Intranasal gonadotropin-releasing hormone agonist (GnRHa) for luteal-phase support following GnRHa triggering, a novel approach to avoid ovarian hyperstimulation syndrome in high responders.

OBJECTIVE: To study whether intranasal GnRH agonist (GnRHa) can be effectively used for luteal support in high-responder patients undergoing fresh-embryo transfer after ovulation induction with the use of GnRHa. DESIGN: Retrospective cohort study. SETTING: Private fertility clinic. PATIENT(S): Forty-six high-responder patients were administered a GnRHa ovulation trigger to avoid ovarian hyperstimulation syndrome (OHSS), followed by 2 weeks of daily intranasal GnRHa (nafarelin) for luteal-phase support. No additional progesterone supplementation was administrated. INTERVENTION(S): Intranasal GnRHa for luteal-phase support. MAIN OUTCOME MEASURE(S): The primary outcome was ongoing clinical pregnancy rate. RESULT(S): High median progesterone levels were measured at midluteal phase and on the day of the first positive pregnancy test (190 nmol/L on both measures). We obtained 24 (52.1%) ongoing clinical pregnancies. None of the patients developed OHSS. CONCLUSION(S): Intranasal GnRHa is effective in achieving luteal-phase support in high-responder patients triggered with GnRHa and avoiding OHSS.

p27 and its ubiquitin ligase Skp2 expression in endometrium of IVF patients with repeated hormonal stimulation.

This preliminary study examined a possible effect of long duration repeated hormonal stimulation on the endometrium using a molecular tool. The expression of the hormone stimulated, cell cycle regulators, p27 and its ligase S-phase kinase-interacting protein2 (Skp2), were assessed in 46 endometrial samples of patients who underwent repeated IVF cycles (3-21). Skp2 protein is usually undetectable in normal tissue and can be demonstrated only in rapidly dividing cells. Samples from non-stimulated, normal cycling women served as control group A. Samples of endometrial carcinoma served as control group B. In secretory endometrium, the expression of p27 was found to be lower and Skp2 higher in the study group compared with control group A. Moreover, in 25% of patients of the study group, Skp2 expression was significantly higher (P < 0.05) compared with control group A, reaching concentrations demonstrated in endometrial carcinoma. The findings of this study suggest that repeated hormone stimulation cycles may disrupt endometrial physiology, potentially towards abnormal proliferation. These changes in protein expression are described for the first time in IVF patients and should be further investigated.

Evaluation of the clinical efficacy of Gonazon implants in the treatment of reproductive pathologies, behavioral problems, and suppression of reproductive function in the male dog.

Efficacy of a slow-release gonadotropin-releasing hormone (GnRH)-agonist implant (Gonazon) was assessed in 53 male dogs presented with benign prostatic hyperplasia (BPH), hypersexuality, aggressive behavior (either alone or in combination), excessive micturition, or to suppress fertility. Changes in testosterone (T) and estradiol (E2) concentrations and size of testes and prostate were monitored on Weeks 0, +8, and +26 after implantation. Additional measurements during and after this period were performed in 35 dogs. Clinical signs were assessed by the owners. All implants except one were retained throughout the study. Full downregulation of testicular function (T<0.35 nmol/L) was achieved in 46 dogs, five dogs showed partial downregulation (T = 0.36 to 0.47 nmol/L), one dog did not respond, and another one displayed a transient downregulation on Week +18. On Week +8, mean T and E2 levels were reduced by 96% and 62%, respectively, and did not further decrease. Full downregulation (T<0.35 nmol/L) lasted between 6 to >22 mo in most dogs except two. Compared with pretreatment values, mean testicular and prostatic size was reduced (P<0.00001) by 54% and 52%, respectively, on Week +8 and by 68% and 64%, respectively, on Week +26. Relative reduction of prostatic size was more marked in dogs with BPH than in healthy ones on Week +8 (P<0.05) and Week +26 (P<0.02), and clinical signs of BPH disappeared rapidly after implantation. Dogs affected with BPH were significantly older (P<0.001) than nonaffected ones (9.7 vs. 2.5 yr). Hypersexuality was more common in dogs<3 yr of age, and treatment clearly improved clinical signs. Age significantly affected the response to treatment in aggressive dogs; 75% of the cases responded with an improvement. The only minor and possibly treatment-related events observed were a short-lasting exacerbation of clinical signs of BPH (two dogs), increased weight gain (three dogs), and anxiety (three dogs) with one of these dogs developing a blunt coat. These results demonstrate the clinical efficacy and overall safety of the Gonazon implants.

