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Lead acetate (Pb) is an environmental toxicant widely reported to distort testicular functions. Methanol extract of Sida corymbosa leaves (SC) possesses antioxidant and anti-inflammatory properties. This study was designed to evaluate the role of SC on lead acetate-induced alteration in testicular functions. Thirty adult male Wistar rats were grouped randomly and equally into six and treated as follows: control, Pb (15 mgkg-1 ), SC (100 mgkg-1), SC (200 mgkg-1), Pb+SC (100 mgkg-1), and Pb+SC (200 mgkg-1 ) respectively. Administrations were orally done for 54 days. Computer-aided sperm analyzer, ELISA, spectrophotometry, immunohistochemistry, and PCR techniques were used. Pb significantly reduced follicle-stimulating hormone, luteinizing hormone, testosterone, androgen receptors expression, 3β- and 17β-hydroxysteroid dehydrogenase, sperm concentration, progressive sperm motility, viability, catalase, superoxide dismutase activities, and BCL-2. Pb significantly increased abnormal sperm morphology, malondialdehyde, 8- hydroxydeoxyguanosine, BAD, TNF-α, and IL-6. The combination of SC and Pb significantly reverses the hormones, steroidogenic enzymes, sperm quality, testicular oxidant, antioxidant enzymes, testicular DNA damage, apoptosis, and inflammation when compared with the Pb group. Anti-apoptosis, antioxidant, and anti-inflammatory activities of Sida corymbosa improve lead acetate-induced testicular functions alteration in Wistar rats. [ABSTRACT FROM AUTHOR]

Curcuma longa, best known for its culinary application as the main constituent of curry powder, has shown potential impact on the reproductive system. This study aimed to investigate the efficacy of Curcuma longa extract (CLE) on Kidney‐Yang deficiency mice induced by hydrocortisone and the possible roles in testosterone secretion in Leydig cells. We evaluated male sexual behaviour, reproductive organ weight, testosterone levels, and histological tissue changes in hydrocortisone‐induced mice. CLE effectively reversed hydrocortisone‐induced Kidney‐Yang deficiency syndrome by improving sexual behaviour, testis and epididymis weight, testosterone levels and reducing pathological damage. Our in vitro study further indicated that CLE stimulated testosterone production via upregulating the mRNA and protein expression of steroidogenic enzymes in Leydig cells. It significantly improved H89‐inhibited protein expression of StAR and cAMP‐response element‐binding (CREB), as well as melatonin‐suppressed StAR protein expression. The data obtained from this study suggest that CLE could alleviate Kidney‐Yang deficiency symptoms and stimulate testosterone production by upregulating the steroidogenic pathway. This research identifies CLE as a potential nutraceutical option for addressing testosterone deficiency diseases. [ABSTRACT FROM AUTHOR]

Butorphanol is a synthetic opioid analgesic medication that is primarily used for the management of pain. Butorphanol may have an inhibitory effect on androgen biosynthesis and metabolism in rat immature Leydig cells. The objective of this study was to investigate the influence of butorphanol on androgen secretion by rat Leydig cells isolated from the 35-day-old male rats. Rat Leydig cells were cultured with 0.5–50 μM butorphanol for 3 h in vitro. Butorphanol at 5 and 50 μM significantly inhibited androgen secretion in immature Leydig cells. At 50 μM, butorphanol also blocked the effects of luteinizing hormone (LH) and 8bromo-cAMP-stimulated androgen secretion and 22R-hydroxycholesterol- and pregnenolone-mediated androgen production. Further analysis of the results showed that butorphanol downregulated the expression of genes involved in androgen production, including Lhcgr (LH receptor), Cyp11a1 (cholesterol side-chain cleavage enzyme), Srd5a1 (5α-reductase 1), and Akr1c14 (3α-hydroxysteroid dehydrogenase). Additionally, butorphanol directly inhibited HSD3B1 (3β-hydroxysteroid dehydrogenase 1) and SRD5A1 activity. In conclusion, butorphanol may have side effects of inhibiting androgen biosynthesis and metabolism in Leydig cells. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) plays a crucial role in follicular growth and stimulates steroid hormone production in bovine follicles. Steroid hormones are synthesized through the actions of steroidogenic enzymes, specifically STAR, CYP11A1, HSD3B, and CYP19A1 in both theca cells (TCs) and granulosa cells (GCs), under the influence of gonadotropins. Particularly, estradiol 17β (E2) assumes a central role in follicular development and selection by activating estrogen receptors β (ESR2) in GCs. We assessed ESR2 mRNA expression in GCs of developing follicles and investigated the impact of IGF-1 on the mRNA expression of ESR2, CYP19A1, FSHR, and LHCGR, STAR, CYP11A1, and HSD17B in cultured GCs and TCs, respectively. Additionally, we assessed the influence of IGF-1 on androstenedione (A4), progesterone (P4), and testosterone (T) production in TCs. Small-sized follicles (< 6 mm) exhibited the highest levels of ESR2 mRNA expression, whereas medium-sized follicles (7–8 mm) displayed higher levels than large-sized follicles (≥ 9 mm) (P < 0.05). IGF-1 increased the mRNA expression of ESR2, CYP19A1, and FSHR in GCs of follicles of both sizes, except for FSHR mRNA in medium-sized follicles (P < 0.05). IGF-1 significantly elevated mRNA expression of LHCGR, STAR, CYP11A1, and CYP17B in TCs of small- and medium-sized follicles (P < 0.05). Moreover, IGF-1 augmented the production of A4 and P4 but had no impact on T production in TCs of small- and medium-sized follicles. Taken together, our findings indicate that IGF-1 upregulates steroidogenic enzymes and steroid hormone production, underscoring the crucial role of IGF-1 in follicle development and selection.

Using a rat model of type 1 diabetes (T1D) obtained by treatment with streptozotocin, an antibiotic that destroys pancreatic β‐cells, we evaluated the influence of subsequent hyperglycemia on the morphology and physiology of the Harderian gland (HG). HG is located in the medial corner of the orbit of many terrestrial vertebrates and, in rodents, is characterized by the presence of porphyrins, which being involved in the phototransduction, through photo‐oxidation, produce reactive oxygen species activating the autophagy pathway. The study focused on the expression of some morphological markers involved in cell junction formation (occludin, connexin‐43, and α‐tubulin) and mast cell number (MCN), as well as autophagic and apoptotic pathways. The expression of enzymes involved in steroidogenesis [steroidogenic acute regulatory protein (StAR), and 3β‐hydroxysteroid dehydrogenase (3β‐HSD)] and the level of lipid peroxidation by thiobarbituric acid reactive species assay were also evaluated. The results strongly indicate, for the first time, that T1D has a negative impact on the pathophysiology of rat HG, as evidenced by increased oxidative stress, morphological and biochemical alterations, hyperproduction and secretion of porphyrins, increased MCN, reduced protein levels of StAR and 3β‐HSD, and, finally, induced autophagy and apoptosis. All the combined data support the use of the rat HG as a suitable experimental model to elucidate the molecular damage/survival pathways elicited by stress conditions. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) plays a crucial role in follicular growth and stimulates steroid hormone production in bovine follicles. Steroid hormones are synthesized through the actions of steroidogenic enzymes, specifically STAR, CYP11A1, HSD3B, and CYP19A1 in both theca cells (TCs) and granulosa cells (GCs), under the influence of gonadotropins. Particularly, estradiol 17β (E2) assumes a central role in follicular development and selection by activating estrogen receptors β (ESR2) in GCs. We assessed ESR2 mRNA expression in GCs of developing follicles and investigated the impact of IGF-1 on the mRNA expression of ESR2, CYP19A1, FSHR, and LHCGR, STAR, CYP11A1, and HSD17B in cultured GCs and TCs, respectively. Additionally, we assessed the influence of IGF-1 on androstenedione (A4), progesterone (P4), and testosterone (T) production in TCs. Small-sized follicles (< 6 mm) exhibited the highest levels of ESR2 mRNA expression, whereas medium-sized follicles (7–8 mm) displayed higher levels than large-sized follicles (≥ 9 mm) (P < 0.05). IGF-1 increased the mRNA expression of ESR2, CYP19A1, and FSHR in GCs of follicles of both sizes, except for FSHR mRNA in medium-sized follicles (P < 0.05). IGF-1 significantly elevated mRNA expression of LHCGR, STAR, CYP11A1, and CYP17B in TCs of small- and medium-sized follicles (P < 0.05). Moreover, IGF-1 augmented the production of A4 and P4 but had no impact on T production in TCs of small- and medium-sized follicles. Taken together, our findings indicate that IGF-1 upregulates steroidogenic enzymes and steroid hormone production, underscoring the crucial role of IGF-1 in follicle development and selection. [ABSTRACT FROM AUTHOR]

