Preclinical Evidence on Plant-Derived Aphrodisiacs and Male Reproductive Function: Mechanisms, Hormonal Modulation, and Translational Implications

The alarming increase in the number of diabetic patients worldwide raises concerns regarding the impact of the disease on global health, not to mention on social and economic aspects. Furthermore, the association of this complex metabolic disorder with male reproductive impairment is worrying, mainly due to the increasing chances that young individuals, at the apex of their reproductive window, could be affected by the disease, further contributing to the disturbing decline in male fertility worldwide. The cornerstone of diabetes management is glycemic control, proven to be effective in avoiding, minimizing or preventing the appearance or development of disease-related complications. Nonetheless, the possible impact of these therapeutic interventions on male reproductive function is essentially unexplored. To address this issue, we have made a critical assessment of the literature on the effects of several antidiabetic drugs on male reproductive function. While the crucial role of insulin is clear, as shown by the recovery of reproductive impairments in insulin-deficient individuals after treatment, the same clearly does not apply to other antidiabetic strategies. In fact, there is an abundance of controversial reports, possibly related to the various study designs, experimental models and compounds used, which include biguanides, sulfonylureas, meglitinides, thiazolidinediones/glitazones, bile acid sequestrants, amylin mimetics, as well as sodiumglucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP1), α-glucosidase inhibitors and dipeptidyl peptidase 4 (DPP4) inhibitors. These aspects constitute the focus of the current review.

Mice with a targeted disruption (knock-out) of the PRL gene (PRL-KO) were used to study the physiological role of PRL in the control of male neuroendocrine functions related to reproduction. Compared with normal males, PRL-KO mice had significant reductions in median eminence dopamine content, plasma LH levels, LH and FSH secretion in vitro (per mg pituitary), and weights of seminal vesicles and ventral prostate. PRL was not detectable in incubation medium with pituitaries from PRL-KO mice. No alterations were detected in PRL-KO mice in median eminence norepinephrine, plasma testosterone levels, or testosterone release (per mg testis) in vitro with or without LH. No differences were detected in PRL-KO vs. normal male mice in the interval from housing with normal female mice until conception, rate of pregnancy, or the number of live pups per litter. Pituitary weight in PRL-KO mice was increased (1.78 +/- 0.22 vs. 3.35 +/- 0.20 mg; P < 0.001), presumably due to reduced feedback inhibition and hypertrophy and/or hyperplasia of nonfunctional lactotrophs. These results indicate that the absence of PRL reduces pituitary LH release, attenuates median eminence dopaminergic activity, and affects the growth of seminal vesicles and ventral prostate. Although it was previously shown that PRL can repair the reproductive defect in male pituitary dwarf mice, our current results imply that the PRL deficiency alone is not sufficient to cause male infertility, although there are obvious alterations in reproductive neuroendocrine function in PRL-KO males.

Endogenous opioids seem to regulate hypothalamic gonadotropin release in both males and females, as evidenced by the effects of opioid agonists and antagonists on LHRH release and reproductive hormone levels. The effects of long-term oral administration of opioid analgesics on reproductive function have not been well characterized. The reproductive effects of oxymorphone, a potent opioid agonist, were investigated in male and female Crl:CD(SD) IGS BR rats at oral doses of 0, 5, 10, and 25 mg/kg/day (25 animals/sex/group). Males were treated for approximately 9 weeks (mated after 4 weeks of dosing). Females were treated for 14 days before mating, and through Gestation Day (GD) 7. Estrous cycling was evaluated during the premating period. On GD15, pregnancy status and the numbers of corpora lutea, implantation sites, live and dead embryos were determined. Epididymal and testicular sperm counts and epididymal sperm motility and morphology were evaluated in males. Two males given 25 mg/kg/day died. Behavioral changes and deficits in body weight gain occurred at all doses. There were no effects of oxymorphone on reproductive function or sperm parameters in males. The estrous cycle was prolonged in females given 25 mg/kg/day (mean of 5.3 vs. 4.3 days in controls). A small, but consistent decrease in the numbers of corpora lutea (with associated decreases in implantation sites and embryos) occurred in females given > or =10 mg/kg/day. There were no effects on mating or fertility in females. Oxymorphone seems to partially inhibit ovulation in female rats, with no significant effects on male reproductive outcome.

