Aim: To study the contraceptive effect of the crude extracts of Curcuma longa in male albino rats. Methods: Rats were fed orally with Curcuma longa aqueous and 70 % alcoholic extract for 60 days (500 mg·kg-1·...Aim: To study the contraceptive effect of the crude extracts of Curcuma longa in male albino rats. Methods: Rats were fed orally with Curcuma longa aqueous and 70 % alcoholic extract for 60 days (500 mg·kg-1· day-1). Results: A reduction in sperm motility and density was observed in both the treated groups. Conclusion: Curcuma longa may have affected the androgen synthesis either by inhibiting the Leydig cell function or the hypo-thalamus pituitary axis and as a result, spermatogenesis is arrested.展开更多
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 de...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 coil strain BL21 StarTM (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.展开更多
The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within...The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non-steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy.展开更多
Aim: To ascertain whether the side effects of gossypol, hypokalemia and irreversibility, could be avoided on dose re-duction. Methods: Seventy-seven male volunteers were divided into 3 groups: control (22 cases), 10 m...Aim: To ascertain whether the side effects of gossypol, hypokalemia and irreversibility, could be avoided on dose re-duction. Methods: Seventy-seven male volunteers were divided into 3 groups: control (22 cases), 10 mg gossypol(29 cases) and 12.5 mg (26 cases). Serum levels of testosterone, FSH and LH were measured by RIA and potassiumby flame photometry. Spema counts and motility were examined before and regularly after treatment for the evaluationof contraceptive efficacy. Results: The average sperm density and motility started to decrease significantly by theend of month 2 of medication and gradually reached the infertility levels ( < 4 million /mL) in both treated groups. Af-ter that the 10 mg group was asked to take the same dose every other day for up to a total observation period of 16-18months for the maintenance of infertility. Subjects in the 12.5 mg group did not take gossypol any more so as to ob-serve the length of the loading dose required, but in a few, a maintenance dose of 12.5 mg every other day was insti-tuted for a few more months. In both treated groups, none of the spouses was pregnant during the maintenance dose pe-riod. Serum levels of potassium, FSH, LH and testosterone were not significantly changed and not a single volunteercomplained of myoasthenia. After cessation of drug administratioin, the semen data returned to pretreatment levels.Conclusion: A regimen with 10 or 12.5 mg of gossypol as the daily loading dose and 35 or 43.75 mg as the week-ly maintenance dose could induce infertility in male volunteers without developing hypokalemia or irreversibility.(Asian J Androl 2000 Dec; 2: 283-287)展开更多
Development of an ideal hormonal contraceptive for man has been the goal of several research workers during thepast few decades. Suppression of pituitary gonadotropic hormones, which in turn would inhibit spermatogene...Development of an ideal hormonal contraceptive for man has been the goal of several research workers during thepast few decades. Suppression of pituitary gonadotropic hormones, which in turn would inhibit spermatogenesis whilemaintaining normal libido and potentia has been the approach for a contraceptive agent. Intramuscularly administeredand orally active testosterone or testosterone in combination with progesterone have been shown to cause inhibition ofspermatogenesis resulting in azoospermia in normal men. Similarly testosterone has been used in combination with go-nadotropin releasing hormone antagonists and agonists to inhibit pituitary gonadotropic hormone release. Immunologicalapproach to neutralize the circulating levels of follicle stimulating hormone has also been shown to cause inhibition ofspermatogenesis. The available literature shows that testosterone causes reversible azoospermia without any significantside effects in Asian population effectively and appears to be a promising chemical for control of fertility in man.展开更多
Aim:To evaluate the safety of the long term vas occlusion with styrene maleic anhydride (SMA) and its non-invasive reversal at the level of accessory reproductive glands (ARGs) in langurs.Methods:The morphology of sem...Aim:To evaluate the safety of the long term vas occlusion with styrene maleic anhydride (SMA) and its non-invasive reversal at the level of accessory reproductive glands (ARGs) in langurs.Methods:The morphology of seminal vesicle and ventral prostate was evaluated by light as well as transmission electron microscopy.Serum clinical chemistry and urine albumin were evaluated in an autoanalyzer using reagent kits.Fructose,acid phosphatase and zinc in the seminal plasma were evaluated spectrophotometrically according to the WHO manual.Serum testosterone, prostate specific antigen and sperm antibodies were evaluated by enzyme-linked immunosorbent assays (ELISA) using reagent kits and hematology was estimated according to standard procedures.Results:The morphological features and secretory activity of the seminal vesicle and prostate were normal as evidenced by the presence of well- developed mitochondria,rough endoplasmic reticulum,Golgi bodies,secretory granules and normal nuclear charac- teristics throughout the course of investigation.Serum testosterone and prostate specific antigen remained unaltered and serum antisperm antibodies level presented negative titres.Urine albumin was nil.Total red blood corpuscles (RBC),white blood corpuscles (WBC),hemoglobin (Hb) and red cell indices,serum protein,glucose,cholesterol, creatinine,creatine kinase (CK),serum glutamate oxalate transaminase (SGOT),serum glutamate pyruvate transami- nase (SGPT),lactate dehydrogenase (LDH),bilirubin,urea,triglycerides and high-density lipoprotein (HDL) did not show appreciable changes following vas occlusion and after its non-invasive reversal.Although fructose,acid phos- phatase (ACP) and zinc in the seminal plasma showed a significant reduction following vas occlusion,it could not be related to the morphology of seminal vesicle and prostate.Conclusion:SMA vas occlusion and its non-invasive reversal do not damage the accessory reproductive organs.展开更多
