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Abstract In the adult rat, neural signals arriving to the ovary via the superior ovarian nerve (SON) modulate progesterone (P4), testosterone (T) and estradiol (E2) secretion. The aims of the present study were to analyze if the SON in the pre-pubertal rat also modulates ovarian hormone secretion and the release of follicle stimulating hormone (FSH) and luteinizing (LH) hormone. P4, T, E2, FSH and LH serum levels were measured 30 or 60 minutes after sectioning the SON of pre-pubertal female rats. Our results indicate that the effects on hormone levels resulting from unilaterally or bilaterally sectioning the SON depends on the analyzed hormone, and the time lapse between surgery and autopsy, and that the treatment yielded asymmetric results. The results also suggest that in the pre-pubertal rat the neural signals arriving to the ovaries via the SON regulate the enzymes participating in P4, T and E2 synthesis in a non-parallel way, indicating that the mechanisms regulating the synthesis of each hormone are not regulated by the same signals. Also, that the changes in the steroids hormones are not explained exclusively by the modifications in gonadotropins secretion. The observed differences in hormone levels between rats sacrificed 30 and 60 min after surgery reflect the onset of the compensatory systems regulating hormones secretion.

Abstract In the present study we analyzed the existence of asymmetry in the secretion of steroid hormones in pre-pubertal female rats treated with unilateral ovariectomy (ULO) or unilateral perforation of the abdominal wall (sham-surgery). Treated rats were sacrificed at different times after surgery. Since sham-surgery had an apparent effect on the age of first vaginal estrous (FVE) and serum levels hormone, the results of the sham surgery groups were used to assess the effects of their respective surgery treatment groups. On the day of FVE, compensatory ovulation (CO) and compensatory ovarian hypertrophy (COH) were similar in animals with ULO, regardless of the ovary remaining in situ. In ULO treated animals, progesterone (P4) levels were higher than in animals with sham-surgery one hour after treatment but lower in rats sacrificed at FEV. Left-ULO resulted in lower testosterone (T) concentration 48 and 72 hours after surgery. In rats with Right-ULO lower T concentrations were observed in rats sacrificed one or 72 hours after surgery, and at FVE. ULO (left or right) resulted in lower estradiol (E2) concentrations one or 72 hours after treatment. In rats with Left-ULO, E2 levels were higher 48 hours after surgery and at FVE. Left-ULO resulted in higher levels of follicle stimulating hormone (FSH) five hours after surgery and at FVE. FSH levels were higher in rats with Right-ULO sacrificed on FVE. The present results suggest that in the pre-pubertal rat both ovaries have similar capacities to secrete P4, and that the right ovary has a higher capacity to secrete E2. Taken together, the present results support the idea that the effects of ULO result from the decrease in glandular tissue and changes in the neural information arising from the ovary.

Abstract The present study tested the hypothesis that if polycystic ovary syndrome (PCOS) results from activating the noradrenergic outflow to the ovary, unilaterally sectioning the superior ovarian nerve (SON) will result in ovulation by the denervated ovary, and the restoration of progesterone (P4), testosterone (T) and estradiol (E2) normal serum level. A single 2 mg dose of estradiol valerate (EV) to adult rats results in the development of a syndrome similar to the human PCOS. Ten-day old rats were injected with EV or vehicle solution (Vh) and were submitted to sham surgery, unilateral or bilateral sectioning of the SON at 24-days of age. The animals were sacrificed at 90 to 92 days of age, when they presented vaginal estrus preceded by a pro-estrus smear. In EV-treated animals, unilateral sectioning of the SON restored ovulation by the innervated ovary and unilateral or bilateral sectioning of the SON normalized testosterone and estradiol levels. These results suggest that aside from an increase in ovarian noradrenergic tone in the ovaries, in the pathogenesis of the PCOS participate other neural influences arriving to the ovaries via the SON, regulating spontaneous ovulation. Changes in P4, T and E2 serum levels induced by EV treatment seem to be controlled by neural signals arising from the abdominal wall and other signals arriving to the ovaries through the SON, and presents asymmetry.

