Prenatal Androgen Exposure Research Articles

Markers of Prenatal Androgen Exposure Correlate With Online Sexual Compulsivity and Erectile Function in Young Men.

Pornography addiction and sexual dysfunction are increasingly prevalent in young men. Previous studies suggest that prenatal androgen exposure plays a role in addiction and sexual functionality. Here, we tested whether lower second-to-fourth finger length ratio (2D:4D) and later age at spermarche, both putative indicators of higher androgen levels in utero, correlate with online sexual compulsivity (OSC scale of ISST), erectile function (IIEF-5), and ejaculatory control (PEPA) in 4,370 young men (age IQR: 25–26 years) of the Cohort Study on Substance Use Risk Factors. Statistical analyses revealed that lower 2D:4D correlated with higher scores on the OSC scale. Moreover, higher age at spermarche correlated with higher OSC scores and decreased erectile function. Interestingly, OSC severity, but not the frequency of pornography use, correlated negatively with erectile function and ejaculatory control. This is the first study to associate two independent proxies of prenatal testosterone level with OSC. These findings provide novel insight into intrauterine predisposition of sexual behavior and related sexual function in adulthood.

22. Assigned Female Infant with Clitoromegaly due to Pre- and Post-Natal Exogenous Testosterone Exposure: A Case Report and Review of the Literature

<h3>Background</h3> Clitoromegaly is an abnormal enlargement of the clitoris that can be congenital or acquired. Both endogenous and exogenous androgen exposure can cause clitoromegaly. We report a case of a 10-month-old assigned female infant with exogenous testosterone exposure resulting in clitoromegaly, with evidence of possible prenatal exposure. There are limited reports of accidental exposure to exogenous androgens in infant females. To our knowledge, only one other case has been reported of possible prenatal exposure causing female infant virilization. <h3>Case</h3> This is a case of a 10-month-old assigned female, born at 39 weeks, referred to our clinic for assessment of clitoromegaly. The enlarged clitoris was first noted by her pediatrician at her six-month exam, although parents state present since birth. Physical exam showed an enlarged clitoris (1.5cm length x 1.5cm width) and an anogenital ratio of 0.5. Laboratory studies revealed significantly elevated total testosterone (826 ng/dL, range for age/sex <10ng/dL) and dihydrotestosterone (851 ng/dL, range <5 ng/dL) levels. Other workup including testing for congenital adrenal hyperplasia, pelvic/adrenal imaging and karyotyping were normal. Patient's father disclosed that he was using topical testosterone gel due to low testosterone levels. At the six-week follow up, the father had discontinued testosterone therapy and infant's labs showed significantly decreased testosterone levels (9.69 ng/dL); given this temporal relationship, the cause of clitoromegaly is likely unintentional exogenous exposure to testosterone. The anogenital ratio of 0.5 is borderline for evidence of prenatal virilization, suggesting possible prenatal androgen exposure via maternal absorption in addition to postnatal exposure. <h3>Comments</h3> This case raises awareness of testosterone absorption in direct physical contacts of those who use topical testosterone gel, leading to unintended hormonal effects. Transdermal testosterone gels are often prescribed to cisgender males with low androgen levels and as a masculinizing hormone therapy in transgender care. Prescribers must educate patients to enact measures to prevent accidental exposure to other household members. The risk of clinically significant absorption may be greater in infants given their high body-surface-area to body weight ratio. Significant early exogenous androgen exposure in assigned female infants has unknown long-term health effects, highlighting the importance of preventing skin contamination with topical testosterone preparations.

An association between body image dissatisfaction and digit ratio among Chinese children and adolescents

Body image dissatisfaction (BID) is a negative evaluation of personal physical characteristics, including dissatisfaction with body shape, gender, sexual organs, appearance and so forth, and it plays an important role in growth and development. The second-to-fourth digit ratio (2D:4D) is recognized as a putative indicator of intra-uterine testosterone to estrogen ratio exposure, and it has been observed that higher levels of fetal testosterone exposure are associated with a lower 2D:4D. The present paper contributes to a better understanding of the biological underpinnings of BID by analyzing BID and the digit ratio (2D:4D). We found that the 2D:4D was positively related to appearance dissatisfaction in boys with first spermatorrhea, which means that low prenatal androgen exposure may increase boys’ dissatisfaction with their appearance. In girls with breast development being lower than Tanner stage II, their 2D:4D was negatively related to their body shape dissatisfaction, which means that high prenatal androgen exposure may increase girls’ dissatisfaction with their body shape. These results suggest that the prenatal androgen exposure level might play an important role in the body image dissatisfaction of the offspring.