The vas deferens is a site which can be exploited for male contraception without undue side effects. The only ef-fective technique available for male contraception is vasectomy, being practiced world wide, despite tha...The vas deferens is a site which can be exploited for male contraception without undue side effects. The only ef-fective technique available for male contraception is vasectomy, being practiced world wide, despite that it is a perma-nent surgical procedure and its successful reversal is not assured. Although no-scalpel vasectomy minimizes surgicalprocedures, the fate of its reversal is akin to that of vasectomy. Several occlusive and non-occlusive vasal procedureswhich claim to be reversible without surgical intervention, possess more disadvantages than advantages. Vas occlusionwith plug, ' Shug' or medical grade silicone rubber, although claimed to produce reversible azoospermia without affect-ing spermatogenesis, requires skilled microsurgery for their implantation and later removal. RISUG^R, a non-scleroticpolymer styrene maleic anhydride (SMA), could be more advantageous than vasectomy and other vas occlusive proce-dures in that it could be a totally non-invasive procedure by 'no-scalpel injection' and 'non-invasive reversal'. It isclaimed to offer long-term contraception without adverse side effects and also to be possible as a male spacing methodby repeated vas occlusion and non-invasive reversal. The drug is currently under multicentre Phase Ⅲ clinical trial.展开更多
Objective: To give an historical record of the research of the World Health Organization (WHO) Task Force to develop methods of male contraception; to examine the social, political, medical, pharmaceutical, funding, a...Objective: To give an historical record of the research of the World Health Organization (WHO) Task Force to develop methods of male contraception; to examine the social, political, medical, pharmaceutical, funding, and other factors that influenced progress; and to suggest reasons why such methods are only now becoming available. Design: Review of basic and clinical research over 30 years. Setting: Task force of a multinational agency and collaborating agencies. Conclusion(s): Through the involvement of many international scientists, the WHO Task Force has uniquely contributed to the exploratory phases of the research in male contraception and by its multicenter contraceptive efficacy studies has accelerated progress towards the ideal hormonal method. Despite an adverse climate involving social and political attitudes, funding constraints, and pharmaceutical industry hesitations, WHO formed coalitions with governments and international agencies to sustain research with results that apply to men in culturally diverse populations and thereby to influence activities across the whole range of global reproductive health and family planning.展开更多
Interest in ion channels as drug targets for contraception has grown with the realization that certain ion channel subunits are located exclusively in sperm. Selective knockdown of ion channel subunits can lead to inf...Interest in ion channels as drug targets for contraception has grown with the realization that certain ion channel subunits are located exclusively in sperm. Selective knockdown of ion channel subunits can lead to infertility without ill effects, and selective inhibitors and/ or openers of these ion channels could interfere with sperm function. In this study, in vivo electmporation (EP) and rete testis microinjection-mediated plasmid DNA were adopted to silence CatSper2 expression, which is essential in sperm hyperactivation. The results showed that high transfection efficiency and expression were achieved by plasmid DNA that was directly injected into the rete testis. As a result of the expression of CatSper2 being blocked, the treatment group showed significantly lower (P〈0.05) hyperactivation rate, fertilization rate in vitro, migration motility in viscoelastic solution and intracellular Ca2+ peak. The low hyperactivation and fertilization rates lasted for 60 days. Meanwhile, analysis of the sperm survival rate and testis histology indicated that in vivo EP had no significant effect on the function of the testis, spermatogenesis or sperm activity. The present study demonstrated that it was feasible to achieve male contraception by silencing the expression of CatSper2, the key protein involved in sperm hvoeractivation.展开更多
Drug treatment remains an active domain in the therapy of male fertility disorders. Although there are only a fewconditions that allow causal treatment, rational approaches are possible in many cases. Best results are...Drug treatment remains an active domain in the therapy of male fertility disorders. Although there are only a fewconditions that allow causal treatment, rational approaches are possible in many cases. Best results are obtained in casesrequiring an anti-inflammatory treatment and in patients with an impaired sperm transport. High-dosage administrationof FSH is a promising new development, aimed particularly at improving the disturbed sperm structures. A careful di-agnostic work-up with elucidation of the underlying disease is essential to achieve a successful therapy.展开更多
