Protective role of hesperidin in finasteride-induced testicular toxicity in adult male Wistar rats: Insights into oxidative stress, apoptosis, and ultrastructure of seminiferous tubules.

A negative impact of finasteride on fertility has been reported, in which over production of reactive oxygen species and apoptosis were implicated. Hesperidin, a plant-derived bioflavonoid with antioxidant and anti-apoptotic effects, may mitigate these adverse effects. In order to investigate the possible protective role of hesperidin against finasteride-induced seminiferous tubules toxicity in adult male Wistar rats, 60 rats were randomized into five groups (I-V) receiving distilled water, 0.5% sodium carboxymethylcellulose solution, hesperidin, finasteride, and combined hesperidin and finasteride respectively. Testicular weight, sperm count and motility were determined. Testicular tissue homogenates were prepared to measure the level of malondialdehyde (MDA), total antioxidant capacity (TAC), reduced glutathione (GSH) and the gene expression of caspase-3 and B-cell lymphoma 2 (Bcl2). Testes were processed for light and electron microscopic evaluation. Johnsen score was calculated. Administration of finasteride resulted in significantly decreased testicular weights, sperm count and motility, Johnsen score, tissue levels of TAC and GSH together with significant increase in tissue MDA. Gene expression revealed significantly increased caspase-3 and decreased Bcl2. Furthermore, finasteride disrupted the seminiferous tubules, causing degenerative changes affecting Sertoli cells and spermatogenic cells. Co-administration of hesperidin with finasteride resulted in improvement in testicular weights, TAC, GSH, Bcl2, Johnsen score, sperm count and motility as well as preservation of the structure of the seminiferous tubules. To conclude, hesperidin was found to have a protective potential on finasteride-induced oxidative stress, apoptosis and testicular structural damage.

Comparative effects of finasteride and minoxidil on the male reproductive organs: A systematic review of in vitro and in vivo evidence.

Finasteride and minoxidil are medicaments commonly prescribed for treating benign prostatic hyperplasia (BPA), hypertension, and/or androgenetic alopecia (AGA). The mechanism of action of finasteride is based on the interference in androgenic pathways, which may lead to fertility-related disorders in men. Minoxidil, however, can act in multiple ways, and there is no consensus that its use can adversely affect male fertility. Since finasteride and minoxidil could be risk factors for male fertility, we aimed to compare their impact on the two reproductive organs testis and epididymis of adult murine models, besides testis/epididymis-related cells, and describe the mechanism of action involved. For such, we used the PRISMA guideline. We included 31 original studies from a structured search on PubMed/MEDLINE, Scopus, and Web of Science databases. For in vivo studies, the bias analysis and the quality of the studies were assessed as described by SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation). We concluded that finasteride and minoxidil act as hormone disruptors, causing oxidative stress and morphological changes mainly in the testis. Our results also revealed that finasteride treatment could be more harmful to male reproductive health because it was more associated with reproductive injuries, including damage to the epididymis, erectile dysfunction, decreased libido, and reduced semen volume. Thus, this study contributes to the global understanding of the mechanisms by which medicaments used for alopecia might lead to male reproductive disorders. We hope that our critical analysis expedites clinical research and reduces methodological bias. The registration number on the Prospero platform is CRD42022313347.

Cocoyam (Colocasia esculenta) modulates some parameters of testosterone propionate-induced rat model of benign prostatic hyperplasia.

The increased global prevalence of benign prostatic hyperplasia (BPH) and the promising potentials of functional foods in ameliorating it led to this study which reported the effect of aqueous ethanol extract of cocoyam (Colocasia esculenta) tuber on some biochemical indices in testosterone propionate (TP) induced benign prostatic hyperplasia (BPH) rats. Thirty male albino rats were randomly assigned into 6 groups of 5 rats each. Group 1 (negative control) received 3 mg/kg of TP and normal saline, group 2 (positive control) received 3 mg/kg of TP and 5 mg/kg of finasteride; groups 3, 4, and 6 rats received 3 mg/kg of TP and 100, 200 and 400 mg/kg of ethanol extracts of cocoyam respectively while group 5 (normal control) received olive oil + normal saline. The study lasted for 28 days. The negative control had increased prostate weight (p < 0.05), decreased body weight gain, prostatic superoxide dismutase, catalase and glutathione concentrations; no differences (p > 0.05) in the serum total cholesterol, triacylglycerol, Very Low Density Lipoprotein, High Density Lipoprotein, Low Density Lipoprotein concentration but increased (p < 0.05) prostate levels of interleukin 10, prostate specific antigen, testosterone, total proteins and malondialdehyde relative to the normal control. Finasteride or the C. esculenta tuber extract modulated most of these parameters as corroborated by histology of the prostate. The percentage yield of the C. esculenta tuber extract was 1.56% and 23 phenolic compounds were characterized in the tuber. The study showed the potentials of C. esculenta tuber in the management of BPH.

