Prenatal Androgen Research Articles

Is Alcohol Consumption Pattern Dependent on Prenatal Sex-Steroids? A Digit Ratio (2D:4D) Study Among University Students.

There is evidence that alcohol consumption is influenced by prenatal sex steroids (as measured by digit ratio [2D:4D]). Here, we clarify the effect size of the relationship in a student (rather than a patient) population. There were 258 (169 women) participants. Digit length was measured directly with calipers. Alcohol use was evaluated by the Polish version of Alcohol Use Disorders Identification Test (AUDIT) and operationalized as total AUDIT scores and grams of alcohol/week. Digit ratios were sexually dimorphic (males < females). There were negative correlations between right 2D:4D and Dr-l (right 2D:4D minus left 2D:4D) and AUDIT scores and grams of alcohol/week in both sexes. Relationships varied from small (r = -0.29) to large (r = -0.69) and they were stronger in males in comparison to females and for right 2D:4D in comparison to Dr-l. In males only, there were small (r = 0.21) to moderate (r = 0.31) positive associations with body size (height, weight, and mean right digit length) and alcohol consumption. Multiple regression analyses showed relationships between digit ratios remained significant but those for body size did not. Alcohol consumption was negatively related to 2D:4D, suggesting high prenatal testosterone and low prenatal estrogen are linked to its consumption. Correlations varied in strength from small to large with the strongest found for right 2D:4D and for males. Positive relationships between body size and alcohol were small to moderate, confined to males, and were not independent of digit ratios. Prenatal androgenization may influence alcohol drinking patterns in non-clinical individuals.

Multisystem Health Consequences of Prenatal Hyperandrogenism in Offspring

Objective: Prenatal hyperandrogenism, characterized by elevated androgen levels during pregnancy, has significant multisystem impacts on offspring health. This review systematically examines the effects of prenatal hyperandrogenism on the cardiovascular, metabolic, reproductive, and behavioral health of offspring. By analyzing existing research, this review aims to provide a comprehensive understanding of the long-term health impacts of prenatal hyperandrogenism, offering insights for clinical management and prevention of related diseases. Mechanism: A comprehensive search was performed in PubMed database with the key words: “hyperandrogenemia and child”, “hyperandrogenemia and offspring”, “androgen excess and child”, “androgen excess and offspring”, “prenatal hyperandrogenism”, “prenatal androgen excess”, and a combination of these terms to find quality articles published from 1995 to 2024. Findings in Brief: Elevated prenatal androgen levels disrupt normal fetal development, leading to long-term consequences such as cardiovascular dysfunction, including hypertension and cardiac hypertrophy, and metabolic abnormalities such as insulin resistance and metabolic syndrome. It has a significant impact on the long-term health of the offspring’s reproductive system, with potential links to conditions such as polycystic ovary syndrome (PCOS). Furthermore, prenatal hyperandrogenism is associated with increased risks of neuropsychiatric disorders, including autism spectrum disorder (ASD) and anxiety. Conclusions: Elevated prenatal androgen levels disrupt normal fetal development, leading to long-term cardiovascular, metabolic, reproductive, and neuropsychiatric disorders. The underlying mechanisms involve hormonal regulation, placental function, oxidative stress, gene expression alterations, and metabolic programming. Further research is needed to develop effective interventions to mitigate these adverse effects.

Androgen-mediated maternal effects and trade-offs: postnatal hormone development, growth, and survivorship in wild meerkats.

