Male Androgen Levels Research Articles

Baseline and stress-induced steroid plasma levels and immune function vary annually and are associated with vocal activity in male toads (Rhinella icterica)

Theoretical models predict that elevated androgen and glucocorticoid levels in males during the reproductive season promote immunosuppression. However, some studies report decreased stress response during this season. This study investigated annual variation in plasma corticosterone and testosterone levels, plasma bacterial killing ability (BKA), and neutrophil to lymphocyte ratio (NLR) in free-living male toads (Rhinella icterica). Toads were sampled in the field (baseline) and 1 h-post restraint over five months, and we considered the occurrence of vocal activity. Baseline corticosterone, testosterone, and BKA showed higher values during the reproductive period, specifically in calling male toads. The NLR was similar throughout the year, but higher values were observed in calling toads. Moreover, baseline NLR and BKA were positively correlated with both testosterone and corticosterone, suggesting higher steroid levels during reproduction are associated with enhanced cellular and humoral immunity. Despite fluctuation of baseline values, post-restraint corticosterone levels remained uniform over the year, indicating that toads reached similar maximum values throughout the year. Testosterone levels decreased following restraint before one specific reproductive period but increased in response to restraint during and after this period. Meanwhile, BKA decreased due to restraint only after the reproductive period, indicating immune protection and resilience to immunosuppression by stressors associated with steroid hormones during reproduction. Our results show that baseline and stress-induced hormonal and immune regulation varies throughout the year and are associated with vocal activity in R. icterica males, indicating a possible compromise between steroids and immune function in anuran males.

Validating enzyme immunoassays for non-invasive reproductive hormone monitoring in Temminck's pangolin.

Gonadal hormones play a central role in reproductive function and success. As such, quantifying reproductive hormones non-invasively in threatened, vulnerable and endangered wildlife species offers an ideal tool for assessing general and individual reproductive patterns in situ. Whilst the use of faeces as a hormone matrix is often preferred in these cases, the required enzyme immunoassays (EIAs) for measuring faecal androgen (fAM), oestrogen (fEM) and progestagen metabolite (fPM) concentrations must first be validated if a species gets investigated for the first time to ensure biologically relevant patterns can be observed. In this study we aimed to biologically validate the EIAs for monitoring fAM, fEM and fPM concentrations in Temminck's pangolin, Smutsia temminckii. Hormone metabolite concentrations derived from each EIA tested were compared between different age and sex classes. An epiandrosterone EIA effectively measured androgen levels in males, distinguishing between adult and juvenile individuals, as well as both female age classes. Similarly, the tested oestrogen EIA successfully distinguished between adult and juvenile female fEM concentrations, and both tested progestagen EIAs demonstrated adequate differences between fPM concentrations of adult and juvenile females. The now-validated EIAs offer robust tools for a non-invasive monitoring of reproductive activity in Temminck's pangolin. The development of such techniques will allow researchers to assess reproductive hormone patterns of the species in situ, whilst also paving the way for further studies in this field. Despite the small sample size due to the species' conservation status, the study provides a foundation for future research using a robust, validated, non-invasive monitoring tool. The latter can now be implemented in long-term monitoring with larger sample sizes to yield more comprehensive data, aiding in the conservation of Temminck's pangolin.

THU116 Characteristics Of Sleep Disturbance And The Related Hormonal Changes In Patients With Long COVID

