Testosterone and estrogen differently effect Th1 and Th2 cytokine release following trauma-haemorrhage.

The object of the study was to determine whether male and female sex steroids produce divergent effects on Th1 and Th2 cytokine release following trauma-haemorrhage. Recent studies indicate that androgens are responsible for the depressed splenocyte Th1 cytokine release in males following trauma-haemorrhage. In contrast, female mice maintain their Th1 cytokine release capacity following trauma-haemorrhage. Nonetheless, the effect of male and female sex steroids on Th1 and Th2 cytokine release following trauma-haemorrhage remains unknown. Male C3H/HeN mice were castrated and treated with pellets containing either vehicle, 5alpha-dihydrotestosterone (DHT), 17beta-estradiol (estradiol), or a combination of both steroid hormones, for 14 days prior to soft-tissue trauma (i.e. laparotomy) and haemorrhagic shock (35+/-5 mmHg for 90 min followed by adequate fluid resuscitation) or sham operation. Untreated male and female mice, as well as DHT treated female mice, served as control groups. Twenty-four hours later the animals were sacrificed, plasma obtained and splenocytes harvested. Plasma DHT and estradiol levels in treated animals were comparable with intact male and female mice, respectively. A significant depression of splenocyte Th1 cytokines, i.e. IL-2, IFN-gamma, was observed in DHT treated castrated animals, DHT treated females, and untreated males following trauma-haemorrhage, as opposed to maintained Th1 cytokine release in estradiol treated and estradiol/DHT treated castrated animals and females. The release of the anti-inflammatory cytokine IL-10 was markedly increased in DHT treated mice and males subjected to trauma-haemorrhage compared to shams, but decreased in estrogen treated mice and females under such conditions. These results suggest that male and female sex steroids differentially affect the release of Th1 and Th2 cytokines following trauma-haemorrhage and should be further studied for their potential to modulate splenocyte function in trauma victims.     

Current concepts in ejaculatory dysfunction

Although erectile dysfunction has recently become the most well-known aspect of male sexual dysfunction, the most prevalent male sexual disorders are ejaculatory dysfunctions. Ejaculatory disorders are divided into 4 categories: premature ejaculation (PE), delayed ejaculation, retrograde ejaculation, and anejaculation/anorgasmia. Pharmacologic treatment for certain ejaculatory disorders exists, for example the off-label use of selective serotonin reuptake inhibitors for PE. Unfortunately, the other ejaculatory disorders are less studied and not as well understood. This review revisits the physiology of the normal ejaculatory response, specifically explores the mechanisms of anejaculation, and presents emerging data. The neurophysiology of the ejaculatory reflex is complex, making classification of the role of individual neurotransmitters extremely difficult. However, recent research has elucidated more about the role of serotonin and dopamine at the central level in the physiology of both arousal and orgasm. Other recent studies that look at differing pharmacokinetic profiles and binding affinities of the alpha(1)-antagonists serve as an indication of the centrally mediated role of ejaculation and orgasm. As our understanding of the interaction between central and peripheral modulations and regulation of the process of ejaculation increases, the probability of developing centrally acting pharmaceutical agents for the treatment of sexual dysfunction approaches reality.     

Androgènes et sexualité masculine

Testosteron is known to be critical for the right maintenance of masculin sexuality. It acts on all components of sexuality: libido, erection and ejaculation. As far as erection is concerned, one has to emphasize on the fact that only spontaneous nocturnal erections are androgen-dependent unlike erectile responses to visual erotic stimuliThe T can act, at the level of target organes, either as unchanged or as more often observed after reduction to DHT or aromatisation to E2. It is essencially as DHT that the male hormone seems to act on the sexuality at both the central and peripherical levels. The oestrogens even if now shown to have no peripherical action, are still subject to controversy as far as their central action is concerned. Therefore an action at the cerebral level of the oestrogens produced locally can not be definitively eliminated.The concentrations of T required for the re-establishment of the sexual function in case of hypogonadism are closer to the lower limits of normal values. The upper treshold of the action of T on the sexuality, if any, would be at supra-physiological levels.Androgenotherapy of sexual dysfonctionnalities is wittnissing a constant evolution. New and more performing products, as well as novel and less astreignant ways of administration, are already disponible or under evaluation. Moreover, the improvement of plasmic androgen exploration (dosage of free and non-sex hormone-binding globulin bound testosterone) associated to a better understanding of side effects of the androgenic therapeutics may allow in the near futur to reach a consensus on the androgenotherapy indications. As a matter of fact among the population of patients considered eugonadic (based on normal levels of T) and showing a sexual dysfonctionality, two subgroups might be interested: That of elderly patients displaying either an increase of the hormone-binding globulin (SHBG) or a decrease of the non-sex hormone-binding globulin bound testosterone levels and that of young patients suffering from idiopathic impotence. It should be, however, pointed at that the recent character of the different physiopathologic and therapeutic acquisitions requires a validation through larger series and long term studies.     