Background: Paraquat (PQ) is a herbicide that is used globally in the agriculture sector to eradicate unwanted weeds, however it also induces significant damages in various organs of the body such as testes. Tectochrysin (TEC) is an important flavonoid that shows versatile therapeutic potentials. Currently, there is no established antidote to cure PQ-induced testicular toxicity. Objective: The present study was conducted to evaluate the ameliorative effects of TEC against PQ prompted testicular damage. Methods: Sprague-Dawley rats (n = 48) were used to conduct the trial. Rats were allocated in to 4 groups i.e., Control, PQ administrated group (5 mgkg−1), PQ + TEC co-administrated group (5 mgkg−1 + 2.5 mgkg−1) and TEC only administrated group (2.5 mgkg−1). The trial was conducted for 8 weeks. The activity of anti-oxidants and the levels of MDA and ROS were determined by spectrophotometric method. Steroidogenic enzymes as well as apoptotic markers expressions were evaluated by qRT-PCR. The level of hormones and inflammatory indices was quantified by enzyme-linked immunosorbent assay. Results: PQ exposure markedly (P

Polycystic ovary syndrome (PCOS) is a common hormonal disorder that affects women of reproductive age and is characterized by multiple ovarian cysts, irregular menstrual cycles, and excessive androgen hormone production. The present study aimed to investigate the therapeutic efficacy of melatonin in alleviating PCOS-induced alterations in female Wistar rats. PCOS was induced in female albino rats by administering letrozole at a dose of 1 mg/kg for 21 days. A total of 24 rats were randomly selected and divided into four groups: group I (normal control), group II (melatonin treatment), group III (letrozole treatment), and group IV (melatonin therapy for PCOS rats). Physical parameters (body and uterus weight), hormone profile (LH and FSH), and steroidogenic enzyme activities and an oral glucose test were assessed using standard methods. Histological analysis was performed using hematoxylin and eosin staining. The results demonstrated that exogenous melatonin administration significantly improved PCOS symptoms in rats, including reduced body weight gain, changes in organ weight/body weight index, blood glucose level, percentage diestrus phase, testosterone, estradiol, progesterone, and LH/FSH ratio, as well as 3β-HSD and 17β-HSD enzyme activity. Histopathological findings revealed well-developed follicles, decreased cystic follicles, and increased antral follicles, Graafian follicles, and corpus luteum in PCOS rats treated with melatonin. These positive outcomes suggest that exogenous melatonin may hold promise as a valuable remedy for PCOS conditions in female rats. Further research is warranted to fully elucidate the underlying mechanisms and potential clinical applications of melatonin in the context of PCOS.

Background: Ovarian advanced glycation end-products (AGEs) accumulation is associated with ovarian granulosa cells (GCs) dysfunction. Vitamin B6 derivatives positively affected reproduction. The current study was conducted to elucidate the AGEs effects on human luteinized mural GCs steroidogenesis in the presence or absence of pyridoxamine (PM). Methods and results: Isolated GCs of 50 healthy women were divided into four parts and treated with media alone (Control), PM alone, or human glycated albumin (HGA) with/without PM. Main steroidogenic enzymes and hormones were assessed by qRT-PCR and ELISA. The AGE receptor (RAGE) protein was also determined using Western blotting. The non-toxic concentration of HGA increased the expression of RAGE, StAR, 3β-HSD, and 17β-HSD (P < 0.0001 for all) but decreased the expression of CYP19A1 at mRNA levels. The increased RAGE protein expression was also confirmed by western blot analysis. These effects resulted in declined estradiol (E2), slightly, and a sharp rise in progesterone (P4) and testosterone (T) levels, respectively. PM, on its own, ameliorated the HGA-altered enzyme expression and, thereby, corrected the aberrant levels of E2, P4, and T. These effects are likely mediated by regulating the RAGE gene and protein expression. Conclusion: This study indicates that hormonal dysfunctions induced by the AGEs-RAGE axis in luteinized GCs are likely rectified by PM treatment. This effect is likely acquired by reduced expression of RAGE. A better understanding of how AGEs and PM interact in ovarian physiology and pathology may lead to more targeted therapy for treating ovarian dysfunction. [ABSTRACT FROM AUTHOR]

The 3T3-L1 murine adipocyte cell line remains one of the most widely used models to study the mechanisms of obesity and related pathologies. Most studies investigate such mechanisms using mature adipocytes that have been chemically induced to differentiate for 7 days in media containing 25 mM glucose. However, the dysfunctional characteristics commonly observed in obesity including adipocyte hypertrophy, increased expression of inflammatory markers, enhanced production of reactive oxygen species (ROS), increased steroidogenic enzyme expression/activity and production of steroid hormones, are not necessarily mimicked in these cells. The aim of this study was to provide an inexpensive model which represents the well-known characteristics of obesity by manipulating the time of adipocyte differentiation and increasing the concentration of glucose in the cell media. Our results showed a glucose- and time-dependent increase in adipocyte hypertrophy, ROS production and gene expression of the pro-inflammatory cytokine interleukin-6 (IL-6), as well as a time-dependent increase in lipolysis and in the gene expression of the chemokine monocyte chemoattractant protein 1 (MCP1). We also showed that gene expression of the steroidogenic enzymes 11-beta-hydroxysteroid dehydrogenase type 1 (11βHSD1), 17βHSD type 7 and 12, as well as CYP19A1 (aromatase), were significantly higher in the hypertrophic model relative to the control adipocytes differentiated using the conventional method. The increase in 11βHSD1 and 17βHSD12 expression was consistent with the enhanced conversion of cortisone and androstenedione to cortisol and testosterone, respectively. As these characteristics reflect those commonly observed in obesity, hypertrophic 3T3-L1 adipocytes are an appropriate in vitro model to study mechanisms of adipocyte dysfunction in an era where the rise in obesity incidence is a global health concern, and where access to adipose tissue from obese patients are limited. • In vitro 3T3-L1 adipocyte model mimicking dysfunctional adiposity. • Increased glucose and time of differentiation promote adipocyte hypertrophy. • Lipolysis, ROS and inflammatory markers are increased in hypertrophic adipocytes. • Hypertrophic adipocytes show enhanced steroidogenic enzyme expression and activity. [ABSTRACT FROM AUTHOR]

Spix's cavy is a potentially good experimental model for research on reproductive biology and sexual development. The aim of the present study was to evaluate the ontogeny of the steroidogenic enzymes involved in testicular androgen synthesis during prenatal development. Testes were investigated on Days 25, 30, 40 and >50 of gestation. Immunohistochemistry and immunoblotting were used to establish the site and relative amount of androgenic enzymes, including 5α-reductase, cytosolic 17β-hydroxysteroid dehydrogenase (17β-HSDI) and mitochondrial microsomal 3β-hydroxysteroid dehydrogenase (3β-HSDII), throughout prenatal development. The testicular parenchyma began to organise on Day 25 of gestation, with the development of recognisable testicular cords. The mesonephros was established after Day 25 of gestation and the ducts differentiated to form the epididymis, as testicular cords were beginning to proliferate and the interstitium to organise by Day 30 of gestation, continuing thereafter. The androgen-synthesising enzymes 5α-reductase, 17β-HSDI and 3β-HSDII were evident in Leydig cells as they differentiated at all subsequent gestational ages studied. In addition, immunoblotting showed an increase in immunoreactivity for the enzymes at Days 30 and 40 of gestation (P

Physiological mechanisms of seasonal changes in testicular function in birds are not fully elucidated. The balance between androgens and estrogens and testis sensitivity for gonadotropin and gonadal steroids are still unclear. The aim of the study was to examine: (1) the changes in circulating and intra-testicular steroid hormone levels and their relationship; (2) the mRNA expression of testicular gonadotropin, prolactin (PRL), progesterone (P4), androgen, and estrogen receptors, and (3) key steroidogenesis processes-related genes with immunofluorescent localization of aromatase in gander testes during the annual period. Testes from ganders (n = 25) in the first reproduction season were obtained at five breeding stages, i.e., prebreeding (PrB), peak of reproduction (PR), postbreeding (PoB), nonbreeding (NB), and onset of reproduction (OR). Males were kept under breeding conditions. It was found that plasma P4 levels decreased at the PoB and NB stages, whereas intra-testicular P4 was the highest in the NB stage. Intra-testicular estradiol (E2) levels were higher at the PoB and NB stages than the other stages, whereas testosterone (T) levels showed a nearly opposite pattern. The plasma estradiol – to – testosterone ratios were higher at the PrB, PoB and NB stages compared to other stages. The transcript abundances for luteinizing hormone receptor (LHR) , PRL receptor (PRLR) , estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ) also change in testicular tissue during the annual period. Moreover, StAR mRNA expression was upregulated at the PoB and NB stages, and CYP11A1 transcript level was the highest at the PoB stage. Stage-dependent changes in the CYP19A1 mRNA and aromatase protein levels with higher abundances of transcript at PoB and NB stages and protein at the NB stage were observed. Localization and immunofluorescent signal intensity for aromatase also differed in relation to the examined stages. It may be suggested that differential E2 levels, as well as aromatase expression and localization across annual stages are responsible for the seasonal activation/inactivation stages of testis spermatogenesis in domestic ganders. These data strongly suggest a role of aromatase in the control of gander steroidogenesis as changes in this enzyme level are associated with alternation in gonadal steroid hormones. In addition, joint action with others hormones, like PRL and LH, seems to be important in the final effect of seasonal reproduction potential. • Physiological basis of annual testicular function changes in ganders were studied. • Testicular stages were associated with a shift in gonadal steroid biosynthesis. • Testicular stage-related transcript abundances for LHR, PRLR, and ERs were shown. • Upregulation of ERs and CYP19A1 transcripts in non-reproduction stages was found. • Testicular stage-related changes in intensity of aromatase immunoreactivity were noted. [ABSTRACT FROM AUTHOR]