Heat stress can impair the male reproductive function. L-Theanine and dihydromyricetin have biological activities against heat stress; however, their effects on reproductive function in heat-stressed males are unclear. In this study, male mice were given L-theanine, dihydromyricetin, or a combination of both for 28 days, followed by 2 h of heat stress daily for 7 days. All interventions alleviated heat stress-induced testicular damage, improving the testicular organ index, sperm density, acrosome integrity, sperm deformity rate, and hormone levels. Treatment increased the antioxidant enzyme activity and decreased the markers of oxidative and inflammatory stress in the testes. A combination dose of 200 + 200 mg kg-1 d-1 showed the best protective effect. The potential mechanism involves the regulation of HSP27 and HSP70, which regulate the levels of reproductive hormones through the StAR/Cyp11a1/Hsd3b1/Cyp17a1/Hsd17b3 pathway, alleviate inflammation and oxidative stress through the P38/NF-κB/Nrf2/HO-1 pathway, and regulate the Bcl-2/Fas/Caspase3 apoptotic pathway. Overall, L-theanine and dihydromyricetin may play a protective role against heat stress-induced reproductive dysfunction, suggesting their potential use in heat stress-resistant foods.

We aimed to assess the sexual and the reproductive functions in males post COVID-19 infection in Beni-Suef Governorate. One hundred men were recruited in the current study. All participants were assessed by the Arabic validated version of the International Index of the Erectile Function 5 (ArIIEF-5), semen analysis, and Hospital Depression and Anxiety Scale (HADS). Finally, morning testosterone serum level was measured. There were significant decreases in the sperm total motility, the ArIIEF-5 score, and serum total testosterone in the post COVID-19 patients after 3 months when compared to the controls. However, there were significant increases in the sperm total motility, the ArIIEF-5 score, and serum total testosterone in the post COVID-19 patients after 6 months group when compared to the post COVID-19 patients after 3 months group. Moreover, there was a significant increase in the HADS score in the post COVID-19 patients after 3 months when compared to the controls. In contrast, there was a significant decrease in the HADS score in the post COVID-19 patients after 6 months when compared to the post COVID-19 patients after 3 months. Our study had shown temporary impairment of sexual and reproductive functions in post COVID-19 convalescent males especially after 6 months from the onset of the infection.

Background:Concerns remain about the human reproductive toxicity of the widespread per- and polyfluoroalkyl substances (PFAS) during early stages of development.Objectives:We examined associations between maternal plasma PFAS levels during early pregnancy and male offspring reproductive function in adulthood.Methods:The study included 864 young men (age range:18.9–21.2 y) from the Fetal Programming of Semen Quality (FEPOS) cohort established between 2017 and 2019. Plasma samples from their mothers, primarily from the first trimester, were retrieved from the Danish National Biobank and levels of 15 PFAS were measured. Seven PFAS had detectable levels above the limit of detection in of the samples and were included in analyses. Semen quality, testicular volume, and levels of reproductive hormones and PFAS were assessed in the young men. We used weighted quantile sum (WQS) regression to estimate the associations between combined exposure to maternal PFAS and reproductive function, and negative binomial regression to estimate the associations of single substances, while adjusting for a range of a priori–defined fetal and postnatal risk factors.Results:By a 1-unit increase in the WQS index, combined maternal PFAS exposure was associated with lower sperm concentration (; 95% CI: , ), total sperm count (; 95% CI: , ), and a higher proportion of nonprogressive and immotile sperm (5%; 95% CI: 1%, 8%) in the young men. Different PFAS contributed to the associations with varying strengths; however, perfluoroheptanoic acid was identified as the main contributor in the analyses of all three outcomes despite the low concentration. We saw no clear association between exposure to maternal PFAS and testicular volume or reproductive hormones.Discussion:In a sample of young men from the general Danish population, we observed consistent inverse associations between exposure to maternal PFAS and semen quality. The study needs to be replicated in other populations, taking combined exposure, as well as emerging short-chain PFAS, into consideration. https://doi.org/10.1289/EHP10285