Paternal Finasteride Treatment Can Influence the Testicular Transcriptome Profile of Male Offspring-Preliminary Study.

(1) Background: Hormone-dependent events that occur throughout spermatogenesis during postnatal testis maturation are significant for adult male fertility. Any disturbances in the T/DHT ratio in male progeny born from females fertilized by finasteride-treated male rats (F0:Fin) can result in the impairment of testicular physiology. The goal of this work was to profile the testicular transcriptome in the male filial generation (F1:Fin) from paternal F0:Fin rats. (2) Methods: The subject material for the study were testis from immature and mature male rats born from females fertilized by finasteride-treated rats. Testicular tissues from the offspring were used in microarray analyses. (3) Results: The top 10 genes having the highest and lowest fold change values were mainly those that encoded odoriferous (Olfr: 31, 331, 365, 633, 774, 814, 890, 935, 1109, 1112, 1173, 1251, 1259, 1253, 1383) and vomeronasal (Vmn1r: 50, 103, 210, 211; Vmn2r: 3, 23, 99) receptors and RIKEN cDNA 5430402E10, also known as odorant-binding protein. (4) Conclusions: Finasteride treatment of male adult rats may cause changes in the testicular transcriptome of their male offspring, leading to a defective function of spermatozoa in response to odorant-like signals, which are recently more and more often noticed as significant players in male fertility.

The Postnatal Offspring of Finasteride-Treated Male Rats Shows Hyperglycaemia, Elevated Hepatic Glycogen Storage and Altered GLUT2, IR, and AR Expression in the Liver.

BACKGROUND: A growing body of data indicates that the physiology of the liver is sex-hormone dependent, with some types of liver failure occurring more frequently in males, and some in females. In males, in physiological conditions, testosterone acts via androgen receptors (AR) to increase insulin receptor (IR) expression and glycogen synthesis, and to decrease glucose uptake controlled by liver-specific glucose transporter 2 (GLUT-2). Our previous study indicated that this mechanism may be impaired by finasteride, a popular drug used in urology and dermatology, inhibiting 5α-reductase 2, which converts testosterone (T) into dihydrotestosterone (DHT). Our research has also shown that the offspring of rats exposed to finasteride have an altered T-DHT ratio and show changes in their testes and epididymides. Therefore, the goal of this study was to assess whether the administration of finasteride had an trans-generational effect on (i) GLUT-2 dependent accumulation of glycogen in the liver, (ii) IR and AR expression in the hepatocytes of male rat offspring, (iii) a relation between serum T and DHT levels and the expression of GLUT2, IR, and AR mRNAs, (iv) a serum glucose level and it correlation with GLUT-2 mRNA. METHODS: The study was conducted on the liver (an androgen-dependent organ) from 7, 14, 21, 28, and 90-day old Wistar male rats (F1:Fin) born by females fertilized by finasteride-treated rats. The control group was the offspring (F1:Control) of untreated Wistar parents. In the histological sections of liver the Periodic Acid Schiff (PAS) staining (to visualize glycogen) and IHC (to detect GLUT-2, IR, and AR) were performed. The liver homogenates were used in qRT-PCR to assess GLUT2, IR, and AR mRNA expression. The percentage of PAS-positive glycogen areas were correlated with the immunoexpression of GLUT-2, serum levels of T and DHT were correlated with GLUT-2, IR, and AR transcript levels, and serum glucose concentration was correlated with the age of animals and with the GLUT-2 mRNA by Spearman's rank correlation coefficients. RESULTS: In each age group of F1:Fin rats, the accumulation of glycogen was elevated but did not correlate with changes in GLUT-2 expression. The levels of GLUT-2, IR, and AR transcripts and their immunoreactivity statistically significantly decreased in F1:Fin animals. In F1:Fin rats the serum levels of T and DHT negatively correlated with androgen receptor mRNA. The animals from F1:Fin group have statistically elevated level of glucose. Additionally, in adult F1:Fin rats, steatosis was observed in the liver (see Appendix A). CONCLUSIONS: It seems that treating male adult rats with finasteride causes changes in the carbohydrate metabolism in the liver of their offspring. This can lead to improper hepatic energy homeostasis or even hyperglycaemia, insulin resistance, as well as some symptoms of metabolic syndrome and liver steatosis.