Abstract The present study evaluates the participation of the vagus nerve in pre-pubertal rats with unilateral ovariectomy on puberty onset, and on progesterone, testosterone and estradiol serum levels, and the compensatory responses of the ovary. Unilateral vagotomy did not modify the onset of puberty in unilaterally ovariectomized rats. Ovulation rates of animals with the left vagus nerve sectioned and the left ovary in-situ was lower than in rats with only unilateral ovariectomy. Sectioning the left vagus to 32-day old rats with the left ovary in-situ resulted in lower compensatory ovarian hypertrophy than in rats with right unilateral ovariectomy. Twenty-eight or 32-day old animals with sectioning of the right vagus nerve and the right ovary in situ showed higher compensatory ovulation. Twenty-eight -day old rats with the right ovary in situ had higher progesterone and testosterone levels than animals of the same age with the left ovary in-situ. Compared to animals with the right ovary in situ, animals treated at 32-days of age, sectioning the ipsi-lateral vagus nerve resulted in higher progesterone levels. Higher progesterone levels were observed in 28- and 32 days old rats with the left ovary in situ and left vagus nerve sectioned. Thirty-two day old animals with the right ovary in situ and right vagus nerve sectioned had higher progesterone levels than rats of the same age with the left ovary in situ and left vagus nerve sectioned. Left vagotomy to 28-day old rats with the left ovary in situ resulted in higher testosterone levels, a reverse response to that observed in animals with sectioning of the right vagus and the right ovary in situ. Thirty-two day old rats with the left ovary in situ and left vagus nerve sectioned showed lower testosterone levels than animals without vagotomy and with the left ovary in situ. Twenty-eight -day old animals with the left vagus sectioned and left ovary in situ had lower estradiol serum levels than rats without unilateral vagotomy, a response similar to that observed in 32-day old rats with the right ovary in situ and right vagus nerve sectioned. Present results suggest an asymmetric regulation of steroid hormones secretion by the vagus nerve innervations in animals with unilateral ovariectomy, and those differences in testosterone serum levels observed are associated to the ovary remaining in-situ, vagal innervation and age when the animals were treated.

Abstract There is evidence that one gonad has functional predominance. The present study analyzed the acute effects of unilateral ovariectomy (ULO) and blocking the cholinergic system, by injecting atropine sulfate (ATR), on estradiol (E2) serum concentrations during the estrous cycle. The results indicate that ULO effects on E2 concentrations are asymmetric, vary during the estrous cycle, and partially depend on the cholinergic innervation. Perforation of the left peritoneum resulted in lower E2 serum concentrations in the three stages of the estrous cycle. At proestrus, unilateral or bilateral perforation of the peritoneum resulted in lower E2 serum concentrations. ULO of the right ovary (left ovary in situ) resulted in significantly higher E2 concentrations than animals with ULO of the left ovary (right ovary in situ). ATR treatment to ULO rats on D1 resulted in a significant drop of E2 serum concentrations. ULO rats treated with ATR on D2 or P, resulted in an asymmetrical E2 secretion response; when the right ovary remained in situ an increase in E2 was observed, and a decrease when the left ovary remained in situ. The results obtained in the present study suggest that each ovary's ability to compensate the secretion of E2 from the missing ovary is different and varies during the estrous cycle. The results also suggest that the cholinergic system participates in regulating ovarian E2 secretion. Such participation varies according to the ovary remaining in situ and the stage of the estrous cycle of the animal. The results agree with previously stated hypothesis of a neural pathway arising from the peritoneum that participates in regulating E2 secretion, and also supports the idea of cross-talk between the ovaries, via a neural communication, that modulates E2 secretion.

Abstract The presence of asymmetry in the capacity of the left and right ovaries to secrete testosterone was analyzed by studying the effects of hemiovariectomy along the estrus cycle one hour after surgery. The effects of ether anesthesia on hormone serum levels were also analyzed. Bilateral ovariectomy and the extirpation of the left ovary performed on the day of proestrus resulted in significantly lower testosterone levels. Compared to the anesthetized group, the effects of perforating the peritoneum unilaterally varied according to the day of the estrous cycle and the side of the peritoneum surgery was performed on. Injecting atropine sulfate (ATR) to control or anesthetized rats on D1 resulted in a significant increase of testosterone serum levels. The effects of perforating the peritoneum on testosterone levels depended on the cholinergic innervation and varied along the estrous cycle. Blocking the cholinergic system before performing unilateral or bilateral ovariectomy had different effects depending on the day of the estrous cycle. Testosterone plasma levels increased significantly when surgery was performed on the day of diestrus and dropped when surgery was performed on proestrus. Similar effects were observed when the left adrenal was extirpated from animals with the cholinergic system blocked. The results presented herein support the hypothesis of asymmetry in the ovaries' abilities to secrete steroid hormones, and that the capacity to secrete testosterone varies along the estrous cycle.

Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro and may be susceptible to drug-drug interactions when co-administered with CYP3A inhibitors or inducers. The primary objective was to assess the impact of the strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P-gp inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy volunteers following a single 50-mg dose. A total of 32 participants were enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to infinity (AUC inf ) and maximum plasma concentration (C max ) geometric mean for encorafenib increased by 183% and 68.4%, respectively, when co-administered with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2 L/h when coadministered with posaconazole, and plasma terminal half-life (t ½ ) of encorafenib increased from 4.3 to 7.3 h. The AUC inf and C max geometric mean for encorafenib increased by 83.0% and 44.7%, respectively, when co-administered with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 to 16.0 L/h when co-administered with diltiazem, and plasma t ½ of encorafenib increased from 6.6 to 7.9 h. There were no deaths, serious adverse events (AEs), or patient discontinuations due to AEs in parts 1 or 2. The most frequently reported treatment-related AEs were erythema (n = 14; 88%) and headache (n = 11; 69%) in part 1 and headache (n = 7; 44%) in part 2. The results of this study indicate that co-administration of encorafenib with strong or moderate CYP3A4 inhibitors should be avoided., (© 2023 Pfizer Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The steroids corticosterone and dehydroepiandrosterone (DHEA) perform multiple life course functions. Rodent life-course circulating corticosterone and DHEA trajectories are unknown. We studied life course basal corticosterone and DHEA in offspring of rats fed protein-restricted (10% protein, R) or control (20% protein, C), pregnancy diet first letter, and/or lactation second letter, producing four offspring groups-CC, RR, CR, and RC. We hypothesize that 1. maternal diet programs are sexually dimorphic, offspring life course steroid concentrations, and 2. an aging-related steroid will fall. Both changes differ with the plastic developmental period offspring experienced R, fetal life or postnatally, pre-weaning. Corticosterone was measured by radioimmunoassay and DHEA by ELISA. Steroid trajectories were evaluated by quadratic analysis. Female corticosterone was higher than male in all groups. Male and female corticosterone were highest in RR, peaked at 450 days, and fell thereafter. DHEA declined with aging in all-male groups. DHEA: corticosterone fell in three male groups but increased in all-female groups with age. In conclusion, life course and sexually dimorphic steroid developmental programming-aging interactions may explain differences in steroid studies at different life stages and between colonies experiencing different early-life programming. These data support our hypotheses of sex and programming influences and aging-related fall in rat life course serum steroids. Life course studies should address developmental programming-aging interactions.