Many researchers have focused on the preventive and curative effects of garlic (Allium sativum), particularly on cardiovascular diseases and cancer. However, its impacts on the male reproductive system have not been clearly defined. In this study, the effect of chronic consumption of two garlic fractions was tested: one soluble in water (aqueous solution obtained by grinding and centrifugation) and the other one precipitated by ethanol (alcoholic precipitate obtained by precipitation of the aqueous solution), on different variables of male rats' reproductive functions. These two fractions were targeted to try to identify the nature of the active garlic compounds responsible for the different modifications observed on testicular parameters. The observation of seminiferous tubules of rats treated with garlic fractions showed an increased number of tubules deprived of spermatozoa. In addition, garlic fractions induced apoptosis of testicular germ cells (TdT-mediated dUTP-X nick-end labeling [TUNEL] approach) and a decrease of serum testosterone levels and seminiferous tubule DNA concentrations. In summary, our histological and molecular results suggest that one or several substances, soluble in water and precipitated by alcohol, impaired spermatogenesis.

Using pharmacological substances to enhance athletic performance, known as doping, is widespread in sports and bodybuilding. Doping involves substances such as anabolic steroids, selective androgen receptor modulators, peptide hormones, beta-2 adrenergic agonists, and other auxiliary substances that temporarily enhance physical performance. Although perceived as safer alternatives to traditional steroids, they pose significant health risks, including on male reproductive function. The literature was reviewed using electronic databases such as PubMed, Scopus, and Google Scholar, Out of 296 articles published until 2024, 30 were included in the study providing data on the effects of these substances on sexual-reproductive function. Although SARMs do not have adverse effects like steroids, their excessive use can suppress endogenous testosterone production, affecting spermatogenesis. Peptide hormones and beta-2 adrenergic agonists can disrupt hormonal balance, affecting the hypothalamic-pituitary-gonadal (HPG) axis, suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Myostatin inhibitors and excessive consumption of amino acid derivatives can cause hormonal imbalances and oxidative stress, affecting the quality of seminal material. Auxiliary substances with anabolic effects used in doping can have significant adverse effects on male reproductive health, such as suppression of the HPG axis, decreased testosterone, and impaired spermatogenesis. Further studies are needed to understand the exact mechanisms and long-term impact of these substances on reproductive health.

In hermaphrodites, pleiotropic genetic trade-offs between female and male reproductive functions can lead to sexually antagonistic (SA) selection, where individual alleles have conflicting fitness effects on each sex function. Although an extensive theory of SA selection exists for dioecious species, these results have not been generalized to hermaphrodites. We develop population genetic models of SA selection in simultaneous hermaphrodites, and evaluate effects of dominance, selection on each sex function, self-fertilization, and population size on the maintenance of polymorphism. Under obligate outcrossing, hermaphrodite model predictions converge exactly with those of dioecious populations. Self-fertilization in hermaphrodites generates three points of divergence with dioecious theory. First, opportunities for stable polymorphism decline sharply and become less sensitive to dominance with increased selfing. Second, selfing introduces an asymmetry in the relative importance of selection through male versus female reproductive functions, expands the parameter space favorable for the evolutionary invasion of female-beneficial alleles, and restricts invasion criteria for male-beneficial alleles. Finally, contrary to models of unconditionally beneficial alleles, selfing decreases genetic hitchhiking effects of invading SA alleles, and should therefore decrease these population genetic signals of SA polymorphisms. We discuss implications of SA selection in hermaphrodites, including its potential role in the evolution of "selfing syndromes."

Role of nuclear and membrane estrogen signaling pathways in the male and female reproductive tract

Objective: This investigation was undertaken in the hope of delineating the effects of four different treatments on male reproductive biology in a rat model. The effect of cryptorchidism, gonadectomy, pharmacological ablation of Leydig cell function and androgen-treatment was examined; these four treatments illustrate four different factors influencing and controlling male sexual function in a reproducible animal model. Methods: Total body weight, androgen concentration, gonad weight and secondary sex organ weights were measured for the four-abovementioned treatment groups and correlated to function. Results: It was demonstrated that total body weight decreased for all treatment options. The testicular-derived testosterone concentration for EDS-treated and castrated rats was determined to be zero, although adrenal production continues. Testis weight was shown to decrease following testosterone administration as a consequence of feedback inhibition. Both the prostate and seminal vesicles are highly androgen-sensitive, and as such both experienced an increase in weight following testosterone administration. Conclusions: This experimental setup was successful in elucidating the physiological mechanisms involved in male reproductive function. Body weight, the weights of the testes and accessory sex organs and androgen levels were intrinsically related to basal androgen levels.

