Brdt Bromodomains Inhibitors and Other Modern Means of Male Contraception.

Compared to efficient and secure female contraception, a vasectomy and condoms are the only options for men. The choice of male contraceptive methods is limited, so contraception mainly rests on the shoulders of women. Several concepts are considered: testosterone administration--inhibiting pituitary secretion of lutropin (LH) and follicle stimulating hormone (FSH), progestogen--affecting the secretion of gonadotropin and gonadoliberin (GnRH) antagonists. New potential targets for non-hormonal male contraception were discovered: glyceraldehyde-3-phosphate-dehydrogenase (GAPDHS)--specific to male germ cells and voltage-gated cation channel (CatSper). Both are responsible for sperm motility. Drugs such as thioridazine used in schizophrenia treatment and phenoxybenzamine (antihypertensive activity) exhibit a contraceptive effect. Similar action exhibits an analogue of lonidamine--adjudin and an antagonist of retinoic acid receptors (BMS-189453). Researchers are working on a contraceptive vaccine, whose active ingredient is epididymal protease inhibitor (Eppin). Another promising method acts by blocking Bromodomain testis-specific proteins (Brdt) involved in the process of spermatogenesis. JQ1-the Brdt inhibitor causes reversible infertility without affecting the endocrine signaling pathways. A recent discovery of Juno as the binding partner for Izumo1 identifies these proteins as the cell-surface receptor pair, essential for gamete recognition and this interaction can be inhibited by an anti-Juno monoclonal antibody. Our review shows that the situation of men can change and investigators are close to the optimal solution. In the near future men will be able to choose the best contraceptive suited to their needs.

La vitamina A: reguladora de la espermatogénesis / Vitamin A: regulator of spermatogenesis

La vitamina A es esencial para el desarrollo de las células germinales masculinas, la fertili-dad y la espermatogénesis normal. El ácido retinoico, metabolito activo de la vitamina A, es necesario para la maduración de las espermatogonias y la entrada correcta de las células germinales en la profase meiótica en los testículos. La expresión de Stra8, fundamental en la meiosis y la espermatogénesis normal, está directamente relacionada con la disponibilidad del ácido retinoico. Este artículo se centra en el proceso de espermatogénesis y la interacción de la vitamina A con el ciclo seminífero, a fin de explicar la relación existente entre la disminución de los aportes de vitamina A, y las alteraciones presentadas en la espermatogénesis de humanos y algunos animales. También, se consideran los efectos de otros genes implicados en la síntesis de la vitamina A, su transporte y su degradación, y se discuten los posibles mecanismos celu-lares que pueden verse afectados por la falta de señalización de la vitamina A, en particular, la regulación del ciclo celular y la interacción célula-célula, puntos críticos para la esperma-togénesis normal. En esta revisión de los 42 artículos científicos más relevantes del tema, se hizo una búsqueda de información en bases de datos como Science Direct, Scielo, Medline, Redalyc y Pubmed, durante los meses de enero a abril de 2014. Se encontró que en diversos estudios se ha demostrado que se puede controlar in vitro la proliferación de células germinales y su dife-renciación, y además, que un deficiente consumo de vitamina A estaría relacionado con la disminución de la fertilidad masculina.

Vitamin A is essential for the development of male germ cells, male fertility and normal sper-matogenesis. Retinoic acid, an active metabolite of vitamin A, is necessary for the maturation of spermatogonia and the correct entry of germ cells in meiotic prophase in the testicles. Stra8expression, which is essential for normal spermatogenesis and meiosis, is directly related to the availability of retinoic acid. This review of 50 scientific articles relevant to the topic will focus on the process of sperma-togenesis and interaction of vitamin A with the seminiferous cycle, in order to explain the re-lationship between the decrease in vitamin A and alterations in spermatogenesis of humans and some animals. Also, it considers the effects of other genes involved in the synthesis of vitamin A, transport, and degradation. Similarly, potential cellular mechanisms that may be affected by the lack of signs of vitamin A will be discussed, in particular the regulation of cell cycle and cell-cell interactions, which are critical for normal spermatogenesis. In conclusion, studies have shown that you can control in vitro germ cell proliferation, and differentiation and poor intake of vitamin A can be related to a decrease in male fertility.

