Increased germ cell degeneration during postprophase of meiosis is related to increased serum follicle-stimulating hormone concentrations and reduced daily sperm production in aged men

Aged men, known to have high serum gonadotropin levels and reduced spermatogenic potential, were used to study the relationship between serum follicle-stimulating hormone (FSH) and germ cell degeneration. Serum hormones were measured from blood obtained at autopsy. Phase-contrast cytometry was used to enumerate germ cells in homogenates of fixed testes from 13 younger (24-51 yr) and 14 aged (69-90 yr) men. The developmental steps of spermatogenesis during which germ cells degenerate were determined by comparing potential daily sperm production based on primary spermatocytes with daily sperm production based on two different types of spermatids. During spermiogenesis, there was no significant degeneration in the younger or aged men. During postprophase of meiosis, aged men had more (p less than 0.01) germ cell degeneration, significantly lower (p less than 0.05) serum testosterone, and greater (p less than 0.01) serum FSH than did younger men. Germ cell degeneration during postprophase of meiosis was negatively correlated (p less than 0.01) to daily sperm production and significantly (p less than 0.01) related to serum concentrations of FSH. As revealed in these aged men, meiotic germ cell degeneration has a direct effect on daily sperm production and is significantly related to serum FSH concentrations.     

Regulation of testicular function in men: implications for male hormonal contraceptive development

In the adult male, the testes produce both sperm and testosterone. The function of the testicles is directed by the central nervous system and pituitary gland. Precise regulation of testicular function is conferred by an elegant feedback loop in which the secretion of pituitary gonadotropins is stimulated by gonadotropin hormone-releasing hormone (GnRH) from the hypothalamus and modulated by testicular hormones. Testosterone and its metabolites estradiol and dihydrotestosterone (DHT) as well as inhibin B inhibit the secretion of the gonadotropins both directly at the pituitary and centrally at the level of the hypothalamus. In the testes, LH stimulates testosterone synthesis and FSH promotes spermatogenesis, but the exact details of gonadotropin action are incompletely understood. A primary goal of research into understanding the hormonal regulation of testicular function is the development of reversible, safe and effective male hormonal contraceptives. The administration of exogenous testosterone suppresses pituitary gonadotropins and hence spermatogenesis in most, but not all, men. The addition of a second agent such as a progestin or a GnRH antagonist yields more complete gonadotropin suppression; such combination regimens effectively suppress spermatogenesis in almost all men and may soon bring the promise of hormonal male contraception to fruition.     

慢性镉负荷雄性大鼠的睾丸及生殖内分泌功能活动

选择健康SD雄性成年大鼠60只,随机分成对照组（C组）、镉负荷中剂量组（M组）和镉负荷高剂量组（H组）,每天分别饲喂含镉0,5,10mg/kg的大鼠全价饲料,连续6周,研究了镉负荷对大鼠睾丸及生殖内分泌功能活动的影响。结果显示：在整个实验期内,M和H组大鼠睾丸组织中的镉含量极明显上升,锌含量销有下降,与对照组差异不显著;血浆镉、锌含量虽分别表现稍有升高和下降,但与对照组比较无明显差异;H组睾丸精子头计数和每日精子生成量在镉负荷第3周极显著下降,第6周时,M和H组均极明显低于对照组;在整个实验期内,H组大鼠ALP活明显低于C组;LDH－X活性在M和H组大鼠均极明显低于C组;M和H组血浆T水平下降,均低于或显著低于C组;3组间的FSH和LH水平无明显差异。结果提示：慢性镉负荷在睾丸组织中逐步蓄积可引起睾丸一些酶活性改变、精子生成减少及内分泌功能活动低下。     

Gonadotropin releasing hormone (GnRH) agonists in male contraception

A potent gonadotropin releasing hormone (GnRH) agonist, D(Nal2)6 GnRH (Nafarelin) has been administered to two groups of normal men for 16 weeks by two routes in order to assess its effectiveness in suppressing spermatogenesis. In this report 400 micrograms of the GnRH agonist was given daily by constant subcutaneous infusion and the results compared to an earlier study in which 200 micrograms of the same agonist was given as a single daily subcutaneous injection. All subjects in both groups received an intramuscular injection of testosterone enanthate (200 mg) every two weeks to prevent symptoms of androgen deficiency. The higher dose infusion regimen was much more effective in suppressing spermatogenesis than the single daily injection. With infusion treatment, 3 of 7 subjects were azoospermic, a fourth subject had less than 1 million sperm per ml of semen and 5 of 7 subjects had sperm counts less than 5 million per ml. Because of the differences in GnRH dose it is unclear if the enhanced effect seen in the infusion group is the result of the route or dose of drug. Data from experimental animals and short term comparative studies with two routes and two doses suggest that both mechanisms may be operative. In either case, the results are the most promising to date and raise the possibility that constant delivery of a higher dosage of agonist could produce azoospermia in most or all subjects.     