Androgen-induced epigenetic modulations in the ovary.

In recent years, androgens have emerged as critical regulators of female reproduction and women's health in general. While high levels of androgens in women are associated with polycystic ovary syndrome (PCOS), recent evidence suggests that a certain amount of direct androgen action through androgen receptor is also essential for normal ovarian function. Moreover, prenatal androgen exposure has been reported to cause developmental reprogramming of the fetus that manifests into adult pathologies, supporting the Developmental Origins of Health and Disease (DOHaD) hypothesis. Therefore, it has become imperative to understand the underlying mechanism of androgen actions and its downstream effects under normal and pathophysiological conditions. Over the years, there has been a lot of studies on androgen receptor function as a transcriptional regulator in the nucleus as well as androgen-induced rapid extra-nuclear signaling. Conversely, new evidence suggests that androgen actions may also be mediated through epigenetic modulation involving both the nuclear and extra-nuclear androgen signaling. This review focuses on androgen-induced epigenetic modifications in female reproduction, specifically in the ovary, and discusses emerging concepts, latest perceptions, and highlight the areas that need further investigation.

Sex Differences in Sexual Arousal and Finger Length Ratio

ABSTRACT Most men show sexual arousal to one, preferred sex, whereas most women respond to both sexes, regardless of their sexual orientation. A different research program indicates that men have lower second-to-fourth finger length ratios (2D:4D) than women, possibly because men are exposed to higher levels of androgens during prenatal development. We hypothesized that sex differences in sexual arousal patterns are influenced by prenatal androgen exposure and would thus be explained by sex differences in 2D:4D. We measured the sexual response patterns of 139 men and 179 women via genital arousal and pupil dilation to erotic videos, in addition to their 2D:4D. Compared to women, men showed stronger responses to one sex over the other, although this pattern was clearer in genital arousal than pupil dilation. Men also had lower 2D:4D than women. However, there was no evidence that sex differences in sexual arousal related to sex differences in 2D:4D. Thus, whichever factor explains sex differences in sexual arousal patterns may not be reflected in 2D:4D.

Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders

If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F3) in the androgenized lineage. In contrast, following the male germline, F3 male offspring (mF3) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F3 females in the androgenized lineage and eight genes in the obese lineage. In mF3 male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F1 and F2 offspring in the female germline did not develop anxiety-like behavior, while the F2 male offspring (mF2) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.

Digit ratio and its implications on exercise capacity among non-athlete Indian male subjects

Background: The index (2D)-to-ring (4D) finger length ratio (2D:4D) commonly known as digit ratio has been the subject of recent interest and is thought to be related to sports ability, endurance running, disease susceptibility, and myocardial infarction at early age. Sexually dimorphic digit ratio is widely accepted as a putative marker for prenatal androgen exposure with men tends to have smaller ratio. Aim and Objective: The present study was conducted to evaluate any relation between digit ratio and exercise capacity in non-athlete Indian males. Materials and Methods: The study was conducted in the Department of Physiology of Mayo Institute of Medical Sciences, Barabanki, with 50 clinically normal healthy male volunteers. Finger lengths were measured directly using digital Vernier calipers. Exercise tolerance testing was done as per Bruce protocol with Allengers Gemini A-DX treadmill. Results: Two groups of higher (n = 26) and lower (n = 24) finger length ratio (right hand) were formed using median split. Significant difference observed (P = 0.0012, P < 0.05) for exercise capacity or percentage of predicated metabolic equivalents (METs) achieved having higher percentage by the low finger length ratio group. No significant difference observed for METs achieved for the groups. Correlation study shows a significant moderate negative correlation between digit ratio (right) and exercise capacity. Similar correlation was not significant for the left hand. Conclusion: These results suggest that a low digit ratio (right hand) is related to better aerobic capacity and exercise capacity in the males although the exact role of prenatal androgen exposure is unclear.