Reproductive toxicity of Samanea tubulosa on rats / Toxicidade reprodutiva de Samanea tubulosa em ratos

Samanea tubulosa is a plant used for medicinal and feeding purposes. However, ingestion of S. tubulosa pods has been associated with bovine abortion. Thus, the aim of this work was to investigate the effects of diet containing 5% of S. tubulosa pod meal on male and female Wistar rats. Diet was administered to male rats (n = 10) for 60 days before mating. Female rats (n = 10) received the treatment for 30 days, during cohabitation and from gestational day (GD) 0 to GD20. Treated animals were mated with untreated rats. In male rats, plant consumption caused decreased food consumption and 20% fertility index reduction. Litters from treated males presented lower body weight and crownrump length. Female rats treated with the plant increased water and food intake and body weight. Decreases in fertility, fecundity and gestation indices and increase of placenta weight and mean number of corpora lutea were found. Thus, owing to the possible general and reproductive toxic effects, long-term consumption of S. tubulosa is not recommended for phytotherapic or food purposes...

Samanea tubulosa é uma planta utilizada na fitoterapia e na alimentação animal. Entretanto, a ingestão de vagens de S. tubulosa tem sido associada à ocorrência de abortos em bovinos. Assim, o objetivo do trabalho foi investigar os efeitos da dieta contendo 5% de vagens de S. tubulosa em ratos machos e fêmeas Wistar. A dieta foi administrada para ratos machos (n = 10) por 60 dias antes do acasalamento. Ratos fêmeas (n = 10) receberam o tratamento por 30 dias, durante a coabitação e do dia gestacional (GD) 0 ao GD 20. As fêmeas tratadas foram acasaladas com ratos não tratados. Em machos, o consumo da planta causou diminuição no consumo de ração e redução de 20% no índice de fertilidade. A prole de machos tratados apresentou menor ganho de peso e comprimento cabeça cauda. Fêmeas tratadas com a planta apresentaram aumento do consumo de ração e água e do peso corporal. Ainda, foram observadas diminuição na fertilidade, fecundidade e no índice de gestação e aumento do peso da placenta e no número médio de corpos lúteos. Desse modo, em decorrência aos possíveis efeitos tóxicos sistêmicos e reprodutivos, o consumo prolongado de S. tubulosa não é recomendado para fins fitoterápicos ou alimentar...

[Interstitial endocrine apparatus of testes of experimental animals in conditions of chromium-benzene intoxication].

With the use of histological, morphometric and statistical methods there was shown a gonadotropic effect of chromium, benzene and also their mixtures in male mice (CBA x C57Bl6) F1. The established structural changes in the testes of exposed animals showed the suppression of their germinative and endocrine functions. The response of Leydig cells in the chromium group expresses a development of the compensatory process in the relation with the destruction of seminiferous epithelium.

Factores predictivos de recuperación espermática en las azoospermias / Predictive Factors of Successful Sperm Retrieval in Azoospermia

