BACKGROUND Reported declines in sperm counts remain controversial today and recent trends are unknown. A definitive meta-analysis is critical given the predictive value of sperm count for fertility, morbidity and mortality. OBJECTIVE AND RATIONALE To provide a systematic review and meta-regression analysis of recent trends in sperm counts as measured by sperm concentration (SC) and total sperm count (TSC), and their modification by fertility and geographic group. SEARCH METHODS PubMed/MEDLINE and EMBASE were searched for English language studies of human SC published in 1981-2013. Following a predefined protocol 7518 abstracts were screened and 2510 full articles reporting primary data on SC were reviewed. A total of 244 estimates of SC and TSC from 185 studies of 42 935 men who provided semen samples in 1973-2011 were extracted for meta-regression analysis, as well as information on years of sample collection and covariates [fertility group ('Unselected by fertility' versus 'Fertile'), geographic group ('Western', including North America, Europe Australia and New Zealand versus 'Other', including South America, Asia and Africa), age, ejaculation abstinence time, semen collection method, method of measuring SC and semen volume, exclusion criteria and indicators of completeness of covariate data]. The slopes of SC and TSC were estimated as functions of sample collection year using both simple linear regression and weighted meta-regression models and the latter were adjusted for pre-determined covariates and modification by fertility and geographic group. Assumptions were examined using multiple sensitivity analyses and nonlinear models. OUTCOMES SC declined significantly between 1973 and 2011 (slope in unadjusted simple regression models -0.70 million/ml/year; 95% CI: -0.72 to -0.69; P < 0.001; slope in adjusted meta-regression models = -0.64; -1.06 to -0.22; P = 0.003). The slopes in the meta-regression model were modified by fertility (P for interaction = 0.064) and geographic group (P for interaction = 0.027). There was a significant decline in SC between 1973 and 2011 among Unselected Western (-1.38; -2.02 to -0.74; P < 0.001) and among Fertile Western (-0.68; -1.31 to -0.05; P = 0.033), while no significant trends were seen among Unselected Other and Fertile Other. Among Unselected Western studies, the mean SC declined, on average, 1.4% per year with an overall decline of 52.4% between 1973 and 2011. Trends for TSC and SC were similar, with a steep decline among Unselected Western (-5.33 million/year, -7.56 to -3.11; P < 0.001), corresponding to an average decline in mean TSC of 1.6% per year and overall decline of 59.3%. Results changed minimally in multiple sensitivity analyses, and there was no statistical support for the use of a nonlinear model. In a model restricted to data post-1995, the slope both for SC and TSC among Unselected Western was similar to that for the entire period (-2.06 million/ml, -3.38 to -0.74; P = 0.004 and -8.12 million, -13.73 to -2.51, P = 0.006, respectively). WIDER IMPLICATIONS This comprehensive meta-regression analysis reports a significant decline in sperm counts (as measured by SC and TSC) between 1973 and 2011, driven by a 50-60% decline among men unselected by fertility from North America, Europe, Australia and New Zealand. Because of the significant public health implications of these results, research on the causes of this continuing decline is urgently needed.

Temporal trends in sperm count: a systematic review and meta-regression analysis.

Background: Men with epilepsy have reduced fertility, and antiepileptic drugs may affect semen quality. Moreover, animal studies suggest that valproate (VPA) may be associated with testicular atrophy. Objective: To evaluate reproductive function in men with epilepsy. Methods: Sixty men with epilepsy and 41 control men were evaluated for their reproductive health. Fifteen men were taking carbamazepine (CBZ) and 18 men oxcarbazepine (OXC) for partial epilepsy, and 27 men were taking VPA for generalized epilepsy. Reproductive hormones were assayed from serum samples, semen analysis and ultrasonography of the testicles were performed, and testicular volume was calculated. Results: Men on CBZ had low serum dehydroepiandrosterone sulfate concentrations (p Conclusions: CBZ, OXC, and VPA are associated with sperm abnormalities in men with epilepsy. In addition, VPA-treated men with generalized epilepsy who have abnormal sperm may have reduced testicular volume.

Effect of epilepsy and antiepileptic drugs on male reproductive health.