In vivo and in silico evaluation of the ameliorative effect of hesperidin on finasteride-induced testicular oxidative stress in Wistar rats.

Finasteride used for treating benign prostatic hyperplasia is associated with undesirable side effects via oxidative stress related mechanisms. This study employed in vivo and in silico methods to investigate the protective role of hesperidin against testicular toxicity induced by finasteride and the possible molecular mechanisms involved. Male Wistar rats were randomized into four groups of six animals each. Group I (control) were administered distilled water, group II received finasteride (3.1 mg/kg bw), group III received hesperidin (100 mg/kg bw), while group IV were co-administered finasteride and hesperidin. Administration was by gavage for 14 days. The binding propensities of finasteride and hesperidin for 5α-reductase were assessed using in silico docking approach. Finasteride administration caused significant reductions of sperm motility, volume, count, and live/dead ratio, with significant increase in numbers of abnormal sperms. Finasteride treatment also resulted in diminished activities of superoxide dismutase, catalase and glutathione-S-transferase, significant reduction in the concentration of reduced glutathione and ascorbic acid, and increased testicular malondialdehyde level relative to control. Moreover, significant increase in the activities of testicular lactate dehydrogenase and γ-glutamyl transferase was observed, with significant decrease in the activities of acid phosphatase and alkaline phosphatase relative to finasteride-treated rats. Furthermore, hesperidin exhibited favorable binding affinity for 5α -reductase (5AR) in silico compared to finasteride. Co-administration with hesperidin ameliorated finasteride-induced testicular damage by suppressing oxidative stress indices, enhancing antioxidant status, improving sperm parameters and alterations in the activities of marker enzymes, as well as possibly inhibiting the binding of finasteride to 5AR.

Origanum vulgare L. leaves extract alleviates testis and sperm damages induced by finasteride: Biochemical, Immunohistological and apoptosis genes based evidences.

The aim of the current study was to investigate antioxidant, anti-inflammatory and anti-apoptotic effects of Origanum vulgare on finasteride-induced oxidative injury in mouse testis and sperm parameters. Thirty BALB/c mice were divided into 5 groups: negative control, received 0.5 ml/day distilled water; positive control, received 25 mg/kg finasteride orally; and three groups received 100, 200 and 400 mg/kg/day O. vulgare extract plus 25 mg kg-1  day-1 finasteride for 35 days. At day 36, serum luteinising hormone, follicle-stimulating hormone and testosterone, inflammatory cytokines (IL-6, TNF-α, IL-1ß), glutathione peroxidase, superoxide dismutase and nitric oxide levels were assessed. Also, apoptotic changes investigated through genes expression and immunohistochemical staining. Finasteride in 35 days resulted in significant destructive alterations in the testis architecture, suppressed antioxidant enzymes and increased lipid peroxidation. The expression of Bcl-2 was down-regulated, whereas p53 and caspase-3 were up-regulated. Origanum vulgare improved the serum level of hormones and restored the antioxidant defence. 200 and 400 mg/kg/day of O. vulgare alleviated the testis structure and sperm parameters, up-regulated the anti-apoptotic gene Bcl-2 and down-regulated the p53, caspase-3 genes in treated groups. The findings indicate that O. vulgare extract improved function and structure of testis tissue against finasteride-induced testicular toxicity.

Toxicity of the pharmaceuticals finasteride and melengestrol acetate to benthic invertebrates.

