. J Clin Endocrinol Metab 51:179–181

    Article  CAS  PubMed  Google Scholar 

  27. Snowden UE, Khan-Dawood SF, Dawood MY (1984) The effect of naloxone on endogenous opioid regulation of pituitary gonadotropins and prolactin during the menstrual cycle. J Clin Endocrinol Metab 59:292–296

    Article  Google Scholar 

  28. Melis GB, Paoletti AM, Gambacciani M, Mais V, Fioretti P (1984) Evidence that estrogens inhibit LH secretion through opiods in postmenopausal women using naloxone. Neuroendocrinology 39:60–64

    Article  CAS  PubMed  Google Scholar 

  29. Lightman SL, Jacobs HS, Magnuire AK, Mc Garrick G, Jeffcoate SL (1981) Constancy of opioid control of luteinizing hormone in different pathophysiological states. J Clin Endocrinol Metab 52:1260–1263

    Article  CAS  PubMed  Google Scholar 

  30. Veldhuis JD, Kulin HE, Warner BA, Santner SJ (1982) Responsiveness of gonadotropin secretion to infusion of opiate- receptor antagonist in hypogonadotropic individuals. J Clin Endocrinol Metab 55:649–653

    Article  CAS  PubMed  Google Scholar 

  31. Remorgida V, Venturini PL, Anserini P, Salerno E, De Cecco L (1990) Naltrexone in functional hypothalamic amenorrhea and in the normal luteal phase. Obstet Gynecol 76:1115–1120

    CAS  PubMed  Google Scholar 

  32. Genazzani AD, Gastaldi M, Petraglia F, Battaglia C, Surico N, Volpe A, Genazzani AR (1995) Naltrexone administration modulates the neuroendocrine control of luteinizing hormone secretion in hypothalamic amenorrhea. Hum Reprod 10:2868–2871

    Article  CAS  PubMed  Google Scholar 

  33. Genazzani AD, Petraglia F, Gastaldi M, Volpogni C, Gamba O, Genazzani AR (1995) Naltrexone treatment restores menstrual cycles in patients with weight loss-related amenorrhea. Fertil Steril 64:951–956

    Article  CAS  PubMed  Google Scholar 

  34. Yen SSC (1984) Opiates and reproduction: studies in women. In: Delitala G (ed) Opioid modulation of endocrine function. Raven, New York, pp 191–199

    Google Scholar 

  35. Kalra SP, Kalra PS (1984) Neural regulation of luteinizing hormone secretion in the rat. Endocr Rev 4:311–351

    Article  Google Scholar 

  36. Genazzani AD, Strucchi C, Malavasi B, Tortolani F, Vecchi F, Luisi S, Petraglia F (2001) Effects of cyproheptadine, a serotonin receptor antagonist, on endocrine parameters in weight-loss related amenorrhea. Gynecol Endocrinol 15:279–285

    CAS  PubMed  Google Scholar 

  37. Frisch RE (1984) Body fat, puberty and fertility. Biol Rev 59:161–188

    Article  CAS  PubMed  Google Scholar 

  38. Reid RL, Van Vugt DA (1987) Weight-related changes in reproductive function. Fertil Steril 48:905–13

    Article  CAS  PubMed  Google Scholar 

  39. Cameron JL, Nosbich C (1991) Suppression of pulsatile luteinizing hormone and testosterone secretion during short term food restriction in the adult male rhesus monkey (Macaca Mulatta). Endocrinology 128:1532–1540

    Article  CAS  PubMed  Google Scholar 

  40. Cameron JL, Weltzin T, McConaha C, Helmreich DL, Kaye WH (1991) Suppression of reproductive axis activity in men undergoing a 48 hour fast. J Clin Endocrinol Metab 73:35–41

    Article  CAS  PubMed  Google Scholar 

  41. Genazzani AD, Petraglia F, Volpogni C, Gastaldi M, Pianazzi F, Montanini V, Genazzani AR (1993) Modulatory role of estrogens and progestins on growth hormone episodic release in women with hypothalamic amenorrhea. Fertil Steril 60:465–470

