Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain.

For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life. Here we will review and discuss relevant data showing how particular X- and Y-linked genes and epigenetic mechanisms controlling their expression and inheritance are involved, along with or independently of gonadal hormones, in the generation of sex differences in the brain.

Altered production of reproductive neuropeptides in rats subjected to chronic intermittent hypoxia.

Hypobaric hypoxia is a stressful condition known to decrease fertility both in humans and animals. However, the mechanism by which the hypothalamus-pituitary-gonad axis is altered remains unknown. The aim of the present study was to analyze the effects of chronic intermittent and continuous exposure to hypoxia on hypothalamic-pituitary-gonadal axis regulation in male rats. Thirty adult male Wistar rats were assigned to one of the following three groups: control group; chronic intermittent hypoxia: subjected to 600 mbar for 18 h/d five days a week; and chronic continuous hypoxia: subjected to 600 mbar for 23.5 hours/day seven days a week, for 30 days. Plasma luteinizing hormone and testosterone concentration, hypothalamic GnRh, Kiss1 and Rfrp3 mRNA levels and PGE2 content were determined. Levels of Rfrp3, a negative regulator of GnRH and LH release, were higher in intermittently exposed animals than in controls. Levels of Kiss1, a neuropeptide that stimulates the release of GnRH only increased in animals exposed to continuous hypoxia. Plasma luteinizing hormone and testosterone concentrations and body weight were lower in rats subjected to intermittent hypoxia as compared to the remaining groups. GnRh mRNA levels as well as PGE2 content remained unchanged in all groups. Taken together, results suggest that besides the well documented direct effects of hypoxia on the testes, infertility observed in male rats exposed to hypoxia may also be due to overexpression of negative regulators of GnRH and luteinizing hormone release. Intermittent, rather than continuous, to hypoxia exposure would seem to be more detrimental to fertility.

Olfactory conditioned same-sex partner preference in female rats: Role of ovarian hormones.

The dopamine D2-type receptor agonist quinpirole (QNP) facilitates the development of conditioned same-sex partner preference in males during cohabitation, but not in ovariectomized (OVX) females, primed with estradiol benzoate (EB) and progesterone (P). Herein we tested the effects of QNP on OVX, EB-only primed females. Females received a systemic injection (every four days) of either saline (Saline-conditioned) or QNP (QNP-conditioned) and then cohabited for 24h with lemon-scented stimulus females (CS+), during three trials. In test 1 (female-female) preference was QNP-free, and females chose between the CS+ female and a novel female. In test 2 (male-female) they chose between the CS+ female and a sexually experienced male. In test 1 Saline-conditioned females displayed more hops & darts towards the novel female, but QNP-conditioned females displayed more sexual solicitations towards the CS+ female. In test 2 Saline-conditioned females displayed a clear preference for the male, whereas QNP-conditioned females displayed what we considered a bisexual preference. We discuss the effect of dopamine and ovarian hormones on the development of olfactory conditioned same-sex preference in females.

Influence of estrous cycle hormonal fluctuations and gonadal hormones on the ventilatory response to hypoxia in female rats.

Sex hormones may influence many physiological processes. Recently, we demonstrated that hormonal fluctuations of cycling female rats do not affect respiratory parameters during hypercapnia. However, it is still unclear whether sex hormones and hormonal fluctuations that occur during the estrous cycle can affect breathing during a hypoxic challenge. Our study aimed to evaluate respiratory, metabolic, and thermal responses to hypoxia in female rats on different days of the estrous cycle (proestrus, estrus, metestrus, and diestrus) and in ovariectomized rats that received replacement with oil (OVX), estradiol (OVX + E2), or a combination of estradiol and progesterone (OVX + E2P). Ventilation (V E), tidal volume (V T), respiratory frequency (fR), oxygen consumption (VO2), and V E/VO2 were not different during the estrous cycle in normoxia or hypoxia. Body temperature (Tb) was higher during estrus, but decreased similarly in all groups during hypoxia. Compared with intact females in estrus, gonadectomized rats also had lower Tb in normoxia, but not in hypoxia. OVX rats experienced a significant drop in the ventilatory response to hypoxia, but hormonal replacement did not restore values to the levels of an intact animal. Our data demonstrate that the different phases of the estrous cycle do not alter ventilation during normoxia and hypoxia, but OVX animals display lower ventilatory responses to hypoxia compared with ovary-intact rats. Because estradiol and progesterone replacement did not cause significant differences in ventilation, our findings suggest that a yet-to-be-defined non-steroidal ovarian hormone is likely to stimulate the ventilatory responses to hypoxia in females.