The toxicity of endocrinologically active pharmaceuticals finasteride (FIN) and melengestrol acetate (MGA) was assessed in freshwater mussels, including acute (48 h) aqueous tests with glochidia from Lampsilis siliquoidea, sub-chronic (14 days) sediment tests with gravid female Lampsilis fasciola, and chronic (28 days) sediment tests with juvenile L. siliquoidea, and in chronic (42 days) sediment tests with the amphipod Hyalella azteca and the mayfly Hexagenia spp. Finasteride was not toxic in acute aqueous tests with L. siliquoidea glochidia (up to 23 mg/L), whereas significant toxicity to survival and burial ability was detected in chronic sediment tests with juvenile L. siliquoidea (chronic value (ChV, the geometric mean of LOEC and NOEC) = 58 mg/kg (1 mg/L)). Amphipods (survival, growth, reproduction, and sex ratio) and mayflies (growth) were similarly sensitive (ChV = 58 mg/kg (1 mg/L)). Melengestrol acetate was acutely toxic to L. siliquoidea glochidia at 4 mg/L in aqueous tests; in sediment tests, mayflies were the most sensitive species, with significant growth effects observed at 37 mg/kg (0.25 mg/L) (ChV = 21 mg/kg (0.1 mg/L)). Exposure to sublethal concentrations of FIN and MGA had no effect on the (luring and filtering) behaviour of gravid L. fasciola, or the viability of their brooding glochidia. Based on the limited number of measured environmental concentrations of both chemicals, and their projected concentrations, no direct effects are expected by these compounds individually on the invertebrates tested. However, organisms are exposed to contaminant mixtures in the aquatic environment, and thus, the effects of FIN and MGA as components of these mixtures require further investigation.

Postnatal exposure to finasteride causes different effects on the prostate of male and female gerbils.

The development and maintenance of prostate function depend on a fine balance between oestrogen and androgen levels. Finasteride inhibits 5α-reductase, which is responsible for the conversion of testosterone into its most active form, dihydrotestosterone. Enzymes that metabolize these hormones have a highly relevant role in both the normal prostate metabolism and in the occurrence of pathological conditions. There are few studies on the impact of finasteride on male prostate development and fewer studies on the female prostate and possible intersexual differences. Therefore, we treated male and female gerbils from 7 to 14 days in postnatal life with a high dose of finasteride (500 µg/kg/day); the prostate complexes were then removed and submitted to immunohistochemistry, immunofluorescence and three-dimensional reconstruction. In addition, hormonal serum dosages were administered. Treatment with finasteride resulted in an increased thickness of the periductal smooth musculature in the prostate of both male and female gerbils, such as well as a reduction in the thickness of developing prostate alveoli in both sexes. In addition, intersexual differences were observed as increased epithelial proliferation and decreases in the number of developing alveoli in females. Together, the data indicate that postnatal exposure to finasteride causes greater changes in the female gerbil prostate than in the male.

Low-dose in utero exposure to finasteride promotes developmental changes in both male and female gerbil prostates.

The prostate is an accessory reproductive gland that is sensitive to the action of exogenous compounds known as endocrine disrupters that alter normal hormonal function. Finasteride is a widely used chemical that acts to inhibit the conversion of testosterone in its most active form, dihydrotestosterone. It is known that intrauterine exposure to finasteride causes changes in the male prostate even at low dosages; however, it is not known whether these dosages are capable of causing changes in the female prostate, which is present in a large number of mammalian species, including humans. In the present study, histochemistry, immunohistochemistry, immunofluorescence, serological dosages, and three-dimensional reconstruction techniques were employed to evaluate the effects of intrauterine exposure to a low dose of finasteride (100 µg.BW/d) on postnatal prostate development in male and female Mongolian gerbils. The results indicate that the gerbil female prostate also undergoes alterations following intrauterine exposure to finasteride, exhibiting a thickening of periductal smooth muscle and increased stromal proliferation. There are also intersex differences in the impact of exposure on the expression of the androgen receptor, which was increased in males, and of the estrogen-α receptor, which was decreased in the male prostate but unchanged in females. Altogether, this study indicates there are sex differences in the effects of finasteride exposure even at low dosages.

Long-term treatment with finasteride induces apoptosis and pathological changes in female mice.

