Use of intranasal luteinizing hormone-releasing hormone agonist in uterine leiomyomas

Nine women harboring uterine leiomyomas have been treated with subcutaneous injections and then with intranasal insufflation of luteinizing hormone-releasing hormone agonist for a total treatment period of 6 months. After initial stimulation, mean serum estradiol progressively decreased and stabilized at 36.8 +/- 4.9 pg/ml for the rest of the treatment period. The volume of uterine leiomyomas has been reduced by an average of 71%. Side effects and hot flushes were less severe and better tolerated than reported after sole subcutaneous administration.     

Utilization of luteinizing hormone-releasing hormone agonist in pulmonary leiomyomatosis

A patient presenting a recurrent episode of pulmonary leiomyomatosis has been treated with the LH-RH agonist buserelin at a dosage of 200 micrograms tid SC for 7 days, then 500 micrograms SC daily for a total period of 6 months. Basal serum E2 was suppressed during treatment and varied between 62 and 180 pmol/ml (mean, 129.4 +/- 14.5). Pulmonary symptoms completely disappeared during treatment, but no objective regression of the pulmonary lesions was observed. Because of the uncertainty of response of benign metastasizing leiomyomas to castration and because of the reversibility of the medical treatment, LH-RH agonist may be preferred to surgical castration in this pathology.     

Dose-related inhibition of acute luteinizing hormone response during luteinizing hormone-releasing hormone agonist treatment for uterine leiomyoma

Twenty-six women with uterine leiomyoma were treated for 6 months with subcutaneous injections of the luteinizing hormone-releasing hormone agonist buserelin. Eight women received 200 micrograms daily, eight women received 350 micrograms daily, and 10 women after initial administration of 200 micrograms every 8 hours for 7 days, 500 micrograms of buserelin was administered daily. After 1, 3, and 6 months of treatment, serum luteinizing hormone levels were measured before and 4 and 8 hours after the administration of buserelin. The area under the curve for acute luteinizing-hormone response was then individually calculated. The inhibition of acute luteinizing hormone response during luteinizing hormone-releasing hormone agonist treatment was proportional to the dosage used and remained constant during the treatment period.     

Postcoital contraceptive effects of agonist analogs of luteinizing hormone-releasing hormone.

Various analogs of synthetic hypothalamic luteinizing hormone-releasing hormone (LH-RH) were evaluated for agonistic (ovulation-inducing), postcoital contraceptive, and direct uterotrophic activities. All analogs showing agonistic activity also possessed the ability to terminate pregnancy, as did LH-RH; there appeared to be a direct relationship between agonistic and postcoital potency and activity. The highly potent and active LH-RH agonist, D-[Ala]6-des-[Gly]10-pro9-ethylamide-LH-RH, proved to be the most potent and active postcoital preimplantational and postimplantational antifertility agent. In contrast to LH-RH, none of the analogs tested in the hypophysectomized animal produced a uterotrophic effect, revealing a selective extrapituitary effect of the parent hormone. The collective data demonstrate that peptides derived from LH-RH and bearing agonistic properties can terminate pregnancy postcoitally, via disruption of the pituitary-ovarian reproductive complex. Possible mechanisms are discussed, and the use of members of this neurohormonal class as potential profertility agents should be weighed with caution.     

Uterine leiomyosarcoma diagnosed during treatment with agonist of luteinizing hormone-releasing hormone for presumed uterine fibroid

Medical treatment with an LH-RH agonist may be used in selected cases of uterine fibroids. Although rare, rapid increase in uterine or fibroid volume may suggest an underlying leiomyosarcoma that would require prompt surgical intervention. Close monitoring of the response to treatment with an LH-RH agonist is essential.     

Human anti-luteinizing hormone-releasing hormone antibodies in patients treated with synthetic luteinizing hormone-releasing hormone

One hundred sixty-three patients who were given synthetic LH-RH therapeutically underwent monitoring of serum IgG anti-LH-RH antibodies. Five of the patients showed specific binding to antibodies. Development of anti-LH-RH antibodies was not limited to those patients with a congenital deficiency of LH-RH. Urticarial responses occurred in four patients, only one of whom had IgG antibodies. Patients who had IgG antibodies or an urticarial response underwent monitoring of their serum IgE anti-LH-RH antibodies, but none had a positive binding response. The refractory state which has been reported in patients in whom similar antibodies to LH-RH develop was not invariably observed among these patients.     