Pharmaceutical treatment for the so-called idiopathic oligozoospermia (I. O.) is possible and effective in a fairproportion of patients with the syndrome provided that appropriate investigative procedures may identify...Pharmaceutical treatment for the so-called idiopathic oligozoospermia (I. O.) is possible and effective in a fairproportion of patients with the syndrome provided that appropriate investigative procedures may identify the major disor-der or its level of disruption, this abnormality is reversible and appropriate prognostic indices for the treatment's successare devised and validated. According to the evidence available, minimal evaluation and prognostic indices for treatmenteligibility in normogonadotropic men with I.O. include a routine work-up but, mainly, microscopical assessment ofspermatogenesis and appraisal of Sertoli cell's functional capacity. Published data indicate that men with hypospermato-genesis without maturational arrest, respond favorably to agents stimulating Sertoli cells and germinal epithelium withincreased sperm production. Furthermore, Sertoli cell activity as judged by cell-specific indices such as inhibin B secre-tion, may provide additional discriminating power to the microscopical picture of the testis. In this context, precise i-dentification of the causative factor(s), together with the establishment of prognostic indices are the most important cri-teria on which the decision, for or against medical treatment in I. O., should be based. Obviously, further basic re-search and clinical trials are urgently needed in this particular field, and this should be a major task for clinical androlo-gists. (Asian J Androl 2000; 2: 25 - 32)展开更多
Aim: To analyze factors influencing the efficacy of hormonal suppression of spermatogenesis for male contraception. Methods: A nested case-control study was conducted, involving 43 subjects, who did not achieve azoo...Aim: To analyze factors influencing the efficacy of hormonal suppression of spermatogenesis for male contraception. Methods: A nested case-control study was conducted, involving 43 subjects, who did not achieve azoospermia or severe oligozoospermia when given monthly injections of 500 mg testosterone undecanoate (TU), defined as partial suppressors compared with 855 subjects who had suppressed spermatogenesis (complete suppressors). Sperm density, serum testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations at the baseline and the suppression phase were compared between partial and complete suppressors. Polymorphisms of androgen receptor (AR) and three single nucleotide variants and their haplotypes of FSH receptor (FSHR) genes determined by polymerase chain reaction (PCR) and DNA sequencing technique were compared between 29 partial and 34 complete suppressors. Results: Baseline serum LH level was higher and serum LH as well as FSH level during the suppression phase was less suppressed in partial suppressors. Additionally, in a logistic regression analysis larger testis volume, higher serum FSH concentrations alone, or interaction of serum LH, FSH, testosterone and sperm concentrations were associated with degree of suppression. The distribution of polymorphisms of AR or FSH receptor genes did not differ between partial and complete suppressors. In cases with incomplete FSH suppression (FSH 〉 0.2 IU/L), the chances of reaching azoospermia were 1.5 times higher in the subjects with more than 22 CAG triplet repeats. Conclusion: Partial suppression of spermatogenesis induced by 500 mg TU monthly injections is weakly influenced by hormonal and clinical features but not polymorphism in AR and FSHR genes.展开更多
Hyperactivation is one of the most critical parts for fertilization, cAMP generated by soluble adenylyl cyclase (sAC) is necessary to activate sperm and is a prerequisite for sperm hyperactivation. The aim of this s...Hyperactivation is one of the most critical parts for fertilization, cAMP generated by soluble adenylyl cyclase (sAC) is necessary to activate sperm and is a prerequisite for sperm hyperactivation. The aim of this study is to investigate the function of sAC in hyperactivation in male rats. Four siRNAs of sAC gene were designed and separately transformed into rat sperm using electrotransformation method. Cultured for 12 and 24 h, physiological and biochemical indexes of these sperm were analyzed, and the expressions of some hyperactivation-related genes were detected using real-time PCR. We demonstrated 26.3-30.8% and 49.1-50.5% reduction in sAC at the protein by Western blot and mRNA levels by real-time PCR, respectively. The results showed that two siRNAs, Actb-717 and Actb-4205, were the best RNAi sites for silencing sAC. The VCL (curvilinear velocity) and ALH (amplitude of lateral head displacement) of RNA interference (RNAi)-transfected sperm were reduced, cAMP and protein phosphorylation in RNAi transfected sperm were also decreased. The hyperactivation-related genes, such as CatSper2, LDHC and PKA, were downregulated in the sperm, which sAC was knockdown. These findings demonstrated that sAC might play a critical role in cAMP signaling in the rat sperm hyperactivation, and downregulated sAC gene might prevent the expression of these hyperactivation-ralated genes resulting in sperm dysfunction. These findings suggest that these hyperactivation-ralated genes and sAC are functionally related in sperm hyperactivation and sAC falls into an expanding group of sperm proteins that appear to be promising targets for the development of male contraceptives.展开更多
Progress in development of a simple, effective reversible male contraceptive has been difficult due to the indispensable role of testosterone in spermatogenesis and maintenance of secondary sexual characters. Efforts ...Progress in development of a simple, effective reversible male contraceptive has been difficult due to the indispensable role of testosterone in spermatogenesis and maintenance of secondary sexual characters. Efforts are in progress to develop methods, which do not interfere with testosterone production. These include blockade of FSH action by immunization against FSH or FSHR, and interfere with sperm maturation by interfering with estrogen action or by immunization against epididymal or sperm specific proteins. An evaluation of these various approaches for practical application is also presented.展开更多