Abstract. Artificial and natural energy drinks are both taken for increased energy, physical stamina, and alertness, although they differ in composition. This study investigated the effects of artificial and natural energy drinks on the testicular milieu in male pubertal rats. Eighteen Wistar rats were randomly divided into 3 groups of 6 rats each and all animals had access to food ad libitum. Group 1: (control) received water only; Group 2: (artificial energy drink- AED) received AED; Group 3: (natural energy drink- NED) received NED. A dose of 1.41ml/day/150g animal was administered and this lasted for 28 days. Sperm and testicular variables, biochemical parameters, and hormonal assays were carried out. There were significant decreases in the levels of testosterone, Lactate dehydrogenase, glucose, 3β-Hydroxysteroid dehydrogenase, and 17β- Hydroxysteroid dehydrogenase activities in AED and NED groups when compared to the control group. There was a marked increment in sperm abnormalities in the NED group when compared to AED and control groups. Also, the intake of AED led to an elevated level of Glucose-6-phosphate dehydrogenase compared to the control while a significant reduction was observed in the NED group when compared to the AED group. Artificial and natural energy drinks although consumed for strength and vigor distorted epididymis and testicular integrity via alteration of the testicular metabolism, lowering sperm quality and androgenic hormones in pubertal male Wistar rats. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is one of the chemicals that cause dysfunction and infertility in testicles. Therefore, it is crucial to develop effective treatments against this damage. In this study, the effects of Hesperidin (HESP), a flavonoid in testicular toxicity induced by BPA in rats, on oxidative stress, inflammation, apoptosis, histological damage, spermatogenesis, steroidogenic enzymes and reproductive hormones were investigated. Our study used 52 Sprague Dawley male rats weighing 250–300 g, and four experimental groups were formed. From the experimental groups, 1 ml of olive oil was administered to the control group, HESP at a dose of 50 mg/kg to the HESP group, BPA at a dose of 100 mg/kg to the BPA group, HESP at a dose of 50 mg/kg to the BPA + HESP group and 100 mg/kg BPA was administered intragastrically (ig) for 14 days. We determined that BPA administration causes apoptosis, histological damage, inflammation, oxidative stress and toxic effects on spermatogenesis and steroidogenic enzymes in testicles. We observed that the administration of HESP with BPA attenuated oxidative stress, inflammation and apoptosis resulting in therapeutic effects on both steroidogenic enzymes and spermatogenesis and reproductive hormones (FSH, LH and testosterone). Our findings from this study clearly showed that while HESP treatment alleviates oxidative damage, inflammation and apoptosis in testicles of rats treated with BPA, it has regulatory effects on steroidogenic enzymes, spermatogenesis and serum reproductive hormones. [ABSTRACT FROM AUTHOR]

Anabolic steroids are frequently used to increase the growth rate of meat-producing animals. Exposure to an anabolic-androgenic steroid, nandrolone decanoate (ND), is associated with expressional reduction of testicular steroidogenic enzymes. However, the effect of withdrawal of ND exposure on the expression of these testicular molecules has not been thoroughly explored. The current research investigated expression changes of testicular steroidogenic enzymes in rats at several recovery periods (2, 6, and 12 weeks) after the stop of ND treatment with different doses (2 and 10 mg/kg body weight) for 12 weeks. Body and testis weights were recorded, and transcript levels of molecules were determined by quantitative real-time polymerase chain reaction (PCR). The immunohistochemistry was used to examine the changes of immuno-intensities of molecules. At 6 and 12 weeks of the recovery period, the 10 mg/kg ND-treated rats were lighter than other experimental groups. The interstitial compartment vanished by ND treatment filled up as the recovery period became longer. The expression of steroidogenic acute regulatory protein was returned to the control level at 12 weeks of the recovery period. Expression levels of cytochrome P450 side-chain cleavage and 17a-hydroxylase were increased in 2 mg/kg ND-treated group at 6 weeks of the recovery period, and transcript levels of these molecules in 2 and 10 mg/kg ND-treated groups at 12 weeks of the recovery period were significantly lower than the control. Expression levels of 3β-hydroxysteroid dehydrogenase (HSD) type I and 17β-HSD type 3 in 2 mg/kg ND-treated group were comparable with those of control at 12 weeks of the recovery period, but not in 10 mg/kg ND-treated group. Expression of cytochrome P450 aromatase (Cyp19) was reverted to the control level at 2 weeks of the recovery period. Except for Cyp19, there was a visible increase of immuno-staining intensity of other testicular steroidogenic enzymes in the Leydig cells as the recovery period progressed. This research has demonstrated that the cease of ND administration could restore the expression of testicular steroidogenic enzymes close to the normal level. Nevertheless, a relatively long recovery period, compared to the ND-exposure period would be required to retrieve normal expression levels of testicular steroidogenic enzymes.

Hyperprolactinemia has been related to the pathogenesis of impaired glucose tolerance and hyperinsulinemia resulting in overt insulin resistance. Human secreted excess glucocorticoid can get Cushing's syndrome to lead to dyslipidemia, and insulin resistance/type 2 diabetes. Prolactin (PRL) and glucocorticoid might interfere with each other. Hence, this research directed to elucidate the influence of hyperprolactinemia on the release of corticosterone by zona fasciculata-reticularis (ZFR) cells from ovariectomized rats. For hyperprolactinemia, two rat anterior pituitary glands (Aps), or a fragment of cerebral cortex (Cx) for each rat were transplanted under the kidney capsule and mice were kept for 2 months prior to euthanasia. The ZFR cells derived from Cx-grafted and Ap-grafted groups were incubated in the presence of adrenocorticotropic hormone (ACTH), forskolin, IBMX, 8-bromo-cyclic 3': 5'-adenosine monophosphate (8-Br-cAMP), nifedipine, trilostane or steroidogenic precursors at 37oC for 0.5 or 1 hour. The concentration of corticosterone or pregnenolone in the culture media was determined by a radioimmunoassay (RIA). The plasma corticosterone in Ap-grafted rats was significantly elevated than that in Cx-grafted rats. This research demonstrated that hyperprolactinemia enhanced corticosterone production by rat ZFR cells. The action was mediated through enhancing the responsiveness to ACTH stimulation, cyclic AMP (cAMP) cascades, and the activities of steroidogenic enzymes. [ABSTRACT FROM AUTHOR]

Herein is reported, for the first time in the rat Harderian gland (HG), the counteractive action of melatonin (Mlt), a well‐known antioxidant radical scavenger, on the increased oxidative stress damages induced by a pro‐oxidant substance, cadmium (Cd), an environmental pollutant also considered as endocrine disruptor. HG, an infraorbital gland present in almost all terrestrial vertebrates, produces a lipid secretion to lubricate the eyeball, as well as porphyrin/Mlt as light transducers. Moreover, HG is an extra‐gonadal source of steroid sex hormones. Via ex vivo experiments lasting for 24 h, we verified the increased lipid peroxidation in Cd‐treated glands, producing morphological alteration of the glandular epithelium, as well as an increased porphyrins accumulation. Moreover, Cd also induced a decreased protein level of the steroidogenic enzymes steroidogenic acute regulatory (StAR) and 3βHSD, and an increased mast cell number. Results obtained with Mlt cotreatment demonstrated that it decreased the levels of Cd‐induced oxidative damage, with reversal of all the observed modification. Furthermore, the TUNEL assay showed that the increased number of apoptotic cells in Cd‐treated HG was counteracted by the contemporaneous Mlt administration. Results confirmed that Mlt treatment restored the levels of two autophagy markers, LC3 and p62, counteracting the autophagy Cd‐induced. Interestingly, the positive effects of Mlt alone were highlighted by the decreased rate of lipid peroxidation as compared with the control, confirming its antioxidant action. Combined data further confirmed the antioxidant action of Mlt in counteracting the degeneration provoked by reactive oxygen species (ROS) in the rat HG, a tissue extremely susceptible to oxidative stress condition. Research Highlights: –Oxidative stress Cd‐induced produces morphological and biochemical alteration in the rat Harderian gland.–Melatonin cotreatment counteracts all the damages provoked by oxidative disorders.–Melatonin alone reduces the rate of lipid peroxidation, thanks to its antioxidant properties. [ABSTRACT FROM AUTHOR]

Paraquat (PQ) is a noxious herbicide which adversely affects the vital organs including male reproductive system. Sudachitin (SCN) is a naturally occurring flavonoid that demonstrates a wide range of biological potentials. The current study was designed to investigate the alleviative potential of SCN to avert PQ-induced testicular toxicity in rats. Forty-eight male rats (Rattus norvegicus) were apportioned into four groups including control, PQ (5 mg/kg), PQ + SCN (5 mg/kg + 30 mg/kg), and SCN (30 mg/kg) only treated group. Our findings elucidated that PQ treatment reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and its antioxidant genes as well as the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSR) and glutathione peroxidase (GPx), while elevating the levels of reactive oxygen species (ROS), and malondialdehyde (MDA). Furthermore, PQ intoxication upregulated the expressions of Keap-1 while downregulating the expression of 3-beta hydroxysteroid dehydrogenase (3β-HSD), 17-beta hydroxysteroid dehydrogenase (17β-HSD), and steroidogenic acute regulatory protein (StAR). Moreover, sperm anomalies were increased following the exposure to PQ. Besides, PQ exposure decreased the levels of plasma testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) while increasing the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), interleukin-1beta (IL-1β), and cyclooxygenase-2 (COX-2). Additionally, PQ treatment escalated the expressions of cysteinyl aspartate-specific proteases-3 (Caspase-3) and Bcl-2-associated X-protein (Bax) while downregulating the expressions of B-cell lymphoma-2 (Bcl-2). Furthermore, PQ exposure disrupted the normal architecture of testicular tissues. However, SCN treatment remarkably protected the testicular tissues via regulating the aforementioned disruptions owing to its antioxidant, anti-inflammatory, and androgenic potential., (© 2024 Wiley Periodicals LLC.)

