Daily Oral Administration of the Novel Androgen 11ß-MNTDC Markedly Suppresses Serum Gonadotropins in Healthy Men.

BACKGROUND: 11ß-methyl-19-nortestosterone (11ß-MNT) is a modified testosterone (T) with androgenic and progestational activity. A single oral dose of the prodrug, 11ß-MNT dodecylcarbonate (11ß-MNTDC), was well tolerated in healthy men. METHODS: We conducted a randomized, double-blind study at 2 academic medical centers. 42 healthy men (18-50 years) were randomized to receive oral placebo or 11ß-MNTDC, 200 or 400 mg daily, for 28 consecutive days. Primary outcome (safety and tolerability) measures were assessed twice per week. Subjects underwent serial blood sampling over 24 hours on days 1 and 28 to assess secondary outcomes: pharmacokinetics (serum drug concentrations); pharmacodynamics of 11ß-MNTDC (serum sex steroids and gonadotropins); and mood and sexual function (via validated questionnaires). RESULTS: There were no serious adverse events. No participants discontinued because of an adverse event or laboratory test abnormality. 11ß-MNTDC resulted in a dose-related increase in serum 11ß-MNTDC and 11ß-MNT concentrations sustained over 24 hours. Administration of 11ß-MNTDC resulted in a marked suppression of serum gonadotropins, T, calculated free T, estradiol, and SHBG over the treatment period (P < 0.01). Adverse effects that may be related to 11ß-MNTDC included weight gain, acne, headaches, fatigue, and mild mood changes, with 5 men reporting decreased libido and 3 decreased erectile/ejaculatory function. Serum low-density lipoprotein cholesterol, weight (~2 kg), hematocrit, and hemoglobin increased and serum high-density lipoprotein cholesterol decreased in both 11ß-MNTDC groups. CONCLUSION: Daily oral 11ß-MNTDC for 28 days in healthy men markedly suppressed serum gonadotropin and T concentrations without serious adverse effects. These results warrant further evaluation of 11ß-MNTDC as a potential male oral contraceptive.

Field-testing a single-dose immunocontraceptive in free-ranging male capybara (Hydrochoerus hydrochaeris): Evaluation of effects on reproductive physiology, secondary sexual characteristics, and agonistic behavior.

Controlling wildlife populations to mitigate human-wildlife conflicts and the spread of zoonotic diseases is an ever-growing necessity. The objective of this study was to evaluate a single-dose anti-gonadotropin-releasing hormone vaccine (GonaCon, USDA/NWRC, Fort Collins, CO, USA) as a non-lethal alternative for population control in free-ranging, synanthropic male capybara. In addition to infertility efficacy of this treatment, potential effects on the alpha male's secondary sexual characteristics and agonist behavior need to be assessed because any alterations in these factors could lead to population management failure. The treatment group (n = 3) received 1 mL of the anti-GnRH vaccine, intramuscularly, and the control group (n = 2) a 1 mL sham vaccine. Reproductive behavior and social group dynamics were monitored for 30 days prior to inoculation (June 2017) with continuous observations occurring during the study period. Antifertility effects were assessed by conducting exams of testicular morphology, semen characteristics, and histological analysis (after 270 days via hemi-gonadectomy). Compared to the control group, the testicles of the treated males had severe atrophy (P <  0.05), oligozoospermia and greater numbers of sperm cells in a static developmental phase. Courtship and agonistic alpha male behavior were not altered, and the group's social integrity was maintained. Results indicate there was 100% infertility in capybara males, observed throughout the study period of 18 months, and equally important, the male's alpha characteristics were not affected by the treatment, which is imperative for successful capybara population control efforts.

Rationalising drug delivery using nanoparticles: a combined simulation and immunology study of GnRH adsorbed to silica nanoparticles.