Differential effects of testosterone metabolites in the neonatal period on open-field behavior and lordosis in the rat

Two experiments were done to compare the effects of neonatal exposure to testosterone and its major metabolites, dihydrotestosterone (DHT) and estradiol (E₂), on the development of sex differences in open-field behavior in the rat. In Experiment 1 female rats administered either testosterone propionate (TP), DHT, or estradiol benzoate (EB) were found as adults to have low activity scores, more typical of adult males, when compared to the high scores of oil-treated females. In Experiment 2 the adult open-field behavior of female rats treated neonatally with testosterone or the metabolites was compared to that of male rats treated from Day 1 to 10 of life with the aromatizing enzyme inhibitor, androst-1,4,6-triene-3,17-dione (ATD). These same animals were later tested for lordotic behavior after gonadectomy and priming with EB and progesterone. All male animals and female animals exposed neonatally to testosterone or to either of the metabolites had suppressed open-field activity scores compared to oil-treated females. However, the lordotic behavior of females exposed to DHT and of males exposed to ATD was not defeminized and was comparable to that of oil-treated females. These observations were discussed in terms of a role for the androgenic actions of testosterone in establishing sex differences in nonreproductive behavior in the rat.     

Regulation of pro-gonadotropin-releasing hormone gene expression by sex steroids in the brain of male and female rats

The fine modulation of gonadotropin gene expression and secretion is well recognized to be regulated by sex steroids through their direct action both at the anterior pituitary level and on the pulsatile pattern of GnRH secretion at the hypothalamic level. Since the influence of sex steroids on hypothalamic GnRH mRNA levels remains to be elucidated, quantitative in situ hybridization was used to study the effect of sex steroids on cellular levels of pro-GnRH mRNA in adult rats of both sexes. The effects of 14-day gonadectomy as well as administration of 17 beta-estradiol (E2, 0.25 micrograms) or dihydrotestosterone (DHT, 100 micrograms) twice a day during 14 days to gonadectomized animals were evaluated. In addition, the effect of progesterone (P, 2 mg, twice daily) alone or in the presence of E2 was also studied in ovariectomized animals. Hybridization was performed using a 35S-labeled cDNA probe encoding rat pro-GnRH and the corresponding mRNA levels were assessed by counting the number of silver grains overlying labeled neurons. In male rats, castration induced a highly significant 65% increase (compared to intact rats) in the mean number of grains per neuron. Administration of E2 or DHT to castrated animals completely prevented the post castration rise in pro-GnRH mRNA levels. In female animals, the effect of ovariectomy was less striking than in the male, a 25% increase (P less than 0.001) being observed. Treatment with E2 or DHT also completely prevented the increase in pro-GnRH mRNA levels induced by ovariectomy. Moreover, treatment with P in ovariectomized animals markedly potentiated the inhibitory effect of E2 on pro-GnRH mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Central and peripheral action of testosterone propionate on scent gland morphology and marking behaviour in the Mongolian gerbil

Scent gland size and activity and frequency of marking under standard conditions were compared in five groups of male and female gerbils: (1) intact, sham-operated controls, (2) intact with scent glands excised, (3) gonadectomized, (4) gonadectomized injected with 1000 μg testosterone propionate (TP) on alternate days, and (5) gonadectomized with a low dose (25 μg) TP applied topically to the ventral scent gland on alternate days. The animals were housed in individual cages and tested for marking in an open field arena with plastic pegs.The scent gland is not required in either sex for the behavioural act of marking. Topical application of a dose of TP too low to exert a systematic effect restored the scent gland but not marking. Injection of sufficient TP to restore seminal vesicle weight restored marking, as well as the scent glands.It was concluded that in the male, both marking behaviour and scent gland size are controlled by the testes. The effect of androgens on marking is mediated directly through the central nervous system, and not through peripheral stimulation of the glands.Females have smaller glands and mark less than males. The ovaries appear to have little control over marking frequency, and some control over scent gland size. It is possible to stimulate marking behaviour to supernormal levels by TP injection, but not by topical application.     

Cyproterone acetate diminishes sexual activity in male rabbits.

Cyproterone acetate (CA) was injected daily in eleven rabbits for 3 weeks at a dose of 20 mg/day, and for a further week at a dose of 40 mg/day. After 3 weeks of treatment, the ejaculation frequency was reduced but other measures of sexual behaviour were not significantly changed. There was no reduction in the fructose concentration of the semen, but the volume of the ejaculates decreased. The vesicular glands from the experimental animals showed histological changes typical of those occurring after castration. It was concluded that CA reduced the activity of at least one of the accessory sex glands as well as sexual behaviour. This lends support to the current hypothesis that the endocrine regulation of rabbit sexual behaviour differs from that of the rat.     

Effects of chronic D-Leu6, des-Gly10-gonadotropin releasing hormone ethylamide on male sex tissues

The chronic administration of superactive agonists of gonadotropin releasing hormone (GnRH-A) have been reported to have a direct inhibitory effect on the sex tissues of the male rat. In an attempt to confirm or refute this statement, adult male rats were either left intact or were castrated and then treated daily for 14 days with either testosterone (T), dihydrotestosterone (DHT) or sesame oil (vehicle). Half of the intact and castrate animals also received daily injections of 200 ng of the GnRH agonist, D-Leu6, des-Gly10-GnRH ethylamide for 14 days. Twenty-four hours after completing treatment, blood levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and T were measured by radioimmunoassay and the ventral prostate gland (VP), seminal vesicle (SV) and penis were weighed. After 2 weeks of GnRH-A treatment, the plasma T level was reduced from 2506 +/- 170 (pg/ml +/- SEM) in the intact, nontreated animals to 907 +/- 69 in the intact, GnRH-A-treated group, indicating that the dosage of GnRH-A used in this study had an inhibiting effect on T secretion. No differences were observed in the VP, SV and penile weights between the castrate, GnRH-A and the castrate, nontreated groups. When exogenous T or DHT was given for 14 days to these castrated animals, the concomitant administration of GnRH-A did not appear to have any effect on the plasma T levels or the sex accessory tissue weights. These data suggest that GnRH-A itself does not appear to have a direct inhibitory or stimulatory effect on the sex tissues of the adult male rat.     

Effect of steroid milieu on gonadotropin-releasing hormone-1 neuron firing pattern and luteinizing hormone levels in male mice

GnRH neuronal function is regulated by gonadal hormone feedback. In males, testosterone can act directly or be converted to either dihydrotestosterone (DHT) or estradiol (E2). We examined central steroid feedback by recording firing of green fluorescent protein (GFP)-identified GnRH neurons in brain slices from male mice that were intact, castrated, or castrated and treated with implants containing DHT, E2, or E2 + DHT. Castration increased LH levels. DHT or E2 alone partially suppressed LH, whereas E2 + DHT reduced LH to intact levels. Despite the inhibitory actions on LH, the combination of E2 + DHT increased GnRH neuron activity relative to other treatments, reflected in mean firing rate, amplitude of peaks in firing rate, and area under the curve of firing rate vs. time. Cluster8 was used to identify peaks in firing activity that may be correlated with hormone release. Castration increased the frequency of peaks in firing rate. Treatment with DHT failed to reduce frequency of these peaks. In contrast, treatment with E2 reduced peak frequency to intact levels. The frequency of peaks in firing rate was intermediate in animals treated with E2 + DHT, perhaps suggesting the activating effects of this combination partially counteracts the inhibitory actions of E2. These data indicate that E2 mediates central negative feedback in males primarily by affecting the pattern of GnRH neuron activity, and that androgens combined with estrogens have a central activating effect on GnRH neurons. The negative feedback induced by E2 + DHT to restore LH to intact levels may mask an excitatory central effect of this combination.     

Aromatization and the induction of male sexual behavior in male, female, and androgenized female hamsters

Eight weeks after gonadectomy male, female, and androgenized [10 μg testosterone propionate (TP), 24 hr after birth] female hamsters were given daily treatment with: 150 μg dihydrotestosterone (DHT), 5 μg estradiol benzoate (EB), 150 μg DHT + 5 μg EB, 150 μg DHT + 1 μg EB, 30 μg DHT + 5 μg EB, 30 μg DHT + 1 μg EB, or the oil vehicle. Treatment of castrated male hamsters with 5 μg EB fully restored mounting but relatively few of these animals intromitted and none ejaculated. Treatment with 150 μg DHT restored all components of male sexual behavior but only in a small proportion of the males. Combined treatment with EB and DHT restored mounts, intromissions, and ejaculations in the majority of the males. Although as little as 30 μg DHT + 1 μg EB restored the full complement of male behavior, the males which received 150 μg DHT + 5 μg EB or 150 μg DHT + 1 μg EB required fewer intromissions to achieve ejaculation than the males which received 30 μg DHT + either dose of EB. The response of the androgenized females was similar to that of the males except that the androgenized females had lower intromission rates and none ejaculated. Relatively few of the nonandrogenized females responded to EB and DHT treatment and those that did mounted only a few times each test. These results demonstrate that both EB and DHT can stimulate male sexual behavior in the hamster and that the sensitivity to EB and DHT for copulatory behavior is determined by early postnatal androgen exposure.     

Sexual differences in 5′-deiodinase activity in the harderian gland of Syrian hamsters and the effect of pinealectomy: Regulation by androgens

Sexual differences on thyroxine 5′-deiodinase (5′-D) in the Harderian gland of Syrian hamsters were investigated. We compared the 24-h profile of 5′-D activity in male and female hamsters, observing a clear rhythm in males but not in females. Female values were always significantly higher than male ones. After pinealectomy day/night variations in male 5′-D activity at the time points studies were abolished, results that are in correlation with serum thyroid hormones. We also studied the regulation by androgen of the enzyme activity. Basal 5′-D activity increased in castrated males and levels fell when animals were implanted with testosterone or its product 5α-dihydrotestosterone (DHT). Female 5′-D activity was also inhibited by androgens. As only the addition of DHT in the presence of epitestosterone, an inhibitor of the conversion of testosterone on DHT, in castrated males was able to decrease 5′-D activity to control animal levels, we suggest a probable direct effect of DHT by itself. © 1996 Wiley-Liss, Inc.     

Age-related changes in sexual function and steroid-hormone receptors in the medial preoptic area of male rats

Testosterone is the main circulating steroid hormone in males, and acts to facilitate sexual behavior via both reduction to dihydrotestosterone (DHT) and aromatization to estradiol. The mPOA is a key site involved in mediating actions of androgens and estrogens in the control of masculine sexual behavior, but the respective roles of these hormones is not fully understood. As males age they show impairments in sexual function, and a decreased facilitation of behavior by steroid hormones compared to younger animals. We hypothesized that an anatomical substrate for these behavioral changes is a decline in expression and/or activation of hormone receptor-sensitive cells in the mPOA. We tested this by quantifying and comparing numbers of AR- and ERα-containing cells, and Fos as a marker of activated neurons, in the mPOA of mature (4–5 months) and aged (12–13 months) male rats, assessed one hour after copulation to one ejaculation. Numbers of AR- and ERα cells did not change with age or after sex, but the percentage of AR- and ERα-cells that co-expressed Fos were significantly up-regulated by sex, independent of age. Age effects were found for the percentage of Fos cells that co-expressed ERα (up-regulated in the central mPOA) and the percentage of Fos cells co-expressing AR in the posterior mPOA. Interestingly, serum estradiol concentrations positively correlated with intromission latency in aged but not mature animals. These data show that the aging male brain continues to have high expression and activation of both AR and ERα in the mPOA with copulation, raising the possibility that differences in relationships between hormones, behavior, and neural activation may underlie some age-related impairments.     