Androgen receptors (AR) are crucial in the control of male sexual behavior and sex preference. AR are particularly concentrated in areas related with the neuroendocrine control of sex preference including the medial amygdala (MeA), the ventromedial nucleus of the hypothalamus (VMH), the bed nucleus of the stria terminalis (BNST), the medial preoptic area (MPOA), the nucleus accumbens (Acb), the suprachiasmatic (SCh) and supraoptic (SO) nuclei, but also seem to be important for the control of reproductive processes in the hippocampus (CA1-CA4 and dentate gyrus, DG). In the present study we analyzed the density of AR in these brain areas of adult male rats with sexual preference (established in a three-compartment box). Same-sex preference was produced in male rats by the prenatal administration of the aromatase inhibitor, letrozole (0.56 μg/kg/ml s.c. G10-22) that usually produces 1-2 animals per litter with same sex preference, while the others retain a female sex preference. We also included a group of proestrus females that had a clear preference for a sexually active male. AR were analyzed by immunocytochemistry using PG21 as primary antibody. We also measured total plasma testosterone concentrations by radioimmunoassay. In males with same sex preference there was a specific AR overexpression in CA3 and CA4 that suggests a feminized pattern because females in proestrus trend to show a higher density of AR in these hippocampal areas. Sex differences in AR density were found in the anterior cingulate cortex (ACg) and frontoparietal cortex (FrPa). Serum levels of testosterone did not differ between groups. Data are discussed based on the role of AR in the hippocampus., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Maternal obesity (MO) induces negative consequences in the offspring development. Adiposity phenotype is associated with maternal diet at early pregnancy and DNA methylation marks in the RXRα promotor at birth. Glucocorticoids play an important role in the regulation of metabolism through the activation of nuclear hormone receptors such as the RXRα protein. The aim of the study was to analyze steroid hormone changes at the end of pregnancy in the obese mother and RXRα gene methylation in the umbilical cord. For this purpose, in a well-established MO model, female Wistar rats were fed either standard chow (controls: C) or high-fat obesogenic diet (MO) before and during pregnancy to evaluate at 19 days of gestation (19 dG): 1) maternal concentration of circulating steroid hormones in MO and C groups, 2) maternal and fetal weights, 3) analysis of correlation between hormones concentration and maternal and fetal weights, 4) DNA methylation status of a single locus of RXRα gene near the early growth response (EGR-1) protein DNA binding site, and 5) RXRα mRNA and protein expressions in umbilical cords. Our results demonstrate that at 19 dG, MO body weight before and during pregnancy was higher than C; MO progesterone and corticosterone serum concentrations were higher and estradiol lower than C. There were not differences in fetal weight between male and female per group, therefore averaged data was used; MO fetal weight was lower than C. Positive correlations were found between progesterone and corticosterone with maternal weight, and estradiol with fetal weight, while negative correlation was observed between corticosterone and fetal weight. Additionally, male umbilical cords from MO were hypermethylated in RXRα gene compared to male C group, without differences in the female groups; mRNA and protein expression of RXRα were decreased in F1 male but not in female MO compared to C. In conclusion, MO results in dysregulation of circulating steroid hormones of the obese mothers and low fetal weight in the F1, modifying DNA methylation of RXRα gene as well as RXRα mRNA and protein expression in the umbilical cord in a sex-dependent manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chavira-Suárez, Reyes-Castro, López-Tenorio, Vargas-Hernández, Rodríguez-González, Chavira, Zárate-Segura, Domínguez-López, Vadillo-Ortega and Zambrano.)

Estrogen replacement therapy (ERT) is an effective treatment for symptoms associated with climacteric and depression some women experience during perimenopause and menopause. The antidepressant-like effects of ERT may depend on the type of estrogen, age, and time when restitution is initiated after hormonal decline. Prolame is a synthetic steroid with estrogenic and antidepressant-like effects that may produce fewer adverse effects. We hypothesize that such actions of prolame on females depend on age and the duration of hormone deprivation period. We assessed the antidepressant-like effects of 17β-estradiol (E 2 ) and prolame in young and middle-aged rats across different post-ovariectomy (Ovx) time frames. Independent groups of young adults and middle-aged female rats were tested in the forced swimming test (FST) at 3, 8, 16, and 24 weeks post-Ovx. Prolame and E 2 were administered in a sub-chronic schedule consisting of three injections before the FST. Likewise, the utero-trophic effects of these hormones were analyzed. We found that E 2 and prolame reduced immobility in young