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Treatment of leiomyomata uteri with leuprolide acetate depot: a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group.

The purpose of this study was to evaluate efficacy and safety parameters in women with leiomyomata uteri treated with the GnRH agonist leuprolide acetate depot, 3.75 mg intramuscularly every 4 weeks for 24 weeks. One hundred twenty-eight patients were enrolled in a randomized, double-blind, placebo-controlled multicenter study involving 13 investigative centers. Mean uterine volume decreased by 36% at 12 weeks and 45% at 24 weeks of leuprolide therapy. Patients treated with placebo had increased in mean uterine volume of 16% at 12 weeks and 5% at 24 weeks. Seventy-seven percent of leuprolide-treated patients had a more than 25% reduction in uterine volume, compared with 9% of placebo-treated controls. Mean uterine volume returned to pre-treatment size 24 weeks after cessation of leuprolide treatment. The majority of patients had resolution or improvement of their fibroid-related symptoms after 24 weeks of leuprolide treatment. Of 38 leuprolide-treated patients presenting with menorrhagia, 37 (97%) had resolution of this symptom at the time of the final visit. Although 95% of women treated with leuprolide acetate experienced some side effects related to hypoestrogenism, only five patients (8%) terminated treatment prematurely. We conclude that leuprolide acetate depot treatment of leiomyomata uteri is safe and causes significant but temporary reductions in uterine size and fibroid-related symptoms.

Adult

Subcutaneous low dose leuprolide acetate depot versus leuprolide acetate for women undergoing ovarian stimulation for in-vitro fertilization.

A total of 100 women undergoing ovarian stimulation with gonadotrophin-releasing hormone agonist (GnRHa) and a human menopausal gonadotrophin (HMG) for in-vitro fertilization (IVF) participated in this randomized comparative study. Leuprolide acetate at a dose of 0.5 mg/day s.c. (n = 52, group I), or low-dose leuprolide acetate depot at a dose of 1.88 mg s.c. (n = 48, group II), was started on days 21-23 of the cycle. Stimulation with 225 IU/day HMG was started after pituitary desensitization had been achieved. The luteal phase was supported by human chorionic gonadotrophin (HCG) i.m. injection. There were no statistical differences in baseline oestradiol (24.5 +/- 4.8 versus 21.9 +/- 4.5 pg/ml) and follicle stimulating hormone (FSH) concentrations (3.9 +/- 1.9 versus 3.2 +/- 1.8 mIU/ml), and concentrations on the day of HCG administration of oestradiol (1657 +/- 245 versus 1512 +/- 165 pg/ml), luteinizing hormone (LH; 6.2 +/- 4.8 versus 5.6 +/- 4.3 mIU/ml) and FSH (10.6 +/- 2.8 versus 10.8 +/- 3.6 mIU/ml). There were also no statistical differences in the HMG dosage (26.8 +/- 1.8 versus 28.5 +/- 1.5), the number of oocytes retrieved (7.6 +/- 3.0 versus 8.1 +/- 4.3), the number of oocytes fertilized (5.3 +/- 2.1 versus 5.6 +/- 3.0) and the number of embryos transferred (3.5 +/- 1.3 versus 3.4 +/- 1.6). There was no evidence of a premature LH surge in either group, but two patients appeared to have a poor response in the leuprolide acetate group (group I). There were 11 pregnancies (21.2%) after the use of leuprolide acetate and 12 pregnancies (25.0%) in those given leuprolide acetate depot; no statistical difference existed between these two groups. Thus, a s.c. low-dose leuprolide acetate depot injection may offer a useful alternative for pituitary suppression in ovarian stimulation for IVF.

Adult

Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. The Leuprolide Study Group.

In a phase III, open, multicenter study we evaluated the safety and efficacy of the depot formulation of leuprolide (7.5 mg. injected intramuscularly every 4 weeks) in patients with stage D2 prostate cancer who had not previously received systemic treatment. Serum testosterone, luteinizing hormone and plasma leuprolide levels were monitored during the 24-week study period. Median interval to onset of castrate testosterone levels was 21 days and mean testosterone levels decreased to within the castrate range by week 3 of treatment. After onset of castrate levels there were no escapes (defined as 2 consecutive values of greater than 50 ng./dl.) of testosterone levels during the 24 weeks. Suppression of testosterone did not differ significantly from that observed in patients receiving the daily subcutaneous injection of leuprolide acetate in the first 24 weeks of another study. Objective response (no progression) to treatment occurred in 81% of 53 evaluable patients and adverse (related and unrelated) events were reported in 45 of the 56 patients. The response rate and incidence of adverse events in this study did not differ significantly from those occurring with the daily formulation. We conclude that the depot formulation of leuprolide is safe and effective in the treatment of advanced prostatic cancer, and that the safety and efficacy of this formulation do not differ significantly from those of the daily subcutaneous formulation.