Androgenetic alopecia is the most common type of alopecia, and it affects humans of both genders. Finasteride is a type II selective 5α-reductase inhibitor that is administered orally to treat androgenetic alopecia and benign prostatic hyperplasia in human males. However, its effect on the vital organs of females is unknown. This study was designed to investigate the effects of finasteride on the vital organs such as liver, kidney, and heart of female mice. To study the prospective effects of finasteride, female mice were orally administered two doses of finasteride (0.5 and 1.5 mg/kg) once daily for 35 days, and serum levels of various biochemical parameters and histopathology of various organs were examined. The results showed that serum levels of alkaline phosphatase were significantly increased by both high- and low-dose finasteride, whereas cholesterol was significantly increased by the high dose only. Creatine kinase was significantly increased by the high and low doses, whereas glucose was significantly decreased by both doses. Histopathological analysis and DNA damage assays showed that finasteride has adverse effects within both the short and the long periods in female mice. In addition, the proapoptotic genes Bax and caspase-3 were significantly increased by high dose finasteride, whereas the antiapoptotic gene Bcl-2 was significantly decreased by the low and high doses. In conclusion, finasteride is not currently approved for therapeutic use in females, and the findings in this study suggest caution in any future consideration of such use.

Distinct Transcriptional Profiles of the Female, Male, and Finasteride-Induced Feminized Male Anogenital Region in Rat Fetuses.

A short anogenital distance (AGD) in males is a marker for incomplete masculinization and a predictor of adverse effects on male reproductive health. For this reason, AGD is used to assess the endocrine disrupting potential of chemicals for risk assessment purposes. The molecular mechanisms underpinning this chemically induced shortening of the AGD, however, remains unclear. Although it is clear that androgen receptor-mediated signaling is essential, evidence also suggest the involvement of other signaling pathways. This study presents the first global transcriptional profile of the anogenital tissue in male rat fetuses with chemically induced short AGD, also including comparison to normal male and female control animals. The antiandrogenic drug finasteride (10 mg/kg bw/day) was used to induce short AGD by exposing time-mated Sprague Dawley rats at gestation days 7-21. The AGD was 37% shorter in exposed male fetuses compared with control males at gestation day 21. Transcriptomics analysis on anogenital tissues revealed a sexually dimorphic transcriptional profile. More than 350 genes were found to be differentially expressed between the 3 groups. The expression pattern of 4 genes of particular interest (Esr1, Padi2, Wnt2, and Sfrp4) was also tested by RT-qPCR analyses, indicating that estrogen and Wnt2 signaling play a role in the sexually dimorphic development of the anogenital region. Our transcriptomics profiles provide a stepping-stone for future studies aimed at characterizing the molecular events governing development of the anogenital tissues, as well as describing the detailed Adverse Outcome Pathways for short AGD; an accepted biomarker of endocrine effects for chemical risk assessment.

Stability Study of Finasteride: Stability-Indicating LC Method, In Silico and LC-ESI-MS Analysis of Major Degradation Product, and an In Vitro Biological Safety Study.

Stability studies of the pharmaceutically important compound finasteride were conducted in order to evaluate decomposition of the drug under forced degradation conditions. A simple stability-indicating liquid chromatography method was developed and validated for the evaluation of finasteride and degradation products formed in pharmaceutical preparations and the raw material. Isocratic LC separation was achieved on a C18 column using a mobile phase of o-phosphoric acid (0.1% v/v), adjusted to pH 2.8 with triethylamine (10% v/v) and acetonitrile (52:48 v/v), with a flow rate of 1.0 mL min-1. The alkaline degradation kinetics of the drug were also evaluated and could be best described as second-order kinetics under the experimental conditions applied for the tablets and raw material. Based on in silico studies and molecular weight confirmation, a comprehensive degradation pathway for the drug and the identity of its major product could be suggested without complicated isolation or purification processes. Furthermore, a biological safety study was performed to evaluate the effect of the degraded sample in relation to the intact molecule. The results showed that the degraded sample affected the cell proliferation. Therefore, these studies show that special care must be taken during the manipulation, manufacture and storage of this pharmaceutical drug.

Protective effect of DA-9401 in finasteride-induced apoptosis in rat testis: inositol requiring kinase 1 and c-Jun N-terminal kinase pathway.