Treatment of uterine leiomyomata with a luteinizing hormone-releasing hormone agonist: the possibility of nonsurgical management in selected perimenopausal women

OBJECTIVE: To evaluate the efficacy of luteinizing hormone-releasing hormone agonist (LH-RH-a) in the treatment of leiomyomata. DESIGN: A retrospective randomized trial. SETTING: Hospital department of obstetrics and gynecology. PATIENTS: Twenty-five women, ages 36 to 54 years with symptomatic uterine leiomyomata, were divided into two groups according to the responsiveness to LH-RH-a: group A patients reached menopause after LH-RH-a, whereas resumption of menstruation occurred within 12 weeks after cessation of therapy in group B. INTERVENTIONS: Luteinizing hormone-releasing hormone agonist was administered intranasally three times a day with 150 micrograms insufflation of one spray in each nostril (total dose: 900 micrograms/d). MAIN OUTCOME MEASURES: Efficacies of treatment were assessed in terms of uterine volume, hemoglobin concentrations, serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and bone density during and after treatment. RESULTS: In both groups, hemoglobin concentrations increased significantly after 16 weeks of treatment. A significant reduction in uterine volume was observed in both groups. After completing therapy, there was no further significant change in uterine volume in group A, whereas uterine volume in group B returned to pretreatment values. Serum LH and FSH concentrations were suppressed during treatment, but those gonadotropins in group A increased significantly up to the menopausal levels after treatment. Serum E2 concentrations in both groups showed consistent suppression by the end of the first treatment cycle. After cessation of therapy, serum E2 levels on group A remained in the castrate range, whereas E2 in group B returned to pretreatment levels, concomitant with the return of normal ovulation. CONCLUSIONS: Intranasal administration of LH-RH-a was successful in significantly decreasing uterine volume and increasing hemoglobin concentration in premenopausal women with leiomyomata.     

Inhibition of ovulation during discontinuous intranasal luteinizing hormone-releasing hormone agonist dosing in combination with gestagen-induced bleeding

Four groups of eight or nine normal cycling volunteers with regular menstrual cycles had daily blood sampling during two pretreatment, two treatment, and two posttreatment cycles. Intranasal doses of 100, 200, and 300 micrograms of (D-Ser[TBU]6-des-Gly-NH210) luteinizing hormone-releasing hormone (LH-RH) ethylamide were administered every 12 hours and compared with a 400-micrograms dose given every 24 hours during two periods of 21 days followed by a drug-free interval of 7 days. Five milligrams of medroxyprogesterone acetate was taken orally on days 17 to 21. Serum luteinizing hormone was elevated during the first 2 weeks of treatment, and serum follicle-stimulating hormone was increased only during the first 2 days of treatment. At 100 to 300 micrograms/12 hours serum estradiol was stimulated up to preovulatory levels, whereas at 400 micrograms/24 hours most values were in the early follicular phase range. Ovarian ultrasonography revealed the transient development of preovulatory-like follicles in 8 of 12 studied cycles. Serum progesterone values were less than 2 ng/ml in 57.3%, between 2 and 5 ng/ml in 27.9%, and greater than 5 ng/ml in 14.7%. Withdrawal bleeding occurred during the pause in 97% of treatment cycles. Nine of 13 breakthrough bleedings happened in the groups given 100-micrograms and 300-micrograms/12 hours. Recovery cycles showed slightly prolonged follicular phases with normal luteal phases. No changes were observed in routine laboratory measurements. In conclusion, intermittent administration of appropriate LH-RH agonist dosing in combination with a progestogen would effectively block ovulation while preserving adequate cyclic estradiol secretion and could be an alternative contraceptive approach.     

Gonadotroph and corpus luteum responses to two successive intranasal doses of a luteinizing hormone-releasing hormone agonist at different days after the midcycle luteinizing hormone surge

Two successive intranasal doses (300 micrograms at 8:00 A.M. and 6:00 P.M.) of the luteinizing hormone-releasing hormone (LH-RH) agonist (D-Ser[TBU]6-des-Gly-NH2(10))LH-RH ethylamide (Buserelin) were administered on days 1 to 10 after the midcycle luteinizing hormone (LH) surge in 33 normally cycling women. Maximal stimulation of gonadotropins was observed at 4 hours and was of higher amplitude in the first 2 days after the LH surge. The response to the second dose was markedly blunted, showing pituitary refractoriness. On each day of treatment there was a progressive increase of serum estradiol, which was maximal (threefold) 4 hours after the second dose of Buserelin. Serum progesterone (P) levels were not significantly changed on days 1 to 4, but they were increased by 50% at 10 hours on days 5 to 10. Daily blood samples revealed that following treatment on days 1 to 4 after the midcycle LH surge, serum P profiles were lower than in control cycles, without change in the length of the luteal phase. Starting on treatment day 5, a precocious luteolysis was induced, as illustrated by an early fall in serum P levels and shortening of the luteal phase (1 to 4 days). All posttreatment control cycles were normal. The results of this time study indicate that an appropriate treatment with an intranasal Buserelin administered at any time between days 1 to 10 after the midcycle LH surge impair luteal function and could lead to a new postcoital contraceptive approach.     

