Endogenous testosterone and mortality in male hemodialysis patients: is it the result of aging?
Gungor Ozkan,Kircelli Fatih,Carrero Juan Jesus,Asci Gulay,Toz Huseyin,Tatar Erhan,Hur Ender,Sever Mehmet Sukru,Arinsoy Turgay,Ok Ercan
Clinical journal of the American Society of Nephrology : CJASN
BACKGROUND AND OBJECTIVES:Low serum testosterone levels in hemodialysis (HD) patients have recently been associated with cardiovascular risk factors and increased mortality. To confirm this observation, we investigated the predictive role of serum total testosterone levels on mortality in a large group of male HD patients from Turkey. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS:A total of 420 prevalent male HD patients were sampled in March 2005 and followed up for all-cause mortality. Serum total testosterone levels were measured by ELISA at baseline and studied in relation to mortality and cardiovascular risk profile. RESULTS:Mean testosterone level was 8.69 ± 4.10 (0.17 to 27.40) nmol/L. A large proportion of patients (66%) had testosterone deficiency (<10 nmol/L). In univariate analysis, serum testosterone levels were positively correlated with creatinine and inversely correlated with age, body mass index, and lipid parameters. During an average follow-up of 32 months, 104 (24.8%) patients died. The overall survival rate was significantly lower in patients within the low testosterone tertile (<6.8 nmol/L) compared with those within the high tertile (>10.1 nmol/L; 64 versus 81%; P = 0.004). A 1-nmol/L increase in serum testosterone level was associated with a 7% decrease in overall mortality (hazard ratio 0.93; 95% confidence interval 0.89 to 0.98; P = 0.01); however, this association was dependent on age and other risk factors in adjusted Cox regression analyses. CONCLUSIONS:Testosterone deficiency is common in male HD patients. Although testosterone levels, per se, predicted mortality in this population, this association was largely dependent on age.
Anti-Müllerian hormone, a Sertoli cell-derived marker, is decreased in plasma of male patients in all stages of chronic kidney disease.
Eckersten D,Giwercman A,Bruun L,Christensson A
Male patients with terminal renal failure are often infertile and exhibit an abnormal sex hormone pattern in plasma. We studied patients in all chronic kidney disease (CKD) stages to determine plasma levels of anti-Müllerian hormone (AMH), a Sertoli cell-derived marker, and other sex hormones. Seventy-eight male patients with CKD stages 1-5 and a median age of 40 years (22-50 years), as well as 20 healthy controls with a median age of 37 years (26-44 years), were enrolled. The CKD patients were evenly distributed; 18 with CKD stages 1-2, 19 with CKD stage 3, 19 with CKD stage 4, and 22 with CKD stage 5. Cystatin C, follicle-stimulating hormone, luteinizing hormone, prolactin, sex hormone-binding globulin, testosterone, and AMH levels in plasma were analysed. AMH was analysed using the Ansh Labs UltraSensitive AMH assay. Several changes occurred in plasma levels of sex hormones in male patients with CKD. Plasma AMH levels were lower in CKD stages 1-4 by 30% (p = 0.041) and by 70% (p < 0.001) in CKD stage 5 compared with controls. Plasma luteinizing hormone and prolactin levels were higher and testosterone levels were lower compared with controls. The pathophysiological role of this reduction in AMH is unclear, but can be linked to altered Sertoli cell function.
The vulnerable man: impact of testosterone deficiency on the uraemic phenotype.
Carrero Juan Jesús,Stenvinkel Peter
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Testosterone deficiency or hypogonadism is a common finding in men undergoing dialysis, to a great extent a consequence of the failing kidney per se. Testosterone restoration in hypogonadism is common practice among endocrinologists. However, there is currently little awareness of this condition among both uremic patients and nephrologists, and in many cases, testosterone deficiency remains unscreened and untreated. This review article summarizes our current understanding of the role of testosterone deficiency at the crossroad of cardiometabolic complications of patients with chronic kidney disease. Pathways discussed include, among others, the plausible role of testosterone deficiency in the development of anaemia and ESA hyporesponsiveness, muscle catabolism, endothelial dysfunction, cognitive dysfunction, decreased libido, cardiovascular disease and mortality. As there are limited sources to guide decision-making, we also review existing testosterone replacement therapy studies in the context of CKD as well as considerations for side and adverse effects. This review makes a case for consideration of screening and better management of hypogonadism in men undergoing dialysis.
Changes in fertility and hormone replacement therapy in kidney disease.
Holley Jean L,Schmidt Rebecca J
Advances in chronic kidney disease
Infertility is common among men and women with CKD and fertility is usually restored with successful kidney transplantation. There are many causes of infertility in those on dialysis, including sexual dysfunction and impaired spermatogenesis and ovulation resulting from an altered hormonal milieu. There is little information about infertility in CKD, but it is clear that ESRD results in low rates of pregnancy in women. Early reports of increased pregnancy rates in women on nocturnal hemodialysis suggest that this modality may improve the abnormal reproductive hormonal milieu of ESRD; small studies of men on dialysis also suggest this. Just as the specific causes of infertility in men and women with CKD/ESRD are unknown, we also lack information about the appropriateness of hormone replacement in these patients. This paper reviews these linked issues, pointing out the lack of data upon which to base clinical decision-making about these quality-of-life issues in our CKD/ESRD patients.
Prevalence of subnormal testosterone concentrations in men with type 2 diabetes and chronic kidney disease.
Dhindsa Sandeep,Reddy Anand,Karam Jyotheen Sukhmoy,Bilkis Sayeeda,Chaurasia Archana,Mehta Aditya,Raja Keerthi P,Batra Manav,Dandona Paresh
European journal of endocrinology
BACKGROUND:One-third of men with type 2 diabetes have subnormal testosterone concentrations along with inappropriately normal LH and FSH concentrations. It is not known if the presence of renal insufficiency affects free testosterone concentrations in men with type 2 diabetes. HYPOTHESIS:We hypothesized that type 2 diabetic men with chronic renal disease (CKD; estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2)) have lower free testosterone concentrations than men with normal renal function (eGFR ≥ 60 ml/min per 1.73 m(2)). STUDY DESIGN AND SETTING:This is a retrospective chart review of patients attending diabetes and nephrology clinics. Men with type 2 diabetes who had the following information available were included in the study: testosterone (total and free) done by LC/MS-MS followed by equilibrium dialysis, sex hormone binding globulin, LH, FSH and prolactin concentrations. PARTICIPANTS:We present data on T and gonadotropin concentrations in 111 men with type 2 diabetes and CKD (stages 3-5) and 182 type 2 diabetic men without CKD. RESULTS:The prevalence of subnormal free testosterone concentrations was higher in men with type 2 diabetes and CKD as compared to those without CKD (66% vs 37%, P < 0.001). Men with CKD had a higher prevalence of hypergonadotropic hypogonadism (26% vs 5%, P < 0.001) but not of hypogonadotropic hypogonadism (HH; 40% vs 32%, P = 0.22). There was an increase in the prevalence of hypergonadotropic hypogonadism with decreasing eGFR. Fifty-two percent of men with renal failure (CKD stage 5) had hypergonadotropic hypogonadism and 25% had HH. In men with CKD, the hemoglobin concentrations were lower in those with subnormal free T concentrations as compared to men with normal free T concentrations (119 ± 19 vs 128 ± 19 g/l, P = 0.04). CONCLUSIONS:Two-thirds of men with type 2 diabetes and CKD have subnormal free T concentrations. The hypogonadism associated with CKD is predominantly hypergonadotropic.
A maternal low protein diet during pregnancy and lactation in the rat impairs male reproductive development.
Zambrano E,Rodríguez-González G L,Guzmán C,García-Becerra R,Boeck L,Díaz L,Menjivar M,Larrea F,Nathanielsz P W
The Journal of physiology
Nutrient restriction during pregnancy and lactation impairs growth and development. Recent studies demonstrate long-term programming of function of specific organ systems resulting from suboptimal environments during fetal life and development up to weaning. We determined effects of maternal protein restriction (50% control protein intake) during fetal development and/or lactation in rats on the reproductive system of male progeny. Rats were fed either a control 20% casein diet (C) or a restricted diet (R) of 10% casein during pregnancy. After delivery mothers received either C or R diet until weaning to provide four groups: CC, RR, CR and RC. We report findings in male offspring only. Maternal protein restriction increased maternal serum corticosterone, oestradiol and testosterone (T) concentrations at 19 days gestation. Pup birth weight was unchanged but ano-genital distance was increased by maternal protein restriction (P < 0.05). Testicular descent was delayed 4.4 days in RR, 2.1 days in CR and 2.2 days in RC and was not related to body weight. Body weight and testis weight were reduced in RR and CR groups at all ages with the exception of CR testis weight at 270 days postnatal age (PN). At 70 days PN luteinizing hormone and T concentrations were reduced in RR, CR and RC. mRNA for P450 side chain cleavage (P450scc) was reduced in RR and CR at 21 days PN but was unchanged at 70 days PN. Fertility rate was reduced at 270 days PN in RC and sperm count in RR and RC. We conclude that maternal protein delays sexual maturation in male rats and that some effects only emerge in later life.
Comparative morphophysiological evaluation of the testis of adult Wistar rats fed low protein-energy diet and dosed with aqueous extracts of Cuscuta australis.
Ozegbe P C,Omirinde J O
Nigerian journal of physiological sciences : official publication of the Physiological Society of Nigeria
Cuscuta australis (C. australis) seed and stem are historically used by the local population as dietary supplement for the management of infertility. This study, therefore, evaluated the effect of orally administered aqueous extracts of C. australis seed and stem, 300 mg/kg body weight/day for seven days, on the testis of the adult Wistar rat fed either low or normal protein-energy diets. The control group received water. The relative weight of the testis was non-significantly increased (p>0.05) in the Low Protein-energy diet-Water-treated (LPWA), Low Protein-energy diet-Seed-treated (LPSE) and Normal Protein-energy diet-Seed-treated (NPSE) groups relative to the Normal Protein-energy diet-Water-treated (NPWA). The weight of the testis was also non-significantly increased (p˃0.05) in the Low Protein-energy diet-Stem-treated (LPST), but decreased in the Normal Protein-energy diet-Stem-treated (NPST), relative to LPWA and NPWA. Heights of germinal epithelium were significantly decreased (p<0.05) in the LPWA, LPSE and LPST relative to the NPWA, NPSE and NPST. Diet significantly influenced (p<0.001) the effect of stem extract on the height of germinal epithelium. The NPSE, LPSE, NPST, LPST and LPWA showed significantly decreased (p<0.001) plasma levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) relative to NPWA. The LPWA, LPSE and NPST also showed significantly decreased (p<0.001) levels of testosterone relative to NPWA and LPST. Diet significantly influenced (p<0.001) the effect of seed on the level of LH. Seed-diet interactions significantly affected the levels of FSH (p<0.001) and LH (p<0.05), but not testosterone. Diet significantly influenced (p<0.001) the effects of stem extract on the levels of FSH, LH and testosterone. Stem-diet interactions significantly affected (p<0.001) the levels of FSH, LH and testosterone. Our data suggest that the aqueous extract of C. australis stem is more potent than the seed extract and that dietary protein-energy intake may influence the efficacy of orally administered aqueous extracts of C. australis.
Testosterone alters maternal vascular adaptations: role of the endothelial NO system.
Chinnathambi Vijayakumar,Balakrishnan Meena,Ramadoss Jayanth,Yallampalli Chandrasekhar,Sathishkumar Kunju
Hypertension (Dallas, Tex. : 1979)
Sex steroid hormones estradiol and progesterone play an important role in vascular adaptations during pregnancy. However, little is known about the role of androgens. Plasma testosterone (T) levels are elevated in preeclampsia, mothers with polycystic ovary, and pregnant African American women, who have endothelial dysfunction and develop gestational hypertension. We tested whether increased T alters vascular adaptations during pregnancy and whether these alterations depend on endothelium-derived factors, such as prostacyclin, endothelium-derived hyperpolarizing factor, and NO. Pregnant Sprague Dawley rats were injected with vehicle (n=12) or T propionate [0.5 mg/Kg per day from gestation day 15-19; n=12] to increase plasma T levels 2-fold, similar to that observed in preeclampsia. Telemetric blood pressures and endothelium-dependent vascular reactivity were assessed with wire-myograph system. Phospho-endothelial NO synthase and total endothelial NO synthase were examined in mesenteric arteries. Mean arterial pressures were significantly higher starting from gestation day19 until delivery in T-treated dams. Endothelium-dependent relaxation responses to acetylcholine were significantly lower in mesenteric arteries of T-treated dams (pD(2) [-log EC(50)]=7.05±0.06; E(max)=89.4±1.89) compared with controls (pD(2)=7.38±0.04; E(max)=99.9±0.97). Further assessment of endothelial factors showed NO-mediated relaxations were blunted in T-treated mesenteric arteries (E(max)=42.26±5.95) compared with controls (E(max)=76.49±5.06); however, prostacyclin- and endothelium-derived hyperpolarizing factor-mediated relaxations were unaffected. Relaxation to sodium nitroprusside was unaffected with T-treatment. Phosphorylations of endothelial NO synthase at Ser(1177) were decreased and at Thr(495) increased in T-treated mesenteric arteries without changes in total endothelial NO synthase levels. In conclusion, increased maternal T, at concentrations relevant to abnormal clinical conditions, cause hypertension associated with blunting of NO-mediated vasodilation. T may induce the increased vascular resistance associated with pregnancy-induced hypertension.
[Expression and role of nitric oxide synthase in the testis and epididymis of Macaca fascicularis].
Sun Li,Ren Ya-Ping,Jiang Wei,Zhang Mei-Yan,Hou Qiao-Yan
Zhonghua nan ke xue = National journal of andrology
OBJECTIVE:To investigate the expression and the role of nitric oxide synthase (NOS) in the testis and epididymis of macaca fascicularis. METHODS:The immunohistochemical ABC method was used to observe the localization of nitric oxide synthase in the testis and epididymis of the macaca fascicularis. RESULTS:(1) nNOS immunoreactivity was found in the spermatogenic cells of seminiferous tubules, the epithelia of epididymal efferent ducts, sperm and the endothelia of blood vessels; (2) iNOS was expressed in the epididymal efferent duct, the sperm inside the duct, and the myoid cells and endothelia of blood vessels; (3) eNOS immunoreactivity was detected in the interstitial cells of the testis, the epididymal efferent duct, the sperm inside the duct, and the myoid cells and endothelia of blood vessels. CONCLUSION:NOS is extensively expressed in the testis and epididymis of the macaca fascicularis and it may play an important role in such processes as spermatogenesis, sperm maturation and testosterone secretion.
Chronic depletion of gonadal testosterone leads to blood-brain barrier dysfunction and inflammation in male mice.
Atallah Afnan,Mhaouty-Kodja Sakina,Grange-Messent Valérie
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
A dysfunction in the blood-brain barrier (BBB) is associated with many neurological and metabolic disorders. Although sex steroid hormones have been shown to impact vascular tone, endothelial function, oxidative stress, and inflammatory responses, there are still no data on the role of testosterone in the regulation of BBB structure and function. In this context, we investigated the effects of gonadal testosterone depletion on the integrity of capillary BBB and the surrounding parenchyma in male mice. Our results show increased BBB permeability for different tracers and endogenous immunoglobulins in chronically testosterone-depleted male mice. These results were associated with disorganization of tight junction structures shown by electron tomography and a lower amount of tight junction proteins such as claudin-5 and ZO-1. BBB leakage was also accompanied by activation of astrocytes and microglia, and up-regulation of inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin 1 beta (IL-1β), and tumor necrosis factor (TNF). Supplementation of castrated male mice with testosterone restored BBB selective permeability, tight junction integrity, and almost completely abrogated the inflammatory features. The present demonstration that testosterone transiently impacts cerebrovascular physiology in adult male mice should help gain new insights into neurological and metabolic diseases linked to hypogonadism in men of all ages.
Translational Perspective on the Role of Testosterone in Sexual Function and Dysfunction.
Podlasek Carol A,Mulhall John,Davies Kelvin,Wingard Christopher J,Hannan Johanna L,Bivalacqua Trinity J,Musicki Biljana,Khera Mohit,González-Cadavid Nestor F,Burnett Arthur L
The journal of sexual medicine
INTRODUCTION:The biological importance of testosterone is generally accepted by the medical community; however, controversy focuses on its relevance to sexual function and the sexual response, and our understanding of the extent of its role in this area is evolving. AIM:To provide scientific evidence examining the role of testosterone at the cellular and molecular levels as it pertains to normal erectile physiology and the development of erectile dysfunction and to assist in guiding successful therapeutic interventions for androgen-dependent sexual dysfunction. METHODS:In this White Paper, the Basic Science Committee of the Sexual Medicine Society of North America assessed the current basic science literature examining the role of testosterone in sexual function and dysfunction. RESULTS:Testosterone plays an important role in sexual function through multiple processes: physiologic (stimulates activity of nitric oxide synthase), developmental (establishes and maintains the structural and functional integrity of the penis), neural (development, maintenance, function, and plasticity of the cavernous nerve and pelvic ganglia), therapeutically for dysfunctional regulation (beneficial effect on aging, diabetes, and prostatectomy), and phosphodiesterase type 5 inhibition (testosterone supplement to counteract phosphodiesterase type 5 inhibitor resistance). CONCLUSION:Despite controversies concerning testosterone with regard to sexual function, basic science studies provide incontrovertible evidence for a significant role of testosterone in sexual function and suggest that properly administered testosterone therapy is potentially advantageous for treating male sexual dysfunction.
Testosterone-induced modulation of nitric oxide-cGMP signaling pathway and androgenesis in the rat Leydig cells.
Andric Silvana A,Janjic Marija M,Stojkov Natasa J,Kostic Tatjana S
Biology of reproduction
Testosterone, acting as a systemic and local factor, is one of the major regulatory molecules that initiate and maintain testicular function. In the present study, different experimental approaches were used to evaluate the role of testosterone in regulation of the nitric oxide (NO)-cGMP pathway in Leydig cells derived from normal and hypogonadotropic male rats treated with testosterone for 24 h and 2 wk. Real-time quantitative PCR and Western blot analysis revealed increased inducible NO synthase (NOS2) expression followed by increased NO secretion from Leydig cells ex vivo after continuous treatment with testosterone for 2 wk in vivo. The cGMP-specific phosphodiesterases Pde5, Pde6, and Pde9 were up-regulated, whereas PRKG1 protein was decreased after a 2-wk testosterone treatment. Induction of Nos2 and Pde5 in Leydig cells was blocked by androgen receptor antagonist. In experimental hypogonadotropic hypogonadism, expression of NOS2 was significantly reduced, and treatment with testosterone increased NOS2 expression above control levels. PDE5 protein level was unchanged in hypogonadal rats, whereas treatment of hypogonadal rats with testosterone significantly increased it. In contrast, hypogonadism and testosterone replacement reduced PRKG1 protein in Leydig cells. In vitro treatment with testosterone caused gradually increased Nos2 gene expression followed by increased nitrite and cGMP production by purified Leydig cells. In summary, testosterone up-regulated NO signaling via increased NOS2 expression and contributed to down-regulation of cGMP signaling in Leydig cells. Thus, testosterone-induced modulation of NO-cGMP signaling may serve as a potent autocrine regulator of testicular steroidogenesis.
[Nitric oxide and nitric oxide synthase related to male reproduction].
Ji Jiajia,Zhao Yanfang,Chen Guoyuan
Wei sheng yan jiu = Journal of hygiene research
Nitric oxide (NO) may be a kind of signal molecule which may have multiplicate physiological function such as secondary messenger, neurotransmitter and effect molecule. NO may play a crucial role in organism. The production of NO can not get away from nitric oxide synthase (NOS) which may distribute in almost all kind of organs of male reproductive system. NO and NOS may have the function of bifunctional regulation for reproduction. In this paper, the regulatory function of NO and NOS on male reproductive system were reviewed.
Effects of opioid (tramadol) treatment on testicular functions in adult male rats: The role of nitric oxide and oxidative stress.
Ahmed Marwa A,Kurkar Adel
Clinical and experimental pharmacology & physiology
Nowadays, tramadol hydrochloride is frequently used as a pain reliever, and for the treatment of premature ejaculation. Decreased semen quality was noted in chronic tramadol users. The present study aimed to elucidate the effects of tramadol on the testicular functions of adult male rats. A total of 40 albino adult male rats were divided into control and tramadol groups, with 20 rats for each group. Rats of the tramadol group were subcutaneously injected with 40 mg/kg three times per week for 8 weeks. The control group received normal saline 0.9%. Blood samples from each animal were obtained. Plasma levels of different biochemical substances were determined. Nitric oxide was measured in testicular tissue samples. Those samples together with epididymal tissue samples were processed for histopathological examination. Tramadol significantly reduced plasma levels of luteinizing hormone, follicle-stimulating hormone, testosterone and total cholesterol, but elevated prolactin and estradiol levels compared with the control group. In addition, tramadol increased the testicular levels of nitric oxide and lipid peroxidation, and decreased the anti-oxidant enzymes activities significantly compared with the control group. The tramadol group showed decreased sperm count and motility, and numbers of primary spermatocytes, rounded spermatid and Leydig cells. Immunohistochemical examinations showed that tramadol increased the expression of endothelial nitric oxide synthase in testicular tissues. The present study showed that tramadol treatment affects the testicular function of adult male rats, and these effects might be through the overproduction of nitric oxide and oxidative stress induced by this drug.
Involvement of nitric oxide synthase in the mechanism of histamine-induced inhibition of Leydig cell steroidogenesis via histamine receptor subtypes in Sprague-Dawley rats.
Mondillo Carolina,Pagotto Romina María,Piotrkowski Bárbara,Reche Cecilia Gabriela,Patrignani Zoraida Judith,Cymeryng Cora Beatriz,Pignataro Omar Pedro
Biology of reproduction
This study was conducted to shed light on the so far unexplored intracellular mechanisms underlying negative modulation of Leydig cell steroidogenesis by histamine (HA). Using the MA-10 cell line and highly purified rat Leydig cells as experimental models, we examined the effect of the amine on biochemical steps known to be modulated by HA or involved in LH/hCG action. In agreement with previous findings, HA at 10 microM showed a potent inhibitory effect on hCG-stimulated steroid synthesis, regardless of the gonadotropin concentration used. Moreover, HA decreased not only LH/hCG-induced cAMP production but also steroid synthesis stimulated by the permeable cAMP analog dibutyryl cAMP (db-cAMP). Considering the post-cAMP sites of HA action, it is shown herein that HA markedly inhibited db-cAMP-stimulated steroidogenic acute regulatory (STAR) protein expression, as well as steps catalyzed by P450-dependent enzymes, mainly the conversion of cholesterol to pregnenolone by cholesterol side-chain cleavage enzyme (CYP11A). The antisteroidogenic action of HA was blocked by addition of the phospholipase C (PLC) inhibitor U73122, and HA significantly augmented inositol triphosphate (IP3) production, suggesting a major role for the PLC/IP3 pathway in HA-induced inhibition of Leydig cell function. Finally, HA increased nitric oxide synthase (NOS) activity, and the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) markedly attenuated the effect of the amine on steroid synthesis. On the basis of our findings, HA antagonizes the gonadotropin action in Leydig cells at steps before and after cAMP formation. NOS activation is the main intracellular mechanism by which HA exerts its antisteroidogenic effects.
Expression of nitric oxide synthase isoforms in the testes of pigs.
Kim H C,Byun J S,Lee T K,Jeong C W,Ahn M,Shin T
Anatomia, histologia, embryologia
This study examined the expression of three isoforms of nitric oxide synthase (NOS) in the testes of pigs. Immunohistochemical studies demonstrated the presence of nNOS, eNOS and iNOS in interstitial cells, primary spermatocytes and spermatids. Positive immunoreactions for eNOS and iNOS were detected in peritubular myoid cells. Some vascular endothelial cells were positive for nNOS and eNOS. The expression of nitrotyrosine was detected in interstitial cells. In addition, the histochemical study revealed that all the interstitial cells were stained positively for NADPH-diaphorase, although some spermatids and vascular endothelial cells displayed moderate enzymatic activity. These findings suggest that three isoforms of NOS are expressed in the testis of pig and that they play important roles in the biology of interstitial cells that produce testosterone, as well as in spermatogenesis in the seminiferous tubules.
Nitric oxide (NO) stimulates steroidogenesis and folliculogenesis in fish.
Singh Vinay Kumar,Lal Bechan
Reproduction (Cambridge, England)
The present study was undertaken to understand the physiological significance of the existence of nitric oxide synthase (NOS)/nitric oxide (NO) system in fish ovary. For this, two doses of NO donor, sodium nitroprusside (SNP, 25 µg and 50 µg) and NOS inhibitor, N-nitro-l-arginine methyl ester (l-NAME, 50 µg and 100 µg)/100 g body weight were administered during the two reproductive phases of reproductive cycle of the Clarias batrachus During the late-quiescence phase, high dose of l-NAME decreased the NO, testosterone, 17β-estradiol, vitellogenin contents in serum and ovary and activities of 5-ene-3β-hydroxysteroid dehydrogenases (3β-HSD) and 17β-hydroxysteroid dehydrogenases (17β-HSD) in ovary, whereas higher dose of SNP increased these parameters. l-NAME also reduced oocytes-I but increased perinucleolar oocytes in the ovary, whereas SNP treatment increased the number of advanced oocytes (oocytes-I and II) than the perinucleolar oocytes when compared with control ovary. During the mid-recrudescence phase, both doses of SNP increased NO, testosterone, 17β-estradiol and vitellogenin in serum and ovary; however, l-NAME treatment lowered their levels. The activities of ovarian 3β-HSD and 17β-HSD were also stimulated by SNP, but l-NAME suppressed their activities compared to the control. The SNP-treated ovaries were dominated by oocyte-II and III stages, whereas l-NAME-treated ovary revealed more perinucleolar oocytes and oocytes-I and practically no advanced oocytes. Expression of endothelial NOS (eNOS), inducible NOS (iNOS) and neuronal NOS (nNOS) was augmented by the SNP and declined by l-NAME treatments as compared to the control. This study, thus, provides distinct evidence of NO-stimulated steroidogenesis, vitellogenesis and folliculogenesis in fish.
Existence of a nitric oxide synthase/nitric oxide system in fish testis and its role in modulation of androgenesis.
Lal B,Dubey N
Fish physiology and biochemistry
Fish testis is equipped with different isoforms of nitric oxide synthase (NOSs) and is capable of producing nitric oxide (NO). Cellular sources of NO in the catfish testis are germ cells, Leydig cells, and macrophages. Production of testicular NO is under endocrine inhibitory control. Expression of NOSs exhibits seasonality and that depends on the reproductive status of fish. Leydig cells are highly sensitive to chemical as well as biological NO. NO inhibits testosterone production by the testis in vivo as well as by the isolated Leydig cells in vitro.
Preoptic neuronal nitric oxide synthase induction by testosterone is consistent with a role in gating male copulatory behavior.
Sanderson Nicholas S R,Le Brandon,Zhou Zifei,Crews David
The European journal of neuroscience
Copulatory behaviors are generally dependent on testicular androgens in male vertebrates, being eliminated by castration and reinstated by testosterone administration. It is postulated that a critical factor in this hormonal gating is up-regulation of neuronal nitric oxide synthase (nNOS) in the preoptic area, and consequent enhanced nitric oxide synthesis in response to stimuli associated with a receptive female. Previous studies have suggested that nNOS protein is more abundant in behaviorally relevant preoptic regions of testosterone-exposed animals than in hormone-deprived controls. This study sought to elucidate the molecular events underlying this apparent up-regulation by examining preoptic nNOS mRNA abundance at several time points following testosterone administration in a castration and replacement paradigm. Castrated male whiptails (Cnemidophorus inornatus) were implanted with testosterone, and at four time points over the subsequent 18 days their sexual behavior was tested. A rostral periventricular area previously implicated in hormonal gating of male-typical copulatory behavior was then excised by laser microdissection, and nNOS transcript abundance was assessed by quantitative PCR. As neither this technique nor nNOS mRNA measurements have previously been performed in this area of the brain, expression was concomitantly assayed on adjacent sections by in situ hybridization or NADPH diaphorase histochemistry. Results are consistent with transcriptional up-regulation of nNOS by testosterone and a central role for the enzyme in mediating hormonal gating of copulatory behavior.
Nitric oxide synthase in diabetic rat testicular tissue and the effects of pentoxifylline therapy.
Sönmez Mehmet Fatih,Kılıç Eser,Karabulut Derya,Çilenk KübraTugce,Deligönül Erkan,Dündar Munis
Systems biology in reproductive medicine
Diabetes is known to be associated with erectile dysfunction, retrograde ejaculation, level of testicular hormone, and a decrease in semen quality, respectively. In this project, we aimed to investigate at the molecular level, the effects of NOS on testes pathology in diabetes and examine the effects of pentoxifylline on healing. A total of 50 Wistar albino male rats were divided into five groups: Group I control; Group II only diabetes; Group III and IV diabetes + pentoxifylline; Group V only pentoxifylline. Group III rats received 50 mg/kg/day pentoxifylline during two months. In comparison, Group IV rats received saline in the first month followed by 50 mg/kg/day of pentoxifylline for the following month. NOS expression in testicular tissue was assessed using qRT-PCR, western blot, and immunohistochemistry. The mean seminiferous tubule diameter, Johnsen's testicular biopsy score, and serum testosterone levels decreased compared to controls. In contrast, the number of apoptotic cells, the levels of nNOS, iNOS and eNOS mRNA, and protein increased when compared to the control. Upon pentoxifylline therapy NOS decreased suggesting that it contributes to this damage and treatment with pentoxifylline may be effective in reversing this damage.
Pro-steroidogenic and pro-spermatogenic actions of nitric oxide (NO) on the catfish, Clarias batrachus: An in vivo study.
Singh Vinay Kumar,Lal Bechan
General and comparative endocrinology
In an earlier study we have demonstrated reproductive-stage dependent, cell specific existence of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS)/NO system in testis of the catfish, Clarias batrachus. The present study is an extension to examine the role of NO in steroidogenesis and spermatogenesis through in vivo administration of a NO donor, sodium nitroprusside (SNP) and a NOS inhibitor, N-nitro-l-arginine methyl ester (l-NAME) during the quiescence and recrudescence phase of the reproductive cycle of the catfish. Effects of these chemicals were assessed on the gonadosomatic index (GSI), levels of circulating & testicular testosterone, NO, activities of 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) in testis, expression of different NOS isoforms and testicular morphology in relation to spermatogenesis. SNP treatment increased the GSI, testicular and circulating testosterone & NO, activities of testicular 3β-HSD & 17β-HSD, and expression of NOS isoforms. It also increased the area and perimeters of interstitium and seminiferous tubules in the testis. It accelerated the spermatogenesis, as was evident from the large number of spermatids/spermatozoa in seminiferous tubules and very few spermatogonial cells/primary spermatocytes in comparison to the control testis. On the contrary, l-NAME significantly suppressed GSI, testosterone & NO levels in serum and testis, and activities of testicular 3β-HSD & 17β-HSD. It also suppressed the expression of NOSs in testis. Though l-NAME did not alter the spermatogonial mitotic proliferation with the advancement of testicular recrudescence, it halted the progression of spermatogenesis (meiotic division and spermatozoa formation) as was clear from the increase in spermatogonial cells and very few advanced germ cells in the seminiferous tubules in l-NAME treated testis, compared to the control testis. The above noted effects were highly pronounced in the recrudescing catfish. Their effects were very marginal and at a particular dose levels of SNP and l-NAME in the quiescent testis. This study distinctly provides evidence of pro-steroidogenic and pro-spermatogenic role of NO. This study also demonstrates the existence of eNOS in fish testis for the first time. The positive feedback control of expression of all isoform of NOS in testis by NO is also noteworthy.
Expression of nitric oxide synthase during germ cell apoptosis in testis of cynomolgus monkey after testosterone and heat treatment.
Guo Jian,Jia Yue,Tao Shi-Xin,Li Yin-Chuan,Zhang Xue-Sen,Hu Zhao-Yuan,Chiang Naomi,Lue Yan-He,Hikim Amiya P Sinha,Swerdloff Ronald S,Wang Christina,Liu Yi-Xun
Journal of andrology
This study investigates the possible involvement of nitric oxide synthase (NOS) in activating germ cell death in monkeys after mild testicular hyperthermia and/or hormonal deprivation. Groups of 8 adult male monkeys received 1 of the following treatments for 12 weeks: 1) 2 empty Silastic implants, 2) 2 testosterone (T) implants, 3) daily exposure of testes to heat (43 degrees C for 30 minutes) for 2 consecutive days, or 4) 2 T implants plus testicular heat exposure. Testicular biopsies were performed before and on days 3, 8, 28, and 84 of the treatment. In control monkey testes, endothelial NOS (eNOS) was observed mainly in Sertoli cells and spermatogonia. No obvious alteration in eNOS levels was detected in any of the treatment group as assessed by Western blotting. Induction of inducible NOS (iNOS) in testes of the 3 treated groups was detected by immunoblotting as early as day 3 after treatment compared with that of controls. Immunocytochemistry further revealed a small increase in iNOS expression in both germ cells and Sertoli cells after T treatment. However, treatment of heat or heat in combination with T markedly induced iNOS expression in germ cells. These data suggest that iNOS, but not eNOS, may be involved in monkey testicular germ cell death after heat and/or T treatment.
Seasonality in expression and distribution of nitric oxide synthase isoforms in the testis of the catfish, Clarias batrachus: role of nitric oxide in testosterone production.
nee Pathak Neelima Dubey,Lal Bechan
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP
Nitric oxide (NO) is a well-recognized versatile signaling molecule. It is produced by catalytic action of nitric oxide synthase (NOS) on L-arginine in a variety of animal tissues. Existence of different isoforms of NOS has been shown in mammalian testis, but report on their presence in the testis of ectothermic vertebrates is non-existent. This study demonstrates the differential expressions of two isoforms of nitric oxide synthase (neuronal-nNOS and inducible-iNOS) like molecules in different cell types in the testis of seasonally breeding catfish, Clarias batrachus through immunohistochemistry. Positive immunoprecipitation of nNOS and iNOS like molecules were detected in germ cells as well as interstitial cells only in the recrudescing and fully mature fish. The immunoreactions differed in intensity and varied with changing reproductive status. Treatment of adult male fish with NO donor, sodium nitroprusside, and a NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME) increased and decreased the total nitrate and nitrite concentration in the testis, respectively. Sodium nitroprusside and L-NAME also induced simultaneous decline and rise in the testicular testosterone level, respectively. These findings, thus, suggest that NOS isoforms are expressed variedly in different cell types in the testis of reproductively active fish. This investigation also suggests that NO inhibits testosterone production in the testis.
Kisspeptin, gonadotrophin-releasing hormone and oestrogen receptor α colocalise with neuronal nitric oxide synthase neurones in prepubertal female sheep.
Bedenbaugh M N,O'Connell R C,Lopez J A,McCosh R B,Goodman R L,Hileman S M
Journal of neuroendocrinology
Puberty is a process that integrates multiple inputs ultimately resulting in an increase in gonadotrophin-releasing hormone (GnRH) secretion. Although kisspeptin neurones play an integral role in GnRH secretion and puberty onset, other systems are also likely important. One potential component is nitric oxide (NO), a gaseous neurotransmitter synthesised by nitric oxide synthase (NOS). The present study aimed to neuroanatomically characterise neuronal NOS (nNOS) in prepubertal female sheep and determine whether oestradiol exerts effects on this system. Luteinising hormone secretion was reduced by oestradiol treatment in prepubertal ovariectomised ewes. Neurones immunoreactive for nNOS were identified in several areas, with the greatest number present in the ventrolateral portion of the ventromedial hypothalamus, followed by the ventromedial hypothalamus, preoptic area (POA) and arcuate nucleus (ARC). Next, we determined whether nNOS neurones contained oestrogen receptor (ER)α and could potentially communicate oestradiol (E ) feedback to GnRH neurones. Neuronal NOS neurones contained ERα with the percentage of coexpression (12%-40%) depending upon the area analysed. We next investigated whether a neuroanatomical relationship existed between nNOS and kisspeptin or nNOS and GnRH neurones. A high percentage of kisspeptin neurones in the POA (79%) and ARC (98%) colocalised with nNOS. Kisspeptin close contacts were also associated with nNOS neurones. A greater number of close contacts were observed in the ARC than the POA. A high percentage of POA GnRH neurones (79%) also expressed nNOS, although no GnRH close contacts were observed onto nNOS neurones. Neither the numbers of nNOS neurones in the POA or hypothalamus, nor the percentage of nNOS coexpression with GnRH, kisspeptin or ERα were influenced by oestradiol. These experiments reveal that a neuroanatomical relationship exists between both nNOS and kisspeptin and nNOS and GnRH in prepubertal ewes. Therefore, nNOS may act both directly and indirectly to influence GnRH secretion in prepubertal sheep.