    Article  CAS  PubMed  Google Scholar 

  42. Genazzani AD, Petraglia F, Gastaldi M, Volpogni C, Gamba O, Massolo F, Genazzani AR (1994) Evidence suggesting an additional control mechanism regulating episodic secretion of luteinizing hormone and follicle stimulating hormone in pre- pubertal children and post-menopausal women. Hum Reprod 9:1807–1812

    Article  CAS  PubMed  Google Scholar 

  43. Genazzani AD, Massolo F, Ferrari E, Gandolfi A, Petraglia F, Genazzani AR (1996) Long-term GnRH-agonist administration revealed a GnRH-independent mechanism stimulating FSH discharge in humans. Eur J Endocrinol 134:77–83

    Article  CAS  PubMed  Google Scholar 

  44. Frish RE, Wyshak G, Vincent L (1980) Delayed menarche and amenorrhea in ballet dancers. N Engl J Med 303:17–19

    Article  Google Scholar 

  45. Genazzani AD, Petraglia F, Algeri I, Gastaldi M, Calvani M, Botticelli G, Genazzani AR (1991) Acetyl-L-Carnitine as a possible drug in the treatment of hypothalamic amenorrhea. Acta Obstet Gynecol Scand 70:487–492

    Article  CAS  PubMed  Google Scholar 

  46. Genazzani AD, Lanzoni C, Ricchieri F, Santagni S, Rattighieri E, Chierchia E, Monteleone P, Jasonni VM (2011) Acetyl-L-Carnitine (ALC) administration positively affects reproductive axis in hypogonadotropic women with functional hypothalamic amenorrhea. J Endocrinol Invest 34:287–291

    Article  CAS  PubMed  Google Scholar 

  47. Biggio G, Sanna E, Serra M, Costa E (1995) GABAa receptors and anxiety. In: Biaggio G (ed) Advances in biochemistry and psychopharmacology, vol 48. Raven, New York

    Google Scholar 

  48. Biggio G, Concas A, Corda MG, Giorgi O, Sanna E, Serra M (1990) GABAergic and dopaminergic transmission in the rat cerebral cortex: effect of stress, anxiolytic and anxiogenic drugs. Pharmacol Ther 48:121–142

    Article  CAS  PubMed  Google Scholar 

  49. Concas A, Serra M, Atsoggiu T, Biggio G (1988) Foot shock and anxuiogenic beta-carbolines increase t-[35S]-butylbicyclophosphorotionate binding in the rat cerebral cortex, an effect opposite to anxiolytic and gamma-aminobutyric acid mimetics. J Neurochem 51:1868–1876

    Article  CAS  PubMed  Google Scholar 

  50. Kalogeras KT, Calogero AE, Kuribayiashi T, Khan I, Gallucci WT, Kling MA, Chrousos GP, Gold PW (1990) In vitro and in vivo effects of triazolobenzodiazepine alprazolam and hypothalamic-pituitary-adrenal function: pharmacological and clinical implications. J Clin Endocrinol Metab 70:1462–1471

    Article  CAS  PubMed  Google Scholar 

  51. Imaki T, Vale W (1993) Chordiazepoxide attenuates stress-induced accumulation of corticotropin releasing factor mRNA in paraventricular nucleous. Brain Res 623:223–228

    Article  CAS  PubMed  Google Scholar 

  52. Imaki T, Xiao-Quan W, Shibasaki Y, Harada S, Chikada N, Takahashi C, Naruse M, Demura H (1995) Chlordiazepoxide attenuates stress-induced activation of neurons, corticotropin-releasing factor (CRF) gene transcription and CRF biosynthesis in the paraventricular nucleus (PVN). Mol Brain Res 32:261–270

    Article  CAS  PubMed  Google Scholar 

  53. Galzigna L, Garbin L, Bianchi M, Marzotto A (1978) Properties of two derivatives of gamma-aminobutyric acid (GABA) capable of abolishing Cardiazol- and bicuculline-induced convulsions in the rat. Arch Int Pharmacodyn Ther 235:73–85

    CAS  PubMed  Google Scholar 

  54. Esposito G, Luparini MR (1997) Pivagabine: a novel psychoactive drug. Arzneimittelforschung 47:1306–1309

    CAS  PubMed  Google Scholar 

  55. Scapagnini U, Matera M (1997) Effects of pivagabine on psychophysical performance and behavioural response in experimental models of stress. Arzneimittelforschung 47:1310–1317