Introducción: El tratamiento estándar de las azoospermias es la recuperación espermática del testículo para inyección intracitoplásmica. El objetivo de este estudio es identificar factores predictivos de recuperación espermática. Material y métodos: Intentamos recuperar espermatozoides mediante extracción espermática del testículo (TESE) en 74 pacientes azoospérmicos. Se estudiaron los niveles séricos de FSH einhibina B (INHB), la histología testicular, la genética, la criptozoospermia y el tamaño testicular. Resultados: La recuperación espermática fue del 47,2% para el total de pacientes, del 36% para las azoospermias no obstructivas y del 100% para las obstructivas. La INHB baja y la FSH alta se correlacionaron con el fracaso en la recuperación espermática. Los puntos de corte obtenidos mediante curvas ROC fueron de 67 pg/ml para la INHB y de 12,2 mUI/ml para la FSH. En ningún paciente con microdeleción Y en AZF a, b se recuperaron espermatozoides. En el 100% de los pacientes con mutaciones CFTR se obtuvieron espermatozoides. La mayor tasa de recuperación espermática fue para las hipoespermatogénesis, seguidas de los bloqueos madurativos y de los solo Sertoli. En todos los pacientes con criptozoospermia se recuperaron espermatozoides. Se encontró una relación entre el tamaño testicular y la recuperación espermática, pero no resultó estadísticamente significativa. Conclusiones: Salvo las microdeleciones en AZF a, b ningún factor predictor descarta a un paciente para TESE. La INHB baja se relaciona mejor que la FSH alta con el fracaso en la recuperación espermática. La recuperación es posible en todos los casos de mutaciones CFTR. La ausencia de células germinales se correlaciona con una alta probabilidad de fracaso en la recuperación espermática. La presencia de criptozoospermia se vincula a una alta probabilidad de éxito en la recuperación espermática (AU)

Introduction: Testicular sperm extraction with intracytoplasmic sperm injection is the standard treatment for azoospermia. The objective of this study is to identify predictive factors of successful sperm retrieval. Materials and methods: Between June 2003 and May 2011, we tried testicular sperm extraction(TESE) in 74 azoospermic patients in the Reproductive Medicine Unit of Son Espases Hospital (Palma de Mallorca). Serum follicle stimulating hormone (FSH) and inhibin B levels, testicular histology, genetic study, presence or not of cryptozoospermia and testicular volume were examined. Results: Spermatozoa were successfully recovered in 47.2% of the total patients, in 36% of nonobstructiveazoospermic patients and in 100% of obstructive azoospermic patients. Low inhibin B and high FSH were correlated to sperm retrieval failure. The cutoff points were determined using ROC curves that were 67 pg/mL for inhibin B and 12.2 mUI/mL for FSH. Spermatozoa were not successfully retrieved in any patient with Y microdeletions in AZF a, b regions. Spermatozoa were successfully retrieved in 100% of the patients with CFTR mutations. The highest spermretrieval rate was for hypospermatogenesis, followed by maturation arrest and Sertoli-cellonly. Spermatozoa were successfully retrieved in all cryptozoospermic patients. Although usinga non-significant test, there seems to be a correlation between higher testicular volume and a higher probability of successful sperm retrieval. Conclusions: Except for Y microdeletions in AZF a, b regions, there is no predictive factor of testicular sperm retrieval to rule out a patient for TESE. Lower inhibin B is more related to spermretrieval failure than higher FSH. Sperm retrieval is possible for all cases of CFTR mutations but in any case of microdeletion Y in AZF a ,b. The lack of germ cells is correlated with a high probability of sperm retrieval failure. The presence of cryptozoospermia is correlated with a high probability of sperm retrieval success. We do not find a statistically significant relation between testicular volume and successful sperm retrieval (AU)

[Combined effects of aluminium and immobilization stress on the reproductive system of male rats].

The evaluation of the isolated and combined effects of aluminum and immobilization stress on the reproductive system of male laboratory rats has been performed. We have established the influence of these factors on spermatogenesis and spermiogenesis: the development of degenerative processes in the testes, on specific hormonal status, apoptosis, increasing abnormal forms of epididymal sperms and reducing their mobility, and on the growth of early embryonic losses. Neither synergistic nor antagonistic effect in the combined aluminum and the stress action has been found.

Pharmacologic development of male hormonal contraceptive agents.