Mammalian reproductive and somatic development is regulated by steroid hormones, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Based largely on information from humans, model organisms, and domesticated animals, testosterone (T) and the GH/IGF-1 system activate sexually differentiated development, promoting male-biased growth, often at a cost to health and survivorship. To test if augmented prenatal androgen exposure in females produces similar developmental patterns and trade-offs, we examine maternal effects in wild meerkats (Suricata suricatta), a non-model species in which adult females naturally, albeit differentially by status, express exceptionally high androgen concentrations, particularly during pregnancy. In this cooperative breeder, the early growth of daughters predicts future breeding status and reproductive success. We examine effects of normative and experimentally induced variation in maternal androgens on the ontogenetic patterns in offspring reproductive hormones (androstenedione, A4; T; estradiol, E2), IGF-1, growth from pup emergence at 1 month to puberty at 1 year, and survivorship. Specifically, we compare the male and female offspring of dominant control (DC or high-T), subordinate control (SC or lower-T), and dominant treated (DT or blocked-T) dams, the latter having experienced antiandrogen treatment in late gestation. Meerkat offspring showed sex differences in absolute T and IGF-1 concentrations, developmental rates of A4 and E2 expression, and survivorship - effects that were sometimes socially or environmentally modulated. Atypical for mammals were the early male bias in T that disappeared by puberty, the absence of sex differences in A4 and E2, and the female bias in IGF-1. Food availability was linked to steroid concentrations in females and to IGF-1, potentially growth, and survival in both sexes. Maternal treatment significantly affected rates of T, E2, and IGF-1 expression, and weight, with marginal effects on survivorship; offspring of DT dams showed peak IGF-1 concentrations and the best survivorship. Maternal effects thus impact offspring development in meerkats, with associated trade-offs: Whereas prenatal androgens modify postnatal reproductive and somatic physiology, benefits associated with enhanced competitiveness in DC lineages may have initial costs of reduced IGF-1, delay in weight gain, and decreased survivorship. These novel data further confirm the different evolutionary and mechanistic pathways to cooperative breeding and call for greater consideration of natural endocrine variation in both sexes.

Correlation of anogenital distance from childhood to age 9 years-a prospective population-based birth cohort-the Odense Child Cohort.

Does anogenital distance (AGD) - distance from the anus to the genitals - correlate from infancy (3 months) to the age of 9 years in boys and girls? In boys, AGD correlated from infancy to 9 years of age, whereas in girls, correlations were weaker, especially between infancy and later childhood. AGD is considered a marker for prenatal androgen action. In males, reduced AGD is associated with testicular cancer, infertility, and lower sperm count. In females, AGD is associated with endometriosis and polycystic ovary syndrome. In the Odense Child Cohort, a prospective population-based birth cohort, pregnant women were enrolled in early pregnancy. AGD and BMI were measured repeatedly in children at ages 3 and 18 months, as well as at 3, 5, 7, and 9 years. AGD was measured from the anus to the scrotum (AGDas) and to the penis (AGDap) in 1022 boys, and to the posterior fourchette and the clitoris in 887 girls repeatedly between the age of 3 months to 9 years. In total, 7706 assessments were made. AGD was adjusted for body weight, and SD scores (the difference between individual AGD and the mean of AGD in the population divided by SD of AGD) were calculated for each child. Pearson correlation coefficient (r) of each measurement was performed to investigate whether individual AGD was stable during childhood. Short predictive values at 3 months (20th percentile) to 9 years were investigated using the AUC produced by the receiver operating characteristic curve. In boys, AGD/body size-index SD score correlated significantly between infancy and 9 years, strongest for AGDas (r = 0.540 P > 0.001). In girls, weaker significant correlation coefficients were found between AGD at infancy and 9 years; higher correlation coefficients were found between AGD from 3 to 9 years (P > 0.001). Short AGDas in infancy predicted short AGDas in boys aged 9 years (AUC: 0.767, sensitivity 0.71, specificity 0.71). The predictive values of short infant AGDap, penile width (in boys), and AGD (in girls) concerning short outcomes at 9 years were low. The AGD measurements are less precisely measurable in girls compared to boys, especially in infancy, resulting in less reproducible measurements. Additionally, because AGD is shorter in girls, the same absolute measurement error is relatively more significant, potentially contributing to greater variability and lower reproducibility in girls. This may contribute to the weaker correlations in girls compared to boys. In boys, AGDas, relative to body size, correlated from infancy to 9 years, suggesting that AGD in infancy can be considered a non-invasive marker of later reproductive health. Further follow-up studies are needed to evaluate long-term individual tracking of AGD as well as assessment of childhood AGD as early marker of adult reproductive health. This study was supported by Odense University Hospital, Denmark, the Region of Southern Denmark, the Municipality of Odense, Denmark, the University of Southern Denmark, Odense Patient data Exploratory Network (OPEN), Denmark, the Danish Research Council (4004-00352B_FSS), Novo Nordisk Foundation, Denmark (grant no. NNF19OC0058266 and NNF17OC0029404), Sygeforsikring Danmark (journalnr. 2021-0173), the Collaborative Foundation between Odense University Hospital and Rigshospitalet, and Helsefonden. There is no conflict of interest of any author that could be perceived as prejudicing the impartiality of the research reported. N/A.