Abstract Disclosure: N. Sunada: None. Y. Nakano: None. Y. Otsuka: None. K. Tokumasu: None. H. Honda: None. Y. Sakurada: None. Y. Matsuda: None. T. Hasegawa: None. D. Omura: None. K. Ochi: None. H. Hagiya: None. K. Ueda: None. H. Kataoka: None. F. Otsuka: None. COVID-19 causes prolonged symptoms called either long COVID or post COVID-19 condition (PCC). Such prolonged conditions have been experienced in approximately one-third of COVID-19 patients even a few months after the acute phase of infection. In Japan, we have recently reported clinical characteristics of long COVID patients who visited our COVID-19 aftercare outpatient clinic (CAC). The major complaints in the early period of the COVID-19 pandemic were fatigue and anxiety and that the severity of the infection status affected the number and duration of persistent symptoms. We have also shown that endocrine factors including anterior pituitary, adrenal and thyroid hormones and male androgen levels might be related to the fatigue symptoms of long COVID. However, the characteristics of long COVID patients with sleep disturbance have yet to be elucidated. The aim of this study was to determine the characteristics of sleep disturbance in patients with long COVID by focusing on the clinical manifestations and the related endocrine data. This study was a single-center retrospective observational study for patients who visited the CAC established in Okayama University Hospital in Japan during the period from Feb. 2021 to Jul. 2022. Out of 363 patients with long COVID after excluding 6 patients, 60 patients (16.5%) (55% males, median age of 38 years) complaining of sleep disturbance were compared with 303 patients (83.5%) (43% males, median age of 40 years) without sleep-related symptoms. Although there were no significant differences in clinical backgrounds and severities of COVID-19 between the two groups, the percentage of long COVID patients with sleep disturbance was significantly increased (50%) among patients infected in the Omicron-dominant phase. Also, the prevalence rate of sleep disturbance in patients when infected in the Omicron phase (24.8%) was two-times higher than that in patients infected in the Delta phase (12.8%). Of note, the percentages of patients with sleep disturbance who also complained of general fatigue, headache, concentration loss, anxiety, low-grade fever and brain-fog symptoms were higher than the percentages of patients without sleep disturbance who had the same complaints. Among the types of sleep disturbance, the percentage of patients who complained of loss of sleep induction (75%) was much higher than the percentage of patients with early-awaking sleep disturbance (6.7%). Endocrine examinations revealed that long COVID patients with sleep disturbance had significantly higher levels of plasma ACTH and lower levels of serum GH, suggesting the presence of hypothalamo-pituitary stress. Collectively, we uncovered that 16.5% of total patients with long COVID, reaching up to half of those in Omicron-dominant phase, complained of sleep disturbance. Endocrine workup also indicated that these manifestations could be associated with increased stress of the hypothalamo-pituitary axis. Presentation: Thursday, June 15, 2023

A Novel Approach for Polycystic Ovary Syndrome Prediction Using Machine Learning in Bioinformatics

Polycystic ovary syndrome (PCOS) is a critical disorder in women during their reproduction phase. The PCOS disorder is commonly caused by excess male hormone and androgen levels. The follicles are the collections of fluid developed by ovaries and may fail to release eggs regularly. The PCOS results in miscarriage, infertility issues, and complications during pregnancy. According to a recent report, PCOS is diagnosed in 31.3% of women from Asia. Studies show that 69% to 70% of women did not avail of a detecting cure for PCOS. A research study is needed to save women from critical complications by identifying PCOS early. The main aim of our research is to predict PCOS using advanced machine learning techniques. The dataset based on clinical and physical parameters of women is utilized for building study models. A novel feature selection approach is proposed based on the optimized chi-squared (CS-PCOS) mechanism. The ten hyper-parametrized machine learning models are applied in comparison. Using the novel CS-PCOS approach, the gaussian naive bayes (GNB) outperformed machine learning models and state-of-the-art studies. The GNB achieved 100% accuracy, precision, recall, and f1-scores with minimal time computations of 0.002 seconds. The k-fold cross-validation of GNB achieved a 100% accuracy score. The proposed GNB model achieved accurate results for critical PCOS prediction. Our study reveals that the dataset features prolactin (PRL), blood pressure systolic, blood pressure diastolic, thyroid stimulating hormone (TSH), relative risk (RR-breaths), and pregnancy are the prominent factors having high involvement in PCOS prediction. Our research study helps the medical community overcome the miscarriage rate and provide a cure to women through the early detection of PCOS.

Prevalence of Testosterone Deficiency in Elderly Male and its Association with Frailty and Mobility at a Tertiary Care Centre.