The world population continues to increase dramatically despite the existence of contraceptive technology. The use of male hormonal contraception may help in preventing un intended pregnancies and managing future population growth. Male hormonal contraception relies on the administration of exogenous hormones to suppress spermatogenesis. Clinical trials have tested several regimens using testosterone, alone or in combination with a progestin. These regimens were shown to be >90% effective in preventing conception and were not associated with serious adverse events.

Recent methodological advances in male hormonal contraception.

Landmark WHO-sponsored trials showed decades ago that male hormonal contraception (MHC) is an effective male-directed contraceptive approach. Considerable progress has been made particularly in the last 5 years, establishing for the first time the reversibility of MHC and its short-term safety. Methodological advances in recent years include the pooling of information and individual-level integrated analysis; the first-time use of centralized semen analysis and fluorescence to detect low sperm concentrations; the establishment of sperm quality reference ranges in fertile men; the measurement of blood steroid concentrations by gas chromatography/mass spectrometry; and the inclusion of placebo groups to delineate clearly possible adverse effects of androgens and progestins in men. We report integrated analyses of factors that are important in predicting suppression and recovery of spermatogenesis after MHC clinical trials for the past 15 years. These are the best data available and will provide guidance and reassurance for the larger-scale Phase III specific regimen efficacy studies that will be required to bring MHC to the population (market).

Alteración de la densidad del volumen de los componentes testiculares asociada con el cisplatino: ¿pueden los antioxidantes ofrecer protección? / Testicular components volume density alteration associated to cis-platinum: can antioxidants offer protection?

Objetivos: Los agentes quimioterapéuticos basados en el cisplatino se utilizan ampliamente en el tratamiento del cáncer testicular, y sus efectos perjudiciales sobre la espermatogénesis se conocen bien. En consecuencia, se emprendió un amplio estudio para evaluar los efectos de los antioxidantes en combinación con el cisplatino en un intento de reducir sus efectos sobre la función espermática de ratas adultas. Métodos: Se realizó un estudio prospectivo a corto placo (13 días) sobre 24 ratas Wistar macho adultas. Se asignó a los animales a uno de 3 grupos (8 por grupo): GI-control, GII-tratado con cisplatino y GIII-cisplatino más superóxido dismutasa y catalasa. Los análisis histológicos incluyeron recuentos de células germinales, relaciones entre células germinales y de Sertoli y estimación de la densidad de volumen de los componentes, así como determinación de las reservas de espermatozoides. Los datos se examinaron mediante análisis de la varianza de una vía al nivel de significación del 5%. Resultados: No se hallaron diferencias entre los grupos en el número de células germinales, las relaciones entre células germinales y de Sertoli, el peso de los órganos (excepto el peso corporal) y las reservas de espermatozoides. Sin embargo, el tratamiento afectó (p<0,05) a la proporción volumétrica de algunos componentes (epitelio tubular, túnica propia, núcleos y estroma de células de Leydig). El componente testicular más prominente, el epitelio seminífero, se redujo (p<0,05) en los animales tratados con cisplatino (GII). Conclusión: El uso de antioxidante en asociación con cisplatino no afectó a la producción de espermatozoides (número de células germinales, relaciones entre células germinales y de Sertoli y reservas de espermatozoides) de ratas adultas. Sin embargo, los antioxidantes limitaron el efecto perjudicial del cisplatino sobre el epitelio de los túbulos seminíferos (AU)