Pulsatile luteinizing hormone-releasing hormone treatment of male hypogonadotropic hypogonadism

Luteinizing hormone-releasing hormone (LH-RH) secretion from the hypothalamus follows a rhythmic pattern, inducing pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion from the pituitary gland. Consideration of this physiologic principle led to the introduction of pulsatile LH-RH therapy via infusion pump for the treatment of different forms of hypogonadotropic hypogonadism. We report on 10 male patients, 16 to 28 years of age, suffering from idiopathic hypogonadotropic hypogonadism (IHH) including Kallman's syndrome (n = 2) and delayed puberty (n = 2). All presented with complete eunuchoidism and had undergone no treatment for their conditions during the previous 2 years. LH-RH was administered in subcutaneous pulses of 4 to 16 micrograms, with a portable infusion pump (ZYKLOMAT, Ferring Corp., Kiel, FRG); treatment periods ranged from 6 to 24 months. With therapy, the subjects improved secretion of LH, FSH and testosterone. Testicular volumes and penis size increased; all patients developed normal secondary sexual characteristics. Spermatogenesis was induced in all patients. The time to onset of spermatogenesis ranged from 3 to 15 months. No major side effects were observed, and no patient dropped out of the study. The results indicate that pulsatile LH-RH therapy is an highly effective treatment for IHH and delayed puberty.     

Efficacy of intranasal or subcutaneous luteinizing hormone-releasing hormone agonist inhibition of ovarian function in the treatment of endometriosis

We have previously reported reversible hypogonadism induced by the intranasal administration of the luteinizing hormone-releasing hormone agonist buserelin as a new therapeutic approach for endometriosis. Thirteen patients were randomized to receive intranasal buserelin (400 micrograms 3 times a day) or subcutaneous buserelin injection (200 micrograms once daily) for a 6- to 9-month period. Both routes of administration were effective in inhibiting serum estradiol levels to near the menopausal range after 1 month of treatment. The two dosage regimens had also a comparable efficacy in alleviating endometriosis symptoms and in reducing the revised American Fertility Society scoring at laparoscopic examination. The implant score mainly decreased by more than 70%. The occurrence of side effects was similar in both groups, and side effects were mainly hot flushes, dyspareunia secondary to decreased vaginal secretion, and decreased libido. Results of hemogram, urinalysis, and serum biochemical and hormonal tests remained in the normal range. The ovulatory cycle rapidly returned after the cessation of treatment, and three pregnancies occurred in six previously infertile patients. Intranasal and subcutaneous buserelin were well accepted and equally effective in inhibiting the pituitary-ovarian function, which caused mild menopausal symptoms but an important regression of endometriosis.     

Pulsatile luteinizing hormone-releasing hormone therapy in women with polycystic ovary syndrome

Induction of ovulation with pulsatile luteinizing hormone-releasing hormone (LH-RH) therapy was attempted in 48 women with polycystic ovary disease (PCOD) and clomiphene citrate (CC) resistant anovulation. Fourteen women ovulated regularly, 23 ovulated variably, but 11 did not ovulate at all. Fifty-two of the 108 cycles of pulsatile LH-RH therapy alone (15 mu gm per pulse, one pulse every 90 minutes) administered through the subcutaneous route were ovulatory. In patients who did not ovulate on subcutaneous LH-RH, treatment with CC (100 mg per day for 5 days) was added to the LH-RH therapy in an additional 33 cycles, of which 21 were ovulatory. In those who did not respond to the combination of treatments, the same dose of LH-RH was administered intravenously: 14 of 29 cycles of intravenous therapy were ovulatory. The overall cumulative conception rate after 6 months of therapy was 60%. When recalculated for ovulatory cycles alone it was 90%, indicating that failure of ovulation was the only cause of the failure of conception. Analysis of the clinical and endocrine findings indicated that failure to ovulate was associated with obesity and hyperandrogenization. Ten of the 23 conceptions ended in miscarriage, 8 within 4 weeks of ovulation. The authors conclude that infertility in patients with PCOD is not optimally corrected by pulsatile LH-RH therapy.