Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates

Objective: To assess the effect of pretreatment with an oral contraceptive (OC) on ovarian cyst formation during pituitary suppression with buserelin acetate.

Design: Prospective randomized trial.

Setting: Academic medical center.

Patient(s): Eighty-three patients who were undergoing IVF-ET treatment.

Intervention(s): Patients in the study group were pretreated with an OC for 14 days starting on the first day of menstruation. The administration of SC buserelin acetate was initiated on the last day of OC administration. Patients in the control group began to receive buserelin acetate on day 2 of menstruation. Hormonal assays and ultrasound scans were performed on the first day of menstruation, and 7, 11, and 14 days after the commencement of buserelin acetate administration. Thereafter, these tests were performed weekly until pituitary suppression was achieved.

Main Outcome Measure(s): Incidence of cyst formation.

Result(s): A cyst developed in 27 patients in the control group (52.9%) and no patients in the study group (odds ratio [OR] = 115; 95% confidence interval [CI] = 10–617). Patients in the study group achieved pituitary suppression faster (median difference [MD] = 7 days; 95% CI = 4–14) and required fewer ampules of gonadotropin (MD = 10; 95% CI = 6–14). They recruited more follicles (MD = 3; 95% CI = 0–5) and had higher pregnancy rates (37.2% versus 33.3%).

Conclusion(s): Pretreatment with an OC abolishes ovarian cyst formation, shortens the time required to achieve pituitary suppression, and decreases gonadotropin requirements without having a negative effect on pregnancy rates.     

The significance of delayed suppression using buserelin acetate and recombinant follicle-stimulating hormone in a long protocol in vitro fertilization program

OBJECTIVE: To determine whether the time taken to achieve ovarian suppression has an impact on ovarian responsiveness and the outcome of IVF-ET. DESIGN: Retrospective analysis. SETTING: An assisted reproduction unit at a university center. PATIENT(S): Patients undergoing a long protocol of IVF-ET that included buserelin acetate therapy initiated on day 2 of the cycle and recombinant FSH. INTERVENTION(S): Patients were divided into two groups according to the duration of buserelin acetate therapy required to achieve pituitary and ovarian suppression (group 1 = 2 weeks, n = 172; group 2 = > or =3 weeks, n = 337). MAIN OUTCOME MEASURE(S): Number of recombinant FSH ampules administered, duration of ovarian stimulation (days), ovarian response, and IVF outcome. RESULT(S): The patients in group 2 had lower mean E2 levels after 5 days and 9 days of stimulation than the patients in group 1. The number of recombinant FSH ampules administered and the number of days of stimulation required were higher in group 2 than in group 1. These differences were prominent in the subgroups of older patients (> or =36 years) and patients who had no evidence of polycystic ovaries on ultrasound examination. The number of oocytes retrieved and fertilized, the cancelation rate, and the pregnancy rate were similar in the two groups. CONCLUSION(S): Prolonged administration of a GnRH agonist to achieve suppression leads to a reduced ovarian response, particularly in women > or =36 years of age, but does not affect the success rate of IVF-ET.     

Effect of a gonadotropin-releasing hormone agonist and gonadotropins on ovarian follicles in cynomolgus monkey: a model for human ovarian hyperstimulation

STUDY OBJECTIVE: To examine the effect on large follicles (greater than or equal to 2 mm) of human menopausal gonadotropin (hMG) and buserelin acetate, a gonadotropin-releasing hormone agonist in monkeys. DESIGN: Experimental. SETTING: Reproductive research laboratory. ANIMALS: Fourteen cyclic cynomolgus monkeys receiving hMG alone for 8 days or buserelin acetate plus 8 (group 1), 12 (group 2), or 16 (group 3) days of hMG administration always starting from day 1 of the cycle. RESULTS: The different treatments were effective in over-riding the specific ovulatory quota of 1, and more large follicles developed in treatments involving long duration and higher doses of hMG. In buserelin acetate plus hMG treatments, the frequency of dissociated follicles and follicles in late atresia were, respectively, lower and higher than in hMG alone treatment. The numbers of recoverable mature oocytes (germinal vesicle breakdown) were similar to the numbers of such oocytes recovered after hyperstimulation performed for human in vitro fertilization and embryo transfer (IVF-ET). However, the number of mature oocytes enclosed in typically preovulatory follicles was very low because there were numerous dysmature follicles. CONCLUSION: These data suggest a deleterious effect of buserelin acetate plus hMG treatments on the recruitable follicles at the time when treatments start. The implications of these observations in the field of human IVF-ET are discussed.     