Aged

Treatment of leiomyomata uteri with short-term leuprolide followed by leuprolide plus estrogen-progestin hormone replacement therapy for 2 years: a pilot study.

Five premenopausal women with leiomyomata uteri were treated with leuprolide for 3 months and demonstrated a reduction in mean uterine volume of 49%. Cyclic conjugated equine estrogens and MPA were added to leuprolide therapy during the ensuing 24 months, with no significant changes in mean uterine volume or peripheral bone density.

Bone and Bones

Treatment of newly diagnosed state D2 prostate cancer with leuprolide and flutamide or leuprolide alone, phase III, intergroup study 0036.

In order to test the hypothesis of complete androgen blockade for advanced prostate cancer (D2CaP), an intergroup trial was instituted in 1985 comparing leuprolide (L) alone to the combination of L with flutamide (F). Eligibility requirements included previously untreated histologically confirmed stage D2CaP, measurable bone or soft tissue metastases, performance status (PS) of 3 or better, acceptable renal and hepatic function, no severe cardiac disease, and no prior or concomitant endocrine therapy. Stratification at entry was on the basis of PS and none or minimal disease (MD) versus severe degree (SD) of bone metastases. Six hundred and seventeen patients were entered into this study between March 1985 and April 1986. At the present time, there is a 3-month difference in the median progression-free survival (13.9 vs 16.9 months; P = 0.039) and a 7.1-month difference in survival (27.9 vs 35.01 months; P = 0.035) favoring L + F. In L + F-treated patients with good PS-MD, the median survival recently has been reached and is 51.9 months vs 39.6 months for L + P patients. The 107 black patients in the study had median survival of 26.4 months vs 33.3 months for whites. Discussions of racial differences in survival as well as other prognostic factors will be presented. The combination of L + F is superior to treatment with L alone. The benefits appear greatest in patients with minimal disease.

Antineoplastic Agents

Leuprolide acetate: serum and follicular fluid concentrations and effects on human fertilization, embryo growth, and granulosa-lutein cell progesterone accumulation in vitro.

Data from various animal models have demonstrated significant extrapituitary effects of gonadotropin-releasing hormone agonists. The purpose of this study was to determine the effects of therapeutic concentrations of leuprolide acetate on human granulosa-lutein cell steroidogenesis, fertilization, and embryo growth rates in vitro. During leuprolide administration, mean serum concentrations of leuprolide were less than 50 ng/ml and were undetectable 48 hours after cessation of administration. There was no effect of leuprolide on progesterone (P) secretion by granulosa-lutein cells cultured in the presence or absence of human chorionic gonadotropin. The effect of leuprolide on embryo growth rates was evaluated with the mouse two-cell embryo culture model and a retrospective review of early embryo growth rates in humans receiving adjunctive leuprolide therapy. There was no measurable effect of leuprolide on early embryo growth in either species. These data indicate that (1) serum and follicular and peritoneal fluid concentrations are undetectable 2 days after discontinuation of leuprolide; (2) there is no measurable effect of leuprolide on human or murine embryo growth rates up to the 8 cell stage in vitro; and (3) there is no measurable effect of leuprolide on granulosa-lutein cell P accumulation.

Animals

Comparison of goserelin and leuprolide in combined androgen blockade therapy.