The aim of hormonal male contraception is to prevent unintended pregnancies by suppressing spermatogenesis. Hormonal male contraception is based on the principle that exogenous administration of androgens and other ho...The aim of hormonal male contraception is to prevent unintended pregnancies by suppressing spermatogenesis. Hormonal male contraception is based on the principle that exogenous administration of androgens and other hormones such as progestins suppress circulating gonadotropin concentrations, decreasing testicular Leydig cell and Sertoli cell activity and spermatogenesis. In order to achieve more complete suppression of circulating gonadotropins and spermatogenesis, a progestin has been added testosterone to the most recent efficacy trials of hormonal male contraceptives. This review focusses on the potential effects of male hormonal contraceptives on cardiovascular risk factors, iipids and body composition, mainly in the target group of younger to middle-aged men. Present data suggest that hormonal male contraception can be reasonably regarded as safe in terms of cardiovascular risk. However, as all trials have been relatively short (〈 3 years), a final statement regarding the cardiovascular safety of hormonal male contraception, especially in long-term use, cannot be made. Older men with at high risk of cardiovascular event might not be good candidates for hormonal male contraception. The potential adversSeffects of hormonal contraceptives on cardiovascular risk appear to depend greatly on the choice of the progestin in regimens for hormonal male contrai:eptives. In the development of prospective hormonal male contraception, data on longer-term cardiovascular safety will be essential.展开更多
Effective regulation of human fertility has global consequences in terms of resource depletion, pollution and pover-ty. Current family planning services predominantly target a female clientele with few significant dev...Effective regulation of human fertility has global consequences in terms of resource depletion, pollution and pover-ty. Current family planning services predominantly target a female clientele with few significant developments in malefertility regulation for over a century. The last two decades have witnessed a gathering interest, initially from the scien-tific community, and laterally from industry, in the development of safe, reliable, reversible methods of contraceptionfor men. This review summarises the methods of male fertility regulation which are currently available and critically ex-amines the published data on novel developments in male hormonal contraception which offer the potential of improvedcontraceptive choice for all in new millennium. (Asian J Androl 2000; 2: 3 - 12)展开更多
Considerable efforts have been made to develop a male contraceptive and the studies have provided very useful infor-mation in this field. At least five different strategies to develop a male contraceptive have been pu...Considerable efforts have been made to develop a male contraceptive and the studies have provided very useful infor-mation in this field. At least five different strategies to develop a male contraceptive have been pursued, namely: inhi-bition of sperm production, interference with sperm function, interruption of sperm transport, prevention of sperm de-position, and prevention of sperm-egg interaction. Of all these approaches, inhibition of sperm production by using an-drogens either alone or in combination with progestins have given the most encouraging results. A nmnber of clinicaltrials substantiate that it is indeed possible to have a reversible, effective and safe hormonal method of contraception. Apostmeiotic and epididymal approach to interfere with sperm function or the secretory and metabolic processes of theepididymis is another attractive option of male contraceptive development. A number of chemical compounds have beenidentified which interfere with sperm function in the epididymis without affecting sperm production, however, the com-pounds evaluated so far were found to be toxic. Interruption of sperm transport through the vas either by vasectomy orpercutaneous intmvasal injection of liquids which form cure-in-place plugs is also an attractive option. However, re-versibility of the methods is of concern in their wide scale use. The major constraint in developing a long-acting male contraceptive seems to be the need for greater investment forproduct development. The clinical trials for evaluating the efficacy and safety of the new products and formulationsstretch over several years and require enormous financial commitment. Nevertheless, the long-term gain of having along-acting reversible contraceptive for men is far greater than the financial commitments over few years. Male attitudetowards using methods of family planning is much more favourable than originally believed. The pharmaceutical indus-try as well as the health care providers therefore have a greater responsibility. For early development of a contraceptivefor men, it is essential to increase investment and simplify the drug regulatory procedures. The advent of newer tech-nologies coupled with the convergent efforts of scientists will certainly make it possible to have an effective, safe andreversible male contraceptive in the near future.展开更多
Tribenuron-methyl (TM) is a powerful sulfonylurea herbicide that inhibits branched-chain amino acid (BCAA) biosynthesis by targeting the catalytic subunit (CSR1) of acetolactate synthase (ALS). Selective in- d...Tribenuron-methyl (TM) is a powerful sulfonylurea herbicide that inhibits branched-chain amino acid (BCAA) biosynthesis by targeting the catalytic subunit (CSR1) of acetolactate synthase (ALS). Selective in- duction of male sterility by foliar spraying of TM at low doses has been widely used for hybrid seed produc- tion in rapeseed (Brassica napus); however, the underlying mechanism remains unknown. Here, we report greater TM accumulation and subsequent stronger ALS inhibition and BCAA starvation in anthers than in leaves and stems after TM application. Constitutive or anther-specific expression of csrl-lD (a CSR1 mutant) eliminated anther-selective ALS inhibition and reversed the TM-induced male sterile phenotype in both rapeseed and Arabidopsis. The results of TM daub-stem experiments, combined with the observations of little TM accumulation in anthers and reversion of TM-induced male sterility by targeted expression of the TM metabolism gene Bel in either the mesophyll or phloem, suggested that foliar-sprayed TM was polar-transported to anthers mainly through the mesophyll and phloem. Microscopy and immunoblotting revealed that autophagy, a bulk degradation process induced during cell death, was elevated in TM-induced male sterile anthers and by anther-specific knockdown of ALS. Moreover, TM-induced pollen abortion was significantly inhibited by the autophagy inhibitor 3-MA. These data suggested that TM was polar-transported to anthers, resulting in BCAA starvation via anther-specific ALS inhibition and, ulti- mately, autophagic cell death in anthers.展开更多