The long protocol of administration of gonadotropin-releasing hormone agonist is superior to the short protocol for ovarian stimulation for in vitro fertilization.

OBJECTIVE: To investigate whether pituitary desensitization with the gonadotropin-releasing hormone agonist (GnRH-a), buserelin acetate, before the administration of human menopausal gonadotropin (hMG) for ovarian stimulation in in vitro fertilization (IVF) is superior to the simultaneous administration of both hormones at the beginning of the treatment cycle. DESIGN: Prospective randomized study. PATIENTS: Ninety-one patients having their first attempt at IVF. INTERVENTIONS: Patients in group 1 (long protocol) were administered subcutaneous (SC) buserelin acetate 200 micrograms/d from day 1 of the menstrual cycle, and hMG was started only after pituitary desensitization had been achieved at least 14 days later. Patients in group 2 (short protocol) were administered SC buserelin acetate 200 micrograms/d from day 2 and the same dose of hMG used in the long protocol from day 3 of the menstrual cycle. RESULTS: The median total amount of hMG required in both groups was comparable. There were significantly more follicles (P = 0.0001), oocytes (P = 0.0008), fertilized oocytes (P = 0.0001), and cleaved embryos (P = 0.0001), and a higher fertilization rate (P = 0.0047) in patients in group 1. The pregnancy rates per initiated cycle and per embryo transfer were 19.57% and 25.71% in group 1 compared with 8.89% and 16.67% in group 2. CONCLUSIONS: The long protocol is superior in terms of significantly greater follicular recruitment, oocyte recovery and fertilization rates, and significantly greater number of embryos available for transfer. In general, it is the preferred method when GnRH-a are used for ovarian stimulation in IVF.     

A method for rapid generation of transgenic animals to evaluate testis genes during sexual maturation

In certain forms of idiopathic infertility, there is failure of follicle stimulating hormone (FSH) and testosterone (T) to initiate spermatogenesis despite the presence of Sertoli cells and germ cells in the testis. In postnatal rats (up to 11 days of age) and infant monkeys (3–4 months old), robust division and differentiation of spermatogonial stem cells is not discerned, even though serum levels of FSH and T are similar to those found during adulthood. Lack of spermatogenesis together with normal hormone levels is a situation similar to that found in certain categories of male infertility. To investigate this intriguing situation, Sertoli cells were cultured from infant and pubertal rats and monkeys and differential gene expression by testicular Sertoli cells was evaluated by DNA microarray using the Agilent microarray system. To determine the role of candidate genes in regulation of spermatogenesis, transgenic animals over-expressing these genes must be generated. However, present techniques for generation of transgenic animals have limited utility for production of several transgenic animals within a short period of time. Therefore, we have developed a technique for making transgenic animals by the testicular route which is less labor intensive and less time consuming. This technique is also ethically superior since fewer mice are required than in existing alternative methods of transgenesis.     