Using behavioural network mapping to investigate dyadic play in girls with congenital adrenal hyperplasia.

Examining mechanisms underlying sex differences in children's play styles, we studied girls with congenital adrenal hyperplasia (CAH) who provide a test of the relative effects of prenatal androgens versus rearing, and of behavioural similarity versus gender identity and cognitions. In this exploratory study, 40 focal children (girls and boys with and without CAH), aged 3-8 years, played for 14 min with a same-sex peer in a task designed to elicit rough-and-tumble play. Time-indexed ratings of positive affect and vigour of activity were evaluated via network mapping for sex-related differences in both levels and play dynamics (temporal relations among behaviours). Results suggest influences of both gender identity-aligned social cognitions and prenatal androgens: there was greater dyadic synchrony between positive affect for girls (regardless of CAH status) than boys, but girls with CAH displayed positive affect levels and directed vigorous peer play dynamics similar to boys.

DSD-related attitudes and beliefs held by pediatric endocrinologists and urologists: Insights from the North American disorders/differences of sex development (DSD) clinician survey

Disorders/Differences of Sex Development (DSD) encompass congenital conditions with atypical development of chromosomal, gonadal, or anatomical sex. Due to the rarity and complexity of these conditions, strong evidence for clinical practices is scarce, leading to controversies in management. This study, part of a broader project, examines changes over time in the attitudes and beliefs of DSD healthcare providers, focusing on factors contributing to patients' life satisfaction and the influence of medical specialty, gender, and age. Participants included active members of the Pediatric Endocrine Society (PES) and the Societies for Pediatric Urology (SPU) at three time points: 2003-2004 (T1), 2010-2011 (T2), and 2020 (T3). A survey covering predictors of patient life satisfaction, attitudes and beliefs regarding DSD care and outcomes, and participant characteristics was administered. Data were analyzed using descriptive statistics and Generalized Estimating Equations (GEE). Demographics: Participation rates were 56% (PES) and 64.7% (SPU) at T1, 41.1% (PES) and 52.3% (SPU) at T2, and 25.6% (PES) and 51.2% (SPU) at T3. Most participants were male (T1: 70.6%, T2: 61.7%, T3: 70.6%). Factors Affecting Life Satisfaction: Both endocrinologists and urologists ranked "gender identity consistent with assigned sex" as most important. Over time, the endorsement of some factors, such as performing genital surgery at Centers of Excellence, increased, while others, like the influence of prenatal androgen exposure determining gender identity, varied by specialty and gender. Attitudes and Beliefs: Across 18 statements, responses indicated three clusters with strong agreement, moderate agreement, and strong disagreement. Statements on the importance of family background and avoiding gender discordance were consistently endorsed, while those on delaying hypospadias repair until consent were least endorsed. The study highlights variability in beliefs about DSD management over time, influenced by specialty, gender, and age. Despite consensus on some care principles, discrepancies remain, particularly regarding the impact of prenatal androgens and the timing of surgical interventions. These findings underscore the need for regular interdisciplinary communication to align clinical practices with evidence-based guidelines and address subjective beliefs. The survey illustrates evolving perspectives among DSD healthcare providers, emphasizing the need for continued dialogue and education to bridge gaps between clinical evidence and practice. Collaborative efforts, such as the international I-DSD and the U.S. DSD Translational Research Network, are crucial for advancing patient-centered care in this field.

Correlation of Hand Digit Length Ratio, Anogenital Distance, and Severity of Hypospadias among Prepubertal Boys.

Antenatal androgen exposure has been suggested as a contributing factor in hypospadias etiology. This study aimed to investigate the correlation between anogenital distance (AGD), index finger-to-ring finger ratio (2D:4D ratio), and hypospadias severity in prepubertal boys, with the goal of exploring these parameters as potential markers of genital anomalies in utero. A cross-sectional observational study was conducted on boys under 8 years old presenting to our outpatient department (April 2020-December 2022). Those with hypospadias were included in the study group, whereas those without hypospadias formed the comparator group. Confounding factors (age, weight, and height) were accounted for using multivariate linear regression analysis. AGD, 2D:4D ratio, and hypospadias severity were measured during clinical visits, with still images taken for precise measurements. Statistical analysis was performed using the Mann-Whitney U and student's t-tests (software: STATA Version 14). Data were collected for 100 cases of hypospadias (26 proximal and 74 distal) and 50 controls. There was no significant difference in mean age between groups (P = 0.90). AGD was slightly lower in cases (3.44 ± 1.13 cm) compared to controls (3.70 ± 1.43) (P = 0.88). 2D:4D ratios were marginally higher in cases compared to controls (P = 0.12 for both hands). Although our study did not find significant associations between AGD and 2D:4D ratios with hypospadias severity, it offers insights into the role of prenatal androgen in genital development. The lack of significance underscores the need for region-specific research, suggesting AGD and 2D:4D ratio may not universally apply as hypospadias markers.

Evaluation of Digit Ratios in Youth With Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common syndrome often observed during adolescence, characterized by ovulatory dysfunction and hyperandrogenism. It is determined that, when female fetuses are exposed to high levels of androgens, it increases their likelihood of developing PCOS in later ages. The 2D:4D digit ratio, which measures the length of the index finger compared to the ring finger, is a precise anatomical indicator of the degree of prenatal androgen exposure. Higher digit ratios in individuals have been associated with outcomes typically attributed to females. In the adolescent age group, the relationship between PCOS and androgen exposure during the antenatal period is not clear. The study was aimed to evaluate digit ratios in adolescents with PCOS. The study included 38 adolescent girls with PCOS, and 40 healthy adolescent girls were selected as the control group. The digit ratio (2D:4D) was evaluated by digital calipers, and the digit ratios of the patient and control groups were compared. The mean age in the PCOS group was 15.99±1.18 years, while the control group had a mean age of 16.02±1.06 years. The right-hand 2D:4D digit ratio was significantly lower in the PCOS group (0.93±0.02) compared to the control group (1.00±0.01, p<0.001). Similarly, the left-hand 2D:4D digit ratio was also lower in the PCOS group (0.98±0.03) compared to the control group (1.00±0.01, p<0.001). There was a moderate negative correlation between the left-hand 2D:4D ratio and the modified Ferriman-Gallwey score (mFGS) (r=0.53, p=0.01). Nevertheless, there was not a significant association found between the 2D:4D ratio of the right hand and mFGS. This study demonstrates that PCOS patients have significantly lower both-hand 2D:4D ratios than healthy controls, suggesting prenatal androgen exposure. Recognizing anatomic markers in adolescence may predict the development of PCOS. The findings align with previous research linking low digit ratios to androgen exposure and various reproductive outcomes.

MEDIATING ROLE OF PRENATAL ANDROGENS, MUSCLE STRENGTH AND PHYSICAL ACTIVITY ON AGGRESSION IN OBESE AND OVERWEIGHT CHILDREN AND ADOLESCENTS

Obesity in children and adolescents is a global health problem associated with behavioral issues like aggression which can lead to developmental problems. High levels of prenatal androgens may play a role between obesity and aggression. This study examined the relationship between obesity, aggression and the mediating role of prenatal androgens, muscle strength and physical activity in children and adolescents. 118 healthy boys ages 9 to 17 participated and researchers measured their height, weight, body composition, muscle strength, second to fourth finger ratio, physical activity level using PAQ, and aggression using BPAQ. Chi-square test, Pearson's correlation, stepwise linear regression, and Sobel's test were used to examine relationships between variables and test mediation, seeking to identify factors affecting aggressiveness. The study found that aggression is directly related to weight, BMI, muscle mass, body fat and WHR. Obese people were more likely to be aggressive compared to non-obese people. Regression analysis showed that 2D:4D ratio, muscle mass and BMI can predict aggression. The results also showed that only muscle strength mediates the relationship between body mass and aggression. The study found a direct link between aggression and body mass in boys which may be because muscle strength mediates this relationship. The findings agree with the idea that prenatal androgens affect aggression in boys. Obese children with low 2D:4D ratios may need education to change views, values, and increase physical activity.

Investigating the effects of prenatal testosterone exposure (via 2D:4D) and socio-relational factors on 3–6-year-old preschoolers' prosocial choices

Background and aimsProsocial behavior such as helping and sharing develops early in childhood. Yet very few studies have investigated physiological and relational factors shaping prosociality among children. Here, we systematically examined the role of prenatal androgen exposure alongside prestige, dominance, and friendship in 3–6-year-old preschoolers' prosocial sharing with familiar peers. MethodsWe tested a sample of 65 children, predominately of European descent. We used a cost-free direct-interaction prosocial choice task to assess children's prosocial tendencies. Second-to-fourth digit ratio (2D:4D) was used as a retrospective biomarker for prenatal androgen exposure. Prestige was measured through behavioral observations of interaction partners and visual regard, dominance through teacher questionnaires, and friendship via peer preference assessments. ResultsWe found that children acted prosocially when tested with a familiar peer. Children with lower 2D:4D (higher prenatal androgen exposure) behaved more prosocially. Further, there were marginal associations between the donors' prosocial tendencies and their visual regard as a proxy of their prestige (positive effect) and their teacher-rated dominance relative to the recipient (negative effect). Neither age, sex, nor friendship influenced prosocial choices. ConclusionsPrenatal androgen exposure, approximated via 2D:4D, was associated with prosocial behavior. In contrast to previous research in older children, higher exposure was related to stronger prosocial tendencies, which corresponds to earlier findings on fairness in adults. Our findings point towards a potential role of sex steroids in the early development of children's social behavior, but they have to be interpreted with caution due to the small sample size of the current study. Nevertheless, they underscore the importance of integrating biological and psychological perspectives, while also highlighting the significance of studying the development of prosocial behavior within peer groups.

Assessment of Correlation between Genetic Taste Perception Hormonal Fingerprint and Dental Caries Incidence in Schoolgoing Children: An In Vivo Study.

Genetic predilection toward sweeter cariogenic foods mediated by the TAS2R38 gene, tested by phenylthiourea [phenylthiocarbamide (PTC)] compounds. Some individuals find it extremely bitter whereas some find it completely tasteless, being classified as a taster and a nontaster respectively. A majority of nontasters prefer foods with sweeter and stronger flavors, thus making them more susceptible to dental caries. Genetic taste perception is greatly influenced by prenatal androgen exposure represented by hormonal fingerprint, that is, ratio of second to fourth digit lengths (2D:4D ratio), thus making it a precise biomarker to quantify an individual's genetic taste perception and in turn their caries susceptibility. To find a correlation of genetic taste perception with the hormonal fingerprint and dental caries prevalence in children. A total of 96 children were selected at random for the study and divided into two groups based on their gender. A genetic taste perception test was carried out using PTC strips, and they were classified as tasters and nontasters. Then, the hormonal fingerprint was recorded by calculating the ratio of the index finger and ring finger. Following this, decayed, missing, and filled teeth index (DMFT) was recorded. A strong positive correlation was observed among nontasters, with a preference for sweeter foods associated with a high caries index. Conversely, no relationship was found between genetic taste perception and the hormonal fingerprint. The present study positively demonstrates an association of genetic taste perception and dental caries due to an increased preference for sweeter foods among nontasters. Although no correlation was found between the genetic taste perception, the hormonal fingerprint, and the dental caries status of an individual. Kulshrestha A, Shah P, Jagtap C, et al. Assessment of Correlation between Genetic Taste Perception Hormonal Fingerprint and Dental Caries Incidence in Schoolgoing Children: An In Vivo Study. Int J Clin Pediatr Dent 2024;17(6):690-694.

Investigating GABA Neuron-Specific Androgen Receptor Knockout in two Hyperandrogenic Models of PCOS.

Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links developmental or chronic exposure to hyperandrogenism with programming and evoking the reproductive and metabolic traits of PCOS. While critical androgen targets remain to be determined, central GABAergic neurons are postulated to be involved. Here, we tested the hypothesis that androgen signaling in GABAergic neurons is critical in PCOS pathogenesis in 2 well-characterized hyperandrogenic mouse models of PCOS. Using cre-lox transgenics, GABA-specific androgen receptor knockout (GABARKO) mice were generated and exposed to either acute prenatal androgen excess (PNA) or chronic peripubertal androgen excess (PPA). Females were phenotyped for reproductive and metabolic features associated with each model and brains of PNA mice were assessed for elevated GABAergic input to gonadotropin-releasing hormone (GnRH) neurons. Reproductive and metabolic dysfunction induced by PPA, including acyclicity, absence of corpora lutea, obesity, adipocyte hypertrophy, and impaired glucose homeostasis, was not different between GABARKO and wild-type (WT) mice. In PNA mice, acyclicity remained in GABARKO mice while ovarian morphology and luteinizing hormone secretion was not significantly impacted by PNA or genotype. However, PNA predictably increased the density of putative GABAergic synapses to GnRH neurons in adult WT mice, and this PNA-induced plasticity was absent in GABARKO mice. Together, these findings suggest that while direct androgen signaling in GABA neurons is largely not required for the development of PCOS-like traits in androgenized models of PCOS, developmental programming of GnRH neuron innervation is dependent upon androgen signaling in GABA neurons.

Cortical gyrification in women and men and the (missing) link to prenatal androgens.

Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal hormones are likely to influence sex-specific aspects of local gyrification. Classic congenital adrenal hyperplasia (CAH) causes high levels of androgens during gestation in females, whereas levels in males are largely within the typical male range. Therefore, CAH provides an opportunity to study the possible effects of prenatal androgens on cortical gyrification. Here, we examined the vertex-wise absolute mean curvature-a common estimate for cortical gyrification-in individuals with CAH (33 women and 20 men) and pair-wise matched controls (33 women and 20 men). There was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex in five cortical regions, where gyrification was increased in women compared to men. These regions were located on the lateral surface of the brain, specifically left middle frontal (rostral and caudal), right inferior frontal, left inferior parietal, and right occipital. There was no cortical region where gyrification was increased in men compared to women. Our findings do not only confirm prior reports of increased cortical gyrification in female brains but also suggest that cortical gyrification is not significantly affected by prenatal androgen exposure. Instead, cortical gyrification might be determined by sex chromosomes either directly or indirectly-the latter potentially by affecting the underlying architecture of the cortex or the size of the intracranial cavity, which is smaller in women.

Second to fourth digit ratio (2D:4D) as the 'anatomical marker' and reproductive 'hormonal fingerprint' in the occurrence dental plaque accumulation.

Digit ratio (2D:4D), as endocrine fingerprint, can indicate prenatal androgen exposure. It serves as an anatomical marker for various systemic diseases and a few studies relating it to oral health. The present study aims to evaluate the association between digit ratio and susceptibility to dental plaque formation. The study was conducted on young adults aged between 18 and 25 years. Digit ratio and reproductive hormones were measured; dental plaque score and gingival index (GI) were recorded. Data were analysed using the MedCalc. v.20. Male and female participants were categorized into two groups based on their digit ratios being either above or below the calculated average (0.99 for females, 0.98 for males). Those with a digit ratio below the average had a significantly higher mean dental plaque score (p < 0.0001) than those with ratios at or above the average. However, there was no significant difference in the GI between the two groups. Reproductive hormone profiles varied significantly between the higher and lower digit ratio groups for both sexes. Digit ratio may find potential to be used as an anatomical marker to identify the susceptibility to dental plaque build-up.

Associations between 2D:4D from direct and radiographic measurements with handgrip strength in young adult Tuvans

BackgroundDigit ratio (2D:4D) – the relative lengths of the index and ring finger – is sexually dimorphic (male < female), possibly because of the sex-differentiated impact of prenatal androgenization on fetal development in the 1st trimester. The sex difference remains stable with age and has been reported in children, adolescents, and adults from industrialized and non-industrialized societies. Handgrip strength (HGS) also is sexually dimorphic (males > females) and correlates negatively with 2D:4D. AimsTo examine in a sample of young adult Tuvans from Siberia (Russian Federation): i) the association between 2D:4D measured directly from the palms with 2D:4D measured from radiographic images of the same individuals and ii) the associations between 2D:4D and HGS in Tuvan men and women. Study design and subjectsThe study was cross-sectional. Participants were Tuvans (n = 185; 80 men; mean age = 21.02 years). 2D:4D was measured with a caliper from the ventral surface of the palm (both hands) and from radiographic images (left hand). HGS of both hands was measured with a digital hand dynamometer. Body height and weight were measured with an anthropometer and a body composition scale. Results2D:4D ratios and anthropometric measures (including HGS) were sexually dimorphic. Men had lower 2D:4D and higher HGS than women. Direct measures of 2D:4D correlated positively with 2D:4D measured from radiographs. Body mass index (BMI) was a significant predictor of HGS for both sexes. Male right 2D:4D and female right and left 2D:4D correlated negatively with HGS after controlling for the influence of BMI. There were no associations with radiographic measurements of 2D:4D. ConclusionOur findings provide evidence of sexual dimorphism in 2D:4D among young adult Tuvans. Together with previous research on Tuvan children and adolescents, these findings provide clear evidence of 2D:4D sexual dimorphism in pre- and postpubertal Tuvans. The small negative association between 2D:4D and HGS corresponds to similar reports across populations, suggesting that 2D:4D is a weak correlate of muscular fitness.