Urokinase-type plasminogen activator (uPA) is closely related to male reproduction. With the aim of investigating the possibility for uPA as a potential contraceptive target, in the present work, Kunming male mice w...Urokinase-type plasminogen activator (uPA) is closely related to male reproduction. With the aim of investigating the possibility for uPA as a potential contraceptive target, in the present work, Kunming male mice were immunized by human uPA subcutaneous injection at three separate doses for 3 times. Then the potency of the anti-human uPA antibody in serum was analyzed, and mouse fertility was evaluated. Serum antibody titers for human uPA in immunized groups all reached 1:10,240 or higher levels by enzyme linked immunosorbent assay, and mating experiments revealed that pregnancy rates and the mean number of embryos implanted after mating declined obviously (P 〈 0.05) when compared with control groups. However, the mating capacity and reproductive organ weights had no obvious change, and histological analysis of the testes and epididymides also showed normal morphology for immunized male mice. Sperm function tests suggested that the sperm concentration, sperm viability, sperm motility, and in vitro fertilization rate for the cauda epididymis sperm in uPA-immunized groups were lower than those in the controls (P 〈 0.05). Together, these observations indicated that subcutaneous injection human uPA to the male mice could effectively reduce their fertility, and uPA could become a new target for immunocontraception in male contraceptive development.展开更多
文摘Aim: To study the contraceptive effect of the crude extracts of Curcuma longa in male albino rats. Methods: Rats were fed orally with Curcuma longa aqueous and 70 % alcoholic extract for 60 days (500 mg·kg-1· day-1). Results: A reduction in sperm motility and density was observed in both the treated groups. Conclusion: Curcuma longa may have affected the androgen synthesis either by inhibiting the Leydig cell function or the hypo-thalamus pituitary axis and as a result, spermatogenesis is arrested.
基金This study was supported by the National Key Technologies R and D Program (No. 2012BAI31B07 and No. 2006BAI03B12), the National Science Foundationof China (No. 81172694). This project was also funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘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 coil strain BL21 StarTM (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.
文摘The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non-steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy.
文摘Aim: To ascertain whether the side effects of gossypol, hypokalemia and irreversibility, could be avoided on dose re-duction. Methods: Seventy-seven male volunteers were divided into 3 groups: control (22 cases), 10 mg gossypol(29 cases) and 12.5 mg (26 cases). Serum levels of testosterone, FSH and LH were measured by RIA and potassiumby flame photometry. Spema counts and motility were examined before and regularly after treatment for the evaluationof contraceptive efficacy. Results: The average sperm density and motility started to decrease significantly by theend of month 2 of medication and gradually reached the infertility levels ( < 4 million /mL) in both treated groups. Af-ter that the 10 mg group was asked to take the same dose every other day for up to a total observation period of 16-18months for the maintenance of infertility. Subjects in the 12.5 mg group did not take gossypol any more so as to ob-serve the length of the loading dose required, but in a few, a maintenance dose of 12.5 mg every other day was insti-tuted for a few more months. In both treated groups, none of the spouses was pregnant during the maintenance dose pe-riod. Serum levels of potassium, FSH, LH and testosterone were not significantly changed and not a single volunteercomplained of myoasthenia. After cessation of drug administratioin, the semen data returned to pretreatment levels.Conclusion: A regimen with 10 or 12.5 mg of gossypol as the daily loading dose and 35 or 43.75 mg as the week-ly maintenance dose could induce infertility in male volunteers without developing hypokalemia or irreversibility.(Asian J Androl 2000 Dec; 2: 283-287)
文摘Development of an ideal hormonal contraceptive for man has been the goal of several research workers during thepast few decades. Suppression of pituitary gonadotropic hormones, which in turn would inhibit spermatogenesis whilemaintaining normal libido and potentia has been the approach for a contraceptive agent. Intramuscularly administeredand orally active testosterone or testosterone in combination with progesterone have been shown to cause inhibition ofspermatogenesis resulting in azoospermia in normal men. Similarly testosterone has been used in combination with go-nadotropin releasing hormone antagonists and agonists to inhibit pituitary gonadotropic hormone release. Immunologicalapproach to neutralize the circulating levels of follicle stimulating hormone has also been shown to cause inhibition ofspermatogenesis. The available literature shows that testosterone causes reversible azoospermia without any significantside effects in Asian population effectively and appears to be a promising chemical for control of fertility in man.
