Gonadotropin-releasing Hormone Agonist Leuprolide Acetate Research Articles

Improved implantation and live delivered pregnancy rates following transfer of embryos derived from donor oocytes by single injection of leuprolide in mid-luteal phase

To determine if the use of a single injection of one-mg leuprolide acetate in mid-luteal phase can increase pregnancy rates in donor oocyte recipients.Prospective study where couples were made aware of a study using the gonadotropin releasing hormone agonist (GnRHa) triptorelin that in the mid-luteal phase found improved pregnancy rates following embryo transfer in donor oocyte recipients. They were given the option of a single one-mg injection of the GnRHa leuprolide acetate. Pregnancy outcome was compared according to whether leuprolide was given or not. Also compared were the average first serum beta-hCG level in those who conceived according to taking leuprolide or not.Chi-square analysis showed a significantly higher clinical and live delivered pregnancy rate (63.9% and 52.8%) in those supplementing with leuprolide than those who did not (39.5% and 32.9%). Similarly implantation rates were significantly higher (44.2% vs. 25.2%). The average first serum beta-hCG level for those conceiving and taking leuprolide was 294 mIU/mL vs. 325 mIU/mL for those who did not.Similar to triptorelin the mid-luteal injection of leuprolide acetate improves pregnancy outcome in donor oocyte recipients.

Abnormalities of Dorsolateral Prefrontal Function in Women With Premenstrual Dysphoric Disorder: A Multimodal Neuroimaging Study

To investigate the neural substrate of premenstrual dysphoric disorder (PMDD), the authors used [15O]H2O positron emission tomography (PET) regional cerebral blood flow (rCBF) and blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal measurements during working memory in conjunction with a 6-month hormone manipulation protocol. PET and fMRI scans were obtained from women with prospectively confirmed PMDD and asymptomatic comparison subjects while they completed the n-back task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate, leuprolide plus estradiol, and leuprolide plus progesterone. Fifteen patients and 15 matched comparison subjects underwent PET imaging. Fourteen patients and 14 comparison subjects underwent fMRI. For each hormone condition, rCBF was measured with [15O]H2O PET, and BOLD signal was measured with fMRI, both during an n-back working memory paradigm. Global Assessment of Functioning Scale (GAF) scores and clinical characteristics were obtained for each patient before hormone manipulation, and symptoms were measured before and during the protocol. In both the PET and fMRI studies, a main effect of diagnosis was observed, with PMDD patients showing greater prefrontal activation than comparison subjects. In the patient group, the degree to which dorsolateral prefrontal cortex activation was abnormally increased correlated with several dimensions of disease: disability as indicated by GAF scores, age at symptom onset, duration of PMDD, and differences in pre- and postmenses PMDD symptoms. Abnormal working memory activation in PMDD, specifically in the dorsolateral prefrontal cortex, is related to PMDD severity, symptoms, age at onset, and disease burden. These results support the clinical relevance of the findings and the proposal that dorsolateral prefrontal cortex dysfunction represents a substrate of risk for PMDD. The concordance of the fMRI and PET data attests to the neurobiological validity of the results.

Evidence that the Main Adverse Effect of Ganirelix on Pregnancy and Implantation Rates is on the Embryo Rather than the Endometrium

Background: At least in our in vitro fertilization (IVF) center the use of ganirelix in controlled ovarian hyperstimulation (COH) protocols for IVF-embryo transfer (ET) has consistently been associated with lower pregnancy rates than when cetrorelix was used in gonadotropin releasing hormone (GnRH) antagonist protocols or when the GnRH agonist leuprolide acetate was used. Objectives: The objective of the present study was to evaluate the pregnancy rates following frozen ET according to the use of these three agents. The finding of lower pregnancy rates with ganirelix following frozen ET would suggest an adverse effect on the embryo rather than the endometrium. Materials and Methods: Clinical (viable at 8 weeks) and live delivered pregnancy and implantation rates following frozen ET were compared in two age groups ≤35 and 36-39 according to use of ganirelix, cetrorelix or luteal phase leuprolide acetate. Single embryo transfers were excluded. Results: The clinical pregnancy rate per frozen embryo transfer in women aged ≤39 whose embryos were formed using ganirelix was 30.0% (52/173) vs. 42.5% (289/680) for cetrorelix and leuprolide acetate combined (P=.0038). The respective live delivered pregnancy rates were 24.8% (43/173) vs. 34.5% (235/680) (P=.019). Similarly the implantation rates were lower with ganirelix showing a 13.1% (69/525) level vs. 20.9% (406/1931 (P<.0001). Conclusions: The adverse effect that some IVF centers notice when using ganirelix in the COH protocol vs. cetrorelix or leuprolide acetate following fresh ET seems to be an embryo defect rather than an endometrial abnormality.