Assessing the Relationship between Digit Ratio as a Marker for Prenatal Androgen Exposure and Different Blood Pressure Components among North Indian Males: A Pilot Study

Introduction: Digit ratio (2D:4D) has been associated with cardiovascular diseases using association with surrogate markers. Studies showing an association of digit ratio with cardiovascular parameters within normal limits are scarce. Aim: To explore the relation between different blood pressure components and digit ratio in normal young males within physiological range. Materials and Methods: In this cross-sectional pilot study, 25 apparently healthy male volunteers were included. Digit ratio (2D:4D) was measured. Body Mass Index (BMI) was estimated. Peripheral blood pressure, central aortic blood pressure and all four limb blood pressures were measured using periscope arterial health and cardiovascular analysis system. Blood pressure was measured using oscillometric method from all peripheral sites and estimated central aortic pressure by a validated transfer function. Pearson’s correlation studies were performed to assess any preliminary association. Two groups were formed of low and high digit ratio and Student’s t-test was performed to assess any significant difference between the groups. Results: Digit ratio of both hands correlated best with peripheral Diastolic Blood Pressure (DBP) (Right 2D:4D r=0.43, p&lt;0.05/Left 2D:4D r=0.40, p&lt;0.05). No significant association observed for peripheral systolic pressure (p&gt;0.05) and digit ratio of both hands. Significant association observed for all four limb blood pressure components and digit ratio. Pulse pressure components did not show any association with digit ratio. Significant difference of blood pressure components was observed when low and high digit ratio groups were compared. It was observed that blood pressure components were on higher side within the normal limits among the subjects with high digit ratio. Conclusion: Preliminary observations from this pilot study suggests that in normal young adult males digit ratio associate positively with different blood pressure components in normotensive males and has the potential to be used as a potent marker for early changes in cardiovascular diseases.

Digit ratio, a proposed marker of the prenatal hormone environment, is not associated with prenatal sex steroids, anogenital distance, or gender-typed play behavior in preschool age children.

Prenatal hormones have been proposed as key factors impacting child development as well as long-term health and disease. Digit ratio (the ratio of the lengths of the second to fourth digits; 2D:4D) has been proposed as a sexually dimorphic, noninvasive marker of prenatal androgen exposure that can be reliably measured in children and adults. To date, few longitudinal pregnancy cohort studies have examined childhood digit ratio in relation to other relevant measures including prenatal hormones and androgen-sensitive outcomes. To augment the current literature on this topic, we measured right-hand digit ratio in 4-year-old children participating in The Infant Development and the Environment Study, a multicenter longitudinal cohort study that has been following mother-child dyads since the first trimester of pregnancy (n = 321). We assessed sex differences in digit ratio and fit multivariable linear regression models to examine digit ratio in relation to: (1) child sex; (2) maternal sex steroid hormone concentrations in early pregnancy; (3) newborn anogenital distance, another proposed measure of sensitivity to prenatal androgens; and (4) gender-typical play behavior as measured by the Preschool Activities Inventory (PSAI) at age 4. We observed no sex difference in digit ratio; the mean 2D:4D was 0.97 ± 0.05 mm in both sexes. Furthermore, digit ratio was not associated with maternal sex steroid concentrations in early pregnancy, anogenital distance in either sex, or PSAI scores in either sex in covariate-adjusted models. In conclusion, we observed no evidence that early childhood digit ratio was associated with child sex or hormone-sensitive measures in this cohort.