文摘Aim:To evaluate the safety of the long term vas occlusion with styrene maleic anhydride (SMA) and its non-invasive reversal at the level of accessory reproductive glands (ARGs) in langurs.Methods:The morphology of seminal vesicle and ventral prostate was evaluated by light as well as transmission electron microscopy.Serum clinical chemistry and urine albumin were evaluated in an autoanalyzer using reagent kits.Fructose,acid phosphatase and zinc in the seminal plasma were evaluated spectrophotometrically according to the WHO manual.Serum testosterone, prostate specific antigen and sperm antibodies were evaluated by enzyme-linked immunosorbent assays (ELISA) using reagent kits and hematology was estimated according to standard procedures.Results:The morphological features and secretory activity of the seminal vesicle and prostate were normal as evidenced by the presence of well- developed mitochondria,rough endoplasmic reticulum,Golgi bodies,secretory granules and normal nuclear charac- teristics throughout the course of investigation.Serum testosterone and prostate specific antigen remained unaltered and serum antisperm antibodies level presented negative titres.Urine albumin was nil.Total red blood corpuscles (RBC),white blood corpuscles (WBC),hemoglobin (Hb) and red cell indices,serum protein,glucose,cholesterol, creatinine,creatine kinase (CK),serum glutamate oxalate transaminase (SGOT),serum glutamate pyruvate transami- nase (SGPT),lactate dehydrogenase (LDH),bilirubin,urea,triglycerides and high-density lipoprotein (HDL) did not show appreciable changes following vas occlusion and after its non-invasive reversal.Although fructose,acid phos- phatase (ACP) and zinc in the seminal plasma showed a significant reduction following vas occlusion,it could not be related to the morphology of seminal vesicle and prostate.Conclusion:SMA vas occlusion and its non-invasive reversal do not damage the accessory reproductive organs.
文摘The vas deferens is a site which can be exploited for male contraception without undue side effects. The only ef-fective technique available for male contraception is vasectomy, being practiced world wide, despite that it is a perma-nent surgical procedure and its successful reversal is not assured. Although no-scalpel vasectomy minimizes surgicalprocedures, the fate of its reversal is akin to that of vasectomy. Several occlusive and non-occlusive vasal procedureswhich claim to be reversible without surgical intervention, possess more disadvantages than advantages. Vas occlusionwith plug, ' Shug' or medical grade silicone rubber, although claimed to produce reversible azoospermia without affect-ing spermatogenesis, requires skilled microsurgery for their implantation and later removal. RISUG^R, a non-scleroticpolymer styrene maleic anhydride (SMA), could be more advantageous than vasectomy and other vas occlusive proce-dures in that it could be a totally non-invasive procedure by 'no-scalpel injection' and 'non-invasive reversal'. It isclaimed to offer long-term contraception without adverse side effects and also to be possible as a male spacing methodby repeated vas occlusion and non-invasive reversal. The drug is currently under multicentre Phase Ⅲ clinical trial.
文摘Objective: To give an historical record of the research of the World Health Organization (WHO) Task Force to develop methods of male contraception; to examine the social, political, medical, pharmaceutical, funding, and other factors that influenced progress; and to suggest reasons why such methods are only now becoming available. Design: Review of basic and clinical research over 30 years. Setting: Task force of a multinational agency and collaborating agencies. Conclusion(s): Through the involvement of many international scientists, the WHO Task Force has uniquely contributed to the exploratory phases of the research in male contraception and by its multicenter contraceptive efficacy studies has accelerated progress towards the ideal hormonal method. Despite an adverse climate involving social and political attitudes, funding constraints, and pharmaceutical industry hesitations, WHO formed coalitions with governments and international agencies to sustain research with results that apply to men in culturally diverse populations and thereby to influence activities across the whole range of global reproductive health and family planning.
文摘Interest in ion channels as drug targets for contraception has grown with the realization that certain ion channel subunits are located exclusively in sperm. Selective knockdown of ion channel subunits can lead to infertility without ill effects, and selective inhibitors and/ or openers of these ion channels could interfere with sperm function. In this study, in vivo electmporation (EP) and rete testis microinjection-mediated plasmid DNA were adopted to silence CatSper2 expression, which is essential in sperm hyperactivation. The results showed that high transfection efficiency and expression were achieved by plasmid DNA that was directly injected into the rete testis. As a result of the expression of CatSper2 being blocked, the treatment group showed significantly lower (P〈0.05) hyperactivation rate, fertilization rate in vitro, migration motility in viscoelastic solution and intracellular Ca2+ peak. The low hyperactivation and fertilization rates lasted for 60 days. Meanwhile, analysis of the sperm survival rate and testis histology indicated that in vivo EP had no significant effect on the function of the testis, spermatogenesis or sperm activity. The present study demonstrated that it was feasible to achieve male contraception by silencing the expression of CatSper2, the key protein involved in sperm hvoeractivation.
文摘Drug treatment remains an active domain in the therapy of male fertility disorders. Although there are only a fewconditions that allow causal treatment, rational approaches are possible in many cases. Best results are obtained in casesrequiring an anti-inflammatory treatment and in patients with an impaired sperm transport. High-dosage administrationof FSH is a promising new development, aimed particularly at improving the disturbed sperm structures. A careful di-agnostic work-up with elucidation of the underlying disease is essential to achieve a successful therapy.