Silica nanoparticles (SiNPs) have been shown to have significant potential for drug delivery and as adjuvants for vaccines. We have simulated the adsorption of GnRH-I (gonadotrophin releasing hormone I) and a cysteine-tagged modification (cys-GnRH-I) to model silica surfaces, as well as its conjugation to the widely-used carrier protein bovine serum albumin (BSA). Our subsequent immunological studies revealed no significant antibody production was caused by the peptide-SiNP systems, indicating that the treatment was not effective. However, the testosterone response with the native peptide-SiNPs indicated a drug effect not found with cys-GnRH-I-SiNPs; this behaviour is explained by the specific orientation of the peptides at the silica surface found in the simulations. With the BSA systems, we found significant testosterone reduction, particularly for the BSA-native conjugates, and an antibody response that was notably higher with the SiNPs acting as an adjuvant; this behaviour again correlates well with the epitope presentation predicted by the simulations. The range of immunological and hormone response can therefore be interpreted and understood by the simulation results and the presentation of the peptides to solution, paving the way for the future rational design of drug delivery and vaccine systems guided by biomolecular simulation.

Transepithelial transport across the blood-testis barrier.

The blood-testis barrier protects developing germ cells by limiting the entry of xenobiotics into the adluminal compartment. There is strong evidence that the male genital tract can serve as a sanctuary site, an area of the body where tumors or viruses are able to survive treatments because most drugs are unable to reach therapeutic concentrations. Recent work has classified the expression and localization of endogenous transporters in the male genital tract as well as the discovery of a transepithelial transport pathway as the molecular mechanism by which nucleoside analogs may be able to circumvent the blood-testis barrier. Designing drug therapies that utilize transepithelial transport pathways may improve drug disposition to this sanctuary site. Strategies that improve disposition into the male genital tract could reduce the rate of testicular relapse, decrease viral load in semen, and improve therapeutic strategies for male fertility.

Semen quality and interval to sterility in tom cats treated with a 9.4 mg deslorelin implant.

Objectives Gonadotropin-releasing hormone (GnRH) agonists like deslorelin are being increasingly used in tom cats for their efficacy in controlling reproductive behaviour and fertility. Deslorelin implants have been widely available in Europe since 2008. Little, if anything, is known about the interval between treatment and onset of sterility, as well as semen quality, after treatment in tom cats. The purpose of this study was to investigate semen quality and interval to sterility in tom cats treated with a 9.4 mg deslorelin implant. Methods Fifteen healthy adult tom cats were treated with a 9.4 mg deslorelin implant (Suprelorin 12). For each cat, semen collection and a GnRH stimulation test (intramuscular administration of 50 µg gonadorelin [Fertagyl], followed by blood sampling 1 h later, to assay serum testosterone) were performed on the first consultation and then repeated every 15 days until complete sterility was achieved. Semen collection was performed by introducing a 14 cm, open-end feline catheter (Argyle) 9 cm into the distal urethra 10 mins after sedation by intramuscular injection of 100 µg/kg medetomidine (Domitor). Results Semen collection was not successful in all cats at each attempt. In the first month after treatment, the semen of only four cats could be evaluated, while the semen of eight cats could be evaluated during the second and third months of the study. Semen quality (ejaculate volume, progressive motility and morphological abnormalities) improved slightly during the first 19-25 days in 2/4 cats, and in 1/4 cats motility was still very high (80%) 25 days post-treatment (PT), but we have no data regarding fertility prior to treatment in this cat. The last cat never produced spermatozoa. Subsequently, semen quality gradually worsened in all cats from 30 days onwards. At 70 days PT, one cat was still potentially fertile. After 72 days all cats were sterile. Conclusions and relevance Semen quality increased slightly in treated cats during the first month after treatment, and then gradually decreased over the following months. Complete sterility was reached within 40-72 days following implantation.

Variable duration of reproductive suppression in male coyotes (Canis latrans) treated with a high dose of the gonadotrophin-releasing hormone agonist deslorelin.

Effective and humane management strategies for coyotes (Canis latrans) remain elusive. We hypothesised that exposure to a high dose of a gonadotrophin-releasing hormone (GnRH) agonist would cause prolonged suppression of the reproductive axis. Two groups of male coyotes were administered 47mg deslorelin in the form of either five 9.4-mg controlled-release Suprelorin (Peptech Animal Health, Macquarie Park NSW, Australia) implants (n=3) or 10 4.7-mg implants (n=5). In the first group, deslorelin suppressed plasma LH, testosterone and testes volume in two of three coyotes for three breeding seasons. In the second group, two of five deslorelin-treated coyotes had no sperm production after 1 year and plasma LH, FSH, testosterone and testes volume were suppressed. Although plasma gonadotropins and testosterone were suppressed in three treated coyotes in group two, testes volume and sperm production were evident. Because the duration of suppression differed among individual coyotes, we further hypothesised that a variation in deslorelin release underlay the variability. To test this, we analysed in vivo plasma profiles of deslorelin concentrations. These profiles suggested that deslorelin concentrations >100 pg mL-1 are required to maintain suppression in male coyotes. For field implementation, the development of an implant capable of releasing deslorelin for the life of the coyote is necessary.