Testicular and blood steroid levels in aged men

In this study, we have evaluated the hypophyso-gonadal axis in three groups of men aged 60-69, 70-79 and 80-91 years by measuring the intratesticular concentrations of several steroids (pregnenolone, progesterone, DHEA, DHEA-S, testosterone, estradiol) and serum levels of FSH, LH, testosterone, estradiol and sex hormone binding globulin (SHBG). The histological examination of testes revealed normal spermatogenesis in all examined samples. No significant changes in serum hormone and SHBG concentrations as well as in testicular steroid contents among the three groups of patients were found. However, the mean serum SHBG level was three times higher in the oldest men than in other groups and a positive correlation between patient's age and serum SHBG was observed. Therefore, the bioavailability of estradiol in the oldest men was likely diminished. Consequently, the hormonal status in aged men is rather unchanged but great variations observed between patients imply special cautious when the SHBG and estradiol levels are concerned.     

A quantitative assessment of the gametogenic and androgenic properties of testicular steroids in hypophysectomized rats

The ability of testicular steroids to maintain the quantitative aspects of spermatogenesis was compared with reference to their androgenic properties. Hypophysectomized rats were injected daily with 0.2 mg progesterone, 20 alpha-dihydroprogesterone, 3 beta-hydroxy-5 alpha-pregnan-20-one, testosterone or testosterone propionate for 30 days beginning 2 days after the operation. Testosterone propionate was the most potent steroid tested both in terms of its peripheral androgenic effects and its ability to prevent the post-operative decline in the weight of the testis and seminiferous tubules and the numbers of germ cells throughout their differentiation. The natural androgen, testosterone, exhibited weak gametogenic properties and only partly maintained the normal measures of spermatogenesis. Progesterone exhibited low intrinsic androgenic potency yet was significantly more effective than testosterone in maintaining spermatogenesis; it prevented the degeneration of spermatocytes during the later stages of meiotic prophase and the reduction divisions resulting in an increased yield of step 7 spermatids. Low androgenic and gametogenic properties were exhibited by 20 alpha-dihydroprogesterone and 3 beta-hydroxy-5 alpha-pregnan-20-one. These results may indicate that testosterone produced locally in the seminiferous tubules from progesterone is more effective in maintaining spermatogenesis than androgens entering from the circulation. Alternatively, progesterone may act more directly on the germ cells than previously envisaged.     

The effects of methyltestosteone on reproductive function in male greyhounds

Oral administration of methyltestosterone (MT) at 50 mg/dog/day to intact adult male greyhounds for 90 d resulted in decreased (P < 0.05) mean daily sperm output and mean testicular length. Additionally, the mean diameter of seminiferous tubules in MT-treated dogs tended to decrease (P = 0.08). Mean concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH) and concentrations of testosterone in serum were also decreased or tended to decrease (P = 0.0003 to 0.059) at various sampling periods during MT treatment, suggesting alterations in spermatogenesis resulted from decreased serum concentrations of gonadotropins and steroids. Mean daily sperm output, mean testicular length, mean seminiferous tubule diameter and mean concentrations of FSH in serum were not decreased (P > 0.05) at the end of a 90-d recovery period. However, mean concentrations of serum LH and concentrations of testosterone were still lower (P < 0.05) during five of six and one of six sampling times, respectively, during the recovery period than the pretreatment levels, suggesting a prolonged effect of MT treatment on the pituitary/gonadal axis.     

Efficacy of Pulsatile Gonadotropin-Releasing Hormone Therapy in Male Patients: Comparison between Pituitary Stalk Interruption Syndrome and Congenital Hypogonadotropic Hypogonadism