Objectives: Cis-platinum based chemotherapy agents are widely used in treatment of testicular cancer and its deleterious effects on spermatogenesis are well known. Therefore an extensive survey was undertaken to evaluate the effects of antioxidants in combination with Cis-platinum in an attempt to minimize its effects upon spermatogenic function of adult rats. Methods: A short-term prospective study (thirteen days) including twenty-four adult male Wistar rats was performed. Animals were assigned into one of three groups (eight per group): GI-control, GII-Cis-platinum treated and GIII-Cis-platinum plus superoxide dismutase and catalase. Histological analyses included germ cell counts, germ to Sertoli cell ratios and estimation of volume density components as well as the determination of the sperm reserves. Data was examined through one-way analysis of variance at 5% level of significance. Results: Germ cell numbers, germ cell to Sertoli cell ratios, organ weights (except body weight) and sperm reserves presented no differences among groups. However, the volumetric proportion of some components (tubular epithelium, tunica propria, Leydig cell nuclei and stroma) were affected (p<0.05) by treatment. The most prominent testicular component, the seminiferous epithelium was reduced (p<0.05) in Cis-platinum treated animals (GII). Conclusion: The use of antioxidant in association with Cis-platinum did not affect sperm production (germ cell numbers, germ to Sertoli cell ratios and sperm reserves) of adult rats. However, the deleterious effect of Cis-platinum on the seminiferous tubule epithelium was minimized by antioxidants (AU)

Adjudin targeting rabbit germ cell adhesion as a male contraceptive: a pharmacokinetics study.

Adjudin (1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide; formerly called AF-2364) has been shown to inhibit spermatogenesis by disrupting anchoring junctions at the Sertoligerm cell interface. This, in turn, leads to germ cell loss from the seminiferous epithelium, and transient infertility. Adjudin's efficacyin inhibiting spermatogenesis, the recovery of spermatogenesis after cessation of the drug, and side effects were examined in adult male Japanese rabbits. The pharmacokinetics profiles of adjudin in rabbits after oral administration and after intravenous injection were compared. Rabbits received 25 mg/kg adjudin once weekly for 4 consecutive weeks either by intravenous injection or by gavage. Vehicle-treated rabbits were used as controls. At 1, 2, 3, 4, and 8 weeks after treatment, testes were removed for microscopic examination to assess the status of spermatogenesis. Four weeks after intravenous cessation of adjudin, the recovery of spermatogenesis also was monitored. Blood was withdrawn after first administration to measure plasma concentrations of adjudin by high-performance liquid chromatography. Four weeks after intravenous treatment, examination of testis sections showed rapid exfoliation of elongated/elongating spermatids and the presence of large multinucleated cells; more than 95% of germ cells were absent from the seminiferous epithelium. Intravenous treatment showed a more severe disturbance of spermatogenesis compared with gavage treatment, which was correlated with bioavailability of the drug. The areas under the curve for intravenous injection and gavage were 20.11 +/- 1.90 and 2.23 +/- 0.45 mg x h x L(-1), respectively. These results illustrate the potential of adjudin as a male contraceptive, and the efficacy is associated with the bioavailability of the drug.

Male contraception: what is on the horizon?

Male contraception remains an important area of research. Methods can inhibit sperm production or can be targeted to inhibit sperm functions such as motility, orientation or interaction with the egg. Hormonal methods appear to be safe and effective in proof of concept studies but efforts are underway to improve delivery options or lead time until full efficacy is achieved. Nonhormonal methods are based on numerous targets that impact sperm production or function. Several agents that inhibit the sperm-specific or testis-specific targets have been identified and studies in animals have shown promising results.

Progress and prospects in male hormonal contraception.

PURPOSE OF REVIEW: Testosterone functions as a contraceptive by suppressing the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary. Low concentrations of these hormones deprive the testes of the signals required for spermatogenesis and results in markedly decreased sperm concentrations and effective contraception in a majority of men. Male hormonal contraception is well tolerated and acceptable to most men. Unfortunately, testosterone-alone regimens fail to completely suppress spermatogenesis in all men, meaning that in some the potential for fertility remains. RECENT FINDINGS: Because of this, novel combinations of testosterone and progestins, which synergistically suppress gonadotropins, have been studied. Two recently published testosterone/progestin trials are particularly noteworthy. In the first, a long-acting injectable testosterone ester, testosterone decanoate, was combined with etonogestrel implants and resulted in 80-90% of subjects achieving a fewer than 1 million sperm per milliliter. In the second, a daily testosterone gel was combined with 3-monthly injections of depot medroxyprogesterone acetate producing similar results. SUMMARY: Testosterone-based hormone combinations are able to reversibly suppress human spermatogenesis; however, a uniformly effective regimen has remained elusive. Nevertheless, improvements, such as the use of injectable testosterone undecanoate, may lead to a safe, reversible and effective male contraceptive.