Valproic Acid Enhances the Anti-tumor Effect of (-)-gossypol to Burkitt Lymphoma Namalwa Cells.

Burkitt lymphoma is a highly aggressive B-cell neoplasm. New therapeutic methods are needed to overcome the adverse effect of intensive chemotherapy regimens. Valproic acid and (-)-gossypol are two kinds of chemical compounds used as new anti-tumor drugs in recent years. To investigate the anti-tumor effect of valproic acid and (-)-gossypol, Burkitt lymphoma Namalwa cells were cultured and treated with valproic acid and (-)-gossypol at different concentrations. The proliferation of Namalwa cells was dramatically suppressed after the combination treatment with 2 mmol/L valproic acid and 5 µmol/L (-)-gossypol. The combined treatment also enhanced intrinsic apoptosis by down-regulating anti-apoptotic protein Mcl-1. Moreover, the autophagy flux significantly increased in Namalwa cells after combined treatment. However, the enhanced autophagy showed little effect on cell survival with present regimen. The results confirmed that combination of valproic acid and (-)-gossypol had synergistic anti-tumor effect to Burkitt lymphoma Namalwa cells. The related mechanisms might include the down-regulation of anti-apoptotic protein Mcl-1 and avianized pro-survival role of autophagy.

Azoospermia with variable testicular histology after 7 months of treatment with a deslorelin implant in toms.

The main aim of the study was to assess whether the longer use of a GnRH-agonist implant (deslorelin 4.7 mg, Suprelorin) in toms would lead to the suppression of spermatogenesis comparable with histologic appearance in juvenile animals as was previously described in dogs. The other aims were to monitor the progression of the testes size decrease and development of azoospermia 5 to 7 months after treatment with a GnRH-agonist implant. In animals, 5, 6, and 7 months after GnRH-agonist implant insertion, variable histological appearance of germinal epithelium was found, when tubules with elongating spermatids, round spermatids, spermatocytes, and spermatogonia as the most developed germinal cells were found in each group of toms. In all male cats, 5, 6, and 7 months after implant insertion, testosterone concentrations and testes size significantly differed between the first and the last visit. All animals, except one tom castrated 5 months after implant insertion, developed complete azoospermia. However, in this tom, all spermatozoa were immotile. Treatment with the subcutaneous GnRH-agonist implant was well tolerated, and no treatment-related adverse effects were noted. These results reported the efficacy of 4.7-mg deslorelin implant (Suprelorin) during its 7 months of use. The complete azoospermia confirms its contraceptive effect. However, the histologic evaluation revealed a great individual variability in the degree of spermatogenic suppression. The question as to whether spermatogenesis in toms can be suppressed in all males to the level of spermatogonia/primary spermatocytes after prolonged exposure to deslorelin has yet to be answered.

The preparation and application of N-terminal 57 amino acid protein of the follicle-stimulating hormone receptor as a candidate male contraceptive vaccine.

Follicle-stimulating hormone receptor (FSHR), which is expressed only on Sertoli cells and plays a key role in spermatogenesis, has been paid attention for its potential in male contraception vaccine research and development. This study introduces a method for the preparation and purification of human FSHR 57-amino acid protein (FSHR-57aa) as well as determination of its immunogenicity and antifertility effect. A recombinant pET-28a(+)-FSHR-57aa plasmid was constructed and expressed in Escherichia coli strain BL21 Star TM (DE3) and the FSHR-57aa protein was separated and collected by cutting the gel and recovering activity by efficient refolding dialysis. The protein was identified by Western blot and high-performance liquid chromatography analysis with a band of nearly 7 kDa and a purity of 97.4%. Male monkeys were immunized with rhFSHR-57aa protein and a gradual rising of specific serum IgG antibody was found which reached a plateau on day 112 (16 weeks) after the first immunization. After mating of one male with three female monkeys, the pregnancy rate of those mated with males immunized against FSHR-57aa was significantly decreased while the serum hormone levels of testosterone and estradiol were not disturbed in the control or the FSHR-57aa groups. By evaluating pathological changes in testicular histology, we found that the blood-testis barrier remained intact, in spite of some small damage to Sertoli cells. In conclusion, our study demonstrates that the rhFSHR-57aa protein might be a feasible male contraceptive which could affect sperm production without disturbing hormone levels.