ObjectivePulsatile gonadotropin-releasing hormone (GnRH), widely used to induce spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients, can restore the pituitary-testis axis function in men with pituitary stalk interruption syndrome (PSIS). This retrospective study aimed to compare the differences in the long-term efficacy of pulsatile GnRH therapy on PSIS and CHH.MethodsPatients with PSIS (n = 25) or CHH (n = 64) who received pulsatile GnRH therapy for ≥3 months were included in this retrospective study. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, total testosterone, and testicular size were compared.ResultsBaseline characteristics were comparable except for the lower basal testosterone, triptorelin-stimulated peak luteinizing hormone (LH), and follicle-stimulating hormone in patients with PSIS. With similar duration of treatment and a significantly higher GnRH dose (P < .001), small increments in LH (2.82 [1.4, 4.55] vs 5.89 [3.88, 8.02] IU/L; P < .001), total testosterone (0.38 [0, 1.34] vs 2.34 [1.34, 3.66] ng/mL; P < .001), and testicular volume (5.3 ± 4.5 vs 8.8 ± 4.8 mL, P < .05) were observed. However, spermatogenesis rate (52.0% vs 70.3%, P > .05), median time of sperm appearance (14 vs 11 months, P > .05), sperm concentration, and progressive motility were comparable. Basal testicular volume (hazard ratio, 1.13; 95% CI, 1.01-1.27) and peak LH levels (hazard ratio, 1.11; 95% CI, 1.0-1.23) were predictors for early sperm appearance.ConclusionsPulsatile GnRH therapy can improve gonad function and induce spermatogenesis in men with PSIS. However, its efficacy may be inferior to that in CHH.     

Impact of seminal and serum zinc on semen quality and hormonal status: A population-based cohort study of Russian young men

BackgroundTrace elements are important factors in human reproductive health. Among them, special attention is paid to zinc, which is an essential trace element and is necessary for the normal functioning of the male reproductive system and the process of spermatogenesis. The aim of the study was to investigate the association between seminal and serum zinc concentrations and semen quality and reproductive hormone levels in population of Russian young men.MethodsThe study population consisted of 626 young Russian men (median age 22.5 years), recruited from the general population, regardless of their fertility status. Each participant provided semen and blood sample, information about his lifestyle and ethnicity. Semen quality (sperm concentration, motility and morphology), reproductive hormone levels (testosterone, estradiol, LH, FSH and inhibin B), and serum and seminal zinc concentrations were evaluated. The semen samples were analyzed according to the WHO laboratory manual (WHO, 2010). Serum hormones were measured by enzyme immunoassay, zinc concentrations were determined using spectrophotometry and direct colorimetry without deproteinization.ResultsZinc was present in the seminal plasma in a significantly higher concentration than in the blood serum (median serum Zn concentration was 23.6 μmol/L vs seminal Zn concentration 1571.8 μmol/L). The seminal zinc concentration was positively related to the total sperm count, sperm concentration, progressive motility and normal morphology (Spearman’s test: 0.221; 0.286; 0.269; 0.183, respectively, p < 0.001), while the serum Zn concentration was negatively related to serum testosterone and estradiol levels (r = −0.249 and r = −0.096, respectively, p < 0.001−0.05). It was found that the seminal Zn content in men with normal semen quality was higher compared to men with lowered semen quality (means: 6.37 and 5.03 μmol/ejaculate, respectively, p < 0.001). Similarly, the semen volume, total sperm count, sperm concentration, progressive motility, normal morphology and the serum testosterone level in men with the seminal Zn deficiency were lower than in men with the normal seminal Zn content.ConclusionBased on the results of our population-based study, seminal Zn levels were closely associated with semen parameters in young men, so Zn deficiency may be an important risk factor for lowered semen quality. Seminal Zn determinations should be considered as a useful tool in addition to other parameters in assessing male fertility.     

Hormone pretreatment enhances recovery of spermatogenesis in rats after neutron irradiation.

Previous studies showed that a 6-week pretreatment of rats with testosterone plus estradiol enhanced the recovery of spermatogenesis 9 weeks after gamma irradiation, resulting in a dose-modifying factor (DMF) of about 2. To test whether the effect of the hormone treatment was mediated through changes in oxygen tension, thiol levels or DNA repair, we irradiated the testes of rats with neutrons, which depend less on these factors than does low-LET radiation for their cytotoxic action. Control rats and rats treated with testosterone plus estradiol were irradiated with 0.7-2.7 Gy of cyclotron-generated high-energy neutrons. The recovery of spermatogenesis was assessed 9 weeks after irradiation by testis weights, sperm counts and the tubule repopulation indices. Greater recovery of spermatogenesis was observed for all end points, with a DMF of about 2 for rats treated with testosterone plus estradiol compared to the irradiated, cholesterol-treated rats. The equal protection factors for neutrons and gamma rays indicate that oxygen, thiols and repair of DNA damage are unlikely to be involved in the protective effect of the hormone treatment.     