文摘Pharmaceutical treatment for the so-called idiopathic oligozoospermia (I. O.) is possible and effective in a fairproportion of patients with the syndrome provided that appropriate investigative procedures may identify the major disor-der or its level of disruption, this abnormality is reversible and appropriate prognostic indices for the treatment's successare devised and validated. According to the evidence available, minimal evaluation and prognostic indices for treatmenteligibility in normogonadotropic men with I.O. include a routine work-up but, mainly, microscopical assessment ofspermatogenesis and appraisal of Sertoli cell's functional capacity. Published data indicate that men with hypospermato-genesis without maturational arrest, respond favorably to agents stimulating Sertoli cells and germinal epithelium withincreased sperm production. Furthermore, Sertoli cell activity as judged by cell-specific indices such as inhibin B secre-tion, may provide additional discriminating power to the microscopical picture of the testis. In this context, precise i-dentification of the causative factor(s), together with the establishment of prognostic indices are the most important cri-teria on which the decision, for or against medical treatment in I. O., should be based. Obviously, further basic re-search and clinical trials are urgently needed in this particular field, and this should be a major task for clinical androlo-gists. (Asian J Androl 2000; 2: 25 - 32)
文摘Aim: To analyze factors influencing the efficacy of hormonal suppression of spermatogenesis for male contraception. Methods: A nested case-control study was conducted, involving 43 subjects, who did not achieve azoospermia or severe oligozoospermia when given monthly injections of 500 mg testosterone undecanoate (TU), defined as partial suppressors compared with 855 subjects who had suppressed spermatogenesis (complete suppressors). Sperm density, serum testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations at the baseline and the suppression phase were compared between partial and complete suppressors. Polymorphisms of androgen receptor (AR) and three single nucleotide variants and their haplotypes of FSH receptor (FSHR) genes determined by polymerase chain reaction (PCR) and DNA sequencing technique were compared between 29 partial and 34 complete suppressors. Results: Baseline serum LH level was higher and serum LH as well as FSH level during the suppression phase was less suppressed in partial suppressors. Additionally, in a logistic regression analysis larger testis volume, higher serum FSH concentrations alone, or interaction of serum LH, FSH, testosterone and sperm concentrations were associated with degree of suppression. The distribution of polymorphisms of AR or FSH receptor genes did not differ between partial and complete suppressors. In cases with incomplete FSH suppression (FSH 〉 0.2 IU/L), the chances of reaching azoospermia were 1.5 times higher in the subjects with more than 22 CAG triplet repeats. Conclusion: Partial suppression of spermatogenesis induced by 500 mg TU monthly injections is weakly influenced by hormonal and clinical features but not polymorphism in AR and FSHR genes.
基金supported by the National Natural Science Foundation of China (30471243)the National Key Technology R&D Program of China (2011BAD28B02,2012BAD12B10)the Provincial Project for Agricultural Techniques of China (SX2011-189)
文摘Hyperactivation is one of the most critical parts for fertilization, cAMP generated by soluble adenylyl cyclase (sAC) is necessary to activate sperm and is a prerequisite for sperm hyperactivation. The aim of this study is to investigate the function of sAC in hyperactivation in male rats. Four siRNAs of sAC gene were designed and separately transformed into rat sperm using electrotransformation method. Cultured for 12 and 24 h, physiological and biochemical indexes of these sperm were analyzed, and the expressions of some hyperactivation-related genes were detected using real-time PCR. We demonstrated 26.3-30.8% and 49.1-50.5% reduction in sAC at the protein by Western blot and mRNA levels by real-time PCR, respectively. The results showed that two siRNAs, Actb-717 and Actb-4205, were the best RNAi sites for silencing sAC. The VCL (curvilinear velocity) and ALH (amplitude of lateral head displacement) of RNA interference (RNAi)-transfected sperm were reduced, cAMP and protein phosphorylation in RNAi transfected sperm were also decreased. The hyperactivation-related genes, such as CatSper2, LDHC and PKA, were downregulated in the sperm, which sAC was knockdown. These findings demonstrated that sAC might play a critical role in cAMP signaling in the rat sperm hyperactivation, and downregulated sAC gene might prevent the expression of these hyperactivation-ralated genes resulting in sperm dysfunction. These findings suggest that these hyperactivation-ralated genes and sAC are functionally related in sperm hyperactivation and sAC falls into an expanding group of sperm proteins that appear to be promising targets for the development of male contraceptives.
文摘Progress in development of a simple, effective reversible male contraceptive has been difficult due to the indispensable role of testosterone in spermatogenesis and maintenance of secondary sexual characters. Efforts are in progress to develop methods, which do not interfere with testosterone production. These include blockade of FSH action by immunization against FSH or FSHR, and interfere with sperm maturation by interfering with estrogen action or by immunization against epididymal or sperm specific proteins. An evaluation of these various approaches for practical application is also presented.
文摘The aim of hormonal male contraception is to prevent unintended pregnancies by suppressing spermatogenesis. Hormonal male contraception is based on the principle that exogenous administration of androgens and other hormones such as progestins suppress circulating gonadotropin concentrations, decreasing testicular Leydig cell and Sertoli cell activity and spermatogenesis. In order to achieve more complete suppression of circulating gonadotropins and spermatogenesis, a progestin has been added testosterone to the most recent efficacy trials of hormonal male contraceptives. This review focusses on the potential effects of male hormonal contraceptives on cardiovascular risk factors, iipids and body composition, mainly in the target group of younger to middle-aged men. Present data suggest that hormonal male contraception can be reasonably regarded as safe in terms of cardiovascular risk. However, as all trials have been relatively short (〈 3 years), a final statement regarding the cardiovascular safety of hormonal male contraception, especially in long-term use, cannot be made. Older men with at high risk of cardiovascular event might not be good candidates for hormonal male contraception. The potential adversSeffects of hormonal contraceptives on cardiovascular risk appear to depend greatly on the choice of the progestin in regimens for hormonal male contrai:eptives. In the development of prospective hormonal male contraception, data on longer-term cardiovascular safety will be essential.