Porker immunocastration against gonadoliberin (GnRH) secretion has been utilized since 2009; however, consumers are still skeptical of it. This is due to not having full information available on the problem of a boar taint, as well as a lack of research on morphological and molecular changes that may occur in the animal reproductive system and other body systems. The present study aimed to explore the functional status of steroidogenic Leydig cells of the testicular interstitial tissue in immunocastrated Polish Landrace pigs. Analyses were performed using Western blot, immunohistochemistry for relaxin (RLN), insulin-like 3 protein (INSL3), pelleted growth factor receptor α (PDGFRα), cytochrome P450scc, 3β- and 17β-hydroxysteroid dehydrogenases (3β-HSD, 17β-HSD), cytochrome P450arom, and 5α-reductase (5α-RED). Immunoassay ELISA was used to measure the androstenone, testosterone, and estradiol levels in the testis and serum of immunocastrates. We revealed disturbances in the distribution and expression of (i) RLN, indicating an inflammatory reaction in the interstitial tissue; (ii) INSL3 and PDGFRα, indicating alterations in the differentiation and function of fetal, perinatal, or adult Leydig cell populations; (iii) P450scc, 3β-HSD, 17β-HSD, P450arom, and 5α-RED, indicating disturbances in the sex steroid hormone production and disturbed functional status of Leydig cells; as well as (iv) decreased levels of androstenone, testosterone, and estradiol in testicular tissue and serum, indicating the dedicated action of Improvac to reduce boar taint at both the hypothalamic–hypophysis–gonadal axis and local level (Leydig cells). In summary, our study provides a significant portion of knowledge on the function of Leydig cells after immunocastration, which is also important for the diagnosis and therapy of testis dysfunction due to GnRH action failure and/or Leydig cell differentiational–functional alterations. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate uterine lesions, uterine endocrine status and expression of genes involved in uterine differentiation in a rat model of polycystic ovary syndrome (PCOS). The possible involvement of the androgen receptor (AR) was also investigated. PCOS rats showed an increased incidence of uterine epithelial and glandular lesions and elevated serum testosterone level, which was not detected in uterine tissue. Uterine 17β-estradiol, estrone and progesterone were detected in 100%, 75% and 50% of the animals, respectively. This was associated with a decrease in Star and an increase in Hsd17b2 , Srd5a1 and Cyp19a1 , suggesting that uterine steroids are not synthesized de novo in PCOS and that alterations in these enzymes may explain the absence of testosterone and low progesterone. In addition, ESR2 decreased and AR increased, suggesting possible steroid receptor crosstalk. Genes associated with uterine differentiation, PTEN and WNT5a, also showed reduced expression. PCOS rats treated with flutamide, an AR antagonist, were similar to PCOS rats in terms of uterine lesions, serum steroid levels, ESR2, PTEN and WNT5a expression. However, testosterone, AR and aromatase levels were similar to control rats, with decreased expression of ESR1 and HOXA10, suggesting that these expressions are AR dependent. Our results suggest that the primary cause of the observed uterine lesions in the PCOS rat model is the altered endocrine status and consequently changes in genes related to uterine differentiation. • PCOS increases the incidence of uterine epithelial and glandular lesions. • PCOS induces uterine steroid metabolism alterations. • In the uterus, AR and aromatase expression are AR-dependent and an ESR2-ESR1-AR crosstalk is suggested. • In PCOS rats, altered PTEN and WNT5a expression is associated with uterine differentiation changes. [ABSTRACT FROM AUTHOR]

In the early stage of androgen‐sensitive prostate cancer, cancer cells require androgens to grow. Hormone therapy that lowers androgen output or blocks androgen receptor can suppress the growth of this type of prostate cancer. Rutin, a flavonoid derivative of many plants, has numerous pharmacological effects. The objective of this study was to investigate the effect of rutin on androgen biosynthesis in Leydig cells isolated from the testes of pubertal rats. Immature Leydig cells isolated from 35 days‐old male Sprague‐Dawley rats were cultured in vitro with 0.5–50 μM rutin for 3 hr. Rutin significantly inhibited androgen secretion at 0.5, 5 and 50 μM under basal condition (medium only). At 50 μM, rutin also markedly compromised androgen secretion stimulated by 10 ng/ml luteinising hormone and 10 mM 8‐bromoadenosine 3', 5'‐cyclic monophosphate. Further analysis demonstrated that rutin compromised the transcript levels of Scarb1, Cyp11a1 and Hsd3b1 and their proteins expression. Rutin directly inhibited rat testicular CYP17A1, HSD17B3 and AKR1C14 activities at 50 μM. Rutin did not alter mitochondrial membrane potential at up to 50 μM. In conclusion, rutin suppresses androgen biosynthesis in Leydig cells through multiple mechanisms, thereby having benefits for the treatment of androgen‐sensitive prostate cancer. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective To analyze the morphological and functional characteristics of primary macronodular adrenal hyperplasia (PMAH) nodules carrying or not carrying ARMC5 mutations and the consequences of the presence of mutations in terms of the pattern of macronodule composition and functional state. Subjects and methods The analyses were performed by hematoxylin-eosin staining, immunohistochemistry, microdissection of spongiocyte tissue and RT-qPCR of histological sections from 16 patients diagnosed with PMAH with germline (5) or germline/somatic mutations (5) and without mutations (6) in the ARMC5 gene. Results Hyperplastic nodules were predominantly composed of spongiocytes in mutated and nonmutated sections. ARMC5 mRNA expression in spongiocytes was higher in ARMC5-mutated nodules than in ARMC5-nonmutated nodules, and homogenous ARMC5 protein distribution was observed. The presence of arginine-vasopressin receptor (AVP1AR) and ectopic ACTH production were observed in both cell populations regardless of ARMC5 mutations; the numbers of serotonin receptor (5HT4R)- and proliferating cell nuclear antigen (PCNA)-positive cells were higher in macronodules carrying ARMC5 mutations than in those without mutations. Conclusions Our results suggest that the presence of ARMC5 mutations does not interfere with the pattern of distribution of spongiocytes and compact cells or with the presence of AVP1AR, gastric-inhibitory polypeptide receptor (GIPR) and ectopic ACTH. Nevertheless, the higher numbers of PCNA-positive cells in mutated nodules than in nonmutated nodules suggest that mutated ARMC5 can be related to higher proliferation rates in these cells. In conclusion, our results provide more information about the crosstalk among abnormal GPCRs, ectopic ACTH in steroidogenesis and the ARMC5 gene, which may be relevant in understanding the pathogenesis and diagnosis of patients with PMAH.

Glioblastoma (GB) is the most common and aggressive primary brain tumour in adult humans. Therapeutic resistance and tumour recurrence after surgical removal contribute to poor prognosis for glioblastoma patients. Men are known to be more likely than women to develop an aggressive form of GB, and differences in sex steroids have emerged as a leading explanation for this finding. Studies indicate that the metabolism and proliferation of GB‐derived cells are increased by sex steroids, the expression of androgen receptors (ARs) and the synthesis of androgens and oestrogens, suggesting that these hormones have a role in the tumour pathogenesis. The expression of aromatase, the enzyme that converts androgens to oestrogens, has been reported in glial cells and GB cell lines. Thus, it was necessary to test whether the steroidogenic enzymes involved in androgen synthesis are expressed in GB cells. Therefore, here, we investigated the expression of four key enzymes involved in androgen synthesis in human‐derived GB cells. U87 cells were cultured in Dulbecco's modified Eagle medium plus foetal bovine serum and antibiotics on slides for immunocytochemistry or immunofluorescence. U87, LN229 and C6 cells were also cultured in multi‐well chambers to obtain proteins for Western blotting. We used primary antibodies against 3β‐hydroxysteroid dehydrogenase (3β‐HSD), 17α‐hydroxilase/17,20‐lyase (P450c17), 17β‐hydroxysteroid dehydrogenase (17β‐HSD) and 5α‐reductase. Immunocytochemistry, and immunofluorescence results revealed that glioblastoma cells express 3β‐HSD, P450c17, 17β‐HSD and 5α‐reductase proteins in their cytoplasm. Moreover, Western blot analyses revealed bands corresponding to the molecular weight of these four enzymes in the three GB cell lines. Thus, glioblastoma cells have the key enzymatic machinery necessary to synthesize androgens, and these enzymes might be useful targets for new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Castration-resistant prostate cancer (CRPC) is defined by resistance of the tumor to androgen deprivation therapy (ADT). Several molecular changes, particularly in the AR signaling cascade, have been described that may explain ADT resistance. The variety of changes may also explain why the response to novel therapies varies between patients. Testing the specific molecular changes may be a major step towards personalized treatment of CRPC patients. The aim of our study was to evaluate the molecular changes in the AR signaling cascade in CRPC patients. We have developed and validated several methods which are easy to use, and require little tissue material, for exploring AR signaling pathway changes simultaneously. We found that the AR signaling pathway is still active in the majority of our CRPC patients, due to molecular changes in AR signaling components. There was heterogeneity in the molecular changes observed, but we could classify the patients into 4 major subgroups which are: AR mutation, AR amplification, active intratumoral steroidogenesis, and combination of AR amplification and active intratumoral steroidogenesis. We suggest characterizing the AR signaling pathway in CRPC patients before beginning any new treatment, and a recent fresh tissue sample from the prostate or a metastatic site should be obtained for the purpose of this characterization. [ABSTRACT FROM AUTHOR]