Effect of 2-bromo-alpha-ergocryptine (CB 154) on plasma prolactin, LH and testosterone levels, accessory reproductive glands and spermatogenesis in lambs during puberty

Effects of 2-bromo-alpha-ergocryptine (CB 154) on plasma prolactin, luteinizing hormone (LH), and testosterone levels, accessory reproductive glands, and spermatogenesis were studied in lambs during puberty. 18 lambs born during normal lambing season (February and 10 lambs born during the nonlambing period (October) and received a daily injection of CB 154 (2 gm) from the 10th week after birth until the 21st week. Treatment resulted in a highly significant (p less than .001) decrease in the concentration of plasma prolactin, but did not affect LH or testosterone levels. There was no marked decrease in testis weight in the treated animals and the establishment of spermatogenesis was not delayed by the treatment. However, there was a significant decrease in the weight of the seminal vesicles (p less than .01) and in their fructose concentration (p less than .01 and p less than .05). These results indicate that prolactin may play a role in the secretory activity of these glands in the male lamb.     

Experimental mild increase in testicular temperature has drastic,but reversible,effect on sperm aneuploidy in men: A pilot study

In mammals testicular and epididymal temperature increase impairs spermatogenesis. This experimental study investigates the effects of a mild testis temperature increase (i.e. testis temperature remains below core body temperature) on sperm aneuploidy in men. In 5 fertile volunteers a testicular temperature increase was induced by maintaining the testes at suprascrotal position using specially designed underwear for 15 ± 1 h daily for 120 consecutive days. After heating men were followed for next 180 days. A control group (27 men) was recruited. Semen samples were collected before, during and after heating period and analyzed for chromosomes X, Y and 18 for aneuploidy using FISH. A total of 234,038 spermatozoa were studied by FISH. At day 34 of heating, mean sperm aneuploidy values were not modified. From day 34 of heating until day 45 post heating, FISH evaluation was not possible due to the drastic fall of sperm count. At day 45 post-heating total sperm aneuploidy percentage was twice higher than before heating whereas. Sex disomy (sperm XY18), sex chromosome nullisomy (sperm 18) were significantly higher than controls. These effects were completely reversed at 180 days post heat exposure. Conclusion: A mild rise in testicular temperature significantly increases sperm aneuploidies, reflecting an effect on the meiosis stage of spermatogenesis. The effect of heating was reversible and suggests that recovery of aneuploidy to normal values requires at least two cycles of spermatogenesis. Nonetheless, the low number of volunteers was a limitation of this pilot study and warrants further research on larger population.     

Reversible inhibitory effect of the non-steroidal antiandrogen flutamide (SCH 13521) on spermatogenesis in mice

The effects of a prolonged subcutaneous administration of SCH 13521 dissolved in 0.3% hydroxypropyl cellulose (2-8 weeks in daily doses of 0.2 or 1.0 mg amounting to an estimated equivalent of experimental and curative doses used by others in laboratory animals and men) were studied in males of the mouse inbred strain C57BL/6. Following the treatment, the activity of spermatogenesis (expressed as the mean number of seminiferous tubules containing mature sperm and epididymal sperm count) was inhibited while the testis weight was not reduced, obviously due to an absolute increase of the interstitial tissue which was a marked histological feature of the testes, particularly following the higher doses of SCH 13521. Lower doses and shorter-lasting administration of the compound seem to inhibit the activity more effectively because after a prolonged administration reparatory processes tend to be triggered via a stimulatory effect on the synthesis of testosterone in Leydig cells. The solvent alone, hydroxypropyl cellulose, had some inhibitory effect on spermatogenesis. The lymphoid system remained both morphologically and functionally unaffected by SCH 13521 unlike the steroidal antiandrogen cyproterone actetate.     

The relationship between body mass index, semen and sex hormones in adult male

This study was aimed at evaluating the relationship between body mass index, sex hormones and semen characteristics in male adults. 120 male adults aged 20 to 50 years who consented to participate in the study were used. Serum samples collected from each subject were analyzed for Luteinizing hormone (LH), Follicle stimulating hormone (FSH), Prolactin (PRL), Progesterone, Estradiol and testosterone by classical ELISA method. Semen samples obtained by masturbation after 72 hours of abstinence were analyzed for sperm count and motility. The results showed statistically significant correlations at 99% confidence level between body mass index and serum concentrations of progesterone and oestradiol and sperm count. No significant correlations were observed between body mass index and sperm motility, serum concentrations of prolactin, testosterone and luteinizing hormone. In conclusion, this study has shown that statistically significant correlations exist between body mass index, semen characteristics and male sex hormones and may broaden our understanding of the physiology of male fertility/infertility. Keywords: Body mass index, Semen quality, Male sex hormones, Fertility/infertility.     