Background and Objectives:Several cross-sectional and prospective longitudinal studies have shown a progressive decline in Serum (S) Testosterone levels with an increase in age. The clinical consequence of this decline in S Testosterone is not clear from the prevailing data. Several ageing features like decreased libido, Osteo-sarcopenia, anemia, and depressed mood may be associated with reduced androgen levels in elderly males. This study was aimed to study the prevalence of androgen deficiency in elderly males more than 60 years of age presenting to the outpatient department of a tertiary care hospital and its association with frailty and mobility.Methods:A cross-sectional observational study was conducted over two years at a tertiary care hospital in Pune, India. The participants underwent a detailed history and physical examination. Biochemical tests and S total testosterone estimation was done. Mobility was estimated by calculating the time taken to perform the Timed Up and Go test (TUGT). Frailty was calculated by Fried's frailty index. Data are presented as mean ± standard deviation, and a comparison between the groups was made using Mann–Whitney U-test. The categorical variables are presented in frequencies along with respective percentages and were compared using the Chi-square or Fisher's exact test. The data was analyzed using SPSS version 22. A P <.05 was considered statistically significant in all the tests.Results:The mean age of the study participants was 68.37 ± 6.3 years, with a range of 60-88 years. The mean S total testosterone levels were 3.95 ± 2.06 ng/ml with a range of 0.04–25.36 ng/ml. As per the study definition, Ninety-two (21.67%) participants had testosterone deficiency. Three hundred and thirty-three (78.5%) participants had impaired motility represented by a TUGT time of more than 12 seconds. The Frailty index calculated revealed 94 (22.2%) of the study participants to be normal, 263 (62%) to be vulnerable, and 67 (15.8%) of the patients to be frail.Conclusion:The prevalence of testosterone deficiency in the elderly male population was 21.67%. However, there was no association of testosterone deficiency with frailty or impaired mobility. Furthermore, testosterone deficiency was not associated with BMI and hemoglobin levels. In the elderly, testosterone deficiency is associated with low bone mass and therefore imply an increased risk of osteoporotic fractures.

The female effect-how female receptivity influences faecal testosterone metabolite levels, socio-positive behaviour and vocalization in male Southern white rhinoceroses.

Testosterone is known to be essential for sexual maturation as well as for the display of behavioural traits linked to reproduction. At the same time, external factors such as the presence of receptive females may affect testosterone levels, stressing the hormone's substantial role in reproductive success. It is therefore of major interest to investigate the links between androgens, behaviour and the social environment especially in species that rely on a resilient reproduction rate, such as the white rhinoceros (WR). We collected faecal samples of 16 male Southern WR (Ceratotherium simum simum) aged between 1 and 44years from 11 European zoos. Audio and video recordings were simultaneously taken from five of the study males that were sexually mature and had direct contact with receptive females. Our results showed a positive correlation of faecal testosterone metabolite (fTM) concentrations and progressing age up until adulthood followed by a decline in older males. While previous reproductive success did not show any effect, the access to receptive females resulted in higher fTM levels. Thereby, fTM concentrations remained at the same level regardless of the receptivity phase, while social cohesion with respective females, affiliative behaviour as well as call rates of Pant and Hiss distinctly peaked during the receptive compared to the non-receptive periods. Conclusively, the immediate presence of receptive females poses a female effect that enhances the overall androgen levels in males and, thus, might facilitate their reproductive success. However, androgens do not seem to be the main driver of behavioural changes during courtship or mating. By linking endocrinological and socio-behavioural factors, we were able to provide an applicable basis for non-invasive monitoring of reproductive behaviour in male WR in captivity, thereby contributing to deeper understanding of potential reproduction impairments in a species whose population in captivity remains not fully self-sustaining.

Contextual complexity of chemical signals in callitrichids.

In nearly four decades our research and that of others on chemical signaling in callitrichid primates suggest a high degree of contextual complexity in both the use of signals and the response to these signals. We describe our research including observational field studies, behavioral bioassays ("playbacks"), functional imaging, and conditioning studies. Scent marking in both captivity and the wild is used for more than just territorial marking. Social contextual effects are seen in responses by subordinate females responding with ovulatory inhibition only to chemical signals from familiar dominant reproductive females. Males detect ovulation through changes in scent marks. Males responded behaviorally and hormonally to chemical signals of novel ovulating females as a function of their reproductive status (fathers, males paired with a female but not fathers, and single males). Multiple brain areas are activated in males by female chemical signals of ovulation including areas relating to memory, evaluation, and motivation. Furthermore, males can be conditioned to respond sexually to a nonsexual odor demonstrating that learning plays an important role in response to chemical signals. Male androgen and estrone levels changed significantly in response to infant chemical signals as a function of whether the males were fathers or not, whether the odors were from their own versus other infants, as well as the infant's stage of development. Chemical signals in callitrichids are providing a rich source of understanding the context and function of the chemical sensory system and its stimulation of neural, behavioral, and hormonal actions in the recipients.