A Randomized, Controlled Trial of Asoprisnil, a Novel Selective Progesterone Receptor Modulator, in Women With Uterine Leiomyomata

The only effective medical treatment of symptomatic uterine leiomyomas has been the gonadotropin-releasing hormone agonist leuprolide acetate depot, which carries a risk of producing hypoestrogenic symptoms. High-dose progestin therapy has been used to control heavy uterine bleeding (HUB) but may cause breakthrough bleeding. Another option is asoprisnil, a selective progesterone (P) receptor modulator that has mixed P agonist and antagonist actions and is highly uterine-selective. In both primate and human studies, it has induced amenorrhea and suppressed endometrial growth. This randomized prospective, double-blind, placebo-control study, carried out at 28 sites in the United States and 1 in Canada, enrolled 129 women 18 to 49 years of age who had at least one leiomyoma measuring 3 cm or more in diameter or multiple small lesions producing a uterine volume exceeding 200 cm 3 . All participants had normal menses and no other significant pelvic pathology. They received either asoprisnil in a daily oral dose of 5, 10, or 25 mg or a placebo for 12 weeks. Uterine bleeding was monitored by daily diaries, and uterine volume was measured sonographically. The 5-, 10-, and 25-mg doses of asoprisnil suppressed uterine bleeding in 28%, 64%, and 83% of patients, respectively. These patients did not have even light bleeding while being treated. No placebo recipient responded. Dose-related rates of amenorrhea, defined as no bleeding or only spotting, were 16%, 36%, and 70%, respectively. Compared with placebo, treatment with 25 mg daily for 4 and 8 weeks was associated with a statistically significant decrease in leiomyoma volume, and by week 12 it was reduced by 36%. The higher doses of asoprisnil significantly reduced bloating and, in patients given 25 mg daily, pelvic pressure also declined significantly by week 12. Hemoglobin concentrations increased significantly more in all treatment groups than in placebo recipients. Treatment had no apparent effect on pelvic pain or dyspareunia. Hypoestrogenic symptoms were minimal. Endometrial thickness was similar in the treatment and placebo groups at the end of the study, and no hyperplasia or other adverse changes were observed. Asoprisnil therapy appeared to inhibit basal gonadotropin concentrations. There were no clinically significant changes in blood chemistry or blood pressure, and no clinically relevant cervical abnormalities were observed. Adverse effects of all types were similarly frequent in the treatment and placebo groups. These findings support the use of asoprisnil to treat complaints related to uterine leiomyomas, notably HUB and bulk-related symptoms, without significantly altering blood estrogen levels at the same time. Treatment with doses as high as 25 mg daily for 12 weeks was well tolerated.

Marked hyperglycemia after androgen-deprivation therapy for prostate cancer and usefulness of pioglitazone for its treatment

Here we demonstrate 2 patients who showed marked hyperglycemia after androgen-deprivation therapy for prostate cancer and the efficacy of the thiazolidinedione pioglitazone on their glycemic control. Case 1 was a 61-year-old man diagnosed with prostate cancer who had type 2 diabetes mellitus for 7 years. His glycemic control had been good for the previous 5 years because of diet therapy and acarbose administration. He was given the gonadotropin-releasing hormone agonist leuprolide acetate and the androgen receptor antagonist flutamide for the treatment of prostate cancer. After the second injection of leuprolide acetate, fasting glucose and hemoglobin A1c (HbA1c) levels were found to be markedly elevated (22.8 mmol/L and 10.5%, respectively). Case 2 was an 81-year-old man whose fasting glucose and HbA1c had been normal 10 months ago. He was injected with leuprolide acetate for the treatment of prostate cancer. Six months after starting the leuprolide treatment, the patient complained of thirst and weight loss and was diagnosed with diabetes mellitus with a fasting glucose of 19.4 mmol/L and HbA1c of 9.9%. The correct homeostasis model assessment evaluation indexes for pancreatic β-cell function (HOMA-% β) and for insulin sensitivity (HOMA-%S) were reduced in these 2 patients compared with control men. Their serum testosterone and 17 β-estradiol concentrations were depressed. After improvement of hyperglycemia by insulin treatment, their glycemic control remained good after treatment with pioglitazone without use of insulin. The values of HOMA-% β and HOMA-%S increased to control ranges. Insulin resistance after the androgen-deprivation therapy might lead to marked hyperglycemia in these patients.