Gamendazole, an orally active indazole carboxylic acid male contraceptive agent, targets HSP90AB1 (HSP90BETA) and EEF1A1 (eEF1A), and stimulates Il1a transcription in rat Sertoli cells.

Gamendazole was recently identified as an orally active antispermatogenic compound with antifertility effects. The cellular mechanism(s) through which these effects occur and the molecular target(s) of gamendazole action are currently unknown. Gamendazole was recently designed as a potent orally active antispermatogenic male contraceptive agent. Here, we report the identification of binding targets and propose a testable mechanism of action for this antispermatogenic agent. Both HSP90AB1 (previously known as HSP90beta [heat shock 90-kDa protein 1, beta]) and EEF1A1 (previously known as eEF1A [eukaryotic translation elongation factor 1 alpha 1]) were identified as binding targets by biotinylated gamendazole (BT-GMZ) affinity purification from testis, Sertoli cells, and ID8 ovarian cancer cells; identification was confirmed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and Western blot analysis. BT-GMZ bound to purified yeast HSP82 (homologue to mammalian HSP90AB1) and EEF1A1, but not to TEF3 or HBS1, and was competed by unlabeled gamendazole. However, gamendazole did not inhibit nucleotide binding by EEF1A1. Gamendazole binding to purified Saccharomyces cerevisiae HSP82 inhibited luciferase refolding and was not competed by the HSP90 drugs geldanamycin or novobiocin analogue, KU-1. Gamendazole elicited degradation of the HSP90-dependent client proteins AKT1 and ERBB2 and had an antiproliferative effect in MCF-7 cells without inducing HSP90. These data suggest that gamendazole may represent a new class of selective HSP90AB1 and EEF1A1 inhibitors. Testis gene microarray analysis from gamendazole-treated rats showed a marked, rapid increase in three interleukin 1 genes and Nfkbia (NF-kappaB inhibitor alpha) 4 h after oral administration. A spike in II1a transcription was confirmed by RT-PCR in primary Sertoli cells 60 min after exposure to 100 nM gamendazole, demonstrating that Sertoli cells are a target. AKT1, NFKB, and interleukin 1 are known regulators of the Sertoli cell-spermatid junctional complexes. A current model for gamendazole action posits that this pathway links interaction with HSP90AB1 and EEF1A1 to the loss of spermatids and resulting infertility.

A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose.

Women have historically been the focus for development of new contraceptive methods. The National Institutes of Health, World Health Organization, and Institute of Medicine have stressed the need to develop nonhormonal, nonsteroidal male contraceptive agents. We report results from initial dose-ranging studies of a new indazole carboxylic acid analogue, gamendazole. An infertility rate of 100% was achieved in seven out of seven proven-fertile male rats 3 wk after a single oral dose of 6 mg/kg of gamendazole. Fertility returned by 9 wk in four of seven animals, with typical numbers of normal-appearing conceptuses. A fertility rate of 100% returned in four of six animals that became infertile at a single oral dose of 3 mg/kg of gamendazole. No differences in mating behavior were observed in either of the gamendazole-treated groups versus the control (vehicle-only) group. In the animals that showed reversible infertility, a transient increase in circulating FSH levels coincided with an initial decline in inhibin B levels after administration of gamendazole, but no other significant changes in circulating reproductive hormones were observed. Gamendazole inhibited production of inhibin B by primary Sertoli cells in vitro with a median inhibitory concentration of 6.8 thorn+/- 3.0 (SEM) (3/4)x 10(-10) M, suggesting that Sertoli cells are a primary target. A biotinylated gamendazole analogue revealed cytoplasmic and perinuclear binding of gamendazole in primary Sertoli cells. Gamendazole represents the most potent new oral antispermatogenic indazole carboxylic acid to date. Our results, however, demonstrate that additional dose-finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential nonhormonal male contraceptive agent can occur.