SAT-734 HSD3B1 Expression in the Human Immune System

3β-hydroxysteroid dehydrogenase-1 (3βHSD1), catalyzing conversion of dehydroepiandrosterone (DHEA) to Δ 4-androstenedione, is an essential enzyme in the pathway toward production of biologically active androgens such as dihydrotestosterone from the adrenally produced precursor DHEA sulfate, the most predominant steroid hormone in circulation. We previously identified, in the gene (HSD3B1) that encodes 3βHSD1, a germline gain-of-function missense-encoding variant that has now been validated in several studies as predicting more rapid progression in prostate cancer patients treated with gonadal testosterone deprivation. Production of androgens from adrenal precursors is important not just in the context of prostate cancer but in other physiologic and pathophysiologic processes, which could include asthma. Androgens are associated with better lung function in both asthma and healthy cohorts, and increasing circulating androgen levels in males help explain the switchover in asthma being more common in boys than girls but then more common in women than men. A main treatment for asthma, as well as other inflammatory processes, is administration of glucocorticoids, yet unresponsiveness to glucocorticoids in a subset of patients remains a major problem. Systemic glucocorticoid administration suppresses adrenally produced DHEA and DHEA-S, suggesting a depleted pool for biologically active androgen production as a mechanism for glucocorticoid resistance. Our surprising preliminary data support a link between glucocorticoid responsiveness and the more active HSD3B1 allele: patients homozygous for the adrenal-permissive HSD3B1(1245C) allele exhibit better response to oral glucocorticoids than those homozygous for the adrenal-restrictive HSD3B1(1245A), with heterozygous patients falling in the middle. This suggests a model in which patients with the more active (adrenal-permissive) form of 3βHSD1 produce sufficient androgens despite the depleted pool of precursor hormones whereas patients with the less active (adrenal-restrictive) form cannot. To further elucidate the link between 3βHSD1 activity and immune response, we assayed HSD3B1 expression in different types of white blood cells. Leukocyte subsets from asthma patients and healthy controls were purified using fluorescence-activated cell sorting, and HSD3B1 expression was analyzed using qPCR. White blood cells of several types expressed HSD3B1 at levels comparable to or greater than both prostate cancer and placental choriocarcinoma cell lines with very robust 3βHSD1 activity. Further determining the cell type specific expression and activity of this key enzyme is an important step in unraveling the link between the HSD3B1 polymorphism and asthma along with potentially many other immune processes.

Asynchronous breeding in red brocket deer (Mazama americana): seasonal changes in male reproductive characteristics, seminal parameters, androgen levels, and antler cycle

The red brocket deer is the largest species in the genus Mazama and one of the most abundant and widely distributed cervid in the Neotropics. Yet it has been classified as data deficient by the IUCN, and the limited knowledge on its reproductive biology indicates that red brocket bucks do not possess an annual antler cycle and are capable of breeding during antler casting and growth. Here, in parallel to antler cycle, we investigated seasonal changes in morphometric (body weight, neck and chest girth, and testicular volume), endocrine [plasma testosterone and fecal androgen metabolites (FAM) levels] and seminal (total sperm count and sperm motility index) parameters from captive adult red brocket bucks collected on a quarterly basis over a 1-year period. Two out of six males kept hard antlers year-round, three cast antlers from winter to spring, and one carried velvet antlers for longer than 6 months. No clear seasonal patterns of variation in gross morphometry, seminal traits, and hormonal levels were found, and mean values of all collected parameters did not show differences among seasons. Body weight was positively correlated with most morphometric measurements and seminal parameters, while chest girth was positively correlated with neck girth, testicular volume, and total sperm count. Neither androgen levels (both plasma testosterone and FAM) nor hard antler phase correlated with seminal characteristics. Our findings support that red brocket bucks not only exhibit aseasonal and asynchronous antler cycles, but also maintain their secondary sexual characteristics and semen quality unchanged over the year. This apparent lack of photoperiodic stimuli for controlling reproduction along with an absence of relationship between seminal parameters and antler status might make red brockets unique in terms of reproductive biology among deer species.