Reversibility of germinative and endocrine testicular function after long-term contraception with a GnRH-agonist implant in the tom-a follow-up study.

A significantly reduced gonadotropin and testosterone secretion is a well-described result of long-term administration of GnRH agonists in the male dog and cat. To date, no data are available about the duration of efficacy and the reversibility of treatment-induced effects after long-term treatment with a 4.7 mg deslorelin implant. Seven healthy male European Shorthair cats (3.2 ± 0.5 kg, 1-6 years) were treated with a 4.7 mg deslorelin implant. Blood samples (testosterone, T), testicular volume, penile spines, and mating behavior were recorded once weekly. Considering T > 0.5 ng/mL as the biological endpoint, mean duration of efficacy was 78.8 ± 12.9 weeks (range: 61.7-100.7 weeks) with T concentrations increasing rapidly after the last T less than 0.1 ng/mL (basal) (P < 0.0001), and pretreatment T concentrations being reached after 3 weeks. Testicular volume rapidly increased after the first increase of T (P < 0.001) with pretreatment testicular volume being reached after 6.9 ± 3.4 weeks (5-11 weeks). "Normal" libido reoccurred 88.7 ± 12.4 weeks after treatment, and "normal" mating behavior was observed even later. Fertile matings occurred 7 to 42 weeks after the last T less than 0.1 ng/mL with a mean of 4.0 ± 0.0 kittens, and 13.6 to 47.6 weeks afterwards testicular histology revealed normal spermatogenesis. The present data confirm that the use of slow-release GnRH-agonist implants containing deslorelin in tomcats represents an effective and safe reversible alternative for long-term contraception; however, as number of animals is low, further fertility trials are recommended.

Male contraception: history and development.

Although the twentieth century has seen great strides in the development of female contraception, not a single new agent has been introduced as an approved method for common use for male contraception. Condoms (considered uncomfortable by some) and vasectomy (a permanent invasive procedure) are the only options provided to men, leaving an undue burden on women to bear contraceptive responsibility. Significant developments have, however, been made with regard to hormonal and nonhormonal contraception, and minor, reversible, procedural contraception. This article reviews the currently available, soon to be available, and theoretically possible methods of male contraception.

Dose and durational effects of the gonadotropin-releasing hormone agonist, deslorelin: the male rat (Rattus norvegicus) as a model.

Gonadotropin-releasing hormone (GnRH) agonists are routinely used to suppress the reproductive axis of many mammals, especially in zoos. Current treatments are reversible. There is a need to develop nonreversible agents, and this study investigates the effects of high-dose and long-duration exposure to the GnRH agonist, deslorelin, in the rat model. Studies indicate that the follicle-stimulating hormone (FSH) gonadotropin is predominantly affected, and following high-dose exposure to deslorelin for a long duration, the ability of gonadotropes to synthesize FSH may be compromised, perhaps permanently. Understanding the mechanisms by which such persistent suppression of FSH occurs may facilitate the development of novel next-generation contraceptives. It is hypothesized that direct testicular effects of GnRH agonists may play a critical role in the efficacy of GnRH agonists in male contraception.

Reversible suppression of sexual activity in tomcats with deslorelin implant.