文摘Effective regulation of human fertility has global consequences in terms of resource depletion, pollution and pover-ty. Current family planning services predominantly target a female clientele with few significant developments in malefertility regulation for over a century. The last two decades have witnessed a gathering interest, initially from the scien-tific community, and laterally from industry, in the development of safe, reliable, reversible methods of contraceptionfor men. This review summarises the methods of male fertility regulation which are currently available and critically ex-amines the published data on novel developments in male hormonal contraception which offer the potential of improvedcontraceptive choice for all in new millennium. (Asian J Androl 2000; 2: 3 - 12)
文摘Considerable efforts have been made to develop a male contraceptive and the studies have provided very useful infor-mation in this field. At least five different strategies to develop a male contraceptive have been pursued, namely: inhi-bition of sperm production, interference with sperm function, interruption of sperm transport, prevention of sperm de-position, and prevention of sperm-egg interaction. Of all these approaches, inhibition of sperm production by using an-drogens either alone or in combination with progestins have given the most encouraging results. A nmnber of clinicaltrials substantiate that it is indeed possible to have a reversible, effective and safe hormonal method of contraception. Apostmeiotic and epididymal approach to interfere with sperm function or the secretory and metabolic processes of theepididymis is another attractive option of male contraceptive development. A number of chemical compounds have beenidentified which interfere with sperm function in the epididymis without affecting sperm production, however, the com-pounds evaluated so far were found to be toxic. Interruption of sperm transport through the vas either by vasectomy orpercutaneous intmvasal injection of liquids which form cure-in-place plugs is also an attractive option. However, re-versibility of the methods is of concern in their wide scale use. The major constraint in developing a long-acting male contraceptive seems to be the need for greater investment forproduct development. The clinical trials for evaluating the efficacy and safety of the new products and formulationsstretch over several years and require enormous financial commitment. Nevertheless, the long-term gain of having along-acting reversible contraceptive for men is far greater than the financial commitments over few years. Male attitudetowards using methods of family planning is much more favourable than originally believed. The pharmaceutical indus-try as well as the health care providers therefore have a greater responsibility. For early development of a contraceptivefor men, it is essential to increase investment and simplify the drug regulatory procedures. The advent of newer tech-nologies coupled with the convergent efforts of scientists will certainly make it possible to have an effective, safe andreversible male contraceptive in the near future.
文摘Tribenuron-methyl (TM) is a powerful sulfonylurea herbicide that inhibits branched-chain amino acid (BCAA) biosynthesis by targeting the catalytic subunit (CSR1) of acetolactate synthase (ALS). Selective in- duction of male sterility by foliar spraying of TM at low doses has been widely used for hybrid seed produc- tion in rapeseed (Brassica napus); however, the underlying mechanism remains unknown. Here, we report greater TM accumulation and subsequent stronger ALS inhibition and BCAA starvation in anthers than in leaves and stems after TM application. Constitutive or anther-specific expression of csrl-lD (a CSR1 mutant) eliminated anther-selective ALS inhibition and reversed the TM-induced male sterile phenotype in both rapeseed and Arabidopsis. The results of TM daub-stem experiments, combined with the observations of little TM accumulation in anthers and reversion of TM-induced male sterility by targeted expression of the TM metabolism gene Bel in either the mesophyll or phloem, suggested that foliar-sprayed TM was polar-transported to anthers mainly through the mesophyll and phloem. Microscopy and immunoblotting revealed that autophagy, a bulk degradation process induced during cell death, was elevated in TM-induced male sterile anthers and by anther-specific knockdown of ALS. Moreover, TM-induced pollen abortion was significantly inhibited by the autophagy inhibitor 3-MA. These data suggested that TM was polar-transported to anthers, resulting in BCAA starvation via anther-specific ALS inhibition and, ulti- mately, autophagic cell death in anthers.
文摘Urokinase-type plasminogen activator (uPA) is closely related to male reproduction. With the aim of investigating the possibility for uPA as a potential contraceptive target, in the present work, Kunming male mice were immunized by human uPA subcutaneous injection at three separate doses for 3 times. Then the potency of the anti-human uPA antibody in serum was analyzed, and mouse fertility was evaluated. Serum antibody titers for human uPA in immunized groups all reached 1:10,240 or higher levels by enzyme linked immunosorbent assay, and mating experiments revealed that pregnancy rates and the mean number of embryos implanted after mating declined obviously (P 〈 0.05) when compared with control groups. However, the mating capacity and reproductive organ weights had no obvious change, and histological analysis of the testes and epididymides also showed normal morphology for immunized male mice. Sperm function tests suggested that the sperm concentration, sperm viability, sperm motility, and in vitro fertilization rate for the cauda epididymis sperm in uPA-immunized groups were lower than those in the controls (P 〈 0.05). Together, these observations indicated that subcutaneous injection human uPA to the male mice could effectively reduce their fertility, and uPA could become a new target for immunocontraception in male contraceptive development.