In utero exposure to maternal stressful life events and risk of polycystic ovary syndrome in the offspring: The Raine Study

BackgroundPCOS is the most common endocrine disorder in reproductive age women. The origins of PCOS are unknown but experimental and limited human evidence suggests that greater prenatal exposure to androgens may predispose to PCOS. Experimental evidence suggests that maternal stressors may affect reproductive function in the offspring via changes in prenatal androgen exposure. In this present study, we aim to investigate whether maternal stressful life events during pregnancy are associated with polycystic ovary morphology (PCOM) or polycystic ovary syndrome (PCOS) in adolescent offspring. MethodIn a large population-based pregnancy cohort study (The Raine Study) continuously followed from prenatal life through to adolescence we examined the association between maternal stressful life events during pregnancy in both early and late gestation, and subsequent circulating concentrations of ovarian and adrenal androgens, PCOM and PCOS in the normal menstrual cycle of offspring age 14–16 years. Maternal stressful life events were prospectively recorded during pregnancy at 18 and 34 weeks using a 10-point questionnaire. Female offspring (n = 223) completed a questionnaire about their menstrual cycles, underwent a clinical examination for hirsutism (Ferriman-Gallwey score) and transabdominal pelvic ultrasound examination to determine ovarian morphology according to standardized criteria for classification of PCOM. Plasma samples were obtained at day 2–6 of the normal menstrual cycle for measurement of androgens. PCOM was defined according to the international consensus definition, 2003 and the evidence-based guideline for the assessment and management of PCOS, 2018. PCOS was diagnosed according to Rotterdam criteria and National Institute of Health (NIH) criteria. Multivariate linear and logistic regression analyses were used to examine the associations between maternal stressful life event exposure and ovarian morphology (PCOM), circulating ovarian and adrenal androgens (clinical and biochemical hyperandrogenism (hirsutism)) and presence of PCOS. ResultsOf 223 recruited adolescent girls, 78 (35.9%) and 68 (31.3%) had PCOM by the 2003 and 2018 criteria respectively, while 66 (29.6%) and 37 (16.6%) had PCOS, using Rotterdam and NIH criteria, respectively. Most girls (141/223, 63.2%) were exposed to at least one stressful life event in early gestation and around half (121/223, 54.3%) were exposed to at least one stressful life event in late gestation. Maternal stressful life events in early gestation were associated with a statistically significant lower prevalence of PCOM when applying the 2003 criteria [adjusted odds ratio [aOR] and 95% confidence intervals (CI): 0.74 (95% CI: 0.55; 0.99)], and a similar association was detected when applying the 2018 PCOM criteria (aOR, 0.69, 95% CI: 0.50; 0.95)]. Maternal stressful life events in early gestation were also associated with lower circulating concentrations of testosterone (β = −0.05, 95% CI: −0.09; −0.004) and androstenedione (β = −0.05, 95% CI: −0.10; −0.002) in the offspring. No similar effects for PCOM or circulating androgens were detected in late gestation. No statistically significant associations between maternal stressful life events in early or late gestation with PCOS (neither Rotterdam nor NIH criteria) in adolescence were detected. The prospective collection of maternal stressful life events during both early and late gestation and direct measurement of PCOM, PCOS and circulating androgens in adolescence and key co-variates implies minimal possibility of recall, information bias and selection bias. ConclusionMaternal exposure to stressful life events in early gestation is associated with significantly reduced circulating ovarian and adrenal androgen concentrations in adolescence (testosterone and androstenedione), and an indication of fewer cases of polycystic ovary morphology (PCOM) defined by the 2003 international consensus definition and by the 2018 international evidence-based guideline, but has no effect on polycystic ovary syndrome (PCOS), diagnosed using either Rotterdam or NIH criteria.

No evidence for a difference in 2D:4D ratio between youth with elevated prenatal androgen exposure due to congenital adrenal hyperplasia and controls

The second-to-fourth digit ratio (2D:4D) has been associated with sexual dimorphism, with a lower 2D:4D in males. A large body of research has relied on the 2D:4D as a proxy for prenatal androgen exposure, and includes reports of relationships between 2D:4D and a wide range of human traits. Here, we examine the validity of the 2D:4D proxy by studying the association between 2D:4D and classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, a condition characterized by excessive prenatal exposure to androgens during most of the gestational period. To this end, we retrospectively examine 513 serial radiographs of the left hand obtained clinically in 90 youth with classical CAH (45 female) and 70 control youth (31 female). Replicating previous reports, we observe associations of the 2D:4D with sex (lower 2D:4D in males) and age (increase of 2D:4D through development). However, we find no evidence for differences in 2D:4D between CAH and controls (full sample: β = −0.001 (−0.008, 0.006); females: β = −0.004 [−0.015, 0.007]; males: β = 0.001, [−0.008, 0.011]). Although our findings do not rule out a small association between the 2D:4D and CAH, they cast doubt on the usefulness of the 2D:4D as a biomarker for prenatal androgen exposure in behavioral research.