Abstract Glioblastoma (GB) is the most common and aggressive primary brain tumour in adult humans. Therapeutic resistance and tumour recurrence after surgical removal contribute to poor prognosis for glioblastoma patients. Men are known to be more likely than women to develop an aggressive form of GB, and differences in sex steroids have emerged as a leading explanation for this finding. Studies indicate that the metabolism and proliferation of GB‐derived cells are increased by sex steroids, the expression of androgen receptors (ARs) and the synthesis of androgens and oestrogens, suggesting that these hormones have a role in the tumour pathogenesis. The expression of aromatase, the enzyme that converts androgens to oestrogens, has been reported in glial cells and GB cell lines. Thus, it was necessary to test whether the steroidogenic enzymes involved in androgen synthesis are expressed in GB cells. Therefore, here, we investigated the expression of four key enzymes involved in androgen synthesis in human‐derived GB cells. U87 cells were cultured in Dulbecco's modified Eagle medium plus foetal bovine serum and antibiotics on slides for immunocytochemistry or immunofluorescence. U87, LN229 and C6 cells were also cultured in multi‐well chambers to obtain proteins for Western blotting. We used primary antibodies against 3β‐hydroxysteroid dehydrogenase (3β‐HSD), 17α‐hydroxilase/17,20‐lyase (P450c17), 17β‐hydroxysteroid dehydrogenase (17β‐HSD) and 5α‐reductase. Immunocytochemistry, and immunofluorescence results revealed that glioblastoma cells express 3β‐HSD, P450c17, 17β‐HSD and 5α‐reductase proteins in their cytoplasm. Moreover, Western blot analyses revealed bands corresponding to the molecular weight of these four enzymes in the three GB cell lines. Thus, glioblastoma cells have the key enzymatic machinery necessary to synthesize androgens, and these enzymes might be useful targets for new therapeutic approaches.

Castration-resistant prostate cancer (CRPC) is defined by resistance of the tumor to androgen deprivation therapy (ADT). Several molecular changes, particularly in the AR signaling cascade, have been described that may explain ADT resistance. The variety of changes may also explain why the response to novel therapies varies between patients. Testing the specific molecular changes may be a major step towards personalized treatment of CRPC patients. The aim of our study was to evaluate the molecular changes in the AR signaling cascade in CRPC patients. We have developed and validated several methods which are easy to use, and require little tissue material, for exploring AR signaling pathway changes simultaneously. We found that the AR signaling pathway is still active in the majority of our CRPC patients, due to molecular changes in AR signaling components. There was heterogeneity in the molecular changes observed, but we could classify the patients into 4 major subgroups which are: AR mutation, AR amplification, active intratumoral steroidogenesis, and combination of AR amplification and active intratumoral steroidogenesis. We suggest characterizing the AR signaling pathway in CRPC patients before beginning any new treatment, and a recent fresh tissue sample from the prostate or a metastatic site should be obtained for the purpose of this characterization.

Porker immunocastration against gonadoliberin (GnRH) secretion has been utilized since 2009; however, consumers are still skeptical of it. This is due to not having full information available on the problem of a boar taint, as well as a lack of research on morphological and molecular changes that may occur in the animal reproductive system and other body systems. The present study aimed to explore the functional status of steroidogenic Leydig cells of the testicular interstitial tissue in immunocastrated Polish Landrace pigs. Analyses were performed using Western blot, immunohistochemistry for relaxin (RLN), insulin-like 3 protein (INSL3), pelleted growth factor receptor α (PDGFRα), cytochrome P450scc, 3β- and 17β-hydroxysteroid dehydrogenases (3β-HSD, 17β-HSD), cytochrome P450arom, and 5α-reductase (5α-RED). Immunoassay ELISA was used to measure the androstenone, testosterone, and estradiol levels in the testis and serum of immunocastrates. We revealed disturbances in the distribution and expression of (i) RLN, indicating an inflammatory reaction in the interstitial tissue; (ii) INSL3 and PDGFRα, indicating alterations in the differentiation and function of fetal, perinatal, or adult Leydig cell populations; (iii) P450scc, 3β-HSD, 17β-HSD, P450arom, and 5α-RED, indicating disturbances in the sex steroid hormone production and disturbed functional status of Leydig cells; as well as (iv) decreased levels of androstenone, testosterone, and estradiol in testicular tissue and serum, indicating the dedicated action of Improvac to reduce boar taint at both the hypothalamic–hypophysis–gonadal axis and local level (Leydig cells). In summary, our study provides a significant portion of knowledge on the function of Leydig cells after immunocastration, which is also important for the diagnosis and therapy of testis dysfunction due to GnRH action failure and/or Leydig cell differentiational–functional alterations.

Objective: The impact of the anti-depressant therapy on gonadal function has been recognized and discussed over the years. However, data to supplement our understanding of the impact of arjunolic acid (AA) therapies in protecting against FXT-induced gonadal dysfunction is lacking clear scientific evidence. Hence, this study aimed to investigate the possible effect of AA on fluoxetine-induced altered testicular function in rats., Methods: After 14 days acclimatization, Thirty-six (36) adult male rats were randomly divided into 6 groups (n=6). Rats in groups 1 received normal saline (10mL/kg); groups 2 & 3 were given AA (1.0mg/kg body weight) and AA (2.0mg/kg body weight), respectively; whereas, rats in group 4 were given FXT (10mg/kg/p.o/day), and groups 5 & 6 were given a combination of FXT (10mg/kg) + AA (1.0mg/kg body weight); and FXT (10mg/kg) + AA (2.0mg/kg body weight), respectively., Results: The results shows that FXT significantly altered testicular steroidogenic enzymes (3ß-HSD and 17ß-HSD) and proton pump ATPase (Na+/K+ ATPase, Ca2+ ATPase and H+ ATPase) activities, as well as testicular architecture when compared with controls. More so, FXT caused oxido-inflammation and apoptosis, as evidence by increases in MDA, MPO, TNF-α, IL-1ß, Caspase 3 and p53. However, AA at a different dose significantly ameliorated the destructive impacts of FXT on steroidogenic enzymes, proton pump ATPase as well as increased Bcl-2, SOD, CAT, GSH and improved testicular architecture in rats., Conclusions: AA reverses fluoxetine-induced alterations in testicular steroidogenic enzymes and membrane-bound ionic pump through suppression of oxido-inflammatory stress and apoptosis.

Background: Paraquat (PQ) is a herbicide that is used globally in the agriculture sector to eradicate unwanted weeds, however it also induces significant damages in various organs of the body such as testes. Tectochrysin (TEC) is an important flavonoid that shows versatile therapeutic potentials. Currently, there is no established antidote to cure PQ-induced testicular toxicity., Objective: The present study was conducted to evaluate the ameliorative effects of TEC against PQ prompted testicular damage., Methods: Sprague-Dawley rats (n = 48) were used to conduct the trial. Rats were allocated in to 4 groups i.e., Control, PQ administrated group (5 mgkg -1 ), PQ + TEC co-administrated group (5 mgkg -1  + 2.5 mgkg -1 ) and TEC only administrated group (2.5 mgkg -1 ). The trial was conducted for 8 weeks. The activity of anti-oxidants and the levels of MDA and ROS were determined by spectrophotometric method. Steroidogenic enzymes as well as apoptotic markers expressions were evaluated by qRT-PCR. The level of hormones and inflammatory indices was quantified by enzyme-linked immunosorbent assay., Results: PQ exposure markedly (P < 0.05) disturbed the biochemical, spermatogenic and histological profile in the rats. Nevertheless, TEC treatment considerably (P < 0.05) increased CAT, GPx GSR and SOD activity, besides decreasing MDA and ROS contents. TEC administration also increased sperm viability, count and motility. 17β-HSD, 3β-HSD, StAR and Bcl-2 expressions were also increased following TEC administration. The supplementation of TEC substantially (P < 0.05) decreased Bax, Caspase-3 expression and the levels of inflammatory markers i.e., interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) activity. Additionally, the levels of plasma testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were increased following TEC supplementation. Furthermore, TEC supplementation considerably decreased sperm structural abnormalities and histomorphological damages of the testes. The mitigative role of TEC might be due to its anti-inflammatory, anti-apoptotic, androgenic and anti-oxidant potentials., Conclusion: Taken together, it is concluded that TEC can be used as a potential candidate to treat testicular toxicity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective Nandrolone decanoate (ND) is an anabolic-androgenic steroid frequently used for clinical treatment. However, the inappropriate use of ND results in the reduction of serum testosterone level and sperm production. The suppressive effect of ND on testosterone production has not been investigated in detail. The present study was designed to examine the effect of ND on the expression of steroidogenic enzymes in the rat testis. Methods Male Sprague Dawley rats at 50 days of age were subcutaneously administrated with either 2 or 10 mg of ND/kg body weight/week for 2 or 12 weeks. The changes of transcript and protein levels of steroidogenic enzymes in the testis were determined by real-time polymerase chain reaction and western blotting analyses, respectively. Moreover, immunohistochemical analysis was employed to determine the changes of immunostaining intensity of these enzymes. The steroidogenic enzymes investigated were steroidogenic acute regulatory protein, cytochrome P450 side chain cleavage enzyme, 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and cytochrome P450 aromatase. Results The treatment of ND resulted in depletion of Leydig cells and sloughing of germ cells in the testis. The ND treatment caused significant expressional decreases of steroidogenic enzymes at transcript and protein levels, and the destructive effects of ND on the testis were more apparent with a higher dose and a longer period of the treatment. Evident reduction of immunostaining intensity present in Leydig cells was clearly detected by the ND treatment. Conclusion The exposure to ND in young male results not only in histological changes of the testis but also in aberrant gene expression of testicular steroidogenic enzymes, consequently leading into the reduction of testosterone production in the testis and thus likely disruption of spermatogenesis.