rats 3 and 8 weeks after Ovx; in contrast, only prolame produced this effect in middle-aged rats three weeks post-Ovx. E 2 and prolame increased the animals' utero-somatic index at all post-Ovx times, but the action of E 2 and prolame produced a greater response in young adult rats. Our findings showed that the antidepressant-like effects of E 2 and prolame depend on the post-Ovx time frame, age, and estrogen type. Interestingly, our results indicate that, in contrast to E 2 , prolame maintained its antidepressant effect in middle-aged rats., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Problem: The cAMP pathway is involved in important biological processes including immune regulation and hormone signaling. At the feto-maternal unit, cAMP participates in placental function/physiology and the establishment of immunoendocrine networks. Low cAMP in male fetuses cord blood has been linked to poorer perinatal outcomes; however, cAMP placental content and its relationship with immune factors and fetal sex in an infectious condition have not been investigated., Method of Study: Sex-dependent changes in cAMP content and its association with cytokines and antimicrobial peptides expression were studied in human placentas collected from normal pregnancies and with urinary tract infections (UTI). Radioimmunoassay was used to quantify cAMP in placental tissue, while immune markers expression was studied by qPCR. Additionally, cAMP effect on antimicrobial peptides expression was studied in cultured trophoblasts challenged with lipopolysaccharide, to mimic an infection., Results: In UTI, placentas from female neonates had higher cAMP tissue content and increased expression of TNFA, IL1B, and IL10 than those from males, where IFNG was more elevated. While cAMP negatively correlated with maternal bacteriuria and IFNG, it positively correlated with the antimicrobial peptide S100A9 expression in a sex-specific fashion. In cultured trophoblasts, cAMP significantly stimulated β-defensin-1 while reduced the lipopolysaccharide-dependent stimulatory effect on β-defensin-2, β-defensins-3, and S100A9., Conclusion: Our results showed higher cAMP content and defense cytokines expression in placentas associated with female neonates from pregnancies complicated by UTI. The associations between cAMP and bacteriuria/immune markers, together with cAMP's ability to differentially regulate placental antimicrobial peptides expression, suggest a dual modulatory role for cAMP in placental immunity., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Programming of offspring life-course health by maternal nutrition and stress are well studied. At postnatal day 850, we evaluated male and female steroid levels and metabolism in aged offspring of primigravid sister rats bred at 70, 90, 150, or 300 days' life. At 850 days life, male offspring corticosterone was similar regardless of maternal age. Female corticosterone was highest in offspring of 70- and 300-day mothers. Serum dehydroepiandrosterone:corticosterone was lowest in both sexes of offspring of 70- and 300-day mothers. Male and female fat depots were smaller in offspring of 150- than 70- and 90-day mothers. Insulin, glucose, and homeostatic model assessment were similar in all male offspring but higher in female offspring of 70-day mothers than other ages. We conclude, maternal age affects offspring aging in an offspring sex-dependent manner and merits consideration in designing and interpreting programming studies., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: to compare testosterone levels between female depressed patients and female bipolar patients. Methods: Sixty-one female patients with major depressive disorder (MDD) ( n  = 23) or bipolar disorder (BD) ( n  = 38) between 18 and 45 years old were included in the study. Participants were evaluated during a depressive or manic episode with the Hamilton depression rating scale (HDRS) or Young mania rating scale (YMRS), respectively. No patients in the MDD group were taken valproate while in the BD group 14 (36.84%) were taken valproate. Total testosterone (TT) and free testosterone (FT) levels were quantified during the early follicular phase of the cycle, with radioimmunoassay or solid phase enzyme-linked immunoassay. Data were collected from May 2016 to February 2017. Results: Mean TT serum levels were significantly higher in BD patients in comparison to MDD patients. Although age and diagnosis were related to TT levels, however when we added valproate use in the analysis, only the relation between TT and valproate use remained significant. Conclusions: In this sample, TT levels were related to valproate use in patients with BD. More studies regarding the role of testosterone in affective symptoms should be conducted to clarify the relation between testosterone, affective disorders, and medication.KeypointsWe observed that testosterone levels were significant higher in bipolar women compared to women with MDD.The use of valproate could be associated with the testosterone levels in female patients with BD.Evaluation of women suffering BD should include a testosterone levels determination, particularly when they are taking valproate.

We examined the role of the estrogen receptors alpha (ERα) and beta (ERβ) in of the preoptic-anterior hypothalamic area (POA-AHA) in the regulation of ovulation in rats. The number of ERα- and ERβ-immunoreactive (-ir) cells was determined at 09:00, 13:00, and 17:00 h of each stage of the estrous cycle in intact rats. Additionally, the effects of blocking ERα and ERβ on ovulation rate at 09:00 h on diestrus-2 or proestrus day through the microinjection of methyl-piperidino-pyrazole (MPP) or cyclofenil in either side of POA-AHA were evaluated. The number of ERα-ir and ERβ-ir cells in POA-AHA varied in each phase of estrous cycle. Either MPP or cyclofenil in the right side of POA-AHA on diestrus-2 day reduced the ovulation rate, while at proestrus day it was decreased in rats treated in either side with MPP, and in those treated with cyclofenil in the left side. MPP or cyclofenil produced a decrease in the surge of luteinizing hormone levels (LH) and an increase in progesterone and follicle stimulating hormone (FSH). Replacement with synthetic luteinizing hormone-releasing hormone in non-ovulating rats treated with MPP or cyclofenil restored ovulation. These results suggest that activation of estrogen receptors on the morning of diestrus-2 and proestrus day asymmetrically regulates ovulation and appropriately regulates the secretion of FSH and progesterone in the morning and afternoon of proestrus day. This ensures that both, the preovulatory secretion of LH and ovulation, occur at the right time.

Previous studies with perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) indicate that they act as endocrine disruptors, in addition to inducing alterations and damaging reproductive health; however, the biological mechanisms by which these disorders are produced are not yet understood. The aim of this study was to analyze the effect of PFOS and PFOA on in vitro steroidogenic secretion in porcine theca and granulosa cells, with or without gonadotropic stimulation. Granulosa and theca cells were isolated and cultured. Cell nature was performed by immunocytochemistry. PFOS and PFOA effect on steroid secretion was analyzed by chemiluminescence. In the present study, alterations in steroidogenic secretion were found when administering PFOS (0.12, 1.2, 12, 120 or 240μM) or PFOA (0.012, 0.12, 1.2, 12 or 24μM) to theca and granulosa cells. When theca and granulosa cells were stimulated with 500ng/mL LH or 500ng/mL FHS, respectively and immediately followed with 1.2μM of PFOS or PFOA, the perfluorinated compounds inhibited the secretion of steroid hormones in both stimulated cell types. The results indicate that PFOS and PFOA act on steroidogenic ovarian cells as endocrine disruptors, which could affect the dependent functions of sexual steroids., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: ONT-380 (ARRY-380) is a potent and selective oral HER2 inhibitor. This Phase I study determined the MTD, pharmacokinetics (PK) and antitumor activity of ONT-380 in HER2-positive advanced solid tumors, with an expansion cohort of patients with HER2 + MBC. Experimental Design: ONT-380 was administered twice daily (BID) in continuous 28-day cycles. After a modified 3+3 dose-escalation design determined the MTD, the expansion cohort was enrolled. PK properties of ONT-380 and a metabolite were determined. Response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). Results: Fifty patients received ONT-380 (escalation = 33; expansion = 17); 43 patients had HER2 + MBC. Median prior anticancer regimens = 5. Dose-limiting toxicities of increased transaminases occurred at 800 mg BID, thus 600 mg BID was the MTD. Common AEs were usually Grade 1/2 in severity and included nausea (56%), diarrhea (52%), fatigue (50%), vomiting (40%) constipation, pain in extremity and cough (20% each). 5 patients (19%) treated at MTD had grade 3 AEs (increased transaminases, rash, night sweats, anemia, and hypokalemia). The half-life of ONT-380 was 5.38 hours and increases in exposure were approximately dose proportional. In evaluable HER2 + MBC ( n = 22) treated at doses ≥ MTD, the response rate was 14% [all partial response (PR)] and the clinical benefit rate (PR + stable disease ≥ 24 weeks) was 27%. Conclusions: ONT-380 had a lower incidence and severity of diarrhea and rash than that typically associated with current dual HER2/EGFR inhibitors and showed notable antitumor activity in heavily pretreated HER2 + MBC patients, supporting its continued development. Clin Cancer Res; 23(14); 3529-36. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Muscarinic receptors (mAChRs) of the preoptic and anterior hypothalamus areas (POA-AHA) regulate ovulation in an asymmetric manner during the estrous cycle. The aims of the present study were to analyze the effects of a temporal blockade of mAChRs on either side of the POA-AHA performed in diestrus-2 rats on ovulation, the levels of estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH) and the mechanisms involved in changes in ovulation., Methods: Cyclic rats on diestrus-2 day were anesthetized and randomly assigned to the following groups: 1) microinjection of 1 μl of saline or atropine solution (62.5 ng) in the left or right POA-AHA; 2) removal (unilateral ovariectomty, ULO) of the left (L-ULO) or right (R-ULO) ovary, and 3) rats microinjected with atropine into the left or right POA-AHA plus L-ULO or R-ULO. The ovulation rate and the number of ova shed were measured during the predicted estrus, as well as the levels of estradiol, FSH and LH during the predicted proestrus and the effects of injecting synthetic LH-releasing hormone (LHRH) or estradiol benzoate (EB)., Results: Atropine in the left POA-AHA decreased both the ovulation rate and estradiol and LH levels on the afternoon of proestrus, also LHRH or EB injection restored ovulation. L- or R-ULO resulted in a lower ovulation rate and smaller number of ova shed, and only injection of LHRH restored ovulation. EB injection at diestrus-2 restored ovulation in animals with L-ULO only. The levels of estradiol, FSH and LH in rats with L-ULO were higher than in animals with unilateral laparotomy. In the group microinjected with atropine in the left POA-AHA, ovulation was similar to that in ULO rats. In contrast, atropine in the right POA-AHA of ULO rats blocked ovulation, an action that was restored by either LHRH or EB injection., Conclusions: These results indicated that the removal of a single ovary at noon on diestrus-2 day perturbed the neuronal pathways regulating LH secretion, which was mediated by the muscarinic system connecting the right POA-AHA and the ovaries.

Background: The suprachiasmatic nucleus (SCN) and the cholinergic system of various regions of the hypothalamus participate in the regulation of gonadotropin-releasing hormone (GnRH) and gonadotropin secretion, which are necessary for the occurrence of ovulation. In the present study, our goal was to analyse the effects of unilaterally blocking the muscarinic receptors in the SCN on ovulation and steroid secretion., Methods: Cyclic rats were randomly allotted to one of the experimental groups. Groups of 8-14 rats were anaesthetized and microinjected with 0.3 μl of saline or a solution of atropine (62.5 ng in 0.3 μl of saline) into the left or right SCN at 09.00 or 19.00 h during diestrus-1 or on the proestrus day. The rats were euthanized on the predicted day of oestrus, and evaluated ovulation and levels of progesterone and oestradiol. Other groups of 10 rats were microinjected with atropine into the left or right SCNs at 09.00 h on the proestrus day, were euthanized eight h later, and luteinizing hormone (LH) was measured., Results: At 09.00 or 19.00 h during diestrus-1, atropine microinjections into the SCNs on either side did not modify ovulation. The atropine microinjections performed at 09.00 h of proestrus into either side of the SCN blocked ovulation (right SCN: 1/9 ovulated vs. 9/10 in the saline group; left SCN: 8/14 ovulated vs. 10/10 in the saline group). The LH levels at 17.00 h in the rats that were microinjected with atropine at 09.00 h of proestrus were lower than those of the controls. In the non-ovulating atropine-treated rats, the injection of synthetic LH-releasing hormone (LHRH) restored ovulation. Atropine treatment at 19.00 h of proestrus on either side of the SCN did not modify ovulation, while the progesterone and oestradiol levels were lower., Conclusion: Based on the present results, we suggest that the cholinergic neural information arriving on either side of the SCN is necessary for the pre-ovulatory secretion of LH to induce ovulation. Additionally, the regulation of progesterone and oestradiol secretion by the cholinergic innervation of the SCN varies with the time of day, the day of the cycle, and the affected SCN.