Antifertility effects of an LH-RH analogue in male rats and dogs

The antifertility effects of a highly active LH-RH analogue, D-Ser(Bu)6-LH-RH(1-9)nonapeptide-ethylamide (buserelin) were studied in male rats and dogs. Pituitary-testicular function was not impaired by a "physiological" dose of 5 ng/rat; this dose gave reproducible LH release during chronic administration. At higher dose testicular LH receptors and responsiveness to HCG were diminished in intact prepubertal and adult rats. Pituitary inhibition was independent of gonadal or adrenal steroid feedback, and hypothalamic LH-RH as well as pituitary LH and FSH were reduced by 4 weeks treatment of castrate/adrenalectomized rats with 50 ng buserelin. In male dogs, a dose of 2.5 micrograms/kg sc reduced serum testosterone to 6% of controls within 8 weeks of treatment. Treatment was continued for 6 months and testicular involution was found to be reversible within 8 weeks of stopping treatment. LH-RH analogues at "supraphysiological" doses can be used as antifertility agents, but suppression of sexual activity in male dogs under treatment indicates that loss of libido will be a problem.     

On the maintenance of male fertility in the absence of native testosterone secretion: site-directed hormonal therapy in the rat

A method of direct percutaneous injection of testosterone (T)-laden microspheres directly into the testis was used in an attempt to achieve the maintenance of normal intratesticular T concentrations, spermatogenesis, and fertility. Rats were divided into three groups: (1) sham operated/injection controls; (2) animals receiving 250 micrograms/d gonadotropin-releasing hormone (GnRH)-antagonist; and (3) animals receiving GnRH-antagonist as in group 1 plus 20 mg T-laden microspheres/testis. Treatment periods were 45 and 90 days. Serum T, testicular interstitial fluid T, testis weights, epididymal weights, daily sperm production (sperm x 10(6)/g/d), cauda sperm motility, and fertility were assessed in all animals. Gonadotropin-releasing hormone antagonist treatment reduced serum and testicular interstitial fluid to below detectable levels at day 45 and to similar levels at day 90. Supplementation with T-laden microspheres maintained testicular interstitial fluid T at concentrations not different from controls without elevation of serum T concentrations. All other values, including fertility were suppressed by GnRH-antagonist treatment and maintained by supplementation with T-laden microspheres.     

Reversible inhibition of testicular function by a gonadotropin hormone-releasing hormone antagonist in monkeys (Macaca fascicularis)

The potential of a gonadotropin-releasing hormone (GnRH) antagonist to inhibit reproductive functions in a male nonhuman primate (Macaca fascicularis) was evaluated. Continuous infusion of 2 mg/day of [N-Ac-D-Nal(2)1, D-pCl-Phe2, D-Trp3, D-hArg(Et2)6, D-Ala10]-GnRH (RS-68439) via osmotic minipumps for 9 weeks caused immediate and sustained reduction of serum luteinizing hormone and testosterone concentrations and led to azoospermia in three animals and to sperm counts less than 5 X 10(6) in a fourth. Testicular histology showed severe atrophy of Leydig cells and tubules. The endocrine parameters returned to normal within 2 weeks of termination of treatment. Seminiferous tubule function was restored 14 to 18 weeks after treatment, as indicated by normal ejaculate parameters. It is concluded that chronic GnRH antagonist treatment reversibly inhibits pituitary and testicular function in a nonhuman primate. GnRH antagonists may thus have a potential for clinical use in fertility control and in treatment of androgen-dependent tumors.     

Randomized trial of three luteinizing hormone-releasing hormone analogues used for ovarian stimulation in an in vitro fertilization program.

OBJECTIVE: To determine if biochemical differences in luteinizing hormone-releasing hormone analogues (LH-RH-a) have a clinical influence, we studied three of these molecules: buserelin acetate (group B), triptorelin (group T), and leuprorelin (group L). DESIGN: Clinical trial. SETTING: In Vitro Fertilization (IVF) Center. PATIENTS: Two hundred forty-six patients, undergoing their first IVF attempt, were randomly allocated to one group. The analogues were used in a long protocol for ovarian stimulation in an IVF program. RESULTS: After 15 days of LH-RH-a therapy, the follicle-stimulating hormone level was lower in group B (2.9 +/- 1, 4.3 +/- 1.7, 4.8 +/- 2.1 UI/L for B, T, and L groups, respectively; P less than 0.001), although no difference was found in LH and estradiol (E2) levels. After follicular growth stimulation by human menopausal gonadotropins (hMG), E2 level was significantly lower in B group (1,799 +/- 1,101, 2,440 +/- 1,298, 2,137 +/- 1,044 pg/mL for B, T, and L groups, respectively; P less than 0.01), as well as the E2 level per hMG ampule (67 +/- 51, 97 +/- 61, 82 +/- 49 for B, T, and L groups respectively; P less than 0.01). The pregnancy per stimulated cycle rate was not significantly different among the groups. CONCLUSIONS: These results suggest that LH-RH-a could act not only on the pituitary but also on the ovaries. Moreover, these data suggest that buserelin acetate could be preferentially used for high responders and triptorelin for poor responders.     