The aim of the study was to assess the efficacy of using a Gn-RH agonist implant (deslorelin, 4.7 mg, Suprelorin) to control sexual activity of male cats and reestablishment of sexual function after the implant removal 4 mo after placement. Using a control group (Group 1, n = 5), 22 domestic tomcats were given the implant subcutaneously in the region of the right shoulder blade and were then divided into two treatment groups. Animals in Group 2 (n = 14) were observed from the date of implant surgery and the observation lasted for 4 mo. In Group 3 (n = 8) all animals were monitored from the date of implant surgery. Then, after 4 mo, all implants were removed and the toms were observed for a further 4 mo. In all animals during their first visit and then in 1-mo intervals, changes in testosterone concentrations were assessed before (T0) and 4 h after (T4) human chorionic gonadotropin (HCG) administration and testis size was measured. In all tomcats, semen collection was performed, using an electroejaculator, in the course of the first visit and then in 2-mo intervals or at the end of observation. Total sperm count was determined in each semen sample. Two to four animals were castrated at weeks 4, 8, 12, 16, 20, 24, 28 and 32 and histologic assessment of the testes was performed. By evaluation of 200 cross sections of seminiferous tubules, the degree of spermatogenic suppression was assessed and animals in Groups 2 and 3 were assigned into groups according to most tubules with the most developed germ cell observed: G1, spermatocytes; G2, round spermatids; G3, elongating spermatids and G4, elongated spermatids. The mean area of Leydig-cell nuclei was calculated. In animals in Group 2, suppression after implant insertion was monitored. T4 concentrations, testis size, and total sperm count gradually decreased (P < 0.01; P < 0.01; and P < 0.05, respectively) within 4 mo after implantation. Histologic evaluation showed a high individual variation in the degree of suppression of spermatogenesis. In animals in Group 3, the implant was removed 4 mo after insertion and the return of sexual activity was monitored. Within 4 mo, T4 concentration and total sperm count increased to the physiological values of intact toms. Testes gradually increased in size and within 4 mo of implant removal almost reached pretreatment size. According to histologic evaluation of the seminiferous tubules, as early as 1 mo after implant removal, all animals were assigned to G4, with most tubules containing elongated spermatids as the most developed germ cells. Treatment with the long-term subcutaneous Gn-RH agonist implant was well tolerated and no adverse treatment-related effects were noted. These results demonstrated efficacy of 4.7 mg deslorelin implant (Suprelorin) with high variability of the effect onset in tomcats. Furthermore, the study revealed a strong need for complex examination, including testis size measurement, monitoring of hormonal changes, spermatological analysis and histologic evaluation, to declare the animal infertile. After the implant removal, all observed parameters confirmed the reversibility of the method and gradual return of sexual activity in toms.

Delay of puberty and reproductive performance in male dogs following the implantation of 4.7 and 9.4 mg GnRH-agonist deslorelin at an early pre-pubertal age.

CONTENTS: Stray dogs are a significant problem in large cities. Contraception is an important and useful solution to control the growing population of these dogs. Early-age neutering is an effective technique for canine population control; however, surgical neutering may not be possible in various situations. GnRH-agonist implantation has been successful for long-term reversible contraception in dogs. The efficacy of GnRH-agonist implantation on long-term suppression of reproductive performance was observed in male dogs. Eleven 4-month-old dogs were implanted with 4.7, 9.4 mg deslorelin or placebo. Sexual behaviour and testicular size were monitored every 2 months. Ejaculates were collected and evaluated at 8, 12, 15, 18, 24, 30, 32, 34 and 36 months of age. Dogs implanted with placebo were found to be healthy and in normal reproductive status. Most dogs (3/4) implanted with 4.7 mg deslorelin showed male sexual behaviour at age of 34 months old. From this group, two dogs had normal semen quality, while semen could not be collected from the other dog, and after castration, no sperm were obtained following epididymal flushing. One dog implanted 4.7 mg deslorelin and four dogs implanted with 9.4 mg deslorelin remained in the non-pubertal reproductive status at 30-34 months. The delay to puberty was longer in dogs implanted with higher dose of GnRH agonist. Implantation of pre-pubertal dogs with high doses of GnRH agonist will delay the onset of puberty and may be an effective strategy to reduce the number of unwanted breedings.

A single administration of the GnRH antagonist acyline inhibits basal and GnRH-stimulated serum testosterone concentrations in male dogs.