Impact of six months of GnRH agonist therapy for endometriosis. Is there an age-related effect on bone mineral density?

OBJECTIVE: To determine if there is an age-related effect on bone mineral density (BMD) loss with GnRH agonist treatment of endometriosis and, in particular, whether the impact of this therapy in terms of BMD loss is different if it is used at an age prior to attainment of peak BMD than after attaining it. STUDY DESIGN: Data from a randomized, double-placebo-controlled clinical trial comparing efficacy and safety of two GnRH agonists, without add-back, for the treatment of endometriosis, were analyzed. RESULTS: No significant age-related effect was detected for either GnRH agonist on absolute BMD loss with a single, six-month course. However, in women at an age prior to peak BMD, prevention of the natural increase in BMD with these drugs may prevent women from attaining their peak BMD and thus increase their risk of osteoporosis in later life. CONCLUSION: GnRH agonists should be used with caution and perhaps only with strategies designed to minimize the impact on BMD in women prior to attainment of peak BMD.

[Comparative study of the efficiency of gonadotrope releasing hormone (GnRH) analogs for the treatment of endometriosis]. / Endometriosis kezelésére alkalmazott gonadotrop releasing hormon (GnRH) analógok hatékonyságának összehasonlítása.

INTRODUCTION: Endometriosis is one of the most common gynaecological conditions in women of reproductive age. The aim of the authors' study was to compare the relative safety, efficacy and side effects of nafarelin and triptorelin. PATIENTS AND METHODS: They treated 133 patients for six months and followed up for at least an additional 6 months. In the diagnosis of the endometriosis they use the gold standard, the laparoscopy. RESULTS: During the 6-month therapy with analogues, there was a noticeable decline in the symptoms of the disease, there was no significant change in the efficacy and was no difference in main side effects of the two drugs. CONCLUSION: These treatments represent favourable approaches in the management of endometriosis.

Clinical evaluation of three different gonadotrophin-releasing hormone analogues in an IVF programme: a prospective study.

The efficacy and safety of short acting buserelin and nafarelin intranasal spray were compared to long acting leuprorelin depot intramuscular or subcutaneous injection in this prospective study of 157 women undergoing controlled ovarian hyperstimulation (COH) for in-vitro fertilisation (IVF). Patients were allocated to three groups to receive buserelin 150 microg nasal spray three times daily (Group B), nafarelin nasal spray 400 microg twice daily (Group N), or leuprorelin depot 3.75 mg once by intramuscular or subcutaneous injection (Group L) for pituitary desensitisation prior to commencing COH with human menopausal gonadotrophins (hMG) according to the Centre's protocol. The mean (+/-S.D.) age (years) (32.6+/-3.8: Group B, 32.1+/-3.3: Group N versus 32.1+/-3.3: Group L); mean (+/-S.D.) total dosage of hMG (ampoules) (37.5+/-16.1: Group B, 39.8+/-14.2: Group N versus 41.9+/-12.6: Group L) and mean daily dosage of hMG (ampoules) (3.1: Group B, 2.8: Group N versus 3.0: Group L) seen were not statistically significantly different. The duration between starting the different gonadotrophin-releasing hormone (GnRHa) and the beginning of the next menstrual period was also not seen to be statistically significantly different between the three groups (Group B: 10+/-5.5, Group N: 9.1+/-4.1 versus Group L: 8.2+/-3, days). The number of abandoned cycles was higher in Group L (17% versus 11.8%: Group B and 11.3%: Group N) but this difference did not reach statistical significance. The clinical pregnancy rates per oocyte retrieval and per embryo transfer procedure were respectively, 31.1, 35% in Group B, 12.8, 14% in Group N versus 20.5, 23.7 in Group L and were not seen to be statistically significantly different even when ongoing pregnancy rates were compared. Apart from a statistically significantly greater incidence of allergic nasal reactions in the nafarelin group (P=0.001), all other side-effects were not shown to be statistically significantly different between the three groups. We conclude that a single dose of leuprorelin depot can be considered to be as an equally effective alternative to multiple doses of buserelin or nafarelin for pituitary desensitisation in women undergoing COH for IVF.

Efficacy of nafarelin in assisted reproductive technology: a meta-analysis.