It is well known that epilepsy, antiepileptic drugs (AEDs), and the reproductive system have complex interactions. Fertility is lower in both men and women with epilepsy than in the general population. Moreover, reproductive endocrine disorders are more common among patients with epilepsy than among the population in general. These disorders have been attributed both to epilepsy itself and to use of AEDs. The use of the liver enzyme-inducing AEDs phenobarbital, phenytoin and carbamazepine increases serum sex hormone-binding globulin (SHBG) concentrations in both men and women with epilepsy. Over time, the increase in serum SHBG levels leads to diminished bioactivity of testosterone and estradiol, which may result in diminished potency in men and menstrual disorders in some women, and thus to reduced fertility. Liver enzyme-inducing AEDs also reduce the efficacy of oral contraceptives. Valproic acid medication may have effects on serum androgen concentrations and it reduces serum follicle stimulating hormone levels in men with epilepsy. However, the clinical significance of valproic acid-related reproductive endocrine changes in men is unknown. On the other hand, in women, use of valproic acid appears to be associated with a frequent occurrence of reproductive endocrine disorders characterised by polycystic changes in the ovaries, high serum testosterone concentrations (hyperandrogenism) and menstrual disorders. These disorders are especially common among women who have gained weight during valproic acid treatment. There are some discrepancies regarding the reported occurrence of reproductive endocrine disorders in women taking valproic acid for epilepsy. However, most studies also including patients receiving valproic acid for other reasons than epilepsy, and studies in different non-epileptic animal models, have shown an association between valproic acid medication and hyperandrogenism and related reproductive endocrine disorders. From a practical point of view, the length of the menstrual cycles and bodyweight should be monitored in women with epilepsy after commencement of treatment with valproic acid. A serum testosterone assay is helpful in following the possible biochemical endocrine changes. Ultrasonography of the ovaries (preferably transvaginal) is indicated if clinical assessment and serum testosterone measurement imply that there is a clinically significant valproic acid-related reproductive endocrine problem. That would be the case if the menstrual cycles were irregular or prolonged (usually >35 days) and serum testosterone levels elevated, especially with associated weight gain. The endocrine effects of the new AEDs have not been widely studied. However, it seems they may offer an alternative if reproductive endocrine problems emerge during treatment with the older AEDs.

Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy.

Infertility affects up to 12% of all men, and sexual dysfunction occurs frequently in men of reproductive age, causing infertility in some instances. In infertile men, hypoactive sexual desire and lack of sexual satisfaction are the most prevalent types of sexual dysfunction, ranging from 8.9% to 68.7%. Erectile dysfunction and/or premature ejaculation, evaluated with validated tools, have a prevalence of one in six infertile men, and orgasmic dysfunction has a prevalence of one in ten infertile men. In addition, infertile men can experience a heavy psychological burden. Infertility and its associated psychological concerns can underlie sexual dysfunction. Furthermore, general health perturbations can lead to male infertility and/or sexual dysfunction. Erectile dysfunction and male infertility are considered proxies for general health, the former underlying cardiovascular disorders and the latter cancerous and noncancerous conditions. The concept that erectile dysfunction in infertile men might be an early marker of poor general health is emerging. Finally, medications used for general health problems can cause sperm abnormalities and sexual dysfunction. The treatment of some causes of male infertility might improve semen quality and reverse infertility-related sexual dysfunction. In infertile men, an investigation of sexual, general, and psychological health status is advisable to improve reproductive problems and general health.

Sexual dysfunction and male infertility.

Objective: To compare sexual function and reproductive hormone levels among men with epilepsy who took various antiepileptic drugs (AEDs), untreated men with epilepsy, and normal controls. Methods: Subjects were 85 men with localization-related epilepsy (25 on carbamazepine [CBZ], 25 on phenytoin [PHT], 25 on lamotrigine [LTG], and 10 untreated for at least 6 months [no AED]) and 25 controls. Sexual function scores (S-scores), hormone levels (bioactive testosterone, estradiol), hormone ratios (bioactive testosterone/bioactive estradiol), and gonadal efficiency (bioactive testosterone/luteinizing hormone) were compared among the five groups. Results: S-scores, bioactive testosterone levels, bioactive testosterone/bioactive estradiol, and bioactive testosterone/luteinizing hormone were significantly greater in the control and LTG groups than in the CBZ and PHT groups. Sex hormone binding globulin was significantly higher in the CBZ and PHT groups than in all other groups. S-scores were below the control range in 20% of the men with epilepsy, including 32.0% on CBZ, 24% on PHT, 20% on no AEDs, and 4% on LTG (χ2: p = 0.08 for all four groups; χ2: p = 0.02 for the three AED groups). Bioactive testosterone was below the control range in 28.2%, including 48% on CBZ, 28% on PHT, 20% on no AEDs, and 12% on LTG (χ2: p = 0.02). Among men with epilepsy who had low S-scores, 70.6% had bioactive testosterone levels below the control range as compared to 17.6% among men with normal S-scores (χ2: p Conclusions: Sexual function, bioavailable testosterone levels, and gonadal efficiency in men with epilepsy who took lamotrigine were comparable to control and untreated values and significantly greater than with carbamazepine or phenytoin treatment.

Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy

Male patients receiving antiepileptic drugs (AEDs) have often complained of hyposexuality. Few studies have been done on semen analysis, which is relevant for assessment of potential and possible reproductive outcome in such cases. We evaluated the effect of epilepsy itself and/or phenytoin (PHT) on the male reproductive system. Fifty-five patients with epilepsy (42 with PHT and 13 untreated) and 28 healthy normal controls were studied by semen analysis. Serum samples from 21 of the 55 patients were also analyzed for testosterone, luteinizing hormone (LH), and follicle-stimulating hormone. Results showed lower volume of seminal fluid, spermatozoa concentration, and total sperm count in untreated and PHT-treated patients as compared with controls, although no difference was evident between the patient groups. Morphologically abnormal sperm were more increased in untreated patients than in PHT treated and control subjects. Hormonal analysis showed lower levels of testosterone in 9 patients. LH levels were increased in one third of the patients. Our results suggests an effect of seizures on the male reproductive system, and PHT may have a slight additive (if any) influence.

Neelam Taneja

Papers

Effect of phenytoin on semen.