Finasteride is used to treat male pattern baldness and benign prostatic hyperplasia. This study investigated the toxicity of finasteride and recovery by DA-9401 using Sprague Dawley (SD) rats. Forty adult male SD rats were assigned to four groups: control (CTR), finasteride 1 mg/kg/day (F), finasteride 1 mg/kg + DA-9401 100 mg/kg/day (F + DA 100) and finasteride 1 mg/kg + DA-9401 200 mg/kg/day (F + DA 200). Treatments were by oral delivery once daily for 90 consecutive days. The gross anatomical parameters assessed included: genital organ weight; vas deferens sperm count and sperm motility; testosterone, dihydrotestosterone (DHT) and malondialdehyde levels; and histological and terminal deoxynucleotidyl transferase enzyme mediated dUTP nick-end labeling (TUNEL) staining of testis for spermatogenic cell density, Johnsen's score and apoptosis. Testicular tissue was also used for evaluating endoplasmic reticulum (ER) stress and apoptotic proteins. Epididymis weight, seminal vesicle weight, prostate weight, penile weight and vas deferens sperm motility showed significant differences between the F group and the CTR, F + DA 100 and F + DA 200 groups. There was no significant change in the testosterone level. DHT level decreased significantly in the F group compared with the CTR group. Testis tissue revealed significant changes in spermatogenic cell density, Johnsen's score and apoptotic index. Western blot showed significant changes in the ER stress and apoptotic markers. Finasteride resulted in reduced fertility and increased ER stress and apoptotic markers, which were recovered by administration of DA-9401 in the SD rats.

Increased anxiety-like phenotype in female guinea pigs following reduced neurosteroid exposure in utero.

Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as preterm birth, prenatal stress and intrauterine growth restriction are associated with an increased risk of developing behavioural and mood disorders, particularly during adolescence. These pathologies involve the premature loss or alteration of trophic steroid hormones reaching the fetus leading to impaired neurodevelopment. While the specific programming mechanisms are yet to be fully elucidated, in adult life, dysfunctions of allopregnanolone action are prevalent in individuals with depression, post-traumatic stress disorder and anxiety disorders. The objective of this study was to assess if changes in concentrations of the neurosteroid, allopregnanolone, may be a fetal programming factor in priming the brain towards a negative behavioural phenotype during the childhood to adolescent period using a guinea pig model. Pregnant guinea pigs received either vehicle (45% (2-hydroxypropyl)-ß-cyclodextrin) or the 5α-reductase inhibitor, finasteride (25mg/kg maternal weight) from gestational age 60 until spontaneous delivery (∼71days gestation). Male and female offspring from vehicle and finasteride treated dams were tested at postnatal day 20 (juvenile-equivalence) in an open field arena, and hippocampus and amygdala subsequently assessed for neurological changes in markers of development and GABA production pathways 24h later. Females with reduced allopregnanolone exposure in utero displayed increased neophobic-like responses to a change in their environment compared to female controls. There were no differences in the neurodevelopmental markers assessed; MAP2, NeuN, MBP, GFAP or GAD67 between intrauterine finasteride or vehicle exposure, in either the hippocampus or amygdala whereas GAT1 staining was decreased. This study indicates that an intrauterine reduction in the supply of allopregnanolone programs vulnerability of female offspring to anxiety-like disorders in juvenility without impacting long term allopregnanolone concentrations.

Androgen levels and apoptosis in the testis during postnatal development of finasteride-treated male rat offspring.

INTRODUCTION: The hormone-dependent events that occur throughout the first wave of spermatogenesis, such as the establishment of the number of Sertoli cells (SCs) and spermatogonial stem cells (SSCs) within the seminiferous cords and the setting up of the blood-testis barrier, are important for adult male fertility. Any changes in the T/DHT ratio can result in male subfertility or even infertility. In this study we aimed to evaluate effects of paternal exposure to 5-alpha reductase type 2 inhibitor, finasteride on litter size, androgen levels and germ cell apoptosis in male offspring during postnatal development. MATERIAL AND METHODS: The subjects of the study were 7, 14, 21/22, 28, and 90-day-old Wistar male rats (F1:Fin) born from females fertilized by finasteride-treated rats. Offspring born from untreated parental animals were used as a control group (F1:Control). Animals and the collected testes were weighed, blood and intratesticular levels of T and DHT were measured by ELISA, and the apoptotic index of testicular cells was evaluated by TUNEL technique. RESULTS: We observed difficulties in obtaining male newborns from female rats fertilized by finasteride-treated male rats. In the F1:Fin rats, changes in the body and testes weights occurred, and a lower number of apoptotic cells was found during postnatal maturation of the seminiferous epithelium. Changes in androgen concentrations during the first spermatogenesis wave and adult life were also evident. CONCLUSION: Finasteride treatment of male adult rats may not only cause a decrease in the fertility of parental rats, but also could lead to incorrect, androgen-sensitive course of spermatogenesis in their offspring.