In recent years, the impact of ultrafine nanomaterials on the aquatic organisms and their ecosystems contributed much concern due to their abundance in environment. Several toxicity studies have reported that nanoparticles induced reproductive stress and resulted in reproductive impairment of fishes. The present study was aimed to investigate the stress-induced toxicity of C60 fullerene nanomaterial on various reproductive parameters of the freshwater fish, Anabas testudineus. Fish were exposed to two sublethal concentrations of fullerene C60, one-tenth (5 mg/L) and one-fifth (10 mg/L) of LC50–96 h, for 4, 7, 15, 30, and 60-day durations. At the end of exposure period, the activities of steroidogenic enzymes, 3β-, and 17β-hydroxysteroid dehydrogenase decreased in the testis and ovary thereby indicated that the nanomaterial affected gonadal steroidogenesis. The level of serum testosterone decreased significantly (p < 0.05) in male whereas the level of estradiol showed significant (p < 0.05) reduction in female fish with significant (p < 0.05) increase in the level of serum cortisol in both sexes in concentration- and time-dependent manner. The analysis of the levels of alkali-labile phosphates, plasma calcium, and total protein showed significant (p < 0.05) reduction in female fish without significant changes in male fish, and this could be due to the antiestrogenic action of fullerene C60 nanomaterial. The activity of aromatase enzyme decreased significantly (p < 0.05) in the ovary and brain of female fish, and the decline in the enzyme activity was prominent only in the brain tissue of male fish. The present results suggested that the stress-induced by fullerene C60 exposure provoked reproductive toxicity in the fish, Anabas testudineus. [ABSTRACT FROM AUTHOR]

Orexin A (OXA) is primarily known for its involvement in the regulation of feeding behaviour, energy metabolism and sleep/wake cycle. Nevertheless, studies indicate its engagement in the regulation of the porcine reproductive system. Therefore, the aim of this study was to investigate OXA effect (1, 10, 100 nM), in the presence or absence of the selective orexin receptor type 1 antagonist (SB-3348667; 1 μM), on the gene expression of key steroidogenic enzymes: steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage enzyme (CYP11A1) and 3β-hydroxysteroid dehydrogenase (HSD3B1), as well as on progesterone (P 4) and androstenedione (A 4) secretion. Endometrial and myometrial tissue explants were collected from gilts on days 10 to 11, 12 to 13, 15 to 16 and 27 to 28 of pregnancy, and on days 10 to 11 of the oestrous cycle (n = 5 per studied period of pregnancy or mid-luteal phase of the oestrous cycle). Gene expression was evaluated by real-time PCR. The level of steroid hormones secreted into the culture medium was examined by radioimmunoassay (RIA). In the present study, in the endometrium, OXA significantly stimulated StAR expression on days 12 to 13, CYP11A1 expression on days 27 to 28 and HSD3B1 expression on days 15 to 16 of pregnancy. Further, in this tissue, OXA decreased StAR mRNA level on days 10 to 11, CYP11A1 mRNA level on days 15 to 16, as well as HSD3B1 mRNA level on days 10 to 11 and 12 to 13 of gestation. Regarding the myometrium, OXA stimulated CYP11A1 gene expression on days 15 to 16 of pregnancy. In this tissue, OXA decreased StAR transcript content on days 15 to 16 and CYP11A1 mRNA level on days 27 to 28. We also demonstrated that OXA alone enhanced P 4 secretion in the endometrium on days 10 to 11 and 12 to 13 of gestation. OXA alone has no significant effect on endometrial and myometrial A 4 secretion, whereas OXA in combination with OX1R antagonist increased this hormone secretion during all studied stages of pregnancy. Therefore, we can conclude that OXA may affect de novo synthesis and secretion of P 4 and A 4 in the porcine uterus via participating in the regulation of key steroidogenic enzymes gene expression, as well as modulating steroid hormones secretion during early pregnancy and mid-luteal phase of the oestrous cycle in pigs. However, further research is required to explain the exact role of OXA in the porcine uterus. • OXA may affect gene expression of steroidogenic enzymes in the porcine uterus. • OXA may affect steroid hormones secretion in the porcine uterus. • OXA is one of the factors capable of modifying the uterine steroidogenesis in pigs. [ABSTRACT FROM AUTHOR]

This study examined the effects of pinealectomy in Wistar rats and melatonin replacement therapy on the daily mRNA expression of melatonin (Tph1, Aanat, Asmt, Mt1, Mt2, and Rorα), and steroidogenic (Star, 17βhsd3, and Lhr) related genes as well as clock genes (Rev-erbα, Bmal1, Per1, Per2, Cry1, and Cry2) in testes. The testes of control animals express the Tph1, Aanat, and Asmt and Per2 genes with 24-h rhythms in mRNA, reaching the maximal values during the dark phase. Pinealectomy abolished and melatonin treatment restored the 24-h rhythmicity. Daytime differences in mRNA expression were significant for Star, Lhr, Mt1, Mt2, Rorα, Rev-erbα, Bmal1, Cry1, and Cry2 genes in testes of control rats. Conversely, 17βhsd3 and Per1 mRNA expression did not show a daytime difference in testes of control animals. Pinealectomy abolished the peak time of Mt1 and Mt2 mRNA expression, phase shifted the peak time of Star, Rorα, Rev-erbα, Bmal1, and Cry2 mRNA expression, downregulated the 24-h Lhr mRNA expression, and inverted the peak time of Per1, Per2, and Cry1 mRNA expression to the light phase. The melatonin replacement therapy completely restored the control levels of Lhr, Rev-erbα, and Per1 mRNA expression patterns, partially restored the daily control of Star, Mt2, Rorα, Bmal1, Cry1, and Cry2 mRNA expression but did not re-establish the daily control of Mt1 mRNA expression. This suggests that the daily mRNA expression of these genes is probably driven by pineal melatonin and melatonin treatment restores (partially or completely) the daily control of gene expression patterns. [ABSTRACT FROM AUTHOR]

Arbutin, a widely used skin lightening agent, has raised concerns regarding its potential side effects. In this study, we investigated the impact of arbutin on Leydig cell function using an in vitro model. We measured medium androgen levels, as well as the gene and protein expression related to Leydig cell steroidogenesis. Rat immature Leydig cells from age of 35 days were exposed to arbutin at concentrations ranging from 0.5 to 50 μM for a duration of 3 hrs. Following treatment, we observed a significant inhibition of androgen secretion by Leydig cells at both the 5 and 50 μM concentrations of arbutin. Furthermore, at a concentration of 50 μM, arbutin effectively blocked the stimulatory effects of luteinizing hormone (LH) and 8Br-cAMP on androgen secretion. Subsequent analysis revealed that arbutin downregulated the expression of crucial genes involved in androgen production, including Lhcgr , Hsd3b1 , Cyp17a1 , and Srd5a1. In silico computer program analysis predicted that arbutin exhibits good absorption, possesses a long elimination half-life, and may have other potential toxicity such as hepatoxicity. Taken together, our results demonstrate that arbutin negatively influences Leydig cell function and androgen production, potentially impacting male reproductive health. [Display omitted] Arbutin inhibits androgen biosynthesis of rat Leydig cells. Arbutin inhibits androgen metabolic cascade in rat Leydig cells. Arbutin downregulates Lhcgr, Hsd3b1, Cyp17a1, Srd5a1 expression in Leydig cells. Arbutin reduces Leydig cell protein levels in rat Leydig cells. [ABSTRACT FROM AUTHOR]