Autocrine/paracrine proliferative effect of ovarian GH and IGF-I in chicken granulosa cell cultures.

It is known that growth hormone (GH) and its receptor (GHR) are expressed in granulosa cells (GC) and thecal cells during the follicular development in the hen ovary, which suggests GH is involved in autocrine/paracrine actions in the female reproductive system. In this work, we show that the knockdown of local ovarian GH with a specific cGH siRNA in GC cultures significantly decreased both cGH mRNA expression and GH secretion to the media, and also reduced their proliferative rate. Thus, we analyzed the effect of ovarian GH and recombinant chicken GH (rcGH) on the proliferation of pre-hierarchical GCs in primary cultures. Incubation of GCs with either rcGH or conditioned media, containing predominantly a 15-kDa GH isoform, showed that both significantly increased proliferation as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, proliferating cell nuclear antigen (PCNA) quantification and ((3)H)-thymidine incorporation ((3)H-T) assays in a dose response fashion. Both, locally produced GH and rcGH also induced the phosphorylation of Erk1/2 in GC cultures. Furthermore, GH increased IGF-I synthesis and its release into the GC culture incubation media. These results suggest that GH may act through local IGF-I to induce GC proliferation, since IGF-I immunoneutralization completely abolished the GH-induced proliferative effect. These data suggest that GH and IGF-I may play a role as autocrine/paracrine regulators during the follicular development in the hen ovary at the pre-hierarchical stage.

Hormonal regulation of hepatic drug biotransformation and transport systems.

The human body is constantly exposed to many xenobiotics including environmental pollutants, food additives, therapeutic drugs, etc. The liver is considered the primary site for drug metabolism and elimination pathways, consisting in uptake, phase I and II reactions, and efflux processes, usually acting in this same order. Modulation of biotransformation and disposition of drugs of clinical application has important therapeutic and toxicological implications. We here provide a compilation and analysis of relevant, more recent literature reporting hormonal regulation of hepatic drug biotransformation and transport systems. We provide additional information on the effect of hormones that tentatively explain differences between sexes. A brief discussion on discrepancies between experimental models and species, as well as a link between gender-related differences and the hormonal mechanism explaining such differences, is also presented. Finally, we include a comment on the pathophysiological, toxicological, and pharmacological relevance of these regulations.

Effect of sex differences and gonadal hormones on kainic acid-induced neurodegeneration in the bed nucleus of the stria terminalis of the rat.

Previously we have demonstrated that medial nucleus of the amygdala, which is part of medial extended amygdala, is damaged by status epilepticus induced by kainic acid (KA) and this neurodegeneration was prevents by estrogen replacement. The medial bed nucleus of stria terminalis (BSTM) also belong to medial extended amygdala and it is uncertain whether the gonadal hormones are protective or not against this neurotoxicity in the BSTM. Here we show that a single i.p. injection of KA (9 mg/kg) induces neurodegeneration in the subnuclei of the BSTM of rats with different degrees of intensity in males and females. A differential neuroprotective effect of the gonadal hormones was also observed. In diestrous rats, massive neuronal death similar to that in the ovariectomized females was detected. BSTM neurons of proestrous rats, like the ovariectomized treated with estrogen, were significantly less affected by the KA. Testosterone produced a mild neuroprotective action, but dihydrotestosterone did not protect. A similar pattern was observed in all male groups. This results show that estrogen protects BSTM neurons from KA neurotoxicity and androgens are partially neuroprotective; and probably this effect of androgens is due to conversion to estrogen.

Norepinephrine modulates the effect of neuropeptides in coeliac ganglion on ovarian hormones release: its relationship with ovarian nitric oxide and nerve growth factor.

OBJECTIVE: Ovarian steroids are modulated by neural influences. In this work we investigate whether norepinephrine (NE) modifies the vasoactive intestinal peptide (VIP) or neuropeptide Y (NPY) actions in coeliac ganglion (CG) on the ovarian hormone release, and evaluate the participation of nitric oxide (NO), measured as nitrite, and of inducible nitric oxide synthetase (iNOS) protein, nerve growth factor (NGF) and its trkA receptor gene expression in the ovarian response. METHODS: The study was performed in the ex vivo CG-superior ovarian nerve (SON)-ovary system of rats on diestrus day 2 (D2). CG and ovary were placed in separate compartments connected by the SON and incubated with Krebs-Ringer buffer. After addition of 50 ng/ml VIP, 50 ng/ml NPY, 10-6 M NE, or a mix of VIP+NE or NPY+NE in ganglion, samples from the ovarian compartment were taken at different times throughout 180 minutes to measure progesterone, androstenedione and nitrite levels. RESULTS: VIP and NPY in ganglion induced an increase of progesterone release that was associated for VIP, but not NPY, with a decrease of ovarian nitrite levels, iNOS protein, and NGF/trkA receptor mRNA expression. By contrast, NE in ganglion decreased progesterone, an effect that was suppressed by addition of propranolol in ganglion, and increased nitrites/iNOS and NGF/trkA receptor expression in ovary. GABA A receptor antagonist bicuculline (20 muM) added in ovarian compartment prevented the inhibitory effect on progesterone caused by NE in CG. Androstenedione was not modified under neuropeptides or NE ganglionic stimulation. CONCLUSIONS: Finally, results from VIP+NE or NPY+NE in ganglion showed that ovarian response on D2 induced by VIP or NPY alone is moderated by the opposite action of NE, and occurs only on progesterone, the most sensitive steroid to neural action.

Gonadal hormones decrease temporomandibular joint kappa-mediated antinociception through a down-regulation in the expression of kappa opioid receptors in the trigeminal ganglia.

We have previously demonstrated that activation of kappa-opioid receptor located in the temporomandibular joint (TMJ) of rats induces a significantly greater TMJ antinociception in diestrus females than in proestrus females (higher estradiol serum levels than diestrus) and males. These findings indicate that gonadal hormones decrease TMJ kappa-mediated antinociception. The aim of this study was to investigate some of the mechanisms by which gonadal hormones decrease TMJ kappa-mediated antinociception. Western blot analysis demonstrated a significantly lower kappa-opioid receptor expression in the trigeminal ganglia of intact males than in intact and ovariechtomized (OVX) females and orchidectomized (ORX) males. In females, kappa-opioid receptor expression in the trigeminal ganglia was significantly lower in proestrus than in diestrus and OVX females. Taken together these findings suggest that gonadal hormones, especially male gonadal hormones, down-regulate kappa-opioid receptor expression. Co-application of the NOS inhibitor L-NMMA or the NO-sensitive guanylyl cyclase inhibitor ODQ with the kappa-opioid receptor agonist U50,488 blocked TMJ kappa-mediated antinociception in males and females. These findings suggest that antinociception induced by activation of kappa opioid receptors in the TMJ region is mediated by the L-arginine/NO/cGMP pathway in both sexes. Despite the involvement of the L-arginine/NO/cGMP pathway in TMJ kappa-mediated antinociception in both sexes, gonadal hormones do not diminish the activity of this pathway to decrease TMJ kappa-mediated antinociception. Alternatively, they significantly reduce kappa-opioid receptor expression in the trigeminal ganglia.

Different gender response to serotonergic and noradrenergic antidepressants. A comparative study of the efficacy of citalopram and reboxetine.

BACKGROUND: It is well established that depressive disorders are more prevalent in women; however gender differences in the pharmacological response to antidepressants are not a consistent finding in all reports. It is considered that this discrepancy can be explained by the fact that in most clinical trials drug use for comparative purposes is not completely different. In this study gender differences in antidepressant response with citalopram (CTP), a selective serotonin reuptake inhibitor and reboxetine (RBX), a selective noradrenaline reuptake inhibitor were evaluated in a group of young men and premenopausal women. METHOD: Eighty-six depressed patients 18 to 40 years old participated in an 8-week double-blind clinical trial. Subjects were divided in four groups according to sex and treatment assignation: females treated with CTP (n = 25) or RBX (n = 23), and males treated with CTP (n = 19) or RBX (n = 19). Response was determined using HDRS and BDI. RESULTS: ANOVA analysis considering change in HDRS scores from baseline to last evaluation found a significant interaction between gender and type of treatment. Females treated with CTP showed a significantly greater response than females treated with RBX, while in men no differences were observed for both drugs. LIMITATIONS: Replication using larger sample size and longer treatment periods is required. CONCLUSIONS: These results support previous findings which show that premenopausal women respond better than men to serotonergic antidepressants. They also support that a plausible interaction between gonadal hormones and serotonin may explain gender differences in antidepressant response.