The gonadotropin-releasing hormone agonist leuprolide acetate induces apoptosis and suppresses cell proliferative activity in rectovaginal endometriosis

A gonadotropin-releasing hormone agonist, leuprolide acetate, was administered every 4 weeks for treatment of rectovaginal endometriosis. Degrees of apoptosis (percentage of in situ deoxyribonucleic acid 3′–end-labeled cells) and cell proliferative activity (percentage of cells with immunostaining for proliferating cell protein Ki-67) were examined in endometriotic glands of biopsy specimens taken before and during gonadotropin-releasing hormone agonist therapy. Gonadotropin-releasing hormone agonist induced apoptosis and suppressed cell proliferative activity in endometriotic glands. (Am J Obstet Gynecol 1999;181:750-1.)

Leuprolide, a gonadotropin-releasing hormone agonist, enhances colonization after spermatogonial transplantation into mouse testes

Spermatogonial stem cells can be transplanted from a fertile donor mouse to the testis of an infertile recipient where they establish spermatogenesis and produce spermatozoa. In the present study we investigated whether treatment of recipient mice with the gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate could alter the efficiency of colonization by donor spermatogonial stem cells in the recipient testis. Six recipient mice were treated with busulfan to destroy endogenous spermatogenesis followed by injection of leuprolide acetate to three of the mice. Testis cells from mice carrying the ZFlacZ transgene, which produces β-galactosidase in spermatids, were used as donor cells for transplantation to allow for identification of donor spermatogenesis in the recipient testis by staining for enzyme activity. The extent of donor cell colonization was compared between leuprolide treated recipients and untreated control mice 3 months after transplantation. Efficiency of colonization by donor cells was markedly enhanced in recipient mice treated with the GnRH agonist leuprolide acetate, which makes the technique of spermatogonial transplantation applicable to a wide range of experimental situations. The present study also indicates that this technique can be used as a biological assay system to investigate factors controlling the establishment and progression of spermatogenesis.

Cellular proliferation, estrogen receptor, progesterone receptor, and bcl-2 expression in GnRH agonist-treated uterine leiomyomas

Gonadotropin-releasing hormone (GnRH) agonists are commonly used in the treatment of uterine leiomyomas, but little is known about their histological and cellular effects on these neoplasms. We examined a cellular proliferation index as determined by the nuclear antigen Ki-67 and proliferating cell nuclear antigen (PCNA) expression, estrogen receptor (ER), and progesterone receptor (PR) expression in 27 leiomyomas from patients treated with the GnRH agonist leuprolide acetate (LA) and compared them with 33 untreated controls. All leiomyomas were removed by myomectomies from premenopausal woman after 2 to 6 months of LA treatment or in the follicular phase of the menstrual cycle in the untreated controls. Histological features examined included cellularity, nuclear atypia, vascular changes (dilated, thickened, or thrombosed vessels), edema, calcification, hemorrhage, necrosis, hyalinization, and mitotic activity. Although no difference was found between GnRH-treated and non-treated groups with respect to most histological features examined, immunohistochemical studies showed a significant decrease in the cellular proliferation index, ER, and PR expression in the LA-treated cases compared with nontreated controls. The cellular proliferation index, ER, and PR expression decreased by 85%, 49%, and 36%, respectively, in the LA-treated group as compared with controls ( P < .001). A subset of cases from the LA-treated and nontreated groups were also analyzed with respect to bcl-2 (an inhibitor of apoptosis) expression, and no significant difference between the LA-treated and nontreated groups was observed with both groups showing a strong (>75% of cells) cytoplasmic staining pattern. Results of this study show that LA treatment of leiomyomas results in a decrease in number of cycling cells.

Effectiveness and limitations of the use of the gonadotropin-releasing hormone agonist leuprolide acetate in the diagnosis of delayed puberty in males.