A systematic review identified nine randomized, controlled trials (both published and unpublished) which assessed the efficacy of nafarelin during IVF compared with other gonadotrophin-releasing hormone (GnRH) agonists. The trials included 1,014 women (nafarelin n = 597) in protocols employing three different dosage regimens, long and short stimulation protocols, and three comparative GnRH agonists (buserelin n = 348; triptorelin n = 14, and leuprolide n = 55). The meta-analysis of the data showed that pregnancy rates per embryo transfer with nafarelin were equivalent to those obtained with other GnRH agonists. Nafarelin and other agonists were also comparable in terms of several intermediate IVF outcomes, including fertilization rates, number of oocytes retrieved, peak oestradiol concentrations, and cycle cancellations. Women treated with nafarelin required fewer ampoules of human menopausal gonadotrophin (HMG)/FSH for ovarian stimulation and fewer days of stimulation. Safety results from both the meta-analysis and a qualitative analysis of 12 additional reports suggested that adverse effects were within the accepted tolerance range; the most frequent adverse effects were hypo-oestrogenic symptoms. In conclusion, the overall efficacy of nafarelin was equivalent to that of other GnRH agonists. The possibility that the reduced gonadotrophin requirements in women taking nafarelin will translate into cost savings per IVF treatment cycle requires further study.

Acute exacerbation of chronic maxillary sinusitis during therapy with nafarelin nasal spray.

OBJECTIVE: To describe a case of acute exacerbation of chronic bilateral maxillary sinusitis during therapy with nafarelin nasal spray for chronic pelvic pain and suspected adenomyosis uteri in a patient of 34 years. DESIGN: Case report. INTERVENTIONS: In the follicular stage of the cycle a diagnostic laparoscopy was carried out because of unexplained pelvic pain for 2 years with biopsy of the pelvic peritoneum and of the uterine fundus was done, revealing no pathology. One and a half years ago the patient already had a diagnostic laparoscopy for the same reason without pathological findings. Vaginal ultrasound showed minor signs of adenomyosis uteri (irregular structure of the myometrium with small cysts). One week after the operation, a therapy with nafarelin nasal spray was initiated in order to induce a hypoestrogenic state. Fourteen days later the therapy had to be stopped because of acute exacerbation of chronic maxillary sinusitis and Caldwell Luc operation and turbinoplastic was performed. OUTCOME: Resolution of the acute maxillary sinusitis after operative intervention and termination of the above-mentioned medication, resolution of pelvic pain after therapy with leuprolide after 4 weeks. CONCLUSIONS: To our knowledge, this is the first report of an acute exacerbation of a chronic maxillary sinusitis during the administration of nafarelin nasal spray. Gynecologists prescribing nasal sprays should ask their patients about symptoms of chronic sinusitis. Patients with a history of sinusitis should visit an ear, nose and throat (ENT) specialist before initiating therapy with nasal sprays; alternatively, drugs with a different formulation should be used for down-regulation of the ovarian function in order to avoid this complication.

Crohn's disease mimicking as bowel endometriosis. Are the symptoms reduced by nafarelin acetate?

We report a 27-year-old female with Crohn's disease clinically misdiagnosed with intestinal endometriosis. Her complaints were abdominal pain and fullness, which occurred monthly during her menstrual period. Although we had no histopathological evidence, we diagnosed her as bowel endometriosis on the basis of her clinical course. Since nafarelin acetate therapy started, the symptoms due to mechanical subileus have improved. The transverse colon, a 70 cm segment of the ileum, including the terminal ileum, were resected because of repeated symptoms of bowel obstruction despite prolonged nafarelin therapy. Histopathological findings of the resected specimen revealed Crohn's disease without endometrial tissue. In our patient, an increased cortisol and ACTH secretion, a side effect of nafarelin, was noted during the therapy. This case showed that nafarelin therapy could increase serum concentration of ACTH and cortisol, which was considered to suppress the pathology of Crohn's disease by its anti-inflammatory action. We emphasize that intestinal examination must be performed with Crohn's disease in mind, even if nafarelin acetate is effective.

[Current aspects on the treatment of endometriosis]. / Aktuella aspekter på behandling av endometrios.

The aim of pharmacological treatment of endometriosis is to reduce estrogen levels, which may be achieved using gestagens or GnRH-agonists. The effects of the different hormones are mainly the same, while side effects differ. If the GnRH-agonist dose is modified, or if a low dose of estrogen and/or gestagen is given in addition, the hypo-estrogenic side effects of GnRH-agonists can be reduced. Surgical treatment can often be performed in conjunction with diagnostic laparoscopy. Supplementary hormonal treatment may postpone recurrence. Because endometriosis is in many women a chronically recurring disorder, continuity in the doctor-patient relationship is essential.

Treatment of endometriosis with a decreasing dosage of a gonadotropin-releasing hormone agonist (nafarelin): a pilot study with low-dose agonist therapy ("draw-back" therapy).