A prospective randomized comparison of routine buserelin acetate and a decreasing dosage of nafarelin acetate with a low-dose gonadotropin-releasing hormone agonist protocol for in vitro fertilization and intracytoplasmic sperm injection

OBJECTIVE: To compare the efficacy of a draw-back nafarelin acetate protocol with routine buserelin acetate administration for in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). DESIGN: Prospective clinical study. SETTING: Mie University School of Medicine, Tsu, Mie, Japan. PATIENT(S): One hundred sixty-nine women treated with IVF and 183 women treated with ICSI. INTERVENTION(S): Nafarelin acetate and buserelin acetate in ovarian hyperstimulation in IVF and ICSI were administered. MAIN OUTCOME MEASURE(S): The concentrations of estradiol (E(2)), FSH, LH, gonadotropin dosages; the number of oocytes retrieved, oocytes fertilized, and embryos; and pregnancy rates. RESULT(S): A prospective study was conducted with 44 cycles for 34 couples with nafarelin acetate (group 1) and 47 cycles for 40 couples with buserelin acetate (group 2) with a long IVF protocol; 68 cycles for 46 couples with nafarelin acetate (group 3) and 56 cycles for 39 couples with buserelin acetate (group 4) with a short IVF protocol; 39 cycles for 32 couples with nafarelin acetate (group 5) and 50 cycles for 30 couples with buserelin acetate (group 6) with a long ICSI protocol; and 87 cycles for 60 couples with nafarelin acetate (group 7) and 81 cycles for 61 couples with buserelin acetate (group 8) with a short ICSI protocol. Patients were randomized to receive either full-dose nafarelin acetate (200 microg b.i.d.) treatment for 7 days followed by half-dose nafarelin acetate (200 microg daily) or buserelin acetate (300 microg t.i.d.). There were no statistically significant differences in baseline concentrations of E(2) and FSH, concentrations of E(2), P4, FSH, LH on hCG administration, gonadotropin dosage, the number of oocytes retrieved and embryos transferred, or pregnancy rates between groups 1 and 2, groups 3 and 4, groups 5 and 6, and groups 7 and 8. CONCLUSION(S): Full-dose nafarelin acetate treatment for 7 days followed by half-dose nafarelin acetate ("draw-back" protocol) is an effective new protocol for IVF and ICSI.     

Inhibition of fertility in the male mouse by combined androgen-antiandrogen therapy.

Testosterone enanthate (TE) and oestradiol valerate (EV) in varying dose combinations were subcutaneously injected every alternate day for 10 or 20 days to adult male mouse of proven fertility. Such therapy resulted in suppression of fertility without affecting libido. The main possible cause of fertility inhibition appears to be testicular dysfunction as evidenced by histology and biochemistry of the reproductive organs.     

Clinical predictors for buserelin acetate treatment of uterine fibroids: a prospective study of 40 women

Buserelin acetate, a luteinizing hormone-releasing hormone agonist, is known to be effective in the shrinkage of uterine fibroids. A prospective trial was undertaken (1) to compare the efficacy of intranasal (IN) and subcutaneous (SC) administration of buserelin acetate and (2) to assess if tumor regression correlated with fibroid size and/or patient age. Forty patients were randomly allocated to receive 6 months of either IN buserelin acetate (n = 21) or SC buserelin acetate (n = 19). Four patients did not complete the study and were excluded from statistical analysis. Fibroid regression occurred in all 36 patients. Overall regression to 66% or less of the initial fibroid volume occurred in 70% of subjects. There was no significant difference in fibroid shrinkage between the two administration routes. A significant positive correlation was found between initial fibroid size and subsequent fibroid regression, with larger tumors being more likely to shrink than smaller fibroids. No correlation was found between the patient's age and the extent of fibroid regression.     