    CAS  PubMed  Google Scholar 

  56. Serra M, Concas A, Mostallino MC, Chessa MF, Stomati M, Petraglia F, Genazzani AR, Biggio G (1999) Antagonism by pivagabine of stress-induced changes in GABAa receptor function and corticotropin-releasing factor concentrations in rat brain. Psychoneuroendocrinology 24:269–284

    Article  CAS  PubMed  Google Scholar 

  57. Genazzani AD, Stomati M, Bersi C, Luisi S, Fedalti M, Santuz M, Esposito G, Petraglia F, Genazzani AR (2000) Pivagabine decreases stress-related hormone secretion in women with hypothalamic amenorrhea. J Endocrinol Invest 23:526–532

    Article  CAS  PubMed  Google Scholar 

  58. Ferin M (1999) Stress and the reproductive cycle. J Clin Endocrinol Metab 84:1768–1774

    Article  CAS  PubMed  Google Scholar 

  59. Cameron JL (1996) Regulation of reproductive hormone secretion in primates by short-term changes in nutrition. Rev Reprod 1:117–126

    Article  CAS  PubMed  Google Scholar 

  60. Giglioli B, Multinu A, Lai VR (1997) Role of pivagabine in the treatment of climacteric syndrome. Arzneimittelforschung 47:1317–1321

    Google Scholar 

  61. Barbarino A, Corsello SM, Della Casa S, Tofani A, Sciuto R, Rota CA, Bollanti L, Barini A (1990) Corticotropin-releasing hormone inhibition of growth hormone-releasing hormone- induced growth hormone release in man. J Clin Endocrinol Metab 71:1368–1374

    Article  CAS  PubMed  Google Scholar 

  62. Genazzani AD, Lanzoni C, Ricchieri F, Campedelli A, Rattighieri E, Santagni S, Jasonni VM (2008) Effect of short term sibutramine on gonadotropin spontaneous pulsatile release in normogonadotropinemic amenorrheic subjects. J Chin Clin Med 3:361–369

    CAS  Google Scholar 

  63. Genazzani AD, Gamba O, Petraglia F (1998) Estrogen replacement therapy modulates spontaneous GH secretion but does not affect GH-RH-induced GH response and low T3 syndrome in women with hypothalamic amenorrhea associated to weight-loss. J Endocrinol Invest 21:353–357

    Article  CAS  PubMed  Google Scholar 

  64. Genazzani AR, Facchinetti F, De Leo V, Picciolini E, Franchi F, Parrini D et al (1978) Effect of epimestrol on gonadotropin and prolactin plasma levels and response to luteinizing hormone-releasing hormone/thyrotropin-releasing hormone in secondary amenorrhea and oligomenorrhea. Fertil Steril 30:654–660

    Article  CAS  PubMed  Google Scholar 

  65. Genazzani AD, Meczekalski B, Podfigurna-Stopa A, Santagni S, Rattighieri E, Ricchieri F, Chierchia E, Simoncini T (2012) Estriol administration modulates luteinizing hormone secretion in women with functional hypothalamic amenorrhea. Fertil Steril 97:483–488

    Article  CAS  PubMed  Google Scholar 

  66. Marcus MD, Loucks TL, Berga SL (2001) Psychological correlates of functional hypothalamic amenorrhea. Fertil Steril 76(2):310–316

    Article  CAS  PubMed  Google Scholar 

  67. Berga SL, Marcus MD, Loucks TL, Hlastala S, Ringham R, Krohn MA (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 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alessandro D. Genazzani .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 International Society of Gynecological Endocrinology

About this chapter

Cite this chapter

Genazzani, A.D., Despini, G., Chierchia, E., Benedetti, C., Prati, A. (2016). Pharmacological and Integrative Treatment of Stress-Induced Hypothalamic Amenorrhea. In: Genazzani, A., Tarlatzis, B. (eds) Frontiers in Gynecological Endocrinology. ISGE Series. Springer, Cham. https://doi.org/10.1007/978-3-319-23865-4_9

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-23865-4_9

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-23864-7

  • Online ISBN: 978-3-319-23865-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics