Prenatal Androgen Research Articles

Low digit ratio (2D:4D) is associated with early natural menopause.

ObjectivesIntrauterine environmental conditions may affect the number of primordial follicles and in this way the timing of menopause. The aim of the present study was to investigate association patterns between right hand digit ratio, that is, 2D:4D ‐ as an indicator of prenatal androgen and estrogen exposure, and age at menopause.MethodsOne hundred sixty‐nine women, who had experienced natural menopause, were enrolled in the study. Length of second and fourth finger were measured directly from the palmar side and digit ratios of both hands were calculated. For further analyses the digit ratio of the right hand was used only. Additionally, smoking habits, body weight and body height, body mass index and the number of children were determined. Multiple regression analyses were used to test association patterns between digit ratio and age at menopause, body height, BMI, nicotine consumption as well as number of births and age at menopause.ResultsAge at menopause correlated significantly positively with the digit ratio. A more feminine digit ratio is associated with a higher age at menopause, while a low digit ratio, interpreted as a hint of a higher androgen exposure during prenatal phase was associated with a lower age at menopause.ConclusionsLow digit ratio is associated with an earlier onset of natural menopause.

Lower digit ratio and higher endogenous testosterone are associated with lower empathic accuracy

Empathy is a cornerstone of human sociality. It has important consequences for our interpersonal relationships and for navigating our social world more generally. Although research has identified numerous psychological factors that can influence empathy, evidence suggests that empathy may also be rooted in our biology and, in particular, the gonadal steroid hormone testosterone. To date, much of the research linking testosterone and empathy has focused on the 2D:4D ratio (i.e., the ratio of the lengths of the index and ring fingers), and the results have been mixed. These mixed results, however, may be due to reliance on self-report measures to assess empathy, which can be vulnerable to self-presentation, as well as social-cultural norms about gender/sex differences in empathy. Moreover, although some have argued that digit ratio is an indicator of prenatal androgen exposure, the evidence for this to date is weak. Here, we aimed to follow up on this prior work, using a naturalistic empathic accuracy task in which participants dynamically track, in real-time, the emotional state of targets. We show that lower digit ratio (Study 1; N = 107) and higher circulating testosterone (Study 2; N = 76) are associated with poorer empathic accuracy performance; critically, these effects hold when controlling for sex/gender. In neither study, however, did we find effects on self-reported empathy. Our results highlight the limitations of self-report measures and support the notion that endogenous testosterone levels as well as 2D:4D ratio are related to key social-cognitive competencies like empathic accuracy.

Lower Digit Ratio (2D:4D) Indicative of Excess Prenatal Androgen Is Associated With Increased Sociability and Greater Social Capital.

Positive social interactions are crucial for human well-being. Elevated prenatal exposure to testosterone as indicated by a low second-to-fourth finger length ratio (2D:4D) relates to more aggressive/hostile behavior in men of low 2D:4D, especially in challenging situations. How much people enjoy interacting with others is determined by the personality trait sociability. Given its role in approach and avoidance behavior, sociability might also be influenced by prenatal sex hormones, but studies are inconclusive so far. Here, we investigated the association between 2D:4D and the personality trait sociability complemented by personal social capital and personal social network size, in a population-based cohort of 4998 men. Lower 2D:4D correlated significantly with higher trait sociability, bigger personal social capital, and larger personal social network size. These effects were consistent across both hands separately and their mean value. Furthermore, both factors of sociability (1) liking party and company of friends and (2) isolation intolerance, correlated significantly with the prenatal testosterone marker. The exploratory analysis revealed no link between 2D:4D and responses to the personality trait aggression items or items of anti-social-personality disorder. Our data suggest that prenatal androgen exposure organizes the brain with lasting effects on social behavior.

The influence of maternal androgen excess on the male reproductive axis

Prenatal androgen excess is suspected to contribute to the development of polycystic ovary syndrome (PCOS) in women. Evidence from preclinical female animal models links maternal androgen excess with the development of PCOS-like features and associated alterations in the neuronal network regulating the reproductive axis. There is some evidence suggesting that maternal androgen excess leads to similar reproductive axis disruptions in men, despite the critical role that androgens play in normal sexual differentiation. Here, the specific impact of maternal androgen excess on the male hypothalamic-pituitary-gonadal axis was investigated using a prenatal androgenization protocol in mice shown to model PCOS-like features in females. Reproductive phenotyping of prenatally androgenised male (PNAM) mice revealed no discernible impact of maternal androgen excess at any level of the reproductive axis. Luteinising hormone pulse characteristics, daily sperm production, plasma testosterone and anti-Müllerian hormone levels were not different in the male offspring of dams administered dihydrotestosterone (DHT) during late gestation compared to controls. Androgen receptor expression was quantified through the hypothalamus and identified as unchanged. Confocal imaging of gonadotropin-releasing hormone (GnRH) neurons revealed that in contrast with prenatally androgenised female mice, PNAM mice exhibited no differences in the density of putative GABAergic innervation compared to controls. These data indicate that a maternal androgen environment capable of inducing reproductive dysfunction in female offspring has no evident impact on the reproductive axis of male littermates in adulthood.

Fetal androgen exposure is a determinant of adult male metabolic health

Androgen signalling is a critical driver of male development. Fetal steroid signalling can be dysregulated by a range of environmental insults and clinical conditions. We hypothesised that poor adult male health was partially attributable to aberrant androgen exposure during development. Testosterone was directly administered to developing male ovine fetuses to model excess prenatal androgenic overexposure associated with conditions such as polycystic ovary syndrome (PCOS). Such in utero androgen excess recreated the dyslipidaemia and hormonal profile observed in sons of PCOS patients. 1,084 of 15,134 and 408 of 2,766 quantifiable genes and proteins respectively, were altered in the liver during adolescence, attributable to fetal androgen excess. Furthermore, prenatal androgen excess predisposed to adolescent development of an intrahepatic cholestasis-like condition with attendant hypercholesterolaemia and an emergent pro-fibrotic, pro-oxidative stress gene and protein expression profile evident in both liver and circulation. We conclude that prenatal androgen excess is a previously unrecognised determinant of lifelong male metabolic health.

Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome.

How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1-F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1-F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.

Increased hand digit length ratio (2D:4D) is associated with increased severity of hypospadias in pre-pubertal boys.

Hypospadias is a common congenital male disorder, with much research focusing on prenatal androgen exposure as a causative factor. Whilst digit length ratios were apparent in sexual dimorphism since the nineteenth century, their role in hypospadias remains unknown. The objective of our study was to determine the correlation between digit length (2D:4D) ratio, hypospadias severity, and anogenital distance. Pre-pubertal boys (<3years old) seen intra/postoperatively following hypospadias repair (June 2018-January 2019 inc.) were included. These were age-matched to non-hypospadias controls. Anthropomorphic measurements of digit lengths, penile/glans width, and anogenital distance were measured using digital calipers. Data measurements were collected for 105 boys with hypospadias (60 distal; 45 proximal) and 55 controls. There were significant differences in 2D:4D ratios in each hand (p < 0.001), as well as individual digits (p < 0.001), and a reduced anogenital distance (p < 0.001), when comparing the proximal group with distal or control groups. There were no significant differences in glans width, or between term- and preterm births. This study is the first to demonstrate increased 2D:4D ratios with proximal hypospadias, which also correlate with a shortened anogenital distance. This may provide a non-invasive, potentially antenatal, anthropomorphic measurement, as an indirect indicator of aberrant urogenital development.

Risk-taking behavior, the second-to-fourth digit ratio and psychological features in a sample of cavers.

BackgroundThe risk-taking behavior is largely modulated by the subject’s history, its lifestyles, by the characteristics of the situations with which it is compared, and also by the effects of prenatal androgens. Thus, the personality of the single person is a significant predictor of such way of acting.MethodsThe present study aimed to explore the relationship between Digit Ratio Measurement (2D:4D) and personality factors capable to be good predictors for choosing highly risky activities, such as caving. Furthermore, our purpose was to investigate whether 2D:4D ratio is related to cavers’ affective states and to assess the personological and emotional features of 34 healthy cavers, aged between 24 and 71 years (M = 39.70, SD = 9.81).ResultsData analysis showed several significant correlations between 2D:4D and Deliberate Risk Taking (RTI) and Precautionary Behavior (RTI), confirming that 2D:4D is a reliable index able to predict risk-taking behaviors. Furthermore, data analysis showed that Conscientiousness and its sub-dimension Scrupulousness (BFQ-2) are recurrent among significant correlations; in particular, the latter reports negative correlations with many factors of POMS. Moreover, all participants seemed to have a good attitude to collaboration, in terms of goal-direct strategy, and an adequate management of negative affective states, useful to maintaining a good level of stress within the group. Finally, the BFQ-2 factor Openness to culture seemed to be a predominant feature in the cavers, and this feature could be considered as predictive in the choice of an activity, such as caving, which requires curiosity, perseverance and a great planning of cave exploration.

Measurement of 2D:4D ratios in patients with major depressive disorders: A pilot study

Introduction: Digit ratio or 2D:4D ratio is a sexually dimorphic trait. It is a proxy marker of prenatal androgen exposure and is negatively correlated to prenatal androgens especially, testosterone. Literature search revealed significant correlations between digit ratios and various physiological, psychological or performance traits in adulthood. Objectives: The pilot study was conducted to measure 2D:4D ratios of patients with Major Depressive Disorder (MDD) and to compare it with normal (non-depressed) individuals and also to evaluate the correlation between digit ratios & depression scores. Materials and Methods: The present study was conducted in adults of age group belonging to 25-40 years with MDD (Group 1: n=30), from a tertiary care centre for Psychiatry. Using digital vernier calipers 2D:4D ratio was measured. Diagnosis of depression was done by the psychiatrist using DSM –IV criteria and depression scores were calculated by Hamilton depression rating scale (HDRS). Depression scores using Beck’s Depression Inventory and digit ratios were measured in age and sex matched healthy controls (Group 2: n=30). Results: The Mean ratios of Group 1 (0.9659 0.04161) was found to be lower than Group 2 (0.9788 0.0371). Using standard cutoffs, Group 1 was divided into Low and High digit ratios. The proportion of Group 1 patients with high ratios (84%) was significantly more than those with than low ratios (16%) (p Discussion: The outcomes of the present study were synchronous with reports of higher incidence of depression in females, nationally and globally. This was concurrent with the other reports of the previous studies. This would help us to conduct the future studies even on large study population. Keywords: Digit ratio, 2D:4D ratio, Prenatal testosterone, Depression, Vernier Caliper, Beck’s Inventory.

Does anogenital distance change with age?

It was known that in animals, anogenital distance (AGD), an indicator of prenatal androgen environment, was a stabile phenotype that persists throughout life. However, it is not known whether this applies to humans. In this study, we aimed to investigate whether anogenital distance is stable or not in males. We evaluated a total of 130 men targeted for group 1 (fathers) and group 2 (sons) in each 65 participants. AGD, the distance from anus to the posterior base of the scrotum, was measured with digital calipers. Anthropometric characteristics and testosterone levels of groups were recorded. We studied anogenital index (AGI), by dividing AGD by BMI to control bias of the weight and height, which could influence the measurement of AGD. The mean age of fathers was 61.5±10.2 and that of children was 32.1±5.48 (p=.00). The mean AGD scores were 55.46±10.36 vs. 60.21±10.04 (p=.09) and the mean total testosterone levels were 3.6±1.47 vs. 5.45±2.3 (p=.00) in group 1 and 2 respectively. There was no significant difference in height and weight between the two groups. AGD decreases with age, but further longitudinal studies are needed.

Assesment of anogenital distance as a marker in diagnosis of prostate cancer.

Anogenital distance (AGD), the distance from the sexual organs to the anus, is a sexually dimorphic feature in mammals. In this study, we investigated the relationship between anogenital distance and prostate cancer (PCa). 52 patients diagnosed with PCa and 60 patients with benign prostate hyperplasia as a control group were included in the study. AGDAP (cephalad insertion of the penis to the center of the anus) and AGDAS (posterior base (first fold) of the scrotum to the center of the anus) measurements of patients were done and noted before biopsy. The mean ages of 52 patients diagnosed with PCa and 60 patients with benign prostatic hyperplasia (BPH) were 67.70 ± 7.74 and 67.03 ± 7.89, respectively. There was no statistically significant difference in terms of age and serum testosterone levels of the patients diagnosed with prostate cancer or BPH (p > 0.05). Mean PSA values of patients diagnosed with prostate cancer wto be statistically higher than patients with BPH (p = 0.000). The mean AGDAP measurements of patients diagnosed with prostate cancer were statistically higher than those diagnosed with BPH (p = 0.000) and there was no significant difference in AGDAS measurements.(p = 0.823; p > 0.05). Androgen exposure is thought to play a role in the development PCa. Also AGD may be an indicator of prenatal androgen activity. In our study, we found a direct correlation between AGDAP and PCa. In order to reach a definitive conclusion, randomized controlled trials with larger sample number are needed.

The ratio of anterior anogenital distance to posterior anogenital distance: A novel-biomarker for polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. The etiopathogenesis of the disease remains uncertain. Additionally, a full consensus has not been reached regarding PCOS diagnostic criteria. Several attempts have been made to diagnose PCOS with a simple clinical biomarker, but most of them failed. This study aims to investigate the possible association between PCOS and anogenital distance (AGD), which is an important sign of intrauterine androgen exposure. A prospective cohort study was conducted on 130 women. The study group contained 65 women with PCOS whereas 65 healthy women were recruited for the control group, all between 18 and 40 years in age. The groups were compared in terms of demographics and clinical and laboratory parameters. Both anterior and posterior AGDs and associated ratios were recorded for each woman. The mean ratio of anterior AGD to posterior AGD for the PCOS and control group were 4.4 ± 1.0 and 4.9 ± 1.0, respectively (p = 0.003). Regression analysis demonstrated that this ratio significantly and positively correlated with the waist to hip ratio and negatively correlated with the free androgen index. AGD was initially used to define sexual differentiation of animals. Subsequent human studies showed that boys have longer AGDs than girls. Recent studies supporting the hypothesis that extreme prenatal androgen exposure contributes to PCOS found that AGD in adult PCOS patients was longer than control PCOS patients. However, a novel biomarker other than AGD needs to be identified to standardize these measurements. This work represents the first study to evaluate the ratio of anterior AGD to posterior AGD in PCOS patients. In this study, AGD anterior and posterior measurements were longer in PCOS patients than in controls. However, the strongest predictor of PCOS is the ratio of anterior to posterior AGD.

Кооперативное поведение и агрессия среди молодых мужчин: эффекты пренатальной андрогенизации и социальной среды

Кооперативное поведение и агрессия среди молодых мужчин: эффекты пренатальной андрогенизации и социальной среды

Digit ratio (2D:4D) and its behavioral correlates in infant rhesus macaques (Macaca mulatta).

2D:4D ratios are typically lower in adult human males than females and are linked to numerous sex-differentiated behaviors. 2D:4D ratios are considered an indicator of prenatal androgen exposure; if so, children's 2D:4D ratios would arguably be even better indicators of prenatal androgen exposure since children have experienced fewer postnatal influences than adults. However, sex differences in 2D:4D ratios as well as associations between 2D:4D ratios and sex-typed behaviors in children have been inconsistent. Several studies also report sex differences and behavioral correlates of 2D:4D ratios in adult non-human primates, but little is known about 2D:4D ratios in infant non-human primates. This study examined sex differences in 2D:4D ratios over the first month of life, and associations with behavioral outcomes at 12-24weeks of age, in N=304 infant rhesus macaques. An increase in 2D:4D ratios over the first month of life was found, as well as associations with aggression and play behaviors, but no sex differences in 2D:4D ratios were observed. These results highlight the need for future developmental studies of 2D:4D ratios in order to determine not only their stability and predictive value, but also to discern the mechanism connecting prenatal androgen exposure, 2D:4D ratios, and behavioral outcomes.

Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development

Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development

Femininity in men and masculinity in women is positively related to sociosexuality

Sociosexuality, i.e. individual's willingness to engage in uncommitted sex, is systematically higher in men than in women, and can be considered a male typical trait. However, intrasexual variation in sociosexuality is considerable, with individual femininity/masculinity being one of the factors influencing sociosexuality. The aim of our study was to test, in heterosexual and homosexual men and women from Brazil and the Czech Republic, whether childhood gender nonconformity (CGN) and continuous gender identity in adulthood (CGI) are associated with individual sociosexual orientation (SOI-R). A sample of 1336 heterosexual and homosexual men and women completed questionnaires on CGN, CGI, and SOI-R. In general, correlations show that higher masculinity in heterosexual women and higher femininity in both heterosexual and homosexual men are related to higher sociosexuality. Higher sociosexuality in masculine women can be explained by prenatal or actual androgen effects on sexual libido and can reflect a fast life history strategy. In feminine men, this result might reflect female preferences for feminine characteristics in men and an overall shift towards male femininity which can increase individual fitness. Also, gender nonconforming individuals can be more liberal adopting behaviors which are considered as non-traditional. This study challenges the widely association between masculinity and unrestricted sociosexuality.

Le syndrome des ovaires polykystiques : quelles nouveautés en 2019 ?: Keeping up with PCOS in 2019

PolyCystic Ovary Syndrome (PCOS) is the first endocrinopathy of women of child-bearing age and the leading cause of anovulatory infertility. The pathophysiology of this syndrome is complex and involves genetic traits highlighted by GWAS and epigenetic traits with DNA methylation modifications. Initially described as an ovarian disease, works carried out over recent years were turned towards neuroendocrine disorder involving GABAergic pathways, KNDy neurons and a possible role of prenatal androgen exposure determined by animal models. Clinically, PCOS leads to many complications including psychological and emotional disorders demonstrated in large populations of PCOS women.© 2019 Published by Elsevier Masson SAS. All rights reserved.Cet article fait partie du numéro supplément Les Must de l’Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.

Maternal androgen excess induces cardiac hypertrophy and left ventricular dysfunction in female mice offspring.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is suggested to increase the risk for cardiovascular disease. How PCOS may lead to adverse cardiac outcomes is unclear and here we hypothesized that prenatal exposure to dihydrotestosterone (DHT) and/or maternal obesity in mice induce adverse metabolic and cardiac programming in female offspring that resemble the reproductive features of the syndrome. The maternal obese PCOS phenotype was induced in mice by chronic high-fat-high-sucrose consumption together with prenatal DHT exposure. The prenatally androgenized (PNA) female offspring displayed cardiac hypertrophy during adulthood, an outcome that was not accompanied by aberrant metabolic profile. The expression of key genes involved in cardiac hypertrophy was up-regulated in the PNA offspring, with limited or no impact of maternal obesity. Furthermore, the activity of NADPH oxidase, a major source of reactive oxygen species in the cardiovascular system, was down-regulated in the PNA offspring heart. We next explored for early transcriptional changes in the heart of newly born PNA offspring, which could account for the long-lasting changes observed in adulthood. Neonatal PNA hearts displayed an up-regulation of transcription factors involved in cardiac hypertrophic remodelling and of the calcium-handling gene, Slc8a2. Finally, to determine the specific role of androgens in cardiovascular function, female mice were continuously exposed to DHT from pre-puberty to adulthood, with or without the antiandrogen flutamide. Continuous exposure to DHT led to adverse left ventricular remodelling, and increased vasocontractile responses, while treatment with flutamide partly alleviated these effects. Taken together, our results indicate that intrauterine androgen exposure programmes long-lasting heart remodelling in female mouse offspring that is linked to left ventricular hypertrophy and highlight the potential risk of developing cardiac dysfunction in daughters of mothers with PCOS.

Origins and Impact of Psychological Traits in Polycystic Ovary Syndrome.

Women with polycystic ovary syndrome (PCOS) exhibit compromised psychiatric health. Independent of obesity, women with PCOS are more susceptible to have anxiety and depression diagnoses and other neuropsychiatric disorders. During pregnancy women with PCOS display high circulating androgen levels that may cause prenatal androgen exposure affecting the growing fetus and increasing the risk of mood disorders in offspring. Increasing evidence supports a non-genetic, maternal contribution to the development of PCOS and anxiety disorders in the next generation. Prenatal androgenized rodent models reflecting the anxiety-like phenotype of PCOS in the offspring, found evidence for the altered placenta and androgen receptor function in the amygdala, together with changes in the expression of genes associated with emotional regulation and steroid receptors in the amygdala and hippocampus. These findings defined a previously unknown mechanism that may be critical in understanding how maternal androgen excess can increase the risk of developing anxiety disorders in daughters and partly in sons of PCOS mothers. Maternal obesity is another common feature of PCOS causing an unfavorable intrauterine environment which may contribute to psychiatric problems in the offspring. Whether environmental factors such as prenatal androgen exposure and obesity increase the offspring’s susceptibility to develop psychiatric ill-health will be discussed.

A longitudinal birth cohort study of early life conditions, psychosocial factors, and emerging adolescent sexual orientation

This study tested whether previously reported associations between early life factors and later adolescent sexual orientation could be replicated in another prospective birth cohort, the UK Millennium Cohort Study (MCS). We used data on 9,795 youth from the MCS. Emerging sexual orientation was assessed using measures of sexual attraction to males and females in separate items at 14years. Factors including birthweight, breastfeeding, sibling composition, parental ages, maternal psychopathology, parent-child relationship, and contextual risks were separated into three developmental periods: prenatal (n=5 factors), before 7years (n=6 factors), and after 7years (n=5 factors). We controlled for handedness as a putative marker of prenatal androgen exposure and the possibility of mischievous responding statistically. Girls with greater maternal psychological distress since age 7 and greater pubertal body mass index were more likely to be nonheterosexual but the effect sizes were very small. Among boys there were no significant associations between any early life conditions and later sexual orientation. However, focusing on effect sizes rather than significance levels, there were small associations between preterm birth and nonheterosexuality. The results offer further evidence that psychosocial influences in the development of adolescent sexual orientation are weak or non-existent.