Prenatal Androgen Exposure Induces Anxiety-Like Behavior in Ewes

Introduction: In humans, prenatal androgen excess can lead to a broad spectrum of pathologies in adulthood, including polycystic ovary syndrome (PCOS). Women with PCOS present a variety of reproductive and metabolic disturbances and they also face increased risk to develop neuropsychiatric disorders such as depression and anxiety. Despite the high prevalence, the cause of depressive and anxiety symptoms is not fully elucidated. The use of androgenized ewe models can provide valuable insights into the pathogenesis of PCOS, as they closely mimic the reproductive, neuroendocrine, and metabolic characteristics observed in women with this condition. Method: We studied the impact of prenatal exposure to testosterone propionate on cognitive and behavioral performances of Ile-de-France ewes, using a plethora of behavioral tests for anxiety and cognitive performances. Results: Our findings indicate that prenatal androgenized ewes exhibit markedly elevated levels of anxiety-like behavior compared to control animals, while showing no discernible differences in cognitive performance. Conclusion: These discoveries offer novel perspectives on how maternal androgen excess contributes to anxiogenic effects in PCOS preclinical models, underscoring the ewe’s significance as a model for conducting mechanistic studies to unravel the physiological and molecular aspects of anxiety.

Comorbidities in women with polycystic ovary syndrome: a sibling study

BackgroundPolycystic ovary syndrome (PCOS) has previously been associated with several comorbidities that may have shared genetic, epigenetic, developmental or environmental origins. PCOS may be influenced by prenatal androgen excess, poor intrauterine or childhood environmental factors, childhood obesity and learned health risk behaviors. We analyzed the association between PCOS and several relevant comorbidities while adjusting for early-life biological and socioeconomic conditions, also investigating the extent to which the association is affected by familial risk factors.MethodsThis total-population register-based cohort study included 333,999 full sisters, born between 1962 and 1980. PCOS and comorbidity diagnoses were measured at age 17-45 years through national hospital register data from 1997 to 2011, and complemented with information on the study subjects´ early-life and social characteristics. In the main analysis, sister fixed effects (FE) models were used to control for all time-invariant factors that are shared among sisters, thereby testing whether the association between PCOS and examined comorbidities is influenced by unobserved familial environmental, social or genetic factors.ResultsThree thousand five hundred seventy women in the Sister sample were diagnosed with PCOS, of whom 14% had obesity, 8% had depression, 7% had anxiety and 4% experienced sleeping, sexual and eating disorders (SSE). Having PCOS increased the odds of obesity nearly 6-fold (adjusted OR (aOR): 5.9 [95% CI:5.4-6.5]). This association was attenuated in models accounting for unobserved characteristics shared between full sisters, but remained considerable in size (Sister FE: aOR: 4.5 [95% CI: 3.6-5.6]). For depression (Sister FE: aOR: 1.4 [95% CI: 1.2-1.8]) and anxiety (Sister FE: aOR: 1.5 [95% CI: 1.2-1.8), there was a small decrease in the aORs when controlling for factors shared between sisters. Being diagnosed with SSE disorders yielded a 2.4 aOR (95% CI:2.0-2.6) when controlling for a comprehensive set of individual-level confounders, which only decreased slightly when controlling for factors at the family level such as shared genes or parenting style. Accounting for differences between sisters in observed early-life circumstances influenced the estimated associations marginally.ConclusionHaving been diagnosed with PCOS is associated with a markedly increased risk of obesity and sleeping, sexual and eating disorders, also after accounting for factors shared between sisters and early-life conditions.

The change in handgrip strength, after physical exercise, is moderated by digit ratio (2D:4D): A study among the young adults in Poland.

The digit ratio (2D:4D), the ratio of the lengths of second (2D) to the fourth (4D) fingers, is a proxy indicator of prenatal androgen exposure. On average, males display lower 2D:4D than females. Previous studies have shown that lower 2D:4D ratios were associated with better sports and physical abilities. To assess whether a challenge condition, imposed by intense exercise, could increase handgrip strength (HGS) associated with 2D:4D. This cross-sectional experimental study included 90 healthy young Polish adults (40 males, 50 females). They underwent intense physical exercise, before (7 days) and after which they were measured for HGS and 2D:4D. Height and weight were also measured. Analyses of Covariance were employed to delineate associations. 2D:4D had significant predictive effects on the differences in HGS (DHGS) measured in two occasions, without and after, physical exercises. The lower was the 2D:4D, the higher the DHGS, particularly, for the left hand. The results reconfirmed that the link between prenatal testosterone exposure (indicated by 2D:4D) and physical strength depends on the context, such as a challenged condition.

The association and underlying mechanism of the digit ratio (2D:4D) in hypospadias.

The second-to-fourth digit (2D:4D) ratio is thought to be associated with prenatal androgen exposure. However, the relationship between the 2D:4D ratio and hypospadias is poorly understood, and its molecular mechanism is not clear. In this study, by analyzing the hand digit length of 142 boys with hypospadias (23 distal, 68 middle, and 51 proximal) and 196 controls enrolled in Shanghai Children's Hospital (Shanghai, China) from December 2020 to December 2021, we found that the 2D:4D ratio was significantly increased in boys with hypospadias ( P < 0.001) and it was positively correlated with the severity of the hypospadias. This was further verified by the comparison of control mice and prenatal low testosterone mice model obtained by knocking out the risk gene (dynein axonemal heavy chain 8 [ DNAH8 ]) associated with hypospadias. Furthermore, the discrepancy was mainly caused by a shift in 4D. Proteomic characterization of a mouse model validated that low testosterone levels during pregnancy can impair the growth and development of 4D. Comprehensive mechanistic explorations revealed that during the androgen-sensitive window, the downregulation of the androgen receptor (AR) caused by low testosterone levels, as well as the suppressed expression of chondrocyte proliferation-related genes such as Wnt family member 5a ( Wnt5a ), Wnt5b , Smad family member 2 ( Smad2 ), and Smad3 ; mitochondrial function-related genes in cartilage such as AMP-activated protein kinase ( AMPK ) and nuclear respiratory factor 1 ( Nrf-1 ); and vascular development-related genes such as myosin light chain ( MLC ), notch receptor 3 ( Notch3 ), and sphingosine kinase 1 ( Sphk1 ), are responsible for the limitation of 4D growth, which results in a higher 2D:4D ratio in boys with hypospadias via decreased endochondral ossification. This study indicates that the ratio of 2D:4D is a risk marker of hypospadias and provides a potential molecular mechanism.

Effects of the prenatal and postnatal nurturing environment on the phenotype and gut microbiota of mice with polycystic ovary syndrome induced by prenatal androgen exposure: a cross-fostering study.

The gut microbiome is implicated in the pathogenesis of polycystic ovary syndrome (PCOS), and prenatal androgen exposure is involved in the development of PCOS in later life. Our previous study of a mouse model of PCOS induced by prenatal dihydrotestosterone (DHT) exposure showed that the reproductive phenotype of PCOS appears from puberty, followed by the appearance of the metabolic phenotype after young adulthood, while changes in the gut microbiota was already apparent before puberty. To determine whether the prenatal or postnatal nurturing environment primarily contributes to these changes that characterize prenatally androgenized (PNA) offspring, we used a cross-fostering model to evaluate the effects of changes in the postnatal early-life environment of PNA offspring on the development of PCOS-like phenotypes and alterations in the gut microbiota in later life. Female PNA offspring fostered by normal dams (exposed to an abnormal prenatal environment only, fostered PNA) exhibited less marked PCOS-like phenotypes than PNA offspring, especially with respect to the metabolic phenotype. The gut microbiota of the fostered PNA offspring was similar to that of controls before adolescence, but differences between the fostered PNA and control groups became apparent after young adulthood. In conclusion, both prenatal androgen exposure and the postnatal early-life environment created by the DHT injection of mothers contribute to the development of PCOS-like phenotypes and the alterations in the gut microbiota that characterize PNA offspring. Thus, both the pre- and postnatal environments represent targets for the prevention of PCOS and the associated alteration in the gut microbiota in later life.