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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
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
Fourman LT, Fazeli PK (2015) Neuroendocrine causes of amenorrhea – an update. J Clin Endocrinol Metab 100:812–824
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
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
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
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
Rivier C, Rivier V, Vale W (1986) Stress-induced inhibition of reproductive functions: role of endogenous corticotropin- releasing factor. Science 231:607–609
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
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
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
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
Kamel F, Kubajak CL (1987) Modulation of gonadotropic secretion by corticosterone interaction with gonadal steroids and mechanism of action. Endocrinology 121:561–568
Gala RR (1990) The physiology and mechanisms of the stress- induced changes in prolactin secretion in rat. Life Sci 46:1407–1410
Cannavò S, Curtò L, Trimarchi F (2001) Exercise-related female reproductive dysfunction. J Endocrinol Invest 24:823–832
American Psychiatric Association (1995) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC
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
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
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
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
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
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
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
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
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
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
Quigley ME, Yen SSC (1980) The role of endogenous opiates on LH secretion during the menstrual cycle. J Clin Endocrinol Metab 51:179–181
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
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
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
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
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
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
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
Yen SSC (1984) Opiates and reproduction: studies in women. In: Delitala G (ed) Opioid modulation of endocrine function. Raven, New York, pp 191–199
Kalra SP, Kalra PS (1984) Neural regulation of luteinizing hormone secretion in the rat. Endocr Rev 4:311–351
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
Frisch RE (1984) Body fat, puberty and fertility. Biol Rev 59:161–188
Reid RL, Van Vugt DA (1987) Weight-related changes in reproductive function. Fertil Steril 48:905–13
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
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
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
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
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
Frish RE, Wyshak G, Vincent L (1980) Delayed menarche and amenorrhea in ballet dancers. N Engl J Med 303:17–19
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
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
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
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
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
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
Imaki T, Vale W (1993) Chordiazepoxide attenuates stress-induced accumulation of corticotropin releasing factor mRNA in paraventricular nucleous. Brain Res 623:223–228
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
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
Esposito G, Luparini MR (1997) Pivagabine: a novel psychoactive drug. Arzneimittelforschung 47:1306–1309
Scapagnini U, Matera M (1997) Effects of pivagabine on psychophysical performance and behavioural response in experimental models of stress. Arzneimittelforschung 47:1310–1317
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
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
Ferin M (1999) Stress and the reproductive cycle. J Clin Endocrinol Metab 84:1768–1774
Cameron JL (1996) Regulation of reproductive hormone secretion in primates by short-term changes in nutrition. Rev Reprod 1:117–126
Giglioli B, Multinu A, Lai VR (1997) Role of pivagabine in the treatment of climacteric syndrome. Arzneimittelforschung 47:1317–1321
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
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
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
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
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
Marcus MD, Loucks TL, Berga SL (2001) Psychological correlates of functional hypothalamic amenorrhea. Fertil Steril 76(2):310–316
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
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights 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)