There is mounting evidence that vitamin D 3 regulates female reproductive function critically, while little is known about the function of seasonally variable vitamin D 3 in regulating ovarian steroidogenesis. This study examined the seasonal expressions of vitamin D receptor (VDR), vitamin D metabolic molecules (CYP2R1, CYP27B1, and CYP24A1), and steroidogenic enzymes (P450scc, 3β-HSD, P450c17, and P450arom) in the ovaries of the wild ground squirrels (Citellus dauricus Brandt) during the different breeding seasons. VDR, CYP2R1, CYP27B1, and CYP24A1 were shown to be localized in different types of ovarian cells in the wild ground squirrels during the breeding and non-breeding seasons. Meanwhile, the mRNA levels of VDR , CYP2R1 , CYP27B1 , CYP11A1 , HSD3B1 , CYP17A1 , and CYP19A1 in the ovaries were remarkably higher in the breeding season. Furthermore, RNA-seq data of ovaries revealed that 6036 genes were differentially expressed genes (DEGs); further analysis revealed that several DEGs known to be involved in ovarian steroidogenesis pathway and cellular response to vitamin D pathway were identified. In addition, during the breeding season, the concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and 17β-estradiol were greater in the serum of the wild female ground squirrels. This observation was positively correlated with seasonal changes in the concentration of 25(OH)D 3 , supporting the fact that the 25(OH)D 3 content in the ovaries was significantly higher in the breeding season. These findings suggested that seasonal changes in vitamin D 3 might regulate the ovarian steroidogenesis of the wild female ground squirrels. • Seasonal changes in morphology and histology were observed in the ovaries of the wild ground squirrels. • VDR, CYP2R1, CYP27B1, and CYP24A1 were expressed in the ovaries of the wild ground squirrels. • The 25(OH)D 3 content in the ovaries was significantly higher in the breeding season. • The role of vitamin D 3 in promoting ovarian steroidogenesis may be outside the hypothalamic-pituitary-gonadal (HPG) axis. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of daily consumption of bamboo shoots (BS) on the morphological features and functional status of the female reproductive system in adult with respect to thyroid.Methods: Adult female rats were divided into control and experimental groups of six each. Control group was given normal diet while experimental group was fed BS by 1/3rd replacement of 180 g of their food i.e. 60 g of BS containing 35 g of goitrogens of cyanogenic origin such that each rat likely consumed 6 mg/100 g of body weight per day for a period of 45 d. Morphological features like changes in body weight and organ weight were noted. Key steroidogenic enzyme levels viz Δ5 3 β hydroxysteroid dehydrogenase (HSD) and 17 β HSD along with serum estradiol, estriol and progesterone levels were measured. Estrous cyclicity of the animals monitored regularly followed by histological analysis of thyroid, ovary and uterus at the end of experimentation.Results: Increase in body weight, thyroid gland weight and thyroid stimulating hormone, decrease in serum triiodothyronine and thyroxine, a decrease in ovarian as well as uterine weight and the activity of steroidogenic enzymes Δ5 3 β HSD and β 17 β HSD along with diminished serum estradiol, estriol and progesterone levels were noted; while histological plates showed prominent degenerative changes in both the ovary and uterus. Estrous cyclicity of the treated animals were irregular and almost stopped at diestrous stage of the cycle in the latter stage of the treatment as compared to control.Conclusions: Overall results indicates that BS rich in cyanogenic constituents induces biochemical hypothyroidism in the experimental animals that acts in corroboration to cause morphological and functional alteration of reproductive organs indicating its likely impact in fertility on continued use.

The etiology of cystic ovarian follicles (COF) remains a conundrum with steroidogenic, immunological, and metabolic dysfunctions linked to its development. Studies suggest that COF development may occur as a result of disruption of the insulin signaling pathway and the severity of a negative energy balance in dairy cows, but mid to late lactation cows diagnosed with COF are unlikely to have issues with energy metabolism. Herein, we characterized the mRNA expression of steroidogenic (LHCGR, StAR, CYP11A1, 3β-HSD, CYP19A), immunological (IL-1β, IL-6, IL-8, TLR-4, TNF), and metabolic markers (IGF-1, IRS1) in follicular fluid; and plasma and follicular fluid levels of E2, IL-1β, glucose, and NEFA in early and mid-late lactation COF cows. Lactating dairy cows were diagnosed as having COF (n = 11, follicle >20 mm persistent for 7 days, absence of corpus luteum, and flaccid uterus) while 11 herdmates cycling with a dominant follicle were classified as the control cows. Cows diagnosed with COF were classified as early lactation (COF-E, n = 5) cows,

Morphine is an analgesic in the opiate family, isolated from many plants. It can inhibit androgen biosynthesis by Leydig cells. Whether morphine directly inhibits androgen biosynthesis and underlying mechanism remains unclear. To investigate the influence of morphine on androgen secretion by rat immature Leydig cells (ILCs) and possible mechanism. Rat ILCs were treated with 0.5-50 μM morphine for 3 h in vitro. Morphine at ≥0.5 μM significantly reduced total androgen secretion. Morphine at 50 μM also compromised luteinizing hormone (LH, 10 mg/kg), 8Br-cAMP (1 mM), and 22R-hydroxycholesterol (20 μM) stimulated total androgen, androstanediol, and testosterone secretion, without affecting pregnenolone, progesterone, androstenedione mediated androgen secretion and testosterone and dihydrotestosterone mediated androstanediol secretion. Further analysis revealed that morphine at ≥0.5 μM downregulated Star expression and at ≥5 μM downregulated Cyp11a1 expression. Morphine also significantly reduced STAR (≥0.5 μM) and reduced CYP11A1 (≥5 μM) levels. 0.5 μM naloxone significantly antagonized morphine-mediated action. In conclusion, morphine might cause side effects by suppressing androgen biosynthesis via u opioid receptor., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The epididymal fat is a type of gonadal adipose tissue, which is localized closely to the testis. Even though it has been suggested that the epididymal fat is necessary for maintenance of spermatogenesis in the testis, the influence of epididymal fat on expression of testicular steroidogenic enzymes has not been examined. In the present research, expressional changes of steroidogenic enzymes in the mouse testis after 2 weeks of the surgical partial lipectomy of epididymal fat at different postnatal ages were determined by real-time polymerase chain reaction analysis. The transcript levels of all molecules at 2 months of postnatal age were significantly increased by the lipectomy of epididymal fat. However, the lipectomy at 5 months of postnatal age resulted in decreases of expression levels of all molecules examined in the testis. Except a reduced transcript level of hydroxysteroid 17-beta dehydrogenase 3, there were no significant changes of expression levels of other steroidogenic enzymes by the lipectomy at 8 months of postnatal age. At 12 months of postnatal age, the lipectomy caused a significant increase of transcript level of steroidogenic acute regulatory protein and a significant decrease of transcript level of hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1, without any expressional change of cytochrome P450 side chain cleavage, hydroxysteroid 17-beta dehydrogenase 3, and hydroxysteroid 17-beta dehydrogenase 3 in the testis. These findings suggest that the substances derived from epididymal fat could differentially influence on expression of steroidogenic enzymes in the testis during postnatal period., Competing Interests: The authors declare no potential conflict of interest., (© Copyright 2023 The Korean Society of Developmental Biology.)

The purpose of this study is to evaluate the amphetamine effects on progesterone and estradiol production in rat granulosa cells and the underlying cellular regulatory mechanisms. Freshly dispersed rat granulosa cells were cultured with various test drugs in the presence of amphetamine, and the estradiol/progesterone production and the cytosolic cAMP level were measured. Additionally, the cytosolic-free Ca2+ concentrations ([Ca2+]i) were measured to examine the role of Ca2+ influx in the presence of amphetamine. Amphetamine in vitro inhibited both basal and porcine follicle-stimulating hormone-stimulated estradiol/progesterone release, and amphetamine significantly decreased steroidogenic enzyme activities. Adding 8-Bromo-cAMP did not recover the inhibitory effects of amphetamine on progesterone and estradiol release. H89 significantly decreased progesterone and estradiol basal release but failed to enhance a further amphetamine inhibitory effect. Amphetamine was capable of further suppressing the release of estradiol release under the presence of nifedipine. Pretreatment with the amphetamine for 2 h decreased the basal [Ca2+]i and prostaglandin F2α-stimulated increase of [Ca2+]i. Amphetamine inhibits progesterone and estradiol secretion in rat granulosa cells through a mechanism involving decreased PKA-downstream steroidogenic enzyme activity and L-type Ca2+ channels. Our current findings show that it is necessary to study the possibility of amphetamine perturbing reproduction in females.