Effect of metronidazole on spermatogenesis and FSH, LH and testosterone levels of pre-pubertal rats

Metronidazole, a 5-nitroimidazole drug has been reported to decrease testicular weight, testicular and epididymal spermatid counts and causes abnormal sperm morphology with degeneration of seminiferous tubules with 6 weeks treatment of metronidazole (400 mg/kg, day). In contrast to DNA flow cytometry (FCM), the histological and gravimetric parameters do not allow a rapid, sensitive, objective and multiparameteric evaluation of reproductive toxicants on spermatogenesis. Moreover, the exact mechanisms for such an effect are not entirely clear. The present study was therefore undertaken to assess the effects of intraperitoneal (i.p.) administration of metronidazole 400 mg/kg daily for 30 days on testicular germ cell changes assessed by DNA (FCM) and hormone levels of testosterone, FSH and LH in pre-pubertal rats. A significant reduction in the haploid cell population in metronidazole treated groups as compared to saline treated controls was observed. The mean serum FSH, LH and testosterone value were also lowered in treated animals. Thus, the spermatotoxic effects of metronidazole were probably mediated by decrease in the circulating hormones responsible for spermatogenesis.     

Restoration of spermatogenesis and fertility in azoospermic mutant mice by suppression and reelevation of testosterone followed by intracytoplasmic sperm injection.

Advances in assisted reproduction techniques such as in vitro fertilization and intracytoplasmic sperm injection have made paternity possible for many patients with male infertility. However, at least some sperm or spermatids are required for these techniques to be successful, and patients incapable of producing spermatids cannot be helped. Male mice homozygous for the mutant juvenile spermatogonial depletion (jsd) gene show spermatogonial arrest and an elevated intratesticular testosterone level like many other experimental infertility models such as those with iradiation- or chemotherapy-induced testicular damage. In this category of infertile males, suppression of the testosterone level induces spermatogonial differentiation to the stage of spermatocytes but no further. In the present study with jsd mutant mice, we induced spermatogenesis first to spermatocytes and then to elongated spermatids by suppression of testosterone levels with a GnRH antagonist, Nal-Glu, at a dose of 2500 microg kg(-1) day(-1) for 4 wk and then withdrawal of Nal-Glu. Spermatids were seen in the cross-sections of seminiferous tubules in all mice treated by administration and subsequent withdrawal of Nal-Glu. Four weeks after withdrawal of Nal-Glu, some of the germ cells differentiated into elongated spermatids. Supplementation with testosterone and Nal-Glu after 4 wk of treatment with Nal-Glu alone also induced spermatogenesis similar to the induction by withdrawal of Nal-Glu. Thus, we ascribe the restoration of the differentiation of spermatocytes to spermatids to reelevation of the testosterone level. Furthermore, we successfully rescued male sterility in jsd mice by subsequent intracytoplasmic sperm injection using the elongated spermatids induced by the programmed hormone therapy.     

Long term effects of cyclophosphamide on testicular function.

Thirty men treated in childhood with cyclophosphamide for a mean of 280 days were assessed at a mean of 12.8 years after treatment for hormone concentrations and spermatogenesis. Four were azoospermic, nine oligospermic, and 17 normospermic. There was a significant inverse correlation of sperm density with cyclophosphamide dosage and duration of treatment. After a further mean follow up of 7.2 years three patients who were previously oligospermic and one who was azoospermic had normal sperm counts. All patients had normal sexual characteristics and libido. Serum androgen and prolactin concentrations did not differ significantly between patients and controls. Raised basal and stimulated follicle stimulating hormone concentrations were in keeping with impaired spermatogenesis. All patients had significantly raised luteinising hormone responses on stimulation with luteinising hormone releasing hormone. The results suggest compensated Leydig cell failure, and patients with this condition require long term evaluation of testicular function. Potential recovery of spermatogenesis with time requires appropriate counselling and contraceptive advice.     