OBJECTIVE: To evaluate the efficacy of half-dose GnRH agonist therapy for endometriosis. DESIGN: Prospective, longitudinal pilot study. SETTING: Osaka University Hospital. PATIENT(S): Patients with symptomatic endometriosis. INTERVENTION(S): Fifteen patients were randomized to receive either full-dose nafarelin treatment (200 microgram b.i.d.) for 24 weeks (n = 7) or full-dose nafarelin treatment for 4 weeks followed by half-dose nafarelin treatment (200 microgram daily) for 20 weeks (n = 8). MAIN OUTCOME MEASURE(S): Clinical symptoms and the results of physical examinations. Serum E(2) and carcinoma antigen 125 (CA125) levels, lipid profiles, and urinary levels of the N-telopeptide of type I collagen. Bone mineral density of the lumbar spine. RESULT(S): Subjective and objective manifestations of endometriosis were decreased to a similar extent in both study groups. Adverse effects were markedly reduced with half-dose administration. In the half-dose group, the mean serum E(2) level was significantly suppressed by 4 weeks of treatment with full-dose nafarelin and remained at approximately 30 pg/mL with half-dose nafarelin. Loss of bone mineral density was significantly less with half-dose treatment. CONCLUSION(S): Half-dose administration of nafarelin after pituitary down-regulation with full-dose nafarelin ("draw-back" therapy) is a new protocol for the treatment of endometriosis that is effective and associated with fewer adverse effects.

A comparative study of the acceptability and effect of goserelin and nafarelin on endometriosis.

The effects of goserelin and nafarelin were compared in a prospective, randomized, open, parallel study of 6 months' treatment of 252 women with symptomatic, laparoscopically proven endometriosis. Twenty-eight departments of obstetrics and gynecology in Sweden, Norway, Denmark and Finland were included. Evaluations were made every 3 months for quantification of pain, bleeding and adverse events and convenience of treatment, and at 3 months after the end of treatment, when a control laparoscopy was performed for evaluation of changes in endometriotic lesion size, color and location. Thirty-nine patients withdrew and 113 women given goserelin and 100 women given nafarelin completed the study. There were no statistically significant differences between the groups, either in adverse events or in bleeding. There were no correlations between location, lesion size or type of lesion, and symptom score in either group, or between treatments with regard to change in endometriosis score. In both groups, the percentage of red and black lesions was reduced while the proportion of white lesions increased. The pain score was significantly reduced in both groups. Local irritation in the nasal mucosa was reported in both groups, mostly in the nafarelin-treated group. The goserelin-treated group also reported local symptoms at the injection site. We conclude that there is no statistically significant difference in treatment results or side-effects between goserelin and nafarelin when used for the treatment of endometriosis.

Prevention of estrogen deficiency-related bone loss with human parathyroid hormone-(1-34): a randomized controlled trial.

CONTEXT: Short-term intermittent administration of parathyroid hormone (PTH) prevents bone loss from the spine in women treated with a gonadotropin-releasing hormone (GnRH) analog. However, the effects of a longer period of PTH administration on bone mass in estrogen-deficient women, particularly on the hip and on cortical bone of the total body, are unknown. OBJECTIVE: To determine whether more prolonged PTH administration can prevent estrogen deficiency bone loss from the hip, spine, and total body in young women with endometriosis receiving GnRH analog (nafarelin acetate) therapy. DESIGN: Randomized controlled trial. SETTING: General Clinical Research Center of a tertiary care, university-affiliated hospital. PATIENTS: Forty-three women between the ages of 21 and 45 years with symptomatic endometriosis. INTERVENTION: Nafarelin alone (200 microg intranasally twice daily) or nafarelin plus human parathyroid hormone-(1-34) (hPTH-[1-34]) (40 microg subcutaneously daily). MAIN OUTCOME MEASURES: The primary end points were bone mineral density (BMD) of the anterior-posterior and lateral spine, femoral neck, trochanter, radial shaft, and total body at 12 months of treatment. RESULTS: In the women who received nafarelin alone, the mean (SEM) BMDs of the anterior-posterior spine, lateral spine, femoral neck, trochanter, and total body were 4.9% (0.6%) (P<.001), 4.9% (0.8%) (P<.001), 4.7% (1.1%) (P<.001), 4.3% (0.9%) (P<.001), and 2.0% (0.6%) (P= .003) lower than at baseline after 12 months of therapy. In contrast, coadministration of hPTH-(1-34) increased BMD of the anterior-posterior spine by 2.1% (1.1%) (P=.09) and lateral spine by 7.5% (1.9%) (P=.002) and prevented bone loss from the femoral neck, trochanter, and total body, despite severe estrogen deficiency. Radial shaft BMD did not change significantly in either group. Serum bone-specific alkaline phosphatase and osteocalcin concentrations and urinary excretion of hydroxyproline and deoxypyridinoline increased 2-fold to 3-fold during the first 6 to 9 months of therapy in the women who received nafarelin plus hPTH-(1-34) and then declined. Changes in urinary deoxypyridinolone excretion were strongly predictive (r= 0.85) of changes in spinal BMD in the women who received nafarelin plus hPTH-(1-34). CONCLUSIONS: Parathyroid hormone prevents bone loss from the proximal femur and total body and increases lumbar spinal BMD in young women with GnRH analog-induced estrogen deficiency.