The effects of nitric oxide-cGMP pathway stimulation on dopamine in the medial preoptic area and copulation in DHT-treated castrated male rats

Dopamine (DA) in the medial preoptic area (MPOA) provides important facilitative influence on male rat copulation. We have shown that the nitric oxide-cGMP (NO-cGMP) pathway modulates MPOA DA levels and copulation. We have also shown that systemic estradiol (E(2)) maintains neuronal NO synthase (nNOS) immunoreactivity in the MPOA of castrates, as well as relatively normal DA levels. This effect of E(2) on nNOS probably accounts for at least some of the previously demonstrated behavioral facilitation by intra-MPOA E(2) administration in castrates. Therefore, we hypothesized that stimulation of the MPOA NO-cGMP pathway in dihydrotestosterone (DHT)-treated castrates should restore DA levels and copulatory behaviors. Reverse-dialysis of a NO donor, sodium nitroprusside (SNP), increased extracellular DA in the MPOA of DHT-treated castrates and restored the ability to copulate to ejaculation in half of the animals. A cGMP analog, 8-Br-cGMP, also increased extracellular DA, though not as robustly, but did not restore copulatory ability. The effectiveness of the NO donor in restoring copulation and MPOA DA levels is consistent with our hypothesis. However, the lack of behavioral effects of 8-Br-cGMP, despite its increase in MPOA DA, suggests that NO may have additional mediators in the MPOA in the regulation of copulation. Furthermore, the suboptimal copulation seen in the NO donor-treated animals suggests the importance of extra-MPOA systems in the regulation of copulation.     

Facilitation of Male Sexual Behavior in Syrian Hamsters by the Combined Action of Dihydrotestosterone and Testosterone

Background

Testosterone (T) controls male Syrian hamster sexual behavior, however, neither of T''s primary metabolites, dihydrotestosterone (DHT) and estradiol (E₂), even in highly supraphysiological doses, fully restores sexual behavior in castrated hamsters. DHT and T apparently interact with androgen receptors differentially to control male sexual behavior (MSB), but whether these two hormones act synergistically or antagonistically to control MSB has received scant experimental attention and is addressed in the present study.

Methodology/Principal Findings

Sexually experienced male Syrian hamsters were gonadectomized and monitored 5 weeks later to confirm elimination of the ejaculatory reflex (week 0), at which time they received subcutaneous DHT-filled or empty capsules that remained in situ for the duration of the experiment. Daily injections of a physiological dose of 25 µg T or vehicle commenced two weeks after capsule implantation. MSB was tested 2, 4 and 5 weeks after T treatment began. DHT capsules were no more effective than control treatment for long-term restoration of ejaculation. Combined DHT + T treatment, however, restored the ejaculatory reflex more effectively than T alone, as evidenced by more rapid recovery of ejaculatory behavior, shorter ejaculation latencies, and a greater number of ejaculations in 30 minute tests.

Conclusions/Significance

DHT and T administered together restored sexual behavior to pre-castration levels more rapidly than did T alone, whereas DHT and vehicle were largely ineffective. The additive actions of DHT and T on MSB are discussed in relation to different effects of these androgens on androgen receptors in the male hamster brain mating circuit.     

Copulation patterns in captive hamadryas baboons: a quantitative analysis

For primates, as for many other vertebrates, copulation which results in ejaculation is a prerequisite for reproduction. The probability of ejaculation is affected by various physiological and social factors, for example reproductive state of male and female and operational sex-ratio. In this paper, we present quantitative and qualitative data on patterns of sexual behaviour in a captive group of hamadryas baboons (Papio hamadryas), a species with a polygynous–monandric mating system. We observed more than 700 copulations and analysed factors that can affect the probability of ejaculation. Multilevel logistic regression analysis and Akaike’s information criterion (AIC) model selection procedures revealed that the probability of successful copulation increased as the size of female sexual swellings increased, indicating increased probability of ovulation, and as the number of females per one-male unit (OMU) decreased. In contrast, occurrence of female copulation calls, sex of the copulation initiator, and previous male aggression toward females did not affect the probability of ejaculation. Synchrony of oestrus cycles also had no effect (most likely because the sample size was too small). We also observed 29 extra-group copulations by two non-adult males. Our results indicate that male hamadryas baboons copulated more successfully around the time of ovulation and that males in large OMUs with many females may be confronted by time or energy-allocation problems.     