Progestin receptors: neuronal integrators of hormonal and environmental stimulation.
Blaustein Jeffrey D
Annals of the New York Academy of Sciences
Although it originally was believed that neuronal steroid hormone receptors require binding to cognate ligand for activation, more recent evidence suggests that the receptors can be activated indirectly by other compounds, such as neurotransmitters and growth factors, acting through their own membrane receptors and specific intracellular signaling pathways. For example, as is the case with facilitation of sexual behavior by progesterone, facilitation of sexual behavior by D(1)/D(5) dopamine receptor agonists is blocked by disruption of progestin receptors. Therefore, some dopamine agonists facilitate sexual behavior at least in part by a progestin receptor-dependent mechanism, as does progesterone. This "ligand-independent activation" of neuronal progestin receptors is not limited to dopamine agonists; a variety of other compounds, as well as mating stimulation, facilitate sexual receptivity by a progestin receptor-dependent process. Steroid hormone receptors also can be regulated by afferent input in another way. Various neurotransmitters upregulate or downregulate steroid hormone receptors in some neurons. This, in turn, presumably confers greater or decreased sensitivity to the particular factors that can activate the particular steroid receptor in those particular neurons. Therefore, steroid hormones are but one class of factors that can regulate and activate steroid hormone receptors. Some additional factors that activate steroid hormone receptors have been identified, as have some factors that can regulate concentrations of receptors. Relatively little is known at this time about the range of neurotransmitters, humoral factors, and intracellular signaling pathways that are involved.
Sexual differentiation of the brain requires perinatal kisspeptin-GnRH neuron signaling.
Clarkson Jenny,Busby Ellen R,Kirilov Milen,Schütz Günther,Sherwood Nancy M,Herbison Allan E
The Journal of neuroscience : the official journal of the Society for Neuroscience
Sex differences in brain function underlie robust differences between males and females in both normal and disease states. Although alternative mechanisms exist, sexual differentiation of the male mammalian brain is initiated predominantly by testosterone secreted by the testes during the perinatal period. Despite considerable advances in understanding how testosterone and its metabolite estradiol sexually differentiate the brain, little is known about the mechanism that generates the male-specific perinatal testosterone surge. In mice, we show that a male-specific activation of GnRH neurons occurs 0-2 h following birth and that this correlates with the male-specific surge of testosterone occurring up to 5 h after birth. The necessity of GnRH signaling for the sexually differentiating effects of the perinatal testosterone surge was demonstrated by the persistence of female-like brain characteristics in adult male, GnRH receptor knock-out mice. Kisspeptin neurons have recently been identified to be potent, direct activators of GnRH neurons. We demonstrate that a population of kisspeptin neurons appears in the preoptic area of only the male between E19 and P1. The importance of kisspeptin inputs to GnRH neurons for the process of sexual differentiation was demonstrated by the lack of a normal neonatal testosterone surge, and disordered brain sexual differentiation of male mice in which the kisspeptin receptor was deleted selectively from GnRH neurons. These observations demonstrate the necessity of perinatal GnRH signaling for driving brain sexual differentiation and indicate that kisspeptin inputs to GnRH neurons are essential for this process to occur.
Steroid hormones and sleep regulation.
Terán-Pérez G,Arana-Lechuga Y,Esqueda-León E,Santana-Miranda R,Rojas-Zamorano J Á,Velázquez Moctezuma J
Mini reviews in medicinal chemistry
In the search of the sleep substance, many studies have been addressed for different hormones, responsible for sleep-wake cycle regulation. In this article we mentioned the participation of steroid hormones, besides its role regulating sexual behavior, they influence importantly in the sleep process. One of the clearest relationships are that estrogen and progesterone have, that causing changes in sleep patterns associated with the hormonal cycles of women throughout life, from puberty to menopause and specific periods such as pregnancy and the menstrual cycle, including being responsible for some sleep disorders such as hypersomnia and insomnia. Another studied hormone is cortisol, a hormone released in stressful situations, when an individual must react to an extraordinary demand that threatens their survival, but also known as the hormone of awakening because the release peak occurs in the morning, although this may be altered in some sleep disorders like insomnia and mood disorders. Furthermore neurosteroids such as pregnanolone, allopregnanolone and pregnenolone are involved in the generation of slow wave sleep, the effect has been demonstrated in experimental animal studies. Thus we see that the sleep and the endocrine system saved a bidirectional relationship in which depends on each other to regulate different physiological processes including sleep.
Molecular basis of androgen action on human sexual desire.
Santi Daniele,Spaggiari Giorgia,Gilioli Lisa,Potì Francesco,Simoni Manuela,Casarini Livio
Molecular and cellular endocrinology
Reproduction is a fundamental process for the species maintenance and the propagation of genetic information. The energy expenditure for mating is overtaken by motivational stimuli, such as orgasm, finely regulated by steroid hormones, gonadotropins, neurotransmitters and molecules acting in the brain and peripheral organs. These functions are often investigated using animal models and translated to humans, where the androgens action is mediated by nuclear and membrane receptors converging in the regulation of both long-term genomic and rapid non-genomic signals. In both sexes, testosterone is a central player of this game and is involved in the regulation of sexual desire and arousal, and, finally, in reproduction through cognitive and peripheral physiological mechanisms which may decline with aging and circadian disruption. Finally, genetic variations impact on reproductive behaviours, resulting in sex-specific effect and different reproductive strategies. In this review, androgen actions on sexual desire are evaluated, focusing on the molecular levels of interaction.