In order to evaluate the effectiveness of the gonadotropin-releasing hormone agonist leuprolide acetate in distinguishing gonadotropin deficiency from delayed puberty, a single subcutaneous dose of 20 micrograms/kg of leuprolide acetate was administered at 07.00 h to 14 patients with constitutionally delayed puberty and to 8 gonadotropin-deficient subjects, and serum gonadotropin and testosterone levels were determined at baseline and 1,2,3,6,12, and 24 h thereafter. The increase in gonadotropin and testosterone levels was significant in patients with delayed puberty, so that the mean peak luteinizing hormone and to a lesser degree the mean peak testosterone levels clearly differentiated normally delayed from gonadotropin-deficient puberty. However, when the peak gonadotropin and testosterone concentrations were analyzed individually, there was a considerable overlap between the two groups of males, limiting the usefulness of this test.

Gonadotropin-releasing hormone (GnRH) and GnRH receptor gene expression in human myometrium and leiomyomata and the direct action of GnRH analogs on myometrial smooth muscle cells and interaction with ovarian steroids in vitro.

The objective of the present study was to determine whether GnRH and GnRH receptor are expressed in myometrium and leiomyomata, and if GnRH analogs alone or in the presence of ovarian steroids can modulate the rate of DNA synthesis, proliferation, and transforming growth factor-beta 1 (TGF beta 1) production in myometrial smooth muscle cells in vitro. Reverse transcription-PCR revealed that leiomyomata, unaffected myometrium, and isolated myometrial smooth muscle cells express GnRH and GnRH receptor messenger ribonucleic acid. Furthermore, in a dose-dependent manner, GnRH agonist (leuprolide acetate) inhibited, but GnRH antagonist [D-pGlu1,D-Phe2,D-Trp3.6] (GnRH-Ant1) stimulated, the rate of [3H]thymidine incorporation into myometrial smooth muscle cells (P < 0.05), whereas GnRH-Ant2 (Ac-D-P-Cl-Phe1.2,D-Trp3,D-Arg6,D-Ala10) had no effect. 17 beta-Estradiol (E2) medroxyprogesterone acetate (MPA), and E2 plus MPA (1 micromol/L) stimulated the rate of DNA synthesis by smooth muscle cells (P < 0.05), which was inhibited by GnRH analogs used at 5 micromol/L (P < 0.05). GnRH analogs had no significant effect on myometrial smooth muscle cell proliferation, with the exception of GnRH-Ant1; however, they inhibited the stimulatory action of E2, MPA, and E2 plus MPA in a time-dependent manner (P < 0.05). These cells also synthesized and released approximately 1.32 +/- 0.02 ng/mL total (active plus latent) TGF beta 1, of which 0.73 +/- 0.02 ng/mL was in an active form. E2, MPA, E2 plus MPA, and GnRH analog treatments resulted in an increase in total TGF beta 1 production, whereas GnRH agonist and GnRH-Ant2, but not GnRH-An1, inhibited active TGF beta 1 (P < 0.05). GnRH analogs also inhibited the action of E2 plus MPA on total and active TGF beta 1 production, whereas GnRH-Ant1 further stimulated E2, MPA, or E2 plus MPA action on active TGF beta 1 production (P < 0.05). The data demonstrate for the first time that GnRH and GnRH receptor messenger ribonucleic acid are expressed in myometrium, leiomyomata, and myometrial smooth muscle cells. The local expression of GnRH and receptor along with the direct action of GnRH analogs on the smooth muscle cell DNA synthesis and TGF beta 1 production suggest an autocrine/paracrine role for GnRH in these tissues, a mechanism that may be involved in leiomyomata regression in women receiving GnRH agonist therapy.

Ovarian hyperstimulation syndrome associated with the use of the gonadotropin-releasing hormone agonist leuprolide acetate

Severe ovarian hyperstimulation syndrome occurred after the administration of LA to suppress multicystic ovaries. It is possible that this patient with multiple ovarian cysts, each 2 to 3 cm in size, is at increased risk for a paradoxical stimulatory rather than inhibitory response to GnRH-a.

Immunoreactive epidermal growth factor concentrations in follicular fluid obtained from in vitro fertilization

Immunoreactive epidermal growth factor (EGF) was measured in follicular fluid (FF) obtained at the time of oocyte retrieval for in vitro fertilization from cycles with (91 follicles) and without (128 follicles) the gonadotropin-releasing hormone agonist leuprolide acetate (LA). Follicular fluid immunoreactive EGF levels in the non-LA cycles correlated with androstenedione but not estradiol or progesterone levels from follicles with prophase I oocytes or from all follicles taken together, but not from metaphase I or metaphase II oocyte containing follicles alone. In non-LA cycles, FF immunoreactive EGF levels were lower in follicles that contained metaphase I or II oocytes than prophase I oocytes. Additionally, FF immunoreactive EGF levels were lower in follicles containing metaphase I or II oocytes from non-LA than LA cycles. We conclude that immunoreactive EGF is present in FF. Leuprolide acetate may affect FF immunoreactive EGF levels.

Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropin-releasing hormone agonist suppression are not predictive of pregnancy outcome

In in vitro fertilization (IVF) cycles using gonadotropin-releasing hormone agonist (GnRH-a) suppression, we investigated whether an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration indicates premature luteinization and is associated with a lower pregnancy rate. We retrospectively studied 101 patients treated with the GnRH-a leuprolide acetate, begun in the luteal phase of the prior menstrual cycle and continued until the day of hCG administration. On the day of hCG, 72 patients had P less than 0.9 ng/mL and 29 had less than or equal to 0.9 ng/mL. Patients in the high P group had a significantly greater estradiol level on the day of hCG. No significant difference in clinical pregnancy rates or ongoing pregnancy rates occurred between the low P and high P groups. We conclude that in IVF cycles pretreated with GnRH-a, P levels on the day of hCG are not predictive of conceiving in that cycle.

Immunoreactive epidermal growth factor concentrations in follicular fluid obtained from in vitro fertilization

Immunoreactive epidermal growth factor (EGF) was measured in follicular fluid (FF) obtained at the time of oocyte retrieval for in vitro fertilization from cycles with (91 follicles) and without (128 follicles) the gonadotropin-releasing hormone agonist leuprolide acetate (LA). Follicular fluid immunoreactive EGF levels in the non-LA cycles correlated with androstenedione but not estradiol or progesterone levels from follicles with prophase I oocytes or from all follicles taken together, but not from metaphase I or metaphase II oocyte containing follicles alone. In non-LA cycles, FF immunoreactive EGF levels were lower in follicles that contained metaphase I or II oocytes than prophase I oocytes. Additionally, FF immunoreactive EGF levels were lower in follicles containing metaphase I or II oocytes from non-LA than LA cycles. We conclude that immunoreactive EGF is present in FF. Leuprolide acetate may affect FF immunoreactive EGF levels.

Fibroid and myometrial steroid receptors in women treated with gonadotropin-releasing hormone agonist leuprolide acetate

The reduction in uterine and fibroid volume associated with the chronic administration of a gonadotropin-releasing hormone agonist (GnRH-a) is thought to be secondary to the analogue induced hypoestrogenic state. Our hypothesis was that the concentration of bioactive estrogen receptors (ER) and progesterone receptors (PR) may be important in the regulation of fibroid growth. The purpose of this study was to determine ER and PR content in fibroids and myometria from women pretreated with GnRH-a compared with controls. Tissue was obtained from 20 premenopausal women with uterine fibroids who were randomized to receive either leuprolide acetate depot, 3.75 mg intramuscularly every 28 days for four injections (n = 10) or placebo (n = 10) before myomectomy. The mean fibroid ER and PR content was significantly greater than the mean myometrial ER and PR content. The mean fibroid ER content for GnRH-a-treated patients was significantly greater than in placebo-treated patients (143.3 ± 22.8 versus 36.1 ± 14.3 fmol/mg). The mean fibroid PR and the mean myometrial ER and PR content were not significantly different between treatment groups. Clinically, the significant increase in fibroid ER may be an explanation for the rapid regrowth of fibroids observed after the cessation of GnRH-a therapy.

Equivalency of human menopausal gonadotropin and follicle-stimulating hormone stimulation after gonadotropin-releasing hormone agonist suppression

This study compares the use of human menopausal gonadotropin (hMG) versus follicle-stimulating hormone (FSH), after gonadotropin-releasing hormone agonist (GnRH-a) suppression for in vitro fertilization. Thirty-seven patients were randomized to ovarian stimulation with either hMG or pure FSH. The GnRH-a leuprolide acetate was administered to all patients beginning in the midluteal phase of the prior cycle and continuing until the day of human chorionic gonadotropin (hCG) administration. There were no significant differences between hMG and FSH cycles with regard to the day of hCG administration, mean peak estradiol levels, number of ampules of medication used, and number of oocytes aspirated, embryos transferred, or pregnancies. We conclude that there is no significant difference between hMG and FSH stimulation when used in conjunction with GnRH-a.