Objectives: This study was designed to assess the role of caffeine on fertility parameters in testicular and epididymal tissues of scopolamine‐induced model of amnesia in rats. Methods: Adult male rats were treated with scopolamine with or without caffeine. The modulatory effects of caffeine or scopolamine on fertility parameters were assessed in rats' testicular and epididymal homogenates. Key findings: Scopolamine‐induced sperm abnormalities, reduced steroidogenic enzyme 3β‐Hydroxysteroid dehydrogenase (3β‐HSD) and 17β‐Hydroxysteroid dehydrogenase (17β‐HSD) activities and serum testosterone levels in rats' testicular tissues. Treatment with caffeine increased 3β‐HSD and 17β‐HSD as well as testosterone levels. Caffeine also reversed sperm viability, sperm motility and sperm count in testicular tissues of scopolamine‐treated rats. Furthermore, scopolamine‐induced oxidative damage in rats' epididymal and testicular tissues via reduction of thiol and non‐protein thiol content as well as increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Caffeine attenuated oxidative stress in testicular and epididymal tissues of rats treated with scopolamine via increase in non‐protein and protein thiol levels with concomitant reduction in ROS and MDA levels. Conclusion: This study revealed that caffeine (5 and 25 mg/kg) improved sperm quality, increased steroidogenic enzyme activities and attenuated oxidative damage in testis and epididymis of rats treated with scopolamine. [ABSTRACT FROM AUTHOR]

The quail Coturnix coturnix is a seasonal breeder with a physiological switch on/off of gonadic activity. Photoperiod and temperature are the major environmental factors regulating the spermatogenesis. To more thoroughly comprehend the steroidogenic pathways that govern the seasonal reproductive cycle, we have investigated the localization of StAR protein and steroidogenic enzymes (3β‐HSD, 17β‐HSD, P450 aromatase, and 5α‐Red) as well as androgen and estrogen levels, in the testis of reproductive and nonreproductive quails. We demonstrated that StAR, 3β‐HSD, 17β‐HSD, P450 aromatase, and 5α‐Red were always present in the somatic (Leydig and Sertoli cells) and germ cells (spermatogonia, spermatocytes I and II, spermatids, and spermatozoa). In addition, by western blot analysis, we demonstrated that 17β‐HSD, P450 aromatase, and 5α‐Red showed the highest expression levels during the reproductive testis compared with nonreproductive one. Accordingly, we also found that during the reproductive phase the highest titres of testosterone, 17β‐estradiol, and 5α‐dihydrotestosterone are recorded. In conclusion, our findings demonstrated that in C. coturnix: (a) both somatic and germ cells are involved in the local synthesis of sex hormones; (b) 17β‐HSD, P450 aromatase, and 5α‐Red expressions, as well as testicular androgens and estrogens, increased in reproductive quail testis. This study strongly indicates that the steroidogenic process in quail testis exhibits seasonal changes with the promotion of both androgenic and estrogenic pathways in the reproductive period, suggesting their synergic mechanism in the spermatogenesis regulation. Research Highlights: In the quail, StAR and steroidogenic enzymes are always present in the somatic and germ cells.The steroidogenic process in quail testis exhibits seasonal changes.Androgenic and estrogenic pathways are promoted in the reproductive period. [ABSTRACT FROM AUTHOR]

Per - and polyfluoroalkyl substances (PFASs) are widely used in China, but little is known about the association between prenatal PFASs exposure and fetal reproductive development as well as its potential mechanism. We investigated the effects of cord blood PFASs on fetal reproductive hormones and its potential mechanism in relation to steroidogenic enzymes. Ten selected PFASs (n = 351) including PFOS, PFOA, PFBS, PFDA, PFDoA, PFHpA, PFHxS, PFNA, PFOSA, and PFUA, and two reproductive hormones estradiol (E2) (n = 351) and testosterone (T) (n = 349) were measured in 351 cord blood serum samples from a Chinese birth cohort between 2010 and 2013. Three steroidogenic enzymes including P450arom (n = 125), 3β-HSD1 (n = 123), and 17β-HSD1 (n = 116) were measured in 125 placental tissue samples. Linear regression tested the associations between cord blood PFASs and reproductive hormones in cord blood. Mediation analysis assessed the role of placental steroidogenic enzymes between cord blood PFASs and reproductive hormones. The positive associations between PFOA, PFHxS and E2 levels, PFOS, PFUA, PFNA and T levels, and PFOS, PFUA and T/E2 ratio were significant. PFUA, PFNA, PFDA, PFHxS, and ∑PFASs were associated with higher P450arom levels. PFHxS was also associated with increased 3β-HSD1 and 17β-HSD1 levels. These associations were more pronounced in females than males when stratified by gender. Furthermore, 17β-HSD1 demonstrated mediating effects in the positive association between cord blood PFHxS and E2 levels in females. Our findings suggested the potential impacts of cord blood PFASs on fetal reproductive hormones, in which steroidogenic enzymes may play important roles. These associations were more pronounced in females than males. • Per - and polyfluoroalkyl Substances (PFASs) are widely used in China. • We examined the link of PFASs with reproductive hormones and potential mechanisms. • PFASs were positively associated with E2, T, and T/E2 ratio. • PFASs were positively associated with P450arom, 3β-HSD1, and 17β-HSD1. • PFHxS induced 17β-HSD1 that may lead to increased E2 particularly in females. [ABSTRACT FROM AUTHOR]

Cytochrome P450 17A1 (CYP17A1; EC: 1.14.14.19) is a critically important bifunctional enzyme with nicotinamide adenine dinucleotide phosphate (NADPH) as its cofactor that catalyzes the formation of all endogenous androgens. Its hydroxylase activity catalyzes the 17α-hydroxylation of pregnenolone (PREG)/progesterone (P4) to 17α-OH-pregnenolone/17α-OH-progesterone, and its 17,20-lyase activity converts 17α-OH-pregnenolone/17α-OH-progesterone to dehydroepiandrosterone/androstenedione. Androgens are required for male reproductive development, so androgen deficiency resulting from CYP17A1 inhibition may lead to reproductive disorders. There has been some advances on the study of environmental chemicals inhibiting mammalian CYP17A1 expression but no related review was available so we think it now necessary to review their characteristics and inhibiting properties. [ABSTRACT FROM AUTHOR]

During the past 25 years, the modulation of estrogen action by inhibition of 17β-hydroxysteroid dehydrogenase types 1 and 2 (17β-HSD1 and 17β-HSD2), respectively, has been pursued intensively. In the search for novel treatment options for estrogen-dependent diseases (EDD) and in order to explore estrogenic signaling pathways, a large number of steroidal and nonsteroidal inhibitors of these enzymes has been described in the literature. The present review gives a survey on the development of inhibitor classes as well as the structural formulas and biological properties of their most interesting representatives. In addition, rationally designed dual inhibitors of both 17β-HSD1 and steroid sulfatase (STS) as well as the first inhibitors of 17β-HSD14 are covered. • 17β-HSD1 and 2 inhibitor structures and their biological activities are reviewed. • Emerging dual 17β-HSD1/STS inhibitors and inhibitors of 17β-HSD14 are covered. • The status of inhibitor development and future perspectives are shortly discussed. [ABSTRACT FROM AUTHOR]

Glucocorticoids impair testosterone synthesis by an unknown mechanism. Stallions treated with the synthetic glucocorticoid dexamethasone had testes collected at 6 or 12 hours postinjection. The testicular expression of selected genes encoding nuclear receptors and steroidogenic enzymes was measured. At 6 hours, dexamethasone treatment decreased levels of NR0B2, NR4A1, NR5A1, and NR5A2 messenger RNAs (mRNAs) and NR5A2 mRNA levels remained depressed at 12 hours. In contrast, dexamethasone increased levels of NFKBIA mRNA at both time points. At 6 hours, dexamethasone did not alter levels of NR0B1, NR2F1, NR2F2, NR3C1, CYP11A1, CYP17A1, CYP19A1, DHCR24, GSTA3, HSD3B2, HSD17B3, LHCGR, or STAR mRNAs. In primary cultures of Leydig cells, 10-9 and 10-7M dexamethasone decreased levels of NR4A1 and NR5A1 mRNAs and increased those of NFKBIA mRNA. Our discovery that dexamethasone downregulates NR4A1, NR5A1, and NR5A2 genes, known to be important for testicular functions, may be part of the mechanism by which glucocorticoids acutely decreases testosterone. [ABSTRACT FROM AUTHOR]

Abstract Testicular dysgenesis syndrome includes the hypospadias, cryptorchidism and abnormal fetal testis in male neonate. This is possibly caused by the environmental phthalates, which down-regulate the expression of androgen synthetic genes and Insl3 or directly inhibits steroidogenic enzymes. There are distinct structure-activity relationships (SARs) for phthalate-mediated developmental and reproductive toxicity. Here, we review the SAR for phthalate-mediated testicular dysgenesis syndrome. Of phthalates of straight side chains, C5-C6 ones are the most potent, C4 or C7 are moderate, C3 is weakest, and C1-2 or C8-13 are ineffective. The branching and unsaturation of side chains increases the toxicity. The cycling of side chains does not increase the toxicity. Highlights • There is a SAR difference for phthalate-mediated TDS. • Potency relates to carbon length and branching of ester chain. • C4-C5 straight-chain phthalates are potent disruptors. • C1-2 and C8-C13 straight-chain phthalates are ineffective. • TDS is associated with reduced androgen and INSL3. [ABSTRACT FROM AUTHOR]

Pregnancy is associated with physiological adjustments in order to allow adequate growth and fetal development. In particular, steroids are necessary to maintain in balance numerous functions during gestation. Steroidogenesis in the maternal, placental and fetal compartments and the biological effects of progestins and estrogens that play a pivotal role before and during pregnancy are described. Although it is well-known that androgens are considered as substrate for estrogens biosynthesis, their biosynthesis and functionality in placental and other tissues have been questioned. As compared with healthy pregnancy, steroid hormones levels have been found altered in complicated pregnancies and hormonal treatments have been used is some pathologies. Therefore, the aim of this work was to review the biosynthesis, function and regulation of progestins, androgens and estrogens during gestation. Furthermore, steroid hormones concentrations during healthy and complicated pregnancy as well hormonal therapies for the prevention of miscarriages and preterm deliveries are discussed in the present review. [ABSTRACT FROM AUTHOR]