大鼠睾丸热作用后各类生精细胞DNA分析

目的:探讨热作用后大鼠睾丸各类生精细胞DNA变化和生精功能的改变。方法:雄性Sprague-Dawley大鼠80只,随机分热处理组(43℃,30min)和对照组(22℃,30min),热处理组按热处理后0.5d、1d、3d、6d、10d、25d、35d和50d随机分成8个亚组(n=6),每亚组相应设立对照组(n=4)。应用流式细胞仪,对各组大鼠睾丸各类生精细胞DNA含量进行检测和分析。结果:与对照组相比较,热作用后0.5-35d组4C(初级精母细胞)细胞群和6-50d组1C(精子细胞和精子)细胞群的比例显著降低(P<0.05),3-35d组2C(精原细胞和次级精母细胞)细胞群比例显著升高(P<0.05)。8个实验组4C∶2C和3-35d组1C∶2C均显著低于对照组(P<0.05),1d组1C∶4C显著高于对照组(P<0.05)。结论:热作用后首先引起初级精母细胞数量显著下降,其次为精子细胞及精子。热作用使生精过程多个环节效率降低,流式细胞术是一种研究热作用引起生精功能变化的有效方法,有助于分析各类生精细胞在热损伤后的DNA变化。     

Uterine bleeding in the rhesus monkey in response to various designs of intrauterine devices

To study quantitative menstrual blood loss (MBL), 10 normally rhesus monkeys and 18 ovariectomized, hormonally supplemented monkeys (estradiol and progesterone) were inserted with IUDs: a silastic cylinder and 3 modifications the polyethylene Tatum T device. A 92% increase (p.01) in MBL was noted in the Y-T device monkeys (n=7) and a 70% increase (p.05) in the large oval T ones (n=5). MBL was unaffected by the small oval T, and by the cylindrical Silastic devices after the second postinsertion period. Intermenstrual bleeding was observed in 4 of 7 Y-T device animals but was uncorrelated with MBL. It was concluded that rhesus monkeys may serve as good research models for designing human IUDs.     

Effects of tamoxifen on corpus luteum function and luteal phase length in cynomolgus monkeys

Previous data in nonhuman primates have demonstrated that tamoxifen prolongs the luteal phase without altering reproductive hormone levels. A small study in humans found no effect on menstrual cycle length, but an increase in luteal ovarian steroid levels. In view of these conflicting results, we studied the effect of tamoxifen on corpus luteum (CL) function in monkeys (n = 20). Blood was obtained daily beginning cycle day 8, and sera assayed for estradiol (E2), progesterone (P), luteinizing hormone, and follicle-stimulating hormone. Four days after the midcycle E2 peak, laparoscopy confirmed CL formation, and the animals were administered (1) lactose (n = 7), (2) tamoxifen, 0.5 mg.kg-1.d-1 (n = 6), or (3) tamoxifen, 3.0 mg.kg-1.d-1 (n = 7) for 12 consecutive days. Serum collection continued until cycle day 50 or menses, whichever came first. Results indicate a biphasic response among tamoxifen-treated animals, with 7 of 13 developing prolonged luteal phases. There was, however, no significant difference in luteal phase length among the three groups, although when the two groups given tamoxifen were combined, the difference in luteal phase length versus controls approached significance. No differences were found among peak P levels, mean luteal phase P levels, or mean luteal phase gonadotropin levels. No variables were found to correlate significantly with luteal phase length. These results suggest that luteal phase administration of the antiestrogen tamoxifen does not alter pituitary gonadotropin secretion or CL function. However, tamoxifen does prolong luteal phase length in a subset of monkeys, perhaps via a direct effect on the endometrium.     