Hormonal and behavioural effects of motorboat noise on wild coral reef fish

Anthropogenic noise is an emergent ecological pollutant in both terrestrial and aquatic habitats. Human population growth, urbanisation, resource extraction, transport and motorised recreation lead to elevated noise that affects animal behaviour and physiology, impacting individual fitness. Currently, we have a poor mechanistic understanding of the effects of anthropogenic noise, but a likely candidate is the neuroendocrine system that integrates information about environmental stressors to produce regulatory hormones; glucocorticoids (GCs) and androgens enable rapid individual phenotypic adjustments that can increase survival. Here, we carried out two field-based experiments to investigate the effects of short-term (30 min) and longer-term (48 h) motorboat-noise playback on the behaviour, GCs (cortisol) and androgens of site-attached free-living orange-fin anemonefish (Amphiprion chrysopterus). In the short-term, anemonefish exposed to motorboat-noise playback showed both behavioural and hormonal responses: hiding and aggression increased, and distance moved out of the anemone decreased in both sexes; there were no effects on cortisol levels, but male androgen levels (11-ketotestosterone and testosterone) increased. Some behaviours showed carry-over effects from motorboat noise after it had ceased, and there was no evidence for a short-term change in response to subsequent motorboat-noise playback. Similarly, there was no evidence that longer-term exposure led to changes in response: motorboat noise had an equivalent effect on anemonefish behaviour and hormones after 48 h as on first exposure. Longer-term noise exposure led to higher levels of cortisol in both sexes and higher testosterone levels in males, and stress-responses to an additional environmental challenge in both sexes were impaired. Circulating androgen levels correlated with aggression, while cortisol levels correlated with hiding, demonstrating in a wild population that androgen/glucocorticoid pathways are plausible proximate mechanisms driving behavioural responses to anthropogenic noise. Combining functional and mechanistic studies are crucial for a full understanding of this global pollutant.

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Disagreements about the phenotype of estrogen receptor β (ERβ) knockout mouse, created by removing the DNA-binding domain of the ERβ gene or interruption of the gene with a neocassette (Oliver Smithies ERβ knockout mice [ERβOS-/-]), prompted us to create an ERβ knockout mouse by deleting the ERβ gene with the use of CRISPR/Cas9 technology. We confirmed that the ERβ gene was eliminated from the mouse genome and that no ERβ mRNA or protein was detectable in tissues of this mouse. Overall the phenotype of the ventral prostate (VP) and mammary gland (MG) in ERβcrispr-/- mice was similar to, but more severe than, that in the ERβOS-/-mice. In the VP of 6-mo-old ERβcrispr-/- mice there was epithelial hyperplasia, fibroplasia, inflammation, stromal overgrowth, and intraductal cancer-like lesions. This was accompanied by an increase in Ki67 and P63 and loss in DACH1 and PURα, two androgen receptor (AR) repressors. In the MG there was overexpression of estrogen receptor α and progesterone receptor, loss of collagen, increase in proliferation and expression of metalloproteases, and invasive epithelium. Surprisingly, by 18 mo of age, the number of hyperplastic foci was reduced, the ducts of the VP and MG became atrophic, and, in the VP, there was massive immune infiltration and massive desquamation of the luminal epithelial cells. These changes were coincident with reduced levels of androgens in males and estrogens in females. We conclude that ERβ is a tumor suppressor gene in the VP and MG where its loss increases the activity AR and ERα, respectively.