Depressive symptoms associated with gonadotropin-releasing hormone agonists.

The gonadotropin-releasing hormone (GnRH) agonists are a relatively new class of drugs that are potentially effective in treating disorders that are aggravated either by estrogen or testosterone. GnRH agonists are effective in the treatment of endometriosis, as well as other disorders, such as advanced prostrate cancer, precocious puberty and uterine leiomyomata. While the GnRH agonists reduce the extent of the endometrial lesions and the occurrence of pelvic pain associated with endometriosis, these agents are associated with physical and psychiatric side effects. The adverse effects of these agents are consistent with the physiological effects of ovarian suppression, such as vasomotor instability, vaginal dryness, and headaches. Preliminary results of a prospective, double-blind placebo-controlled study and an open label trial indicates that depressive mood symptoms increase in women treated with GnRH agonist therapy for endometriosis. Additional evidence suggest that sertraline effectively manages depressive mood symptoms associated with GnRH agonist therapy. The reason for the decline in mood on GnRH agonists is postulated to be associated with the decline in estrogen levels. Effective treatment strategies for depressive mood symptoms in women on GnRH agonists therapy may offer insight into the mechanisms of action of estrogen on mood.

Conservative management for perimenopausal women with uterine leiomyomas using Chinese herbal medicines and synthetic analogs of gonadotropin-releasing hormone.

The effects of a long-term intranasal administration of each of the gonadotropin-releasing hormone analogs, buserelin and nafarelin on uterine leiomyomas after conservative treatment using Chinese herbal medicines, Keishi-bukuryo-gan and Shakuyaku-kanzo-to were investigated in 30 perimenopausal women with leiomyomas. Hypermenorrhea and/or dysmenorrhea as a chief complaint was moderately improved by the treatment using Chinese herbal medicines in more than 60% of the patients with less than fist-sized leiomyomas, but not the over fist-sized. Afterwards, continuous treatment using analogs produced a long-term reduction in leiomyomas (less than 60%) along with decreases in the serum levels of luteinizing hormone, follicle-stimulating hormone, estradiol, and the tumor marker CA-125, and adverse effects including slight boneloss. Long-term treatment using Chinese herbal medicines and gonadotropin-releasing hormone analogs for the management of uterine leiomyomas could be beneficial for patients a few years before menopause, though possible side effects of this treatment should be monitored.

Pre or post-operative medical treatment with nafarelin in stage III-IV endometriosis: a French multicenter study.

OBJECTIVES: To determine the effectiveness of a 6-month course of nafarelin in the treatment of stage III-IV endometriosis and to determine if pre-operative use of nafarelin facilitates surgery. DESIGN: Prospective, multicenter, clinical trial. SETTING: Eight university hospitals and two private practice institutions in France. PATIENTS: Fifty-five patients with stage III and IV endometriosis. Two were excluded. INTERVENTIONS: The severity of endometriosis was assessed at the time of laparoscopy and patients were randomized to have either laparosopic surgery at that time following 6 months of nafarelin therapy (n=28), or laparoscopic surgery following 6 months of nafarelin therapy (n=25). All had 200 microg intranasal nafarelin twice a day for 6 months and a second look laparoscopy. MAIN OUTCOME MEASURE: Clinical efficacy, tolerance to the treatment. RESULTS: Efficacy and tolerance to the treatment were the same in both groups. AFS scores compared on both laparoscopies were significantly better if nafarelin was given prior to surgery (P=0.007). CONCLUSIONS: This preliminary study shows that in cases of combined medico-surgical treatment for stage III-IV endometriosis, preoperative medical treatment with GnRH-a gives a better AFS score improvement, but no conclusion was possible whether preoperative treatment facilitates surgery.