Disruption of the sexual differentiation process during critical periods in male rodents produces changes in partner preference and sexual behavior. In this study we used prenatal (gestation days 10-22) letrozole (0.31 and 0.56 μg/kg) to inhibit aromatase and alter normal sexual differentiation of males. These animals and control rats (injected with vehicle) were used when adults to study: a) sexual preference (where the experimental male could choose to interact with a receptive female or a sexually experienced male); b) masculine and feminine sexual behaviors (tested in cylindrical arenas); c) non-contact erections when exposed to a female or a male and, d) serum sex steroids and gonadotropin levels. The results showed that 30% of the males treated with letrozole (0.56 μg/kg) had same-sex preference, 33% displayed lordosis and 63% showed non-contact erections in the presence of a sexually experienced male. However, 44% of these males also exhibited complete masculine sexual behavior towards receptive females. None of the control males displayed lordosis when mounted by another male and very few (12%) showed non-contact erections when exposed to a sexually experienced male. Similar low percentages were found in those males prenatally treated with the low letrozole dose (0.31 μg/kg). No difference was found in the serum levels of testosterone, estradiol, LH and FSH between control and letrozole-treated males regardless of their sexual preference. These results indicate that prenatal selective inhibition of aromatization produces feminization of sexual partner preference, arousal and sexual behavior but does not affect masculine sexual behavior., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The non-invasive monitoring of glucocorticoid hormones allows for the assessment of the physiological effects of anthropogenic disturbances on wildlife. Variation in glucocorticoid levels of the same species between protected and unprotect areas seldom has been measured, and the available evidence suggests that this relationship may depend on species-specific habitat requirements and biology. In the present study we focused on black howler monkeys (Alouatta pigra), a canopy-dwelling primate species, as a case study to evaluate the physiological consequences of living in unprotected areas, and relate them with intragroup competition and competition with extragroup individuals. From February 2006 to September 2007 we collected 371 fecal samples from 21 adults belonging to five groups (two from protected and three from unprotected areas) in Campeche, Mexico. We recorded agonistic interactions within groups and encounters with other groups (1,200 h of behavioral observations), and determined fecal glucocorticoid metabolite (FGM) concentrations with radioimmunoassays. We used linear mixed models and Akaike's information criterion to choose the best model explaining variation in FGM concentrations between protected and unprotected areas calculated from five categorical variables: habitat type (protected vs. unprotected), participation in agonistic interactions, intergroup encounters, sex and female reproductive state, and season. The best model included habitat type, the interaction between habitat type and agonism, and the interaction between habitat type and season. FGM concentrations were higher in unprotected habitats, particularly when individuals were involved in agonistic interactions; seasonal variation in FGM concentrations was only detected in protected habitats. High FGM concentrations in black howler monkeys living in unprotected habitats are associated with increased within-group food competition and probably associated with exposure to anthropogenic stressors and overall food scarcity. Because persistent high GC levels can be detrimental to health and fitness, populations living in disturbed unprotected areas may not be viable in the long-term.

Background: Intragastric or intraperitoneal ethanol (EtOH) treatment inhibits reproductive functions in females and male rats. The area of the hypothalamus where these effects take place is unknown. As the participations of the preoptic-anterior hypothalamic area (POA-AHA) in regulating ovulation is asymmetric, this study aims to analyze the effects on 17β-estradiol(E2 ), progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) serum levels, the messenger ribonucleic acid (mRNA) expression of estrogen receptor alpha (ERα) and beta (ERβ), and ovulation resulting from unilaterally microinjecting water or an EtOH solution into either side of the POA-AHA., Methods: The treatment consisted of microinjecting a 8.6 μM EtOH solution into either side of the POA-AHA. The study was performed on groups of adult cyclic rats at 09.00 hours on diestrus-1, and sacrificed on diestrus-2 at 13.00, on proestrus at 09.00 or 17.00 or on estrus at 09.00 hours. Ovulation rates were assessed in rats sacrificed on estrus. Hormonal serum levels were measured using radioimmunoassay, and as a function of ERα and ERβ mRNA expression in each side of the POA-AHA by reverse transcriptase polymerase chain reaction., Results: EtOH treatment blocked ovulation and the preovulatory release of LH, and lowered E2 levels. Irrespective of the treated POA-AHA side, ERα mRNA expression was consistently lower in the left POA-AHA and higher on the right. EtOH treatment in the left POA-AHA decreased FSH serum levels and lowered ERβ mRNA expression. In turn, EtOH treatment on the right POA-AHA resulted in higher FSH levels and ERβ mRNA expression., Conclusions: The present results show that EtOH blocks the preovulatory surge of LH on the POA-AHA. The effects of EtOH treatment of preovulatory FSH surge on the POA-AHA are asymmetric (stimulative on the right and inhibiting in the left). The effects of EtOH treatment on preovulatory LH and FSH surge could be explained by the inhibition of ERα and ERβ mRNA expression, respectively., (Copyright © 2014 by the Research Society on Alcoholism.)