The initiation of puberty in Atlantic salmon brings about large changes in testicular gene expression that are modulated by the energy status

BackgroundWhen puberty starts before males reach harvest size, animal welfare and sustainability issues occur in Atlantic salmon (Salmo salar) aquaculture. Hallmarks of male puberty are an increased proliferation activity in the testis and elevated androgen production. Examining transcriptional changes in salmon testis during the transition from immature to maturing testes may help understanding the regulation of puberty, potentially leading to procedures to modulate its start. Since differences in body weight influence, via unknown mechanisms, the chances for entering puberty, we used two feed rations to create body weight differences.ResultsMaturing testes were characterized by an elevated proliferation activity of Sertoli cells and of single undifferentiated spermatogonia. Pituitary gene expression data suggest increased Gnrh receptor and gonadotropin gene expression, potentially responsible for the elevated circulating androgen levels in maturing fish. Transcriptional changes in maturing testes included a broad variety of signaling systems (e.g. Tgfβ, Wnt, insulin/Igf, nuclear receptors), but also, activation of metabolic pathways such as anaerobic metabolism and protection against ROS. Feed restriction lowered the incidence of puberty. In males maturing despite feed restriction, plasma androgen levels were higher than in maturing fish receiving the full ration. A group of 449 genes that were up-regulated in maturing fully fed fish, was up-regulated more prominently in testis from fish maturing under caloric restriction. Moreover, 421 genes were specifically up-regulated in testes from fish maturing under caloric restriction, including carbon metabolism genes, a pathway relevant for nucleotide biosynthesis and for placing epigenetic marks.ConclusionsUndifferentiated spermatogonia and Sertoli cell populations increased at the beginning of puberty, which was associated with the up-regulation of metabolic pathways (e.g. anaerobic and ROS pathways) known from other stem cell systems. The higher androgen levels in males maturing under caloric restriction may be responsible for the stronger up-regulation of a common set of (449) maturation-associated genes, and the specific up-regulation of another set of (421) genes. The latter opened regulatory and/or metabolic options for initiating puberty despite feed restriction. As a means to reduce the incidence of male puberty in salmon, however, caloric restriction seems unsuitable.

Normalized second and fourth finger lengths in male and female partners and IVF cycle outcomes.

Hox genes are involved in limb formation during normal embryological development. Their modulation by circulating maternal oestrogens and androgens determines the length of the second and fourth fingers of the adult hand. Do these same intrauterine hormone levels also determine fertility outcomes in the adult? To study the association between the length of the second and fourth fingers of both partners undergoing IVF (as a surrogate of their previous intrauterine exposure to oestrogens and androgens) with treatment outcome after IVF, data corresponding to 256 IVF cycles were analysed. Finger length was normalized to the individual height. In the female partner, a longer normalized second finger length of the left (2DLN) hand, reflecting a high intrauterine exposure to oestrogens, was independently and significantly (P = 0.011) associated with obtaining at least one top-quality embryo in a multivariate model. Conversely, in the male partner a longer normalized fourth finger length of the left hand (4DLN), reflecting a high intrauterine exposure to androgens, was independently and significantly (P = 0.032) associated with obtaining at least one top-quality embryo in the same multivariate model. In the female partner, 2DLN was inversely and significantly (P = 0.01) associated with achievement of pregnancy. Intrauterine exposure to high levels of oestrogens and androgens in females and males, respectively, predisposes to the production of higher-quality embryos under in-vitro conditions during adulthood. Paradoxically, this also seems to result in a lower pregnancy rate.

Morpho-regulation in diverse chicken feather formation: Integrating branching modules and sex hormone-dependent morpho-regulatory modules.

Many animals can change the size, shape, texture and color of their regenerated coats in response to different ages, sexes, or seasonal environmental changes. Here, we propose that the feather core branching morphogenesis module can be regulated by sex hormones or other environmental factors to change feather forms, textures or colors, thus generating a large spectrum of complexity for adaptation. We use sexual dimorphisms of the chicken to explore the role of hormones. A long-standing question is whether the sex-dependent feather morphologies are autonomously controlled by the male or female cell types, or extrinsically controlled and reversible. We have recently identified core feather branching molecular modules which control the anterior-posterior (bone morphogenetic orotein [BMP], Wnt gradient), medio-lateral (Retinoic signaling, Gremlin), and proximo-distal (Sprouty, BMP) patterning of feathers. We hypothesize that morpho-regulation, through quantitative modulation of existing parameters, can act on core branching modules to topologically tune the dimension of each parameter during morphogenesis and regeneration. Here, we explore the involvement of hormones in generating sexual dimorphisms using exogenously delivered hormones. Our strategy is to mimic male androgen levels by applying exogenous dihydrotestosterone and aromatase inhibitors to adult females and to mimic female estradiol levels by injecting exogenous estradiol to adult males. We also examine differentially expressed genes in the feathers of wildtype male and female chickens to identify potential downstream modifiers of feather morphogenesis. The data show male and female feather morphology and their color patterns can be modified extrinsically through molting and resetting the stem cell niche during regeneration.

Effects of Androgens on the Amyloid-β Protein in Alzheimer's Disease.

Age-related androgen depletion has been implicated in compromised neuroprotection and is involved in the pathogenesis of neurodegenerative disease, including Alzheimer's disease (AD), the leading cause of dementia. Emerging data revealed that reduction of both serum and brain androgen levels in males is associated with increased amyloid-β (Aβ) accumulation, a putative cause of AD. It has been demonstrated that androgens can function as the endogenous negative regulators of Aβ. However, the mechanisms by which androgens regulate Aβ production, degradation, and clearance, as well as the Aβ-induced pathological process in AD, are still elusive. This review emphasizes the contributions of androgen to Aβ metabolism and toxicity in AD and thus may provide novel strategies for prevention and therapeutics.

Filial Cannibalism by Male Fish as an Infanticide to Restart Courtship by Self-Regulating Androgen Levels

Parental care is costly for animal parents [1-3], who often desert, abort, or kill their offspring and sometimes even eat them-so-called filial cannibalism [1,4]. A primary adaptive hypothesis for filial cannibalism centers on the expected nutritional benefits from eating offspring (the energy-based [EB] hypothesis [5-7]). However, many empirical studies are inconsistent with the EB hypothesis [8, 9]. One notable case is total filial cannibalism observed in some fishes. The caregiving males of these species eat all eggs and restart reproduction when tending a small number of eggs, as predicted by the EB hypothesis; but, this is puzzling because they can potentially court females even while tending eggs and increase the eggs by additional matings. Here we show that brood termination known as total filial cannibalism in blenniid fish Rhabdoblennius nitidus males is an endocrinological necessity to restart courtship behavior for subsequent mating. Males exhibit androgen-dependent brood cycling, and they are normally incapable of exhibiting courtships during the parental phase [10]. Egg manipulation experiments demonstrated that egg presence in the nest is a key stimulus regulating male androgen levels; they cannot restart courtship until removing all eggs. Furthermore, surprisingly, eggs were sometimes spit out without being consumed, and the occurrence of cannibalization and removal of all eggs was not associated with male condition. These results strongly suggest that the egg cannibalistic and removal behaviors that have been regarded as total filial cannibalism in this species are infanticide or embryocide rather than cannibalism, which serve to increase the males' androgen levels.

Age and socially related changes in fecal androgen metabolite concentrations in free-ranging male giraffes

In many mammal species, androgen levels in males are elevated during periods of mating activity, often to facilitate aggressive behavior between males over access to fertile females. However, this pattern might be less obvious in species with a rather low male-male aggression rate, or in those that are not strictly seasonal breeders. A complex social structure, as well as additional social and environmental factors, might add more to the complexity. Here, we applied a non-invasive method to monitor fecal androgen metabolite (fAM) levels in free-ranging giraffe bulls over a period of months to examine longitudinal patterns of androgen metabolite concentrations in relation to observed male sexual behavior in different age classes. Giraffes are non-seasonal breeders, living in a fission–fusion social system and males show a roaming strategy to search for fertile females. Our results show that season has an impact on fAM levels in free-ranging giraffes, with respective steroid concentrations being higher in summer. In the presence of females, fAM levels of bulls are significantly higher compared to when found in all-male groups, with old adult bulls showing the highest fAM levels. In contrast, young adult bulls have overall slightly higher fAM levels compared to old adult bulls when residing in all male groups. Sexual behavior increases fAM levels only in old adult bulls.

Social and demographic correlates of male androgen levels in wild white-faced capuchin monkeys (Cebus capucinus).

The Challenge Hypothesis, designed originally to explain the patterning of competitive behavior and androgen levels in seasonally breeding birds, predicts that males will increase their androgen levels in order to become more competitive in reproductive contexts. Here we test predictions derived from the Challenge Hypothesis in white-faced capuchin monkeys (Cebus capucinus), a species that has somewhat seasonal reproduction. We analyzed demographic and hormonal data collected over a 5.25-year period, from 18 males in nine social groups living in or near Lomas Barbudal Biological Reserve, Costa Rica. Alpha males had higher androgen levels than subordinates. Contrary to our predictions, neither the number of breeding-age males nor the number of potentially fertile females was obviously associated with androgen levels. Furthermore, male androgen levels were not significantly linked to social stability, as measured by stability of male group membership or recency of change in the alpha male position. Androgen levels changed seasonally, but not in a manner that had an obvious relationship to predictions from the Challenge Hypothesis: levels were generally at their lowest near the beginning of the conception season, but instead of peaking when reproductive opportunities were greatest, they were at their highest near the end of the conception season or shortly thereafter. This lack of correspondence to the timing of conceptions suggests that there may be ecological factors not yet identified that influence ifA levels. We expected that the presence of offspring who were young enough to be vulnerable to infanticide during an alpha male takeover might influence androgen levels, at least in the alpha male, but this variable did not significantly impact results.

Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator.

Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well understood. Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared with females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity.

Prozac affects stickleback nest quality without altering androgen, spiggin or aggression levels during a 21-day breeding test

Pharmaceuticals are increasingly being used in human and veterinary medicine, and their presence in the aquatic environment may present a threat to non-target aquatic organisms. The selective serotonin reuptake inhibitor fluoxetine (Prozac) has been reported to affect diverse behaviours (feeding, aggression, and reproduction) and also the endocrine system (steroid biosynthesis pathway) in fish. To investigate these claims further, and in particular effects on androgen synthesis, male three-spined sticklebacks (Gasterosteus aculeatus) were exposed to fluoxetine at 0, 3.2, 10 and 32μg/L in a flow-through system for 21 days. Their sex was determined prior to exposure using a non-invasive method to collect DNA for determining the genetic sex, reported here for the first time. This was necessary as the exposure required males of a non-breeding status which had not developed secondary characteristics. Post exposure a number of biochemical (serotonin, steroid and spiggin levels) and apical (aggressive behaviour) endpoints were measured. No effects were detected on morphometric parameters, spiggin or androgen (11-ketotestosterone) levels. However, all fluoxetine-exposed male fish had higher cortisol levels in comparison to the control fish, although this effect only persisted throughout the whole exposure duration at the highest concentration (32μg/L). In addition, the ratio of 5-HIAA/5-HT (serotonin metabolite/serotonin) was significantly lower in the brains of males exposed to fluoxetine at all concentrations tested. Although we found no differences in the number of nests built by the males, the quality of the nests produced by the fluoxetine-exposed males was generally inferior consisting only of a basic, rudimentary structure. Males exposed to 32μg/L of fluoxetine displayed a delayed response to a simulated threat (rival male via own mirror image) and were less aggressive (number of bites and attacks) toward their mirror image, but these differences were not statistically significant. In summary, fluoxetine exposure resulted in reduced serotonergic activity in the male three-spined stickleback brain suggesting that the mechanism of action between humans and fish is at least partially conserved. Furthermore, this study provided additional evidence of cross-talk between the serotonergic and stress axes as demonstrated by the perturbations in cortisol levels. This potentially complex interaction at brain level may be responsible for the effects observed on nest quality, an endpoint with serious ecological consequences for this species. Finally, despite our hypothesis (an effect on steroid biosynthesis, based on limited literature evidence), we observed no effects of fluoxetine exposure (at the concentrations and duration employed) on male stickleback androgen levels.