OBJECTIVES: To perform exploratory analyses of data from a controlled trial that assessed the efficacy and tolerability of two antiandrogens, bicalutamide and flutamide, each combined with monthly depot preparations of leuprolide or goserelin, in patients with Stage D2 prostate cancer. One analysis compared goserelin plus antiandrogen therapy with leuprolide plus antiandrogen therapy; a second analysis compared the four combined androgen blockade (CAB) regimens. METHODS: This was a randomized, multicenter trial, open-label for luteinizing hormone releasing hormone analogue (LHRH-A) therapy, double-blind for antiandrogen therapy, with a two-by-two factorial design. Eight-hundred thirteen patients were allocated in a ratio of 2:1 to goserelin therapy (3.6 mg every 28 days) or leuprolide therapy (7.5 mg every 28 days) and 1:1 to bicalutamide therapy (50 mg once a day) or flutamide therapy (250 mg three times a day). The end points of time to progression and survival were assessed with a median of 160 weeks of follow-up. RESULTS: The percentages of progression events (70.9% versus 73.3%) and deaths (54.3% versus 56.8%) were similar for goserelin plus antiandrogen and leuprolide plus antiandrogen therapies. The hazard ratios for goserelin plus antiandrogen therapy to leuprolide plus antiandrogen therapy were 0.99 (95% confidence interval [CI] 0.84 to 1.18; P = 0.92) and 0.91 (95% CI 0.75 to 1.11; P = 0.34) for time to progression and survival, respectively. Goserelin plus antiandrogen and leuprolide plus antiandrogen therapies were generally well tolerated, and the side effects associated with depot administration occurred with a low frequency in the two groups. There were no significant differences among the goserelin plus bicalutamide, goserelin plus flutamide, or leuprolide plus bicalutamide therapy groups, but leuprolide plus flutamide therapy had a significantly poorer outcome than the other three therapies. The side-effect profiles for the four CAB groups were generally similar; diarrhea was more common among patients treated with flutamide and hematuria was more common among patients treated with bicalutamide. CONCLUSIONS: Although the results of these exploratory analyses should be interpreted with caution, they indicate that goserelin plus antiandrogen and leuprolide plus antiandrogen therapies are similarly well tolerated and have equivalent time to progression and survival, and that leuprolide plus flutamide therapy appears to be the least effective of the four CAB regimens.

Adult

The gonadotropin-releasing hormone agonist leuprolide affects the thymus and other non-reproductive systems of female rats.

To evaluate the effects of a gonadotropin-releasing hormone agonist on non-reproductive systems, we administered [D-Leu6,Des-gly10]-GnRH ethylamide (leuprolide; 5 micrograms/day) for 21 days to female Sprague-Dawley rats. In Experiment 1, continuous infusion (Alzet minipumps sc) was compared to injection. Increased thymus and body weights and decreased estradiol and uterine weights were noted for both administration methods. Spleen weight increased only in rats treated by continuous infusion. Ovary, kidney and liver weights did not change. Only leuprolide-injected rats had elevated LH with decreased corticosterone and ACTH levels, possibly related to the injection process. Glucose, insulin, progesterone, FSH and corticosterone/ACTH were not different. In Experiment 2, intact and ovariectomized rats were implanted with minipumps delivering leuprolide or 0.9% NaCl. Body and thymus weights increased, whereas uterine weight and estradiol declined in both leuprolide-treated and ovariectomized rats. No synergism between leuprolide and ovariectomy was noted. Thymosin alpha 1, but not thymosin beta 4, increased in leuprolide-treated ovariectomized rats. Peripheral white blood cell count was elevated in leuprolide-treated intact rats and ovariectomized rats. In bone marrow, non-nucleated cell count declined in leuprolide-treated intact rats, contributing to the decreased total cell count in this group. Nucleated cell count was unaffected. Therefore, thymus weight gain was accompanied only in some cases by functional changes. Our results demonstrate that leuprolide affects non-reproductive systems, in a similar manner to ovariectomy. We suggest that such alterations may be due to the hypoestrogenic environment produced by leuprolide.

Adrenocorticotropic Hormone

Prevention of hypermenorrhea with leuprolide in premenopausal women undergoing bone marrow transplantation.