The objective of this study was to describe testosterone (T) response to GnRH challenge in antagonist-treated dogs over a 30-day period. Eight mongrel dogs were randomly assigned to either the GnRH antagonist acyline 330 µg/kg sc (ACY; n = 4) or a placebo group (PLA; n = 4). The dogs were serially challenged with the GnRH agonist, buserelin 0.2 µg/kg sc on days -1, 1, 3, 7, 10, 14, 21 and 30. On these days, blood samples for T determinations were collected before (-30 min) and 60, 120 and 180 min after the agonist injection. Basal (-30 min) and post-GnRH agonist stimulation T values were compared by anova for repeated measures. Before treatments (day -1), there were no differences in basal T serum concentrations between groups (p > 0.1). After treatments, basal T showed a significant interaction between treatment and day (p < 0.05). Furthermore, when both groups were analysed independently, basal T varied in the ACY (p < 0.01) but not in the PLA group (p > 0.1). On day -1, before treatments, the stimulation tests had only a time effect (p = 0.05) although on days 1 (p < 0.01), 3 (p < 0.01), 7 (p < 0.01), 10 (p < 0.01) and 14 (p < 0.05), the response to the agonist differed between groups, becoming similar on days 21 (p > 0.05) and 30 (p > 0.05). It was concluded that, in dogs, a single administration of the GnRH antagonist prevented canine gonadal axis to physiologically respond to agonistic challenge during 14 days.

The blood-testis barrier and its implications for male contraception.

The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in the mammalian body. It divides the seminiferous epithelium into the basal and the apical (adluminal) compartments. Meiosis I and II, spermiogenesis, and spermiation all take place in a specialized microenvironment behind the BTB in the apical compartment, but spermatogonial renewal and differentiation and cell cycle progression up to the preleptotene spermatocyte stage take place outside of the BTB in the basal compartment of the epithelium. However, the BTB is not a static ultrastructure. Instead, it undergoes extensive restructuring during the seminiferous epithelial cycle of spermatogenesis at stage VIII to allow the transit of preleptotene spermatocytes at the BTB. Yet the immunological barrier conferred by the BTB cannot be compromised, even transiently, during the epithelial cycle to avoid the production of antibodies against meiotic and postmeiotic germ cells. Studies have demonstrated that some unlikely partners, namely adhesion protein complexes (e.g., occludin-ZO-1, N-cadherin-ß-catenin, claudin-5-ZO-1), steroids (e.g., testosterone, estradiol-17ß), nonreceptor protein kinases (e.g., focal adhesion kinase, c-Src, c-Yes), polarity proteins (e.g., PAR6, Cdc42, 14-3-3), endocytic vesicle proteins (e.g., clathrin, caveolin, dynamin 2), and actin regulatory proteins (e.g., Eps8, Arp2/3 complex), are working together, apparently under the overall influence of cytokines (e.g., transforming growth factor-ß3, tumor necrosis factor-α, interleukin-1α). In short, a "new" BTB is created behind spermatocytes in transit while the "old" BTB above transiting cells undergoes timely degeneration, so that the immunological barrier can be maintained while spermatocytes are traversing the BTB. We also discuss recent findings regarding the molecular mechanisms by which environmental toxicants (e.g., cadmium, bisphenol A) induce testicular injury via their initial actions at the BTB to elicit subsequent damage to germ-cell adhesion, thereby leading to germ-cell loss, reduced sperm count, and male infertility or subfertility. Moreover, we also critically evaluate findings in the field regarding studies on drug transporters in the testis and discuss how these influx and efflux pumps regulate the entry of potential nonhormonal male contraceptives to the apical compartment to exert their effects. Collectively, these findings illustrate multiple potential targets are present at the BTB for innovative contraceptive development and for better delivery of drugs to alleviate toxicant-induced reproductive dysfunction in men.

Spermatogenetic inhibition in men taking a combination of oral medroxyprogesterone acetate and percutaneous testosterone as a male contraceptive method.

BACKGROUND: We previously demonstrated in a small pilot study that oral medroxyprogesterone acetate and percutaneous testosterone (OMP/PT) induce reversible spermatogenesis suppression. The aims of this study were to determine the rate of spermatogenetic inhibition and recovery and to obtain preliminary data on efficacy for a larger population under OMP/PT. METHODS: A total of 35 healthy men with normal spermiograms requesting male hormonal contraception were treated with OMP (20 mg/day) and PT (50-125 mg/day) for periods up to 18 months. Couples were included in a contraceptive efficacy phase after a value of ≤1 million/ml spermatozoa was reached between 1 and 3 months of treatment. RESULTS: Sperm counts decreased by 47% at 1 month, reaching 90% at 2 months and 98-100% between 4 and 8 months. At 3 months, 80% of men had ≤1 million/ml spermatozoa. Follicle-stimulating hormone and luteinizing hormone decreased to 35% of pretreatment levels after 1 month of treatment and to 75-80% at 2 and 6 months, respectively. Plasma testosterone and estradiol levels were in the eugonadal range at 3, 6, 9 and 12 months of treatment. Dihydrotestosterone concentrations were 2-4 times higher than pretreatment values. The rate of spermatogenetic recovery was rapid (73 ± 29.5 days). During the efficacy phase (211 months for 25 couples), one pregnancy attributable to poor compliance of the male partner was observed. CONCLUSIONS: OMP/PT efficiently inhibits spermatogenesis in 80% of men, maintains testosterone at physiological levels and avoids the need for parenteral administration, which is poorly accepted by French men. These results justify larger studies to define a more adequate dosage of OMP/PT and to confirm its efficacy and safety.