Although alcohol is widely used, its impact on the male reproductive function is still controversial. Over the years, many studies have investigated the effects of alcohol consumption on sperm parameters and male infertility. This article reviews the main preclinical and clinical evidences. Studies conducted on the experimental animal have shown that a diet enriched with ethanol causes sperm parameter abnormalities, a number of alterations involving the reproductive tract inhibition, and reduced mouse oocyte in vitro fertilization rate. These effects were partly reversible upon discontinuation of alcohol consumption. Most of the studies evaluating the effects of alcohol in men have shown a negative impact on the sperm parameters. This has been reported to be associated with hypotestosteronemia and low-normal or elevated gonadotropin levels suggesting a combined central and testicular detrimental effect of alcohol. Nevertheless, alcohol consumption does not seem to have much effect on fertility either in in vitro fertilization programs or population-based studies. Finally, the genetic background and other concomitant, alcohol consumption-related conditions influence the degree of the testicular damage. In conclusion, alcohol consumption is associated with a deterioration of sperm parameters which may be partially reversible upon alcohol consumption discontinuation.

Male sexual dysfunction remains a complex clinical challenge with limited therapeutic options. Current treatments typically target individual components such as erectile function, sexual motivation, or fertility, but an integrated approach is lacking. This review synthesizes emerging evidence on intranasal oxytocin and highlights its dual capacity to modulate neural circuits and reproductive processes simultaneously. Preclinical studies increasingly show that oxytocin extends beyond traditional pharmacological boundaries. Experimental evidence demonstrates its ability to activate hypothalamic pathways, restore sexual behavioral patterns in previously unresponsive males, and improve sperm quality through a non-invasive delivery route. These findings extend beyond the traditional view of oxytocin as the "love hormone," revealing its broader physiological roles in male reproductive functions. The clinical implications are worth considering, as intranasal oxytocin is emerging as a therapeutic candidate in the management of male sexual dysfunction by enhancing both neural sexual motivation and peripheral reproductive capacity. By acting on central and peripheral systems simultinaeously, this approach may overcome the limitations of current fragmented therapies. It may contribute to an integrated framework for understanding and managing male reproductive disorders. Research also indicates broad translational relevance across species. In livestock production and conservation biology, intranasal oxytocin may offer an animal-friendly alternative to invasive reproductive technologies, supporting natural sexual behavior and improving fertility outcomes. The preclinical evidence is encouraging, but clinical trials in humans are still lacking.

Recent demonstrations that female reproductive physiology is highly responsive to environmental factors have led to a growing appreciation of the extent of variation in reproductive function and the adaptive nature of much of that variation. Male reproductive function has received much less attention from anthropologists, whether as an aspect of human variation, as a possible contributor to population variation in fertility, or as the product of selective pressures. Yet, an understanding of male reproductive function, along with that of females, is obviously important for a complete picture of human evolutionary ecology. We review our current understanding of male reproductive function, its response to environmental factors, and implications for male fecundity. Studies among Western populations indicate that male reproductive function is sensitive to environmental stresses, including weight loss, dietary composition, exercise, disease, and psychological stress. Indices of reproductive physiology among males in some non-Western populations are consistent with the notion that chronic environmental stresses can lead to suppression of testicular function. The specific causes of this suppression are not known, nor are the implications, if any, for male fecundity and fertility understood. Further research on males is called for, including the effects of hormonal changes on reproductive behavior and characterization of reproductive function in a wider range of populations. Evolutionary models of the selection pressures underlying male reproductive function should be helpful in focusing these investigations. © 1995 Wiley-Liss, Inc.