Prenatal androgen exposure affects ovarian lipid metabolism and steroid biosynthesis in rats.

Prenatal androgen exposure affects reproductive functions and has been proposed as an underlying cause of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal androgen exposure on ovarian lipid metabolism and to deepen our understanding of steroidogenesis regulation during adulthood. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. This treatment leads to two different phenotypes: irregular ovulatory and anovulatory animals. Our results showed that prenatally hyperandrogenized (PH) animals displayed altered lipid and hormonal profile together with alterations in steroidogenesis and ovarian lipid metabolism. Moreover, PH animals showed alterations in the PPARg system, impaired mRNA levels of cholesterol receptors (Ldlr and Srb1) and decreased expression of the rate-limiting enzyme of de novo cholesterol production (Hmgcr). Anovulatory PH animals presented an increase of ovarian cholesteryl esters levels and lipid peroxidation index. Together with alterations in cholesterol metabolism, we found an impairment of the steroidogenic pathway in PH animals in a phenotype-specific manner. Regarding fatty acid metabolism, our results showed, in PH animals, an altered expression of Srebp1 and Atgl, which are involved in fatty acid metabolism and triglycerides hydrolysis, respectively. In conclusion, fatty acid and cholesterol metabolism, which are key players in steroidogenesis acting as a source of energy and substrate for steroid production, were affected in animals exposed to androgens during gestation. These results suggest that prenatal androgen exposure leads to long-term effects that affect ovary lipid metabolism and ovarian steroid formation from the very first steps.

Investigation of second to fourth finger length ratio (2D:4D) in patients with bipolar disorder.

Objective:The etiology of bipolar disorder has yet to be fully elucidated, but differences in sex hormones have been suggested to play a role in its pathogenesis. An easily assessed marker of prenatal androgen exposure is the second-to-fourth-digit ratio (2D:4D) of the hand. In this study, we aimed to compare the 2D:4D ratio of patients with bipolar disorder to that of healthy controls.Methods:Seventy patients with bipolar disorder and 70 healthy controls, matched for age and sex, were included in the study. Finger lengths were measured from the palmar digital crease to the tip using a digital vernier caliper.Results:Patients with bipolar disorder had considerably higher right-hand 2D:4D ratios compared to controls. Both the right and left 2D:4D ratios of male patients were significantly greater than those of males in the control group. Female patients showed no differences in right or left 2D:4D ratio compared to healthy controls.Conclusion:These findings suggest that a high 2D:4D digit ratio of right hand is associated with the presence of bipolar disorder in males. Further large-scale, prospective studies are needed to explain the validity of this marker and its relationship with bipolar disorder.

Meconium androgens are correlated with ASD-related phenotypic traits in early childhood in a familial enriched risk cohort

BackgroundPrenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD). This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results.MethodsTo provide an orthogonal measure of fetal exposure, this study used meconium, the first stool of a newborn, to measure prenatal androgen exposure from infants in the Early Autism Risk Longitudinal Investigation (EARLI). EARLI is a familial-enriched risk cohort that enrolled pregnant mothers who already had a child with an ASD diagnosis. In the younger child, we investigated the association between meconium unconjugated (u) and total (t) concentrations of major androgens testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4), and ASD-related traits at 12 and 36 months of age. Traits were measured at 12 months with Autism Observation Scale for Infants (AOSI) and at 36 months with total score on the Social Responsiveness Scale (SRS). One hundred and seventy children had meconium and AOSI, 140 had meconium and SRS, and 137 had meconium and both AOSI and SRS.ResultsSeparate robust linear regressions between each of the log-transformed androgens and log-transformed SRS scores revealed three-way interaction between sex of the child, sex of the proband, and testosterone concentration. In the adjusted analyses, t-T, u-A4, and u-DHEA (P ≤ 0.01) were positively associated with AOSI scores, while u-T (P = 0.004) and u-DHEA (P = 0.007) were positively associated with SRS total score among females with female probands (n = 10). Additionally, higher concentrations of u-T (P = 0.01) and t-T (P = 0.01) predicted higher SRS total score in males with male probands (n = 63).LimitationsSince we explored three-way interactions, this resulted in a limited sample size for some analyses. This study was from an enriched-risk cohort which may limit generalizability, and this study used ASD-assessment scales as outcomes instead of diagnostic categories. Additionally, the novel use of meconium in this study limits the ability to compare the results in this cohort to others due to the paucity of research on meconium.ConclusionsThis study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies.