Stress et Spermatogénèse

Stress, which originates in the brain, can influence spermatogenesis hormonally or via the nervous system. The hormonal route commences with the central secretion of Corticotrophin-Releasing Factor, leading to a fall in LHRH production, a decrease in Leydig cell LH receptors and a decrease in 17 a hydroxylase activity. Thus, in the case of major, prolonged stress, testosterone secretion falls, which in turn affects spermatogenesis. However, given that the testosterone threshold required for normal seminiferous epithelium function is significantly less than the mean circulating level of this hormone, the importance of low intensity stress remains unknown. The nervous route involves catecholaminergic fibres which, in the testis, innervate the Highmore corpus, the vessels, the area adjacent to the Leydig cells, and the basement membrane of seminiferous tubules. The experimental destruction of these fibres leads a regression of the seminiferous epithelium. Moreover, the experimental ablation of the rat anterior neocortex leads to changes in spermatogenesis. Therefore, given that the endocrine system does not seem to be involved in these changes, these results indicate that the highest level of the nervous system may participate in the controlling the germinal epithelium which, all things considered, would tend to support psychosomatic influences. However, given that the number of spermatozoa varies significantly between ejaculate and independantly of the level of testosterone secretion necessary for normal spermatogenesis, it may be hypothesized that it is only when sperm production is low that temporary stress, in aggravating the situation, becomes deleterious to spermatogenesis. Since, under normal conditions, such periods are short, the role of the influence of stress on spermatogenesis can only be relative. Nevertheless, if variations occur during permanently low sperm production, the likelihood of negative effects is increased. Consequently, the impact of stress or psychological factors on spermatogenesis might well depend upon particular circumstances.     

Semen quality and reproductive endocrine function with regard to blood cadmium in Croatian male subjects

In 123 Croatian men with no occupational exposure to metals, the influence of cadmium on reproductive parameters was examined after adjusting for age, smoking, alcohol, and biomarkers of lead, copper, zinc, and selenium. The following variables were measured: blood cadmium (BCd), blood lead (BPb), activity of -aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin, serum copper (SCu), serum zinc (SZn), serum selenium (SSe), activity of glutathione peroxidase (GPx) in blood, testis size, semen quality (including sperm concentration, motility, viability, and morphology), indicators in seminal fluid (the lactate dehydrogenase isoenzyme LDH-C₄, fructose, zinc, acid phosphatase, and citric acid), and hormones in serum (follicle-stimulating hormone – FSH, luteinizing hormone, prolactin, testosterone, and estradiol). The median and range BCd values were 2.94 (0.49-11.93) g/L in 61 smokers and 0.59 (0.20-3.71) g/L in 62 nonsmokers (p<0.0001). Smoking habits (cigarettes/day) highly significantly correlated with BCd (p<0.0001). After adjusting for potential confounding variables by multiple regression, BCd was significantly associated with a decrease in testis size (p<0.03) and an increase in serum estradiol (p<0.005), FSH (p<0.03), and testosterone (p<0.04). Smoking was significantly associated with a decrease in serum prolactin (p<0.006) and LDH-C₄ in seminal fluid (p<0.03). Several reproductive parameters were significantly associated with BPb and ALAD, biomarkers of lead, and/or with SCu, SZn, SSe, and GPx. The necessity of controlling for various metals, and other potential confounders when assessing the influence of a particular metal on reproductive function in men, is emphasized.     

Valproate affects reproductive endocrine function, testis diameter and some semen variables in non-epileptic adolescent goat bucks

Valproate (VPA) is a major antiepileptic drug with a broad spectrum of antiepileptic activity. There is, however, increasing concern about the possible effects of VPA on reproductive endocrine function. This study investigated the effects of valproate, on the endocrine and reproductive system of adolescent, non-epileptic, goat bucks. Nine goat bucks were orally treated with 62.5mg/kg valproate twice daily from 2 to 10 months of age in order to sustain therapeutic plasma concentrations of between 300 and 600 micromol/l. Seven bucks served as controls. Body weights and testicular diameters were recorded. Blood samples were collected for measurement of luteinising hormone (LH), follicle stimulating hormone (FSH) and testosterone three times weekly until sacrifice at approximately 40 weeks of age. Conventional reproductive endpoints were recorded and flow cytometric (FCM) analyses of spermatogenesis, including the sperm chromatin structure were conducted. Valproate-treated bucks had on average a higher body weight, but a lower testis diameter than controls. No significant differences were found for plasma FSH in comparison to controls. Valproate-treated bucks differed significantly from the control group by showing lower plasma concentrations of LH and testosterone and a later onset of puberty. A significantly higher proportion of sperm from valproate-treated bucks showed abnormal chromatin, demonstrating a harmful effect on DNA from valproate treatment. These results demonstrate that valproate was able to induce reproductive effects in goat bucks related to the hypothalamic-pituitary-axis, as well as to the testes.