We report on the use of leuprolide to prevent heavy menstrual bleeding that often occurs before platelet engraftment in premenopausal women undergoing bone marrow transplantation (BMT). Leuprolide, a synthetic analog of gonadotropin-releasing hormone (Gn-RH-a), was given to 34 patients by intravenous bolus injection, 1 mg daily, until platelet recovery. The median duration of therapy was 50 days (range 16-170). When necessary, patients self-administered the drug after discharge from the hospital. No adverse effects could be related directly to the use of leuprolide. Leuprolide effectively prevented menstruation in 25 patients (73%), failed in seven (21%), and two patients were not evaluable. The success of leuprolide therapy was related to the time of onset of treatment, as anticipated from the gradual effect of Gn-RH-a on the menstrual cycle. The failure rate was only 6% (one of 16 patients) when leuprolide was started at least 2 weeks prior to the development of thrombocytopenia, compared to a failure rate of 33% (six of 18 patients) when leuprolide was started at a later time. We conclude that leuprolide as a single agent is a safe and effective method to prevent menstrual bleeding during BMT. Additional studies are needed to determine the best timing for the onset of therapy and the relative benefit of leuprolide compared to other prophylactic approaches in patients with lengthy thrombocytopenia.

Adolescent

Leuprolide versus diethylstilbestrol for metastatic prostate cancer.

We compared the efficacy and safety of the gonadotropin-releasing hormone analogue, leuprolide (1 mg subcutaneously daily), with diethylstilbestrol (DES, 3 mg by mouth daily) in patients with prostate cancer and distant metastases (Stage D2) who had not previously received systemic treatment. Initial therapy (leuprolide or DES) was continued for as long as an objective response was noted; cross-over to the alternative arm occurred at the time of disease progression or intolerable adverse reactions. Ninety-eight patients were randomly assigned to leuprolide, and 101 to DES. Suppression of testosterone and dihydrotestosterone and decreases in acid phosphatase were comparable in the two groups. Patients receiving DES experienced more frequent painful gynecomastia (P less than 0.00001), nausea and vomiting (P = 0.02), edema (P = 0.008), and thromboembolism (P = 0.065) than those receiving leuprolide. The leuprolide group reported more "hot flashes" (P = 0.00001). Overall, 86 per cent of the leuprolide group had an objective response (complete response, 1 per cent; partial response, 37 per cent; stable disease, 48 per cent), as compared with 85 per cent of the DES group (complete, 2 per cent; partial, 44 per cent; stable, 39 per cent). Actual survival rates at one year were 87 per cent for the leuprolide group and 78 per cent for the DES group (P = 0.17). We conclude that leuprolide offers an important alternative treatment that is therapeutically equivalent to and causes fewer side effects than DES for the initial systemic management of metastatic prostate cancer.

Acid Phosphatase

Effect of gelation on the chemical stability and conformation of leuprolide.

PURPOSE: The purpose of this study was to characterize the conformation, aggregation, and stability of leuprolide on gelation. METHODS: Infrared spectra (FTIR) of leuprolide solutions and gels were collected in water, propylene glycol (PG), dimethyl sulfoxide (DMSO), and trifluoroethanol (TFE). Leuprolide solution and gel stability data were obtained by SEC and RP-HPLC. RESULTS: Leuprolide was induced to gel with increasing peptide concentration, introduction of salts, and gentle agitation. Leuprolide dissolved in water (400 mg/ml) demonstrated FTIR spectra consisting of two major bands of equal intensity at 1615 cm(-1) and 1630 cm(-1), similar to inter- and intra-molecular beta-sheet structure in proteins. When samples were gently agitated for 24 hours at 25 degrees C, the formulation was observed to change from a viscous liquid to an opaque gel with a concomitant shift in infrared spectra from the equal intensity bands to mostly 1630 cm(-1), indicating a shift to a preferred beta-sheet structure. Incubation of leuprolide with 20-200 mM salts at 25 degrees C and 37 degrees C also produced gels ranging from clear to cloudy and stringy white precipitates. The gel and precipitate were marked by a shift of the predominant beta-sheet band to 1630 cm(-1) and 1615 cm(-1), respectively. Leuprolide was also observed to gel and/or precipitate in mixtures of water, PG or TFE, but not in DMSO. CONCLUSIONS: Birefringence was noted in many of the firmer gels. Both solutions and gels demonstrated minimal dimer or trimer formation, with no larger order aggregates detected. The chemical stability profile of gelled leuprolide was similar to that of the non-gelled water formulation by RP-HPLC.

Chromatography, High Pressure Liquid

In vitro effects of diethylstilboestrol and the LHRH analogue leuprolide on natural killer cell activity.