Vol. 131, No. 1 Letter to the EditorOpen AccessComment on “Maternal Exposure to Per- and Polyfluoroalkyl Substances (PFAS) and Male Reproductive Function in Young Adulthood: Combined Exposure to Seven PFAS”is accompanied byMaternal Exposure to Per- and Polyfluoroalkyl Substances (PFAS) and Male Reproductive Function in Young Adulthood: Combined Exposure to Seven PFASis a letter which has replyResponse to “Comment on ‘Maternal Exposure to Per- and Polyfluoroalkyl Substances (PFAS) and Male Reproductive Function in Young Adulthood: Combined Exposure to Seven PFAS’” Klaus Abraham Klaus Abraham Address correspondence to Klaus Abraham, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8–10, 10589 Berlin, Germany. Email: E-mail Address: [email protected] https://orcid.org/0000-0003-1895-9909 German Federal Institute for Risk Assessment, Berlin, Germany Search for more papers by this author Published:31 January 2023CID: 018003https://doi.org/10.1289/EHP12457Cited by:1AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Hærvig et al. report on inverse associations between maternal exposure to per- and polyfluoroalkyl substances (PFAS) during early pregnancy and parameters of semen quality in young adulthood, with a quite impressive number of participants (n=864).1 However, I was surprised that Hærvig et al.1 did not discuss co-exposures to other persistent organic pollutants (POPs), in particular polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxins), given that a high correlation can be expected between internal dioxin and PFAS levels.Reduced sperm concentration in Western societies has been discussed for decades, but clear evidence with respect to causal factors is still missing. One of the hypothesized factors is an impact of POPs during critical windows of susceptibility for developmental effects in the perinatal period, for example, on Sertoli cells.2 Dioxins, in particular, have been suspected agents ever since results began emerging from studies of cohorts exposed to very high levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin following the 1976 Seveso accident3,4; a causal relationship is supported by animal data.5 In 2018, the European Food Safety Authority used data from a study of high ambient exposure in a Russian industrial city6 to derive a tolerable weekly intake for dioxins below mean consumption levels observed in several countries.7Both PFAS and dioxins accumulate in the food chain, and consumption of foods of animal origin especially leads to daily low-level background exposures, resulting in their accumulation in the human body.7,8 Therefore, a high correlation of PFAS and dioxin levels can be expected in the mother, fetus, and newborn, and most especially in the infant at the end of the first year of life, after several months of breastfeeding. However, published data are missing.In our study9 of mother–child pairs when the children were 11 months of age, Spearman’s rank correlation coefficients with plasma levels of dioxin International Toxicity Equivalents (I-TEq) were calculated to be 0.77 for perfluorooctanoic acid (PFOA) and 0.54 for perfluorooctane sulfonate (PFOS) (n=74, p<0.0001 in both cases). The correlation of levels of PFOA and dioxin I-TEq is displayed in Figure 1. The corresponding coefficients in the mothers were lower, but still highly significant (p<0.0001). Levels of other lipophilic POPs, including polychlorinated biphenyls and legacy organochlorine pesticides, were also found to have a high correlation with levels of PFOA and PFOS.9 Notably, our study included maternal blood samples collected in the late 1990s, similar to the time frame of the samples used by Hærvig et al.1 Due to regulatory measures,10 the patterns and levels of POPs measured in blood change continuously, and it is unclear whether the same correlations would be observed today.Figure 1. Scatterplot of plasma levels of PFOA and toxic equivalents of dioxins (as I-TEq) in 11-month-old children (n=21 formula-fed, n=53 breast-fed for at least 4 months). Spearman’s rank correlation coefficient r=0.77. Based on data originally reported by Abraham et al.9 Does not include data for 27 children from a dioxin hotspot. Note: I-TEq, International Toxicity Equivalents; PFOA, perfluorooctanoic acid.These data reinforce that associations between PFAS levels and parameters of semen quality require careful interpretation with respect to possible causal relationships and the critical window of exposure. The current evidence, including that from animal studies,5 suggests that the observed diminished semen quality may also be attributable to dioxins that co-occur with PFAS, either singly or in the mixture, or may be related to lifestyle factors altogether.11