[Hormonal contraception in men]. / Hormonale anticonceptie bij de man.

Over the past few decades, female hormonal contraception has been seen to be very successful. However, this has still not resulted in a hormonal contraceptive for men. Certain injectable combinations ofandrogens and progestagens have been found to suppress spermatogenesis. All combinations that have been tested so far suffer from a relative lack of efficacy, a long lag time to achieve azoospermia, requiring the user to undergo one or more semen analyses, a moderate user friendliness, and concerns about the long-term safety and reversibility. It is not to be expected that male hormonal contraception will become a serious alternative to the already existing female equivalent during the coming 5 years.

Intratesticular injection of a zinc-based solution as a contraceptive for dogs.

The objective of the present study was to evaluate, by light and transmission electron microscopy, the efficacy of a single intratesticular injection of a novel zinc-based solution, as a contraceptive for male dogs. Fifteen mongrel dogs were assigned to three groups (five dogs/group). Group 1, the control group, which consisted of animals ranging from 8 mo to 4 yr, was injected with saline solution. Group 2, which consisted of animals ranging from 8 mo to 1 yr old and Group 3, animals ranging from 2 to 4 yr old, were injected with a zinc-based solution (0.2-1.0mL; volume based on testicular width). There were no histopathological changes detected in testes from control dogs. Histological examination of treated groups revealed degeneration, vacuolation, fewer germ cells, formation of multinucleated giant cells, and a lack of elongated spermatids in atrophic seminiferous tubules. Leydig cells had varying degrees of lipid degeneration and necrosis. The majority of seminiferous tubules in all zinc-treated dogs were lined only by Sertoli cells, which were vacuolated. Ultrastructure of testis of treated groups had degenerate Sertoli and Leydig cells, characterized by numerous mitochondria with the lack of a matrix and agglomeration of lysosomal bodies. The cytoplasm of elongated spermatids was characterized by tubules of hyperplastic and hypertrophic smooth endoplasmic reticulum and numerous Golgi apparati. Round spermatids in Golgi phase had lysis of acrosomal vesicles. The degree of histological changes suggested irreversibility. In conclusion, intratesticular injection of a zinc-based solution effectively impaired spermatogenesis.

Intratesticular androgens and spermatogenesis during severe gonadotropin suppression induced by male hormonal contraceptive treatment.

Male hormonal contraceptive regimens function by suppressing gonadotropin secretion, resulting in a dramatic decrease in testicular androgen biosynthesis and spermatogenesis. Animal studies suggest that persistent intratesticular (iT)-androgen production has a stimulatory effect on spermatogenesis in the setting of gonadotropin suppression. We hypothesized that men with incompletely suppressed spermatogenesis (>1,000,000 sperm/mL) during male hormonal contraceptive treatment would have higher iT-androgen concentrations than men who achieved severe oligospermia (

7alpha-methyl-19-nortestosterone (MENT) vs testosterone in combination with etonogestrel implants for spermatogenic suppression in healthy men.

