GnRH

L’ormone che induce il rilascio delle gonadotropine (GnRH) è il principale regolatore della cascata ormonale coivolta nella riproduzione ed è stato isolato dall’area preottica dell’ ipotalamo di mammiferi. E’ un decapeptide ed è rilasciato nel circolo sanguigno a livello della eminenza mediana in modo pulsatile di quantità precise dagli assoni di neuroni i cui terminali sono localizzati nell’ipofisi anteriore. Il rilascio di questo ormone avviene ogni 30-120 minuti il quale regola la biosintesi e la liberazione di LH e FSH dall’ipofisi anteriore. La frequenza di rilascio del GnRH è massima durante l’ovulazione mentre è ridotta al minimo durante la fase luteale. La secrezione di GnRH e’ controllata negativamente da steroidi gonadici mentre neurotrasmettitori ad azione inibitoria quali il GABA, aminoacidi eccitatori (acido glutammico), peptidi oppioidi endogeni, monoamine del sistema noradrenergico, dopaminergico e serotoninergico, acetilcolina, melatonina, ossitocina modulano il rilascio di GnRH.

Sequenza di eventi causati dal GnRH

Ruolo degli aminoacidi nella sequenza del GnRH

GnRH agonisti

GnRH antagonisti

Applicazioni cliniche dei GnRH agonisti e antagonisti

Background Systematic reviews have found that luteinizing hormone – releasing hormone (LHRH) agonists are effectivein treating premenopausal women with early breast cancer. Methods We conducted long-term follow-up (median 12 years) of 2706 women in the Zoladex In premenopausal Patients (ZIPP), which evaluated the LHRH agonist goserelin (3.6 mg injection every 4 weeks) and tamoxifen (20 or 40 mg daily), given for 2 years. Women were randomly assigned to receive each therapy alone, both, or neither, after primary therapy (surgery with or without radiotherapy/chemotherapy). Hazard ratios and absolute risk differences were used to assess the effect of goserelin treatment on event-free survival (breast cancer recurrence, new tumor or death), overall survival, risk of recurrence of breast cancer, and risk of dying from breast cancer, in the presence or absence of tamoxifen. Results Fifteen years after the initiation of treatment, for every 100 women not given tamoxifen, there were 13.9 (95% confidence interval [CI] = 17.5 to 19.4) fewer events among those who were treated with goserelin compared with those who were not treated with goserelin. However, among women who did take tamoxifen, there were 2.8 fewer events (95% CI = 7.7 fewer to 2.0 more) per 100 women treated with goserelin compared with those not treated with goserelin. The risk of dying from breast cancer was also reduced at 15 years: For every 100 women given goserelin, the number of breast cancer deaths was lower by 2.6 (95% CI = 6.6 fewer to 2.1 more) and 8.5 (95% CI = 2.2 to 13.7) in those who did and did not take tamoxifen, respectively, although in the former group the difference was not statistically significant. Conclusions Two years of goserelin treatment was as effective as 2 years of tamoxifen treatment 15 years after starting therapy. In women who did not take tamoxifen, there was a large benefit of goserelin treatment on survival and recurrence, and in women who did take tamoxifen, there was a marginal potential benefit on these outcomes when goserelin was added.

Background: The usefulness of long-term, low-dose gonadotropin-releasing hormone agonist (GnRHa; buserelin acetate) therapy, so-called draw-back therapy, for the treatment of adenomyosis was investigated . Material/Methods: A retrospective observational study was conducted covering the period between January 2003 and March 2008. The subjects consisted of 12 patients with adenomyosis who underwent draw-back therapy for 2 years and had previously received GnRHa. GnRHa was initiated at 900 μg/day (6 nasal sprays/day). When the CA-125 level normalized, the GnRHa dosage was adjusted to 150–750 μg/day to achieve a plasma estradiol (E2) concentration of 20–50 pg/ml (i.e., the therapeutic window). Pain during withdrawal bleeding and chronic pelvic pain were assessed using a visual analogue scale. In addition, bone mineral density (BMD) of the lumbar vertebrae was measured using dualenergy X-ray absorptiometry. Results: The mean GnRHa dose during draw-back therapy was 435 μg/day (2.9 nasal sprays/day). The mean E2 level during draw-back therapy was 36.3±14.3 pg/ml. The intensity of chronic pelvic pain was signifi cantly lower during draw-back therapy than before draw-back therapy, and was nearly eliminated in many patients (4.8±1.2 vs. 0.6±0.7, respectively [p=0.000]). Compared to the severity of vasomotor symptoms during previous regular GnRHa therapy, the severity of vasomotor symptoms during draw-back therapy was signifi cantly lower (3.8±0.7 vs 1.1±0.7, respectively [p=0.000]). The decrease in BMD during a 6-month course of treatment was 0.96±0.9%. Conclusions: GnRHa draw-back therapy allowed maintenance of plasma E2 levels within the therapeutic window. GnRHa can thus be administered for long periods of time while maintaining therapeutic effects on adenomyosis and suppressing adverse events.

In the long-acting GnRHa group (GroupL), patients received 3 In the long-acting GnRHa group (GroupL), patients received 3.6 mg of subcutaneous goserelin acetate (Zoladex􀋓 depot, AstraZeneca Ltd., Kings Langley, U.K.). In the short-acting GnRHa group (Group S), patients were subcutaneously administered 0.5 mg of buserelin acetate (Superfact􀋓, Hoechst AG, Frankfurt, Germany) or leuprolide acetate (Lucrin􀋓, Labratories Abbot France, St. Remy Sur Avre, France) daily at hospital before human chorionic gonadotrophin (hCG) administration.

During ovarian stimulation gonadotrophin-releasing hormone (GnRH) analogues are co-administered in order to prevent premature luteinizing hormone (LH) surges. Premature LH surges are observed in about 20% of stimulated cycles without using GnRH analogues [2,3]. Avoiding the adverse effects of elevated LH-levels, first GnRH agonist analogues were used to supplement the gonadotrophin stimulation. The continuous administration of GnRH agonists causes gonadotrophin suppression through down-regulation and desensitization of the GnRH receptors in the pituitary gland after an initial short period of gonadotrophin hypersecretion [4].

In this study, we aim to evaluate the clinical outcome and patient’s convenience of single administration of long-acting GnRHa (goserelin depot) as compared with multiple daily administrations of short-acting GnRHa (buserelin or leuprorelin).