Prenatal androgen exposure and children's gender-typed behavior and toy and playmate preferences

We report findings from two studies investigating possible relations of prenatal androgen exposure to a broad measure of children's gender-typed behavior, as well as specifically to children's toy and playmate preferences. Study 1 investigated these outcomes for 43 girls and 38 boys, aged 4 to 11 years, with congenital adrenal hyperplasia (CAH, a genetic condition causing increased adrenal androgen production beginning prenatally) compared to similarly-aged, unaffected relatives (41 girls, 31 boys). The predicted sex differences were found for all of the outcome measures. Furthermore, girls with CAH showed increased male-typical and decreased female-typical behavior and toy and playmate preferences compared to unaffected girls. Study 2 investigated the relationship of amniotic fluid testosterone to gender-typed behavior and toy and playmate preferences in typically developing children (48 girls, 44 boys) aged 3 to 5 years. Although the predicted sex differences were found for all of the outcome measures, amniotic fluid testosterone was not a significant correlate, in the predicted direction, of any outcome measure for either sex. The results of study 1 provide additional support for an influence of prenatal androgen exposure on children's gender-typed behavior, including toy and playmate preferences. The results of study 2 do not, but amniotic fluid testosterone may be an insufficiently sensitive measure of early androgen exposure. A more sensitive and reliable measure of prenatal androgen exposure may be needed to consistently detect relations to later gender typed behavior in non-clinical populations.

No credible evidence for links between 2D:4D and COVID-19 outcomes: A probabilistic perspective on digit ratio, ACE variants, and national case fatalities

Research into COVID-19 susceptibility and outcomes are critical, but claims must be carefully evaluated to inform policy decisions. In a recent series of articles, Manning and Fink [1–3] use national-level data to describe associations between case-fatality ratios and male and female finger ratios (2D:4D), a suggested measure of prenatal androgen exposure, as well as angiotensin-converting enzyme (ACE) allele and genotype frequencies. The authors suggest that 2D:4D is linked with ACE variant prevalence, and that higher male 2D:4D is associated with higher case fatality ratios, and point to 2D:4D as a useful prognostic measure for COVID-19 susceptibility. A critical review and robust Bayesian analysis of the hypothesis is described here, finding no conclusive evidence of COVID-19 mortality and 2D:4D, nor associations between 2D:4D and ACE1 allele or ACE2 genotype frequency. This absence of evidence is present for data taken from the second wave of COVID-19 in October 2020. Problematic theoretical grounding, individual-level conclusions drawn from national-level data, and issues with statistical inference in the original articles are discussed. Taken together, the current data offer no clear utility of 2D:4D in determining COVID-19 outcomes.

No relationship between prenatal or early postnatal androgen exposure and autistic traits: evidence using anogenital distance and penile length measurements at birth and 3months of age.

Autism is more prevalent in males than in females. Hypotheses related to the extreme male brain theory of autism suggest that heightened androgen exposure during early development contributes to autistic traits. Whilst prior research focused mostly on the prenatal period, the current study tests the influences of androgen exposure during both the prenatal and the early postnatal periods on autistic traits during childhood. Anthropometric measures that are putative biomarkers of early androgen exposure were employed. Anogenital distance (AGD) was measured at birth and 3months of age in boys and girls. Penile length at birth and 3months of age was also measured in boys. When the children were 9-13years old, a parent-reported questionnaire (the 10-item children's version of the Autism Spectrum Quotient; AQ-10 Child) was used to assess autistic traits in 97 boys and 110 girls. There were no significant associations between any of the AGD or penile length measures and scores on the AQ-10 Child in boys, girls or the entire sample. The current study provides the first test of whether early measurements of AGD and/or penile length predict subsequent autistic traits. The current findings do not support a relationship between prenatal or early postnatal androgen exposure and autistic traits. The current study augments prior research showing no consistent relationship between early androgen exposure and autistic traits.