大鼠睾丸局部热作用对生精细胞Bcl-2及Bax蛋白表达的影响

目的:探讨睾丸局部热作用对大鼠生精细胞凋亡调节蛋白Bcl-2及Bax的影响。方法:雄性Sprague-Dawley大鼠40只,随机分热处理组和对照组,热处理组按热处理后0.5d、1d、3d和6d随机分成4个亚组(n=6),每个亚组相应设立对照组(n=4)。应用免疫组织化学方法检测Bcl-2和Bax在生精细胞的表达。结果:与对照组相比较,热作用后各组Bcl-2阳性细胞表达率及染色阳性细胞Bcl-2含量均显著下降(P<0.01),热作用后各组染色阳性细胞Bax含量均显著增高(P<0.01),除6d组Bax阳性细胞表达率显著下降外(P<0.01),其它各组Bax阳性细胞表达率无差别(P>0.05)。热作用后Bax阳性信号重新分布,从对照组分布在胞浆变成热作用后分布在核周及核。结论:热作用诱导睾丸生精细胞Bcl-2表达下降,Bax表达增高且重新分布。Bcl-2及Bax基因与热诱导生精细胞凋亡发生密切相关。     

Contrasting effects of two hormone replacement therapies on the cardiovascular and mammary gland outcomes in surgically postmenopausal monkeys

OBJECTIVE: The purpose of this study was to compare the effects of two hormone replacement therapies on the intermediate end points of coronary heart disease and mammary gland hyperplasia in postmenopausal monkeys.Study Design: Surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 12 months while receiving no treatment (control, n = 19), conjugated equine estrogens plus continuous medroxyprogesterone acetate (n = 19), or ethinyl estradiol plus norethindrone acetate (n = 21) at doses that were scaled from those doses taken by women. RESULTS: Quantitative coronary angiography revealed that the arteries of the control group and the conjugated equine estrogens plus continuous medroxyprogesterone acetate-treated animals constricted in response to acetylcholine (-5.4% +/- 1.4% and -6.2% +/- 1.5%, respectively), whereas those arteries in the animals in the ethinyl estradiol plus norethindrone acetate group did not (P =.002). The incidence of dobutamine-induced ST-segment depression in the ethinyl estradiol plus norethindrone acetate group (10.5%) was significantly less than in the control group (68.8%, P =.001) or the conjugated equine estrogens plus continuous medroxyprogesterone acetate group (50%, P =.01). Conjugated equine estrogens plus continuous medroxyprogesterone acetate, but not ethinyl estradiol plus norethindrone acetate, induced diffuse epithelial tissue proliferation in the mammary glands (P =.0006). CONCLUSION: Ethinyl estradiol plus norethindrone acetate protected against atherosclerosis-induced endothelium-mediated vasoconstriction of coronary arteries and heart rate-induced myocardial ischemia and did not induce epithelial tissue proliferation (tissue density) in the mammary gland.     

A prospective randomized study of the optimum timing of human chorionic gonadotropin administration after pituitary desensitization in in vitro fertilization.

