La neurohormona GnRH en la mujer / Neurohormone GnRH in the woman

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Optimizing subcutaneous injection of the gonadotropin-releasing hormone receptor antagonist degarelix.

The gonadotropin-releasing hormone (GnRH) receptor antagonist degarelix has several unique characteristics compared to luteinizing hormone-releasing hormone (LHRH) analogs used in the management of prostate cancer. Notable differences of GnRH receptor antagonists include no flare reaction, and a more rapid suppression of testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate-specific antigen (PSA) compared to LHRH analogs. Despite emerging evidence supporting the use of GnRH receptor antagonists over the more widely used LHRH analogs in the management of prostate cancer, physicians may be reluctant to prescribe degarelix. They may be concerned about patient complaints about injection-site reactions (ISRs). The subcutaneous injection of degarelix has been associated with a higher rate of ISRs compared with the intramuscular injections of LHRH analogs. This "How I Do It" article describes techniques and strategies that have been developed by physicians and nurses to reduce the discomfort associated with the subcutaneous delivery of degarelix.

Novel LHRH-receptor-targeted cytolytic peptide, EP-100: first-in-human phase I study in patients with advanced LHRH-receptor-expressing solid tumors.

PURPOSE: To conduct a phase I study determining the safety, pharmacokinetics and preliminary efficacy of EP-100, a novel anticancer drug consisting of natural luteinizing-hormone-releasing hormone (LHRH) ligand linked to a cationic membrane-disrupting peptide. METHODS: Patients with advanced, solid tumors, positive for LHRH receptor by immunohistochemistry (IHC), received EP-100 weekly or twice weekly for 3 of 4 weeks in a 28 day cycle. A modified Fibonacci 3 + 3 dose-escalation schema was used. Initial cohorts received EP-100 once weekly (cohorts 1-7, 0.6-7.8 mg/m(2), n = 21). Later cohorts received doses twice weekly (cohorts 7-11, 7.8-40 mg/m(2), n = 16). RESULTS: LHRH-receptor expression was confirmed by IHC in 52 of 89 consented patients; 37 patients received at least 1 dose. Cohorts receiving doses of 5.2 mg/m(2) and above achieved therapeutic levels from in vitro studies Clearance was rapid (mean half-life 7.1 ± 3.8 to 15.9 ± 3.6 min). The maximum-tolerated dose was not reached at the highest dose evaluated (40 mg/m(2) twice weekly). Grade 2 increase in alanine aminotransferase/serum aspartate aminotransferase in one patient resolved, did not recur upon re-treatment, and was not observed in other patients. The only drug-related adverse event was transient infusion-related dermatologic reactions (10 patients). No complete or partial tumor responses were observed; seven patients had stable disease of 16 weeks. CONCLUSIONS: EP-100 was well tolerated in patients with advanced, LHRH-receptor-expressing solid tumors. The recommended phase 2 dose is 40 mg/m(2) twice weekly for 3 of 4 weeks per cycle.

Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09).

BACKGROUND: Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. METHODS: In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 µg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. FINDINGS: 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12-31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7-14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0-15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and -0·16 mmol/L (-2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and -0·23 mmol/L (-3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]). INTERPRETATION: Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. FUNDING: Cancer Research UK, MRC Clinical Trials Unit.

Application of reproductive hormone peptides for tumor targeting.

Targeted therapy may be a promising approach against cancer because its focus of attention is to enhance the efficacy and to reduce the side effects of antitumor agents through high selectivity. One of targeted strategies is to use tumor-specific ligands as targeting moieties to carry drugs into tumor cells, and use the receptors that expressed on tumor cells as target sites to bind with peptide ligands. The fact that the distributions of reproductive hormone receptors are relatively limited in normal tissues makes it possible to use them as targeted sites and use hormone peptides as targeting moieties for cancer treatment. Until now many tumor targeting approaches with reproductive hormone peptides have been developed, and some of them have been introduced into clinical trials. Here a review is given to discuss the targeted antitumor therapeutic strategies based on gonadotropin-releasing hormone, follicle-stimulating hormones, luteinizing hormone, human chorionic gonadotropin and their receptors.

Effect of active and passive immunization of male and female rats with a recombinantly expressed bonnet monkey pituitary GnRH receptor fragment.

Gonadotropin releasing hormone (GnRH) exerts its action by binding to the specific receptor which belongs to the family of G-protein coupled receptors that are characterized by the presence of seven transmembrane domains linked together by extracellular and intracellular loops. A fragment of the pituitary receptor of the bonnet monkey (Macaca radiata) corresponding to amino acids 164-266 was cloned and expressed in Escherichia coli. This was used to raise antibodies to the receptor in rabbits. Active and passive immunization studies in both male and female rats were carried out using, both the 'overexpressed' fragment, as well as antibodies raised to the receptor fragment. Both active, as well as passive immunization in the male rats brought about an agonistic effect in terms of increase in serum LH level, as well as increase in serum and testicular testosterone levels. However, in the female rats, active immunization with the receptor fragment did not have any effect on the gonadal steroid levels but had a selective effect on the uterine morphology.

Evaluation of the hypothalamic-pituitary-gonadal axis in males with systemic lupus erythematosus.

OBJECTIVE: To evaluate the hypothalamic-pituitary-gonadal axis in male patients with systemic lupus erythematosus (SLE). METHODS: We studied 7 male patients with SLE and compared them with 10 age matched healthy controls. Clinical data, laboratory tests, drugs used, and disease activity for SLE (SLE Disease Activity Index) were determined. The basal serum levels of cortisol, total testosterone (T), free testosterone (FT), androstenedione, dehydroepiandrosterone sulfate (DHEAS), estradiol (E2), prolactin (PRL), luteinizing hormone (LH), and follicle stimulating hormone (FSH) were measured in all individuals. In addition, response of LH and FSH to stimulation with luteinizing hormone releasing hormone (LHRH, 100 microg, intravenously) and response of T and FT to stimulation with human chorionic gonadotropins (HCG, 1500 u intramuscular for 3 days) were examined. RESULTS: Patients with SLE had lower basal levels of T and FT than controls but this difference was not significant. DHEAS and A levels were significantly lower in patients than in controls. The low response of FT after stimulation with HCG indicated diminished testis function (mainly Leidyg cells). In contrast to other studies, the E2 level was significantly lower in patients than in controls. The groups did not differ in LH levels at baseline or after stimulation with LHRH. However, basal levels of FSH were significantly higher in patients. CONCLUSION: These results suggest that the hypothalamic-pituitary-axis function was normal in patients with SLE. The testis had diminished function, shown by reduced response of FT to stimulation with HCG, but possible inhibitory effects of glucocorticoid therapy must be considered.