Prenatal Androgenization Alters the Development of GnRH Neuron and Preoptic Area RNA Transcripts in Female Mice.

Polycystic ovary syndrome (PCOS) is the most common form of infertility in women. The causes of PCOS are not yet understood and both genetics and early-life exposure have been considered as candidates. With regard to the latter, circulating androgens are elevated in mid-late gestation in women with PCOS, potentially exposing offspring to elevated androgens in utero; daughters of women with PCOS are at increased risk for developing this disorder. Consistent with these clinical observations, prenatal androgenization (PNA) of several species recapitulates many phenotypes observed in PCOS. There is increasing evidence that symptoms associated with PCOS, including elevated luteinizing hormone (LH) (and presumably gonadotropin-releasing hormone [GnRH]) pulse frequency emerge during the pubertal transition. We utilized translating ribosome affinity purification coupled with ribonucleic acid (RNA) sequencing to examine GnRH neuron messenger RNAs from prepubertal (3 weeks) and adult female control and PNA mice. Prominent in GnRH neurons were transcripts associated with protein synthesis and cellular energetics, in particular oxidative phosphorylation. The GnRH neuron transcript profile was affected more by the transition from prepuberty to adulthood than by PNA treatment; however, PNA did change the developmental trajectory of GnRH neurons. This included families of transcripts related to both protein synthesis and oxidative phosphorylation, which were more prevalent in adults than in prepubertal mice but were blunted in PNA adults. These findings suggest that prenatal androgen exposure can program alterations in the translatome of GnRH neurons, providing a mechanism independent of changes in the genetic code for altered expression.

Masculinized Second-to-Fourth Digit Ratio (2D:4D Ratio) Is Associated With Lower Cortisol Response in Infant Female Rhesus Monkeys (Macaca mulatta).

The second-to-fourth digit ratio (2D:4D ratio) is considered a postnatal proxy measure for the degree of prenatal androgen exposure (PAE), which is the primary factor responsible for masculinizing the brain of a developing fetus. Some studies suggest that the organizational effects of PAE may extend to the hypothalamic-pituitary-adrenal (HPA) axis response to stress. This study investigates the relationship between 2D:4D ratio and HPA axis functioning using a rhesus monkey (Macaca mulatta) model. Subjects were N = 268 (180 females, 88 males) rhesus monkey infants (3–4 months of age). Plasma cortisol concentrations were assayed from two blood samples obtained during a 25-h experimental social separation stressor at 2- and 7-h post-separation. Subjects’ 2D:4D ratio was measured later in life (Mage = 6.70 years). It was hypothesized that infant rhesus monkeys that exhibited a more masculine-like 2D:4D ratio would show lower levels of circulating cortisol after a social separation and relocation stressor. The results showed that there was a sex difference in the left-hand 2D:4D ratio. The results also showed that there was an overall sex difference in cortisol concentrations and that female, but not male, monkeys that exhibited a more masculine-like right- and left-hand 2D:4D ratio exhibited lower mean stress-induced cortisol concentrations early in life. These findings suggest that higher levels of prenatal androgens in females, as measured by 2D:4D ratio, may be related to an attenuated HPA axis stress-response, as measured by plasma cortisol levels. To the extent that these findings generalize to humans, they suggest that the organizational effects of PAE extend to the infant HPA axis, modulating the HPA axis response, particularly in females.

Second to fourth digit ratio (2D:4D) is associated with dementia in women

Alzheimer's disease is characterized by sex differences that may involve sex hormone exposure during development. Finger length ratios, an indirect measure of prenatal androgen exposure, were found to significantly differ in women with and without dementia. This finding links a relatively feminine in utero development with vulnerability to dementia in women.