The Role of the EGF Receptor in Sex Differences in Kidney Injury.
Zhang Ming-Zhi,Sasaki Kensuke,Li Yan,Li Zhilian,Pan Yu,Jin Guan-Nan,Wang Yinqiu,Niu Aolei,Wang Suwan,Fan Xiaofeng,Chen Jian Chun,Borza Corina,Yang Haichun,Pozzi Ambra,Fogo Agnes B,Harris Raymond C
Journal of the American Society of Nephrology : JASN
BACKGROUND:Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. METHODS:To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines. RESULTS:In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells. CONCLUSIONS:These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.
Low serum testosterone increases mortality risk among male dialysis patients.
Carrero Juan Jesús,Qureshi Abdul Rashid,Parini Paolo,Arver Stefan,Lindholm Bengt,Bárány Peter,Heimbürger Olof,Stenvinkel Peter
Journal of the American Society of Nephrology : JASN
Men treated with hemodialysis (HD) have a very poor prognosis and an elevated risk of premature cardiovascular disease (CVD). In the general population, associations between low testosterone concentrations and cardiovascular risk have been suggested. We performed a prospective observational study involving a well characterized cohort of 126 men treated with HD to examine the relationship between testosterone concentration and subsequent mortality during a mean follow-up period of 41 mo. Independent of age, serum creatinine, and sexual hormone binding globulin (SHBG), testosterone levels inversely and strongly associated with the inflammatory markers IL-6 and CRP. Patients with a clinical history of CVD had significantly lower testosterone levels. During follow up, 65 deaths occurred, 58% of which were a result of CVD. Men with testosterone values in the lowest tertile had increased all-cause and CVD mortality (crude hazard ratios [HRs] 2.03 [95% CI 1.24 to 3.31] and 3.19 [1.49 to 6.83], respectively), which persisted after adjustment for age, SHBG, previous CVD, diabetes, ACEi/ARB treatment, albumin, and inflammatory markers, but was lost after adjustment for creatinine. In summary, among men treated with HD, testosterone concentrations inversely correlate with all-cause and CVD-related mortality, as well as with markers of inflammation. Hypogonadism may be an additional treatable risk factor for patients with chronic kidney disease.
Ovarian function in chronic renal failure: evidence suggesting hypothalamic anovulation.
Lim V S,Henriquez C,Sievertsen G,Frohman L A
Annals of internal medicine
The pathogenesis of ovarian dysfunction in uremia was evaluated in 24 patients by measurements of plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone, prolactin, estradiol, and progesterone basally and after clomiphene, ethinyl estradiol, and bromocriptine. In the 17 premenopausal women, levels of plasma estradiol, progesterone, and FSH were comparable to those found in normal women during the follicular phase of the ovarian cycle; plasma luteinizing hormone was slightly elevated. In most patients, there was an absence of cyclicity. After clomiphene, plasma levels of luteinizing hormone, FSH, and estradiol rose; after ethinyl estradiol, plasma luteinizing hormone levels failed to increase. In seven postmenopausal patients, plasma estradiol was undetectable and gonadotropin levels were markedly elevated. Although plasma prolactin was generally elevated, suppression of prolactin with bromocriptine resulted in resumption of ovulation in only one patient; the other 2 remained amenorrheic. In uremic women, the continued secretion of estrogen, the rise of plasma levels of luteinizing hormone, FSH, and estradiol after clomiphene, and the elevated gonadotropin levels during menopause suggest that the negative estradiol feedback, the tonic gonadotropin secretion, and the pituitary ovarian axis were normal. The positive estradiol feedback associated with cyclic release of luteinizing hormone, however, was impaired as indicated by the prevalence of acyclicity and the failure of luteinizing hormone levels, to rise after ethinyl estradiol.
Estrogen-progesterone therapy for bleeding gastrointestinal telangiectasias in chronic renal failure. An uncontrolled trial.
Bronner M H,Pate M B,Cunningham J T,Marsh W H
Annals of internal medicine
Gastrointestinal telangiectasias cause hemorrhage in patients with chronic renal failure. Therapies using vasoconstrictors, endoscopic application of heat, and surgery have had limited efficacy. Because several reports have suggested that estrogen or estrogen-progesterone therapy may control mucosal bleeding from telangiectasias in patients with hereditary hemorrhagic telangiectasia, we treated seven patients with chronic renal failure and bleeding gastrointestinal telangiectasias with systemic estrogen or estrogen-progesterone in an uncontrolled trial. Bleeding ceased in all patients. Blood transfusion requirements decreased from a mean of 1.2 U/month before treatment to 0.21 U/month after treatment. No significant side effects were noted. Results of this trial indicate the need for controlled investigations of this type of hormonal therapy.
Effect of oral zinc therapy on gonadal function in hemodialysis patients. A double-blind study.
Mahajan S K,Abbasi A A,Prasad A S,Rabbani P,Briggs W A,McDonald F D
Annals of internal medicine
Zinc deficiency may account for the persistence of gonadal dysfunction in a majority of uremic men despite adequate dialysis. Twenty stable patients having hemodialysis three times a week completed a double-blind trial using either 50 mg of elemental zinc as zinc acetate (10 patients) or placebo (10 patients), orally. At the end of the 6-month study period, a significant increase in the mean (+/- SE) plasma zinc (75 +/- 2 micrograms/dL to 100 +/- 2 micrograms/dL, p less than 0.001), serum testosterone (2.8 +/- 0.3 ng/dL to 5.2 +/- 0.5 ng/mL, p less than 0.001), and sperm count (30 +/- 3 million/mL to 63 +/- 5 million/mL, p less than 0.001) occurred in the zinc-treated group, but not in those receiving the placebo. The zinc-treated group also had a significant fall in serum luteinizing hormone (92 +2- 10 mIU/mL to 49 +/- 26 mIU/mL, p less than 0.005) and follicle stimulating hormone (45 +/- 9 mIU/mL to 25 +/- 7 mIU/mL, p less than 0.05), not seen in the placebo group. Patients receiving zinc had an improvement in potency, libido, and frequency of intercourse not found in the placebo group. These results suggest that zinc deficiency is a reversible cause of gonadal dysfunction in patients having regular hemodialysis.