OBJECTIVE: To determine if there is an optimum time for the administration of human chorionic gonadotropin (hCG) after pituitary desensitization with gonadotropin-releasing hormone agonists (GnRH-a) has been achieved before ovarian stimulation for in vitro fertilization (IVF). DESIGN: Prospective randomized study. PATIENTS: Two hundred forty-seven patients undergoing an IVF treatment cycle who were randomly divided into three groups. INTERVENTIONS: All patients were administered subcutaneously buserelin acetate 500 micrograms/d from day 1 of the menstrual cycle. After pituitary desensitization had been achieved at least 14 days later, ovarian stimulation with human menopausal gonadotropin was commenced. Ovarian stimulation, cycle monitoring, oocyte recovery, and IVF and embryo transfer (ET) techniques were identical in all three groups. Patients in group 1 (n = 79) had hCG administered when the mean diameter of the largest follicle had reached 18 mm, at least two other follicles were greater than 14 mm, and serum estradiol (E2) levels were consistent with the number of follicles observed on ultrasound. Patients in groups 2 (n = 84) and 3 (n = 84) had hCG administered 1 day and 2 days, respectively, after the above criteria had been reached. RESULTS: The mean day of hCG administration (P less than 0.01), maximum serum E2 concentration (P = 0.06), number of days of serum E2 rise (P = 0.03), and mean diameter of the largest follicle (P less than 0.0001) were significantly different. There were, however, no significant differences in the mean number of preovulatory and medium size follicles, number of oocytes recovered or embryos transferred. There were also no significant differences in the oocyte recovery, fertilization and cleavage rates, in the number of embryos frozen, or in the pregnancy rates per initiated cycle and per ET. CONCLUSIONS: There is no significant advantage in the precise timing of hCG administration after pituitary desensitization with GnRH-a.     

Immunoneutralization of gonadotropin-releasing hormone and subsequent treatment with testosterone Silastic implants in rats: an approach toward developing a male contraceptive.

STUDY OBJECTIVE: To determine the extent to which increasing doses of exogenous testosterone (T) administered via Silastic implants can restore spermatogenesis and fertility to rats made azoospermic by active immunization against gonadotropin-releasing hormone (GnRH). DESIGN: Male rats were made azoospermic by active immunization against GnRH. Increasing doses of exogenously administered T (via Silastic implants) were administered for 8 weeks, and testicular sperm concentration and ability to impregnate female rats were evaluated. SETTING: Reproductive Endocrinology Laboratory, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, Colorado. ANIMALS: Sexually mature male Sprague Dawley rats (SASCO, Omaha, NE). RESULTS: Suppression of gonadotropins and azoospermia was achieved by actively immunizing rats against GnRH. Testosterone was capable of restoring quantitatively complete spermatogenesis and fertility in GnRH-immunized azoospermic rats. This relationship was dose-dependent, as evidenced by the partial restoration of spermatogenesis and fertility observed in animals replaced with smaller T Silastic implants. CONCLUSION: Gonadotropin-releasing hormone immunization and T-filled Silastic implants may provide a model to study isolated gonadotropin deficiency and for the development of a reversible male contraceptive.     

Antifertility effects of a potent LH-RH antagonist in male and female rats

The antifertility effects of the antagonistic analogue N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10-LH-RH (ORG 30276) were investigated in male and female rats. Male rats were treated with ORG 30276 at doses of 10 micrograms/kg, 100 micrograms/kg, or 1000 micrograms/kg per day for 60 days. The control rats were injected with the vehicle only. The treatment with the highest dose of the antagonist caused a significant decrease in the weights of the anterior pituitaries, testes, seminal vesicles, and ventral prostates and reduced serum and pituitary LH levels. The intermediate dose of the antagonist affected only seminal vesicle weights. The histology of the testes from the rats treated with the highest dose showed that the spermatogenesis was markedly depressed and did not advance beyond the stage of spermatocyte I; the interstitium showed cells of fibroblastic appearance. Twenty days after stopping treatment with the highest dose of the analogue there was a marked recovery of the weight of the testes, seminal vesicles, and ventral prostates. However, the animals were still infertile when caged with female rats. Sixty days after treatment the animals had recovered testicular function and fertility. The offspring were normal, with no evidence of genetic abnormalities. Female rats were injected with ORG 30276 at doses of 10 micrograms/kg, 100 micrograms/kg, or 1000 micrograms/kg per day for 14 days. The treatment with ORG 30276 did not modify body weights, but anterior pituitary and uterine weights were significantly decreased in the group of rats treated with the highest dose of the antagonist. Ovarian weights were decreased significantly in all the three groups treated with ORG 30276.(ABSTRACT TRUNCATED AT 250 WORDS)