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

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

Dose-response studies for pituitary and testicular function in male dogs treated with the GnRH superagonist, deslorelin.

We tested the effect of dose of GnRH superagonist on pituitary and testicular function in a study with four groups of four male dogs. The Controls received blank implants and the other three groups received implants containing 3, 6 or 12 mg deslorelin (D-Trp6-Pro9-des-Gly10-GnRH ethylamide). In all deslorelin-treated groups, there was initially an acute increase in plasma concentrations of LH and testosterone, followed by declines such that both hormones became undetectable after approximately 12 days. There was a dose-response in some of these early aspects of the hormone profiles. With respect to long-term effects of treatment, the 12-mg dose had significantly greater effects than the smaller doses for the duration of minimum testicular volume [366 +/- 77, mean +/- SEM (3 mg), 472 +/- 74 (6 mg), and 634 +/- 59 (12 mg) days], absence of ejaculate [416 +/- 88 (3 mg), 476 +/- 83 (6 mg), and 644 +/- 67 (12 mg) days], undetectable plasma concentrations of LH and testosterone [367 +/- 64 (3 mg), 419 +/- 72 (6 mg), and 607 +/- 69 (12 mg) days], the delay until complete recovery of LH and testosterone secretion [394 +/- 65 (3 mg), 484 +/- 72 (6 mg) and 668 +/- 47 (12 mg) days], and the delay until testes had regrown to normal volume [408 +/- 77 (3 mg), 514 +/- 74 (6 mg), 676 +/- 59 (12 mg) days]. The time taken to restore full ejaculates was also longest for the 12-mg dose: 716 +/- 67 (12 mg) days vs 440 +/- 66 (3 mg) and 538 +/- 83 (6 mg) days after implantation. There was no correlation between delay to recovery of normal ejaculate quality and body mass. We conclude that the dose-response relationship with deslorelin implants is not expressed with respect to the degree of suppression of reproduction, but on the maximum duration of suppression and thus to delay until recovery.

Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men.

CONTEXT: Testosterone (T) plus progestin combinations are the most promising hormonal male contraceptives. Nestorone (NES), a progestin without estrogenic or androgenic activity, when combined with T may be an excellent candidate for male contraception. OBJECTIVE: Our objective was to determine the effect of transdermal NES gel alone or with T gel on gonadotropin suppression. DESIGN AND SETTING: The randomized, unblinded clinical trial was conducted at two academic medical centers. PARTICIPANTS: A total of 140 healthy male volunteers participated. INTERVENTIONS: One hundred subjects were randomized initially (20 per group) to apply NES gel 2 or 4 mg, T gel 10 g, or T gel 10 g plus NES gel 2 or 4 mg daily for 20 d. Because only about half of the subjects in T plus NES 4 mg group suppressed serum gonadotropins to 0.5 IU/liter or less (suboptimal suppression), two additional groups of 20 men were randomized to apply daily T gel 10 g plus NES gel 6 or 8 mg. MAIN OUTCOME VARIABLE: Suppression of serum LH and FSH concentrations to 0.5 IU/liter or less after treatment was the main outcome variable. RESULTS: A total of 119 subjects were compliant with gel applications with few study-related adverse events. NES alone reduced gonadotropins significantly but less than T gel alone. Combined T gel 10g plus NES gel 6 or 8 mg suppressed both serum gonadotropins to 0.5 IU/liter or less in significantly more men than either gel alone. CONCLUSION: Transdermal NES gel alone had gonadotropin suppression activity. Combined transdermal NES (6 or 8 mg) plus T gel demonstrated safe and effective suppression of gonadotropins, justifying a longer-term study of this combination for suppression of spermatogenesis.