Neonatal finasteride administration alters hippocampal α4 and δ GABAAR subunits expression and behavioural responses to progesterone in adult rats.

Allopregnanolone is a neurosteroid that has been reported to fluctuate during early developmental stages. Previous experiments reported the importance of neonatal endogenous allopregnanolone levels for the maturation of the central nervous system and particularly for the hippocampus. Changes in neonatal allopregnanolone levels have been related to altered adult behaviour and with psychopathological susceptibility, including anxiety disorders, schizophrenia and drug abuse. However, the mechanism underlying these changes remains to be elucidated. In the present study we assessed changes in hippocampal expression of α4 and δ GABAA receptor (GABAAR) subunits as a consequence of neonatal finasteride (a 5-α reductase inhibitor) administration during early development (PD6 to PD15) in male rats. We observed that the treatment altered the temporal window of the natural peak in the expression of these subunits during development. Additionally, the level of these subunits were higher than in non-handled and control animals in the adult hippocampus. We observed that in adulthood, neonatal finasteride-treated animals presented an anxiogenic-like profile in response to progesterone administration which was absent in the rest of the groups. In conclusion, these results corroborate the relevance of neonatal maintenance of neurosteroid levels for behavioural anxiety responses in the adult, and point to some of the mechanisms involved in this alterations.

Morphometric-stereological and functional epididymal alterations and a decrease in fertility in rats treated with finasteride and after a 30-day post-treatment recovery period.

OBJECTIVE: To evaluate morphometric-stereological changes in the epididymal caput, sperm quality, and fertility parameters in rats treated with finasteride and after a 30-day post-treatment recovery period. DESIGN: Experimental study in a research laboratory. SETTING: Reproductive biology research laboratory. ANIMAL(S): Male and female Sprague Dawley rats. INTERVENTION(S): Treatment with finasteride (5 mg/kg/day) for 56 days followed by 30 days without treatment. MAIN OUTCOME MEASURE(S): Serum hormone analyses, morphometric-stereological and ultrastructural evaluation of the epididymal caput, sperm transit time, natural mating, in utero insemination, sperm membrane integrity, and fertility parameters. RESULT(S): Serum dihydrotestosterone levels in the finasteride group decreased by ~40% compared with that of control rats. Ultrastructural analysis revealed significant reductions in several morphometric-stereological parameters of the epididymal caput. All parameters recovered significantly in the post-treatment period. There was no alteration in daily sperm production in the finasteride group. However, significant reductions in sperm transit time, motility, sperm membrane integrity, and fertility parameters were observed in rats treated with finasteride. CONCLUSION(S): Treatment with finasteride caused morphometric-stereological and functional changes in the epididymis and in sperm function that led to a reduction in fertility parameters. A 30-day post-treatment recovery period was insufficient to restore normal sperm motility, sperm transit time, and some fertility parameters.

The human relevant potency threshold: reducing uncertainty by human calibration of cumulative risk assessments.

The 2008 National Research Council report "Phthalates and Cumulative Risk Assessment: Tasks Ahead," rejected the underlying premises of TEQ-like approaches - e.g., chemicals are true congeners; are metabolized and detoxified similarly; produce the same biological effects by the same mode of action; exhibit parallel dose response curves - instead asserting that cumulative risk assessment should apply dose addition (DA) to all chemicals that produce "common adverse outcomes" (CAOS). Published mixtures data and a human health risk assessment for phthalates and anti-androgens were evaluated to determine how firmly the DA-CAOS concept is supported and with what level of statistical certainty the results may be extrapolated to lower doses in humans. Underlying assumptions of the DA-CAOS concept were tested for accuracy and consistency against data for two human pharmaceuticals and its logical predictions were compared to human clinical and epidemiological experience. Those analyses revealed that DA-CAOS is scientifically untenable. Therefore, an alternative approach was developed - the Human-Relevant Potency-Threshold (HRPT) - that appears to fit the data better and avoids the contradictions inherent in the DA-CAOS concept. The proposed approach recommends application of independent action for phthalates and other chemicals with potential anti-androgenic properties at current human exposure levels.