In a series of studies of the immunobiological sequelae of oestrogens, the in-vitro effect of diethystilboestrol (DES) and the luteinizing-hormone-releasing-hormone leuprolide (Lupron) on the lytic activity of natural killer (NK) cells have been evaluated. Ficoll-Hypaque gradient-isolated human peripheral blood mononuclear cells (PBMC) were pre-incubated with varying concentrations of DES and leuprolide and the degree of lysis for the human erythroleukemia K-562 cell line was evaluated in a 51Cr-release assay. PBMC pre-incubated with DES exhibited an 82% reduction in the ability of NK cells to lyse K-562 target cells compared with a negligible 3% increase with leuprolide (p less than 0.001) vs. untreated PBMC. The inhibitory effects of DES or leuprolide were not due to cytotoxicity since the viability of PBMC incubated for 18 and 24 h (corresponding to the DES/leuprolide preincubation time and the NK cell assay, respectively) was comparable to that of untreated (control) cells. These observations demonstrate the further suppressive effects of DES on components of immunosurveillance. Pending evaluation of the effect of leuprolide on the activity of NK cells for other target cells, and other parameters of immunologic responsiveness, leuprolide may prove to be a favorable alternative to DES, both in view of its reduced clinical side-effects, and because of the suggested absence of deleterious effects to the immune system. Maintenance of tumour-host equilibrium, and some degree of immunocompetency, in the presence of effective therapy with leuprolide, may prove beneficial in achieving more effective therapy in prostate cancer patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma

Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group.

OBJECTIVE: To evaluate and compare the safety and efficacy of leuprolide versus placebo in managing chronic pelvic pain in women with clinically suspected endometriosis. METHODS: Women 18-45 years of age with moderate to severe pelvic pain of at least 6 months' duration underwent extensive, noninvasive diagnostic testing and laboratory evaluation, including pelvic ultrasound, complete blood count, determination of erythrocyte sedimentation rate, and endocervical cultures. Those with clinically suspected endometriosis were randomized to double-blind treatment for 3 months with depot leuprolide (3.75 mg/mo) or placebo. The accuracy of the clinical diagnosis of endometriosis was evaluated by posttreatment laparoscopy. RESULTS: Of 100 women randomized, 95 completed the study: 49 in the leuprolide group and 46 in the placebo group. Women in the leuprolide group had clinically and statistically significant (P < or = .001) mean improvements from baseline after 12 weeks of therapy in all pain measures. These mean improvements were significantly greater (P < or = .001) than those in the placebo group. At 12 weeks, mean decreases in physician-rated scores for dysmenorrhea, pelvic pain, and pelvic tenderness were 1.7, 1.0, and 0.8 points greater, respectively, in the leuprolide group than in the placebo group (on a four-point scale). Thirty-eight (78%) of 49 and 40 (87%) of 46 patients in the leuprolide and placebo groups, respectively, had laparoscopically confirmed endometriosis after 12 weeks of treatment. No women withdrew from the study because of adverse events. CONCLUSION: Depot leuprolide was effective and safe for treating patients with chronic pelvic pain and clinically suspected endometriosis, confirming the potential of its empiric use in these patients.

Adolescent

Cost comparisons between nafarelin and leuprolide in the treatment of endometriosis.

The objective of this study was to compare the cost and effectiveness of nafarelin versus leuprolide in the treatment of endometriosis. To compare the economic impact of treating endometriosis with leuprolide or nafarelin and to facilitate cost comparisons between the two, we statistically analyzed information concerning the costs of medications for the treatment of endometriosis, outpatient services, and management of adverse effects, as well as other related costs. A national claims database, MarketScan, was used to obtain data on patients with a principal diagnosis of endometriosis who were treated with either leuprolide or nafarelin. During the calendar years 1992-1994, 114 patients with endometriosis had claims for nafarelin, and 343 had claims for leuprolide. There were no significant differences between nafarelin and leuprolide recipients with respect to demographic variables, types of concomitant drug used, types of outpatient service received, or major outpatient diagnostic categorization. In 1994 dollars, the cost of using leuprolide was $326.7 greater than that of using nafarelin. The results of this study suggest that nafarelin is a less expensive alternative to leuprolide for the treatment of endometriosis.

Adult

Sublingual absorption of leuprolide: comparison between human and animal models.