Short-latency effect of testosterone on copulatory behaviour and ejaculation in sexually experienced intact male rats

The effect of a single injection of testosterone on the number of stimuli required to trigger ejaculation and on copulatory behaviour was investigated in sexually experienced intact male rats. An intraperitoneal injection of 100 microgram free testosterone 1 h before testing facilitated the copulatory behaviour and decreased the number of mounts and intromissions needed for ejaculation; the latter effect was obtained in a test in which a constant interval was kept between each intromission.     

Définition et épidémiologie des troubles de l'éjaculation

Ejaculatory dysfunction is a male sexual disorder and comprises premature ejaculation, delayed ejaculation, anorgasmia, anejaculation and retrograde ejaculation. The definition of premature ejaculation is based on three essential criteria: brief ejaculatory latency, loss of control and psychological distress for the patient and/or his partner. Comparison of studies on premature ejaculation is difficult due to the absence of physiological data in the general population on ejaculatory latency, the absence of a precise definition of premature ejaculation and the absence of a questionnaire or standardized and valldated methods of evaluation. However, the rare studies performed since 1990 show high prevalences: about 10% of menoften or always experience premature ejaculation. The prevalence of delayed ejaculation and anorgasmia is estimated to be between 5 and 10%. Ejaculatory dysfunctions are therefore significant health problems with consequences on sexuality, fertility and quality of life.     

Testosterone metabolism in peripheral nerves: presence of the 5 alpha-reductase-3 alpha-hydroxysteroid-dehydrogenase enzymatic system in the sciatic nerve of adult and aged rats

Previous reports from this laboratory indicate that the 5 alpha-reductase, the enzyme which converts testosterone into its "active" metabolite 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone, DHT) is highly concentrated in the white matter structures of the CNS, which are mainly composed of myelinated fibers. No studies have been performed up to now, in order to evaluate the possible presence of the 5 alpha-reductase activity in peripheral myelinated nerves. To this purpose the 5 alpha-reductase activity has been evaluated in the sciatic nerve of the rat and compared to that present in the cerebral cortex and in the subcortical white matter, a central structure mainly composed of myelinated fibers. The study has been performed in normal adult male rats (60-90-day-old) and in aged (20-month-old) animals. The data obtained in 60-90-day-old animals indicate the presence of an active metabolism of testosterone at the level of the sciatic nerve. In this structure, testosterone is actively transformed into DHT and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol); in the sciatic nerve, the formation of DHT is equal to that found in the subcortical white matter and higher than that found in the cerebral cortex. Moreover, at variance with what happens in CNS structures, where 3 alpha-diol is produced only in small amounts, in the sciatic nerve this metabolite is produced in amounts similar to those of DHT. The study in aged rats has shown that in the sciatic nerve, the formation of DHT and particularly that of 3 alpha-diol are much lower than in younger animals. No age-related variations in the 5 alpha-reductase activity in the cerebral cortex and in the subcortical white matter have been observed.     

Male collared lizards,Crotaphytus collaris (Sauria: Crotaphytidae), signal females by broadcasting visual displays

The signalling function of displays broadcast when animals are distant from conspecifics can be difficult to determine. I tested the extent to which visually transmitted broadcast displays given by free‐ranging territorial male collared lizards signalled same‐sex rivals or females. One test involved recording the frequency of broadcast displays, aggressive contests with rivals, and courtship encounters with females during ten reproductive seasons when local sex ratios varied markedly. The frequency of broadcast displays decreased as the ratio of male competitors to females increased. The frequency with which males initiated contests with rivals was not related to the ratio of competitors to females, whereas the frequency of courtship interactions decreased with sex ratio because there were fewer females to court. The behaviour of males that defended territories during two successive seasons showed a similar pattern. Broadcast display frequency was positively correlated with courtship frequency, but not with the frequency of contests with rivals. Lastly, individual males gave more broadcast displays during focal observations when they also engaged in courtship encounters with females than other observations when they engaged in aggressive conflicts with rival males. Although these results do not reject the possibility that broadcast displays may also signal male rivals, they support a major role of these displays in advertisement to females. © 2013 The Linnean Society of London