Testosterone with a progestogen can suppress spermatogenesis for contraception. The synthetic androgen 7alpha-methyl-19-nortestosterone (MENT) may offer advantages because it is resistant to 5alpha-reduction and is therefore less active at the prostate. This study aimed to investigate MENT implants in combination with etonogestrel on spermatogenesis, gonadotropins, and androgen-dependent tissues in comparison with a testosterone/etonogestrel regimen. Healthy men (n = 29) were recruited and randomized to receive 2 etonogestrel implants with either 600-mg testosterone pellets repeated every 12 weeks or 2 MENT implants for up to 48 weeks. Testosterone concentrations in the testosterone group remained in the normal range. Subjects with 2 MENT implants showed peak MENT levels at 4 weeks with testosterone concentrations of 2 nmol/L. Sperm concentrations fell rapidly to less than 1 x 10(6)/mL at 12 weeks in 8 of 10 subjects in the MENT group and 13 of 16 subjects in the testosterone group with equally suppressed gonadotropins. Thereafter, suppression was not maintained in the MENT group, and 6 men noted loss of libido. Fourteen men completed 48 weeks of testosterone treatment, and all became azoospermic. Hemoglobin concentrations rose, and high density lipoprotein-cholesterol (HDL-C) fell in both groups. The MENT group showed a fall in prostate-specific antigen with no change in bone mass. MENT with a progestogen can achieve rapid suppression of spermatogenesis similar to testosterone, but this promising result was not sustained due to a decline in MENT release from the implants. This dose of testosterone, compared with previous studies using a lower dose with a higher dose of etonogestrel, had nonreproductive side effects without any increase in spermatogenic suppression. These data indicate the importance of the doses of progestogen and testosterone for optimum spermatogenic suppression while minimizing side effects.

[Male hormonal contraception]. / Muzská hormonální antikoncepce.

Human reproduction is a complex phenomenon remaining at the center of interest of many medical and extra-medical disciplines and the search for new contraceptive methods is an important part of research effort. The development of effective forms of male hormonal contraception (MHC) is one of the priorities of the World Health Organization (WHO Task Force on Methods of Regulation of Male Fertility). The principle of MHC consists in the suppression of spermatogenesis while preserving all other functional aspects of the male glands (especially the sexual functions, bone metabolism and lean muscle mass). It is possible to stop spermatogenesis by blocking gonadotrophin (FSH and LH) secretion by testosterone administration (isolated or in combination with other hormones). The currently existing variants of MHC are based on testosterone application (which has in the same time the role of substitutive treatment--the so-called androgen "add-back") either in monotherapy (oral, intramuscular, transdermal and subcutaneous form) or in combination with various progestins (levonorgestrel, norethisterone, desogestrel, eronogestrel, medroxyprogesterone), antiandrogens or GnRH analogues. The most promising, at present, seem to be the methods which use a combination of depot testosterone preparations with long-acting progestins. To what extent will the role of MHC be important in the future--this can only be judged after establishing their effectiveness, full reversibility, safe application, acceptability, and financial accessibility in clinical practice.

Pharmacokinetics of testosterone undecanoate injected alone or in combination with norethisterone enanthate in healthy men.

Long-acting injectable testosterone undecanoate (TU) is a promising androgen for male hormonal contraception. As a prerequisite for a planned multicenter male contraceptive efficacy study, we studied the pharmacokinetics of 2 doses of TU alone or in combination with norethisterone enanthate (NETE) in a prospective 2-center study, randomized for TU dose in each center. Twenty healthy male volunteers in each center were administered intramuscular injections of 750 or 1000 mg TU alone or in combination with 200 mg of NETE IM every 8 weeks for 3 injections. There were no significant differences in maximum concentration and area under the curve (AUC) for serum total and free testosterone (T) between the TU 750 and 1000 mg groups, irrespective of whether TU was administered with 200 mg of NETE. TU 1000 mg IM alone or with NETE at 8-weekly intervals resulted in linear increases in average concentration and AUC of serum total and free T with each injection. Accumulation ratios of serum total and free T levels (calculated as 8 weeks post- to preinjection levels) for each period showed significant increases in the TU+ NETE groups. Serum gonadotropins levels and sperm concentration were more consistently suppressed in the TU 1000 mg + NETE group. We conclude that despite some accumulation of T, TU 1000 mg + NETE 200 mg administered every 8 weeks may be preferable for the future contraceptive efficacy study because of more complete suppression of gonadotropins and spermatogenesis.