Leuprolide is a potent luteinizing hormone releasing hormone agonist used for the treatment of hormone-dependent diseases. It is a decapeptide drug currently administered by subcutaneous and intramuscular injection because it is not orally bioavailable. In the present study, sublingual gel formulations of leuprolide were administered to dogs, monkeys and humans. Plasma samples were analyzed by radioimmunoassay. Absorption and pharmacokinetics of leuprolide following sublingual administration were compared and evaluated. It was found that the extent and rate of absorption were similar between humans and monkeys following sublingual dosing of leuprolide formulations. A prolonged absorption of up to approximately 6 h after dosing was observed in both humans and monkeys. The rate and extent of absorption were significantly higher in dogs than in humans. The estimate of absolute bioavailability of leuprolide was 46.7% in dogs compared with 2.7% in monkeys at an equivalent dose of 0.45 mg/kg. Absolute bioavailabilities in humans were 2.0, 2.3 and 2.4% at doses of 1.125, 2.25 and 4.5 mg, respectively. Based on these results, the dog is not an appropriate animal model for evaluating sublingual absorption of leuprolide. This work suggests that monkey is a preferred model for the development and assessment of sublingual formulations of leuprolide.

Administration, Sublingual

Prevention of DMBA-induced rat mammary carcinomas comparing leuprolide, oophorectomy, and tamoxifen.

Leuprolide, a gonadotropin releasing hormone agonist, is currently being evaluated in a pilot study of premenopausal women for the prevention of breast cancer. However, little data is available regarding the efficacy of leuprolide in experimental animal models of carcinoma when administered prior to the carcinogen. In the present study the capacity of leuprolide to prevent tumor development was evaluated by comparing its pretreatment effects in the DMBA-induced rat mammary carcinoma model to pretreatment with tamoxifen and oophorectomy. Fifty-five day old, female Sprague-Dawley rats were randomly allocated to one of four groups: 1) no treatment; 2) oophorectomy two weeks prior to DMBA; 3) leuprolide, 40 microg/kg/day; and 4) tamoxifen, 10 mg/kg/week. All animals received four 5 mg doses of DMBA for a total dose of 20 mg. Leuprolide and tamoxifen treatments began two weeks prior to DMBA and ended one week after DMBA administration. Animals were assessed weekly to determine palpable tumor onset, number, size, and volume. At the conclusion of the study (16 weeks), autopsies were performed and tumor tissue was collected for confirmation of malignancy. Seventy-eight percent of the untreated rats developed tumors. No tumors developed in the oophorectomy group, while the number of rats with tumors was significantly reduced (p<0.05) with both leuprolide (30%) and tamoxifen (21.9%) compared to controls (77.8%). There were no significant differences in the tumor number for each tumor-bearing rat or in tumor volume between treated and control groups. Using our dosage regimen, 'chemical oophorectomy' with leuprolide was not as effective as surgical oophorectomy in the prevention of chemical carcinogenesis by DMBA but was comparable to the results obtained with tamoxifen.

9,10-Dimethyl-1,2-benzanthracene

Leuprolide acetate affects intestinal motility in female rats before and after ovariectomy.

Leuprolide acetate, a gonadotropin-releasing hormone (GnRH) analogue, is currently being proposed to control debilitating symptoms in women with functional bowel disease. Whether leuprolide alters gastrointestinal motility as part of its actions is unknown. This study was designed to assess, using myoelectric techniques in an animal model, the effects of leuprolide on potential mechanisms of neuromuscular function of small intestine. Female rats with (n = 6) or without (n = 8) bilateral ovariectomy were used to study jejunal motility before and after leuprolide therapy. Throughout the study, daily leuprolide dosages of 0.02, 0.2, or 0.4 micrograms/kg were injected into intact rats and 0.02, 0.2, 0.4, 1.0, or 2.5 micrograms/kg into ovariectomized rats. Recordings were made while the rats were fasted and postprandial and before and after leuprolide administration. Under control conditions, migrating myoelectric complexes (MMCs) were found in intact female rats, whether fasted or postprandial. After ovariectomy, postprandial controls and those treated with low-dose leuprolide (0.02, 0.2, and 0.4 micrograms) had typical fed-state patterns and no MMCs, but at 1.0 and 2.5 micrograms the fed state was inhibited and cycling MMCs occurred at a frequency similar to that of fasted controls. Reproductive hormones thus have a significant effect on gastrointestinal motility.

Animals