Abstract
No specific markers of the severity or prognosis of hypothalamic-pituitary-gonadal axis disturbances associated with weight loss amenorrhea (WLA) are currently available. Circulating nitric oxide (NO), which is involved in the control of the reproductive function in women and is correlated with body mass index (BMI), at least in over-weight and obese subjects, might be a marker of the severity and/or progression of WLA. To test this hypothesis, we studied circulatingNO levels in 11 women (age 27.1±1.59 yr) affected by WLA for 5.1±1.0 yr; in all patients hormonal therapy had been discontinued 10.0±3.15 months earlier. NO, determined by measuring its stable catabolite nitrite/nitrates (NOx), was compared with some clinical parameters and sex hormone levels. Subsequently, changes in NOx during pulsatile GnRH therapy (120 ng/kg bw sc every 120 min) were compared with the clinical and hormonal data. Fifteen normal women (27.3±1.6 yr) served as a control group. NOx was significantly lower (p<0.01) in WLA (8.8±2.0 μmol/l) than in control (18.7±2.5 μmol/l) subjects. No correlation between NOx and clinical parameters was noted in either WLA or control subjects. As a result of GnRH therapy, ovulatory cycles reappeared in 91% of WLA women. During the 1st cycle, periovulatory 17β-estradiol levels were 110% higher than those noted in controls. During the 2nd cycle, NOx showed a slight increase in the follicular phase (+12% vs 1st cycle) followed by a drop during the luteal phase (−40% from the follicular phase); indeed, at that time, NOx correlated negatively with progesterone in both WLA (rS −0.32, p<0.05) and control (rS −0.48, p<0.05) subjects. NOx correlated with BMI at the time of the 2nd cycle (rS 0.71, p<0.05) In conclusion, this study shows that in WLA patients: 1) NO is low, as in other conditions of chronic anovulation; 2) it does not correlate with clinical data; 3) it takes longer than sex steroids to increase and show normal-like fluctuations; 4) its fluctuations are restored earlier in patients with greater BMI.
Similar content being viewed by others
References
Munoz MT, Argente J. Anorexia nervosa in female adolescents: endocrine and bone mineral density disturbances. Eur J Endocrinol 2002, 147: 275–86.
Shukovski L, Tsafiriri T. The involvement of nitric oxide in the ovulatory process in the rat. Endocrinology 1995, 40: 2287–90.
Yamahuchi J, Miyazaki T, Iwasaki S, et al. Effects of nitric oxide on ovulation and ovarian steroidogenesis and prostaglandin production in the rabbit. Endocrinology 1997, 138: 3630–7.
Giusti M, Fazzuoli L, Cavallero D, Valenti S. Circulating nitric oxide changes throughout the menstrual cycle in healthy women and in women affected by pathological hyperprolactinaemia on dopamine agonist therapy. Gynecol Endocrinol 2002, 16: 407–12.
Shaarawy M, Nafei S, Abul-Nasr A, et al. Circulating nitric oxide levels in galactorrheic, hyperprolatinemic, amenorrheic women. Fertil Steril 1997, 68: 454–9.
Piccinini F, Rovatti L, Zanni A, Cagnacci A, Volpe A, Facchinetti F. Indirect evidence that estrogen replacement therapy stimulates nitric oxide synthase in postmenopausal women. Gynecol Endocrinol 2000, 14: 142–6.
Stacey E, Korkia P, Hukkanen MV, Polak JM, Rutherford OM. Decreased nitric oxide levels and bone turnover in amenorrheic athletes with spinal osteopenia. J Clin Endocrinol Metab 1998, 83: 3056–61.
Wenger NK, Speroff L, Packard B. Cardiovascular health and diseases in women. N Engl J Med 1993, 329: 247–56.
Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial function in obese women after weight loss over one year. Circulation 2002, 105: 804–9.
Roberts CK, Vaziri ND, Barnard RJ. Effect of diet and exercise intervention on blood pressure, insulin, oxidative stress and nitric oxide availability. Circulation 2002, 106: 2530–2.
Giusti M, Cavagnaro P, Traverso L, Torre R. The role of pulsatile LHRH therapy in women: the treatment of delayed puberty and of hypothalamic amenorrhea. Recenti Prog Med 1990, 81: 724–32.
Valenti S, Giusti M, Guido R, Cavallero D, Giordano G. Opioid tonus and luteinizing hormone secretion in anorexia nervosa: priming effect with serotonin precursor L-5-hydroxytryptophan during pulsatile gonadotropin-releasing hormone administration. Biol Psychiatry 1994, 36: 609–15.
Wang J, Brown MA, Tam SH, Chan MC, Whitworth JA. Effects of diet on measurement of nitric oxide metabolites. Clin Exp Pharmacol Physiol 1997, 24: 418–20.
Imthurn B, Rosselli M, Jaeger AW, et al. Differential effects of hormone-replacement therapy on endogenous nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol valerate and cyproterone acetate or medroxyprogesterone acetate. J Clin Endocrinol Metab 1997, 82: 388–92.
Vasquez JM, Greenblatt RB. Pituitary responsiveness to luteinizing hormone-releasing hormone in different reproductive disorders. A review. J Reprod Med 1985, 30: 591–600.
Ohl J, Lefebvre-Maunoury C, Wittemer C, Nisand G, Laurent MC, Hoffman P. Nitric oxide donors for patients undergoing IVF. A prospective, double-blind, randomized, placebo-controlled trial. Hum Reprod 2002, 17: 2615–20.
Tarlatzis BC, Zepridis L, Grimbizis G, Bontis J. Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update 2003, 9: 61–76.
McCann SM, Haens G, Mastronardi C, et al. The role of nitric oxide (NO) in control of LHRH release that mediates gonadotropin release and sexual behaviour. Curr Pharm Des 2003, 9: 381–90.
Valenti S., Fazzuoli L, Giusti M. Circulating nitric oxide levels increase after anti-androgen treatment in male-to-female transsexuals. J Endocrinol Invest 2003, 26: 522–6.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Valenti, S., Cavallero, D., Fazzuoli, L. et al. Circulating nitric oxide in women affected by weight loss amenorrhea during pulsatile gonadotropin-releasing hormone therapy. J Endocrinol Invest 28, 773–778 (2005). https://doi.org/10.1007/BF03347565
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03347565