Associations of the digit ratio with adolescent behavior problems are inconsistent with an intrauterine androgenic origin.

A low second-to-fourth digit ratio (2D:4D) is a purported biomarker of increased intrauterine androgenic exposure, presumably linked to postnatal behavior. We aimed to examine the associations between 2D:4D and adolescence behavior problems expected from high (externalizing and attention problems) or low (internalizing problems) prenatal androgen exposure. We conducted a cross-sectional study of 1042 Colombian schoolchildren aged 11-18 y. We examined whether caliper-assessed 2D:4D was associated with behavior problems per the Youth Self-Report questionnaire. Mean problem standardized score point differences were estimated between hand- and sex-specific quintiles of 2D:4D with use of multivariable linear regression. Lower right-hand 2D:4D was associated with decreased externalizing and internalizing behavior problem scores. Corresponding lowest-to-median quintile adjusted mean differences (95% CI) were -4.6 (-7.5, -1.7) and -3.5 (-6.4, -0.6) points in boys; and -3.4 (-5.9, -0.9) and -3.5 (-6.2, -0.8) points in girls. Lower right-hand 2D:4D was also related to less attention and thought problems in boys, and to less social problems among girls. Associations were nonlinear, apparent only below 2D:4D medians, and stronger with the right than the left hand. In conclusion, right-hand 2D:4D is related to behavior problems in adolescence in directions that are not fully consistent with an androgenic exposure origin.

Relationship among anogenital distance, adrenal gland volume, and penile length and width at 22-36 weeks of pregnancy.

OBJECTIVES: The subject of current work was to determine the relationship of fetal ultrasonographic biomarkers, including anogenital distance (AGD), adrenal gland volume, and penile length and width in mothers with male fetuses at 22-36 weeks of gestation for the assessment of the effect of fetal adrenal gland producing androgens on the male anogenital structures that are exposed to androgen effects as anogenital region and penis. METHODS: This study is a prospective cross-sectional study conducted in our hospital's outpatient perinatal care unit. One hundred and seventy pregnant women with a male fetus aged 22-36 weeks of gestation were included in the study. The fetal adrenal gland length, width, and depth for the calculation of adrenal volume, AGD, and penile length and width were measured for each participant. The Pearson coefficients were calculated to assess the correlation among these parameters. RESULTS: The adrenal gland volume had a meaningful, positive moderate relationship with both the AGD (r=0.60) and penile length and width (r=0.57 and r=0.59, respectively; p<0.001). The AGD had a positive, strong correlation with the penile length and width (r=0.74 and r=0.76, respectively; p<0.001). CONCLUSIONS: The fetal adrenal gland as one of the androgen sources of the fetus is an influencer of the development of the anogenital and penile region. The findings of the current study support that the adrenal gland considerably affects the masculinization of male fetuses, since there were remarkable correlations among the AGD, adrenal gland volume, and penile length and width.

Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo.

BACKGROUND: Reduced androgen action during early fetal development has been suggested as the origin of reproductive disorders comprised within the testicular dysgenesis syndrome (TDS). This hypothesis has been supported by studies in rats demonstrating that normal male development and adult reproductive function depend on sufficient androgen exposure during a sensitive fetal period, called the masculinization programming window (MPW). The main aim of this study was therefore to examine the effects of manipulating androgen production during different timepoints during early human fetal testis development to identify the existence and timing of a possible window of androgen sensitivity resembling the MPW in rats. METHODS: The effects of experimentally reduced androgen exposure during different periods of human fetal testis development and function were examined using an established and validated human ex vivo tissue culture model. The androgen production was reduced by treatment with ketoconazole and validated by treatment with flutamide which blocks the androgen receptor. Testicular hormone production ex vivo was measured by liquid chromatography-tandem mass spectrometry or ELISA assays, and selected protein markers were assessed by immunohistochemistry. RESULTS: Ketoconazole reduced androgen production in testes from gestational weeks (GW) 7-21, which were subsequently divided into four age groups: GW 7-10, 10-12, 12-16 and 16-21. Additionally, reduced secretion of testicular hormones INSL3, AMH and Inhibin B was observed, but only in the age groups GW 7-10 and 10-12, while a decrease in the total density of germ cells and OCT4+ gonocytes was found in the GW 7-10 age group. Flutamide treatment in specimens aged GW 7-12 did not alter androgen production, but the secretion of INSL3, AMH and Inhibin B was reduced, and a reduced number of pre-spermatogonia was observed. CONCLUSIONS: This study showed that reduced androgen action during early development affects the function and density of several cell types in the human fetal testis, with similar effects observed after ketoconazole and flutamide treatment. The effects were only observed within the GW 7-14 period-thereby indicating the presence of a window of androgen sensitivity in the human fetal testis.

The association between anogenital distance and benign prostatic hyperplasia related lower urinary tract symptoms in Chinese aging men.

PURPOSE: We conducted the study to investigate the relationship between anogenital distance (AGD) and benign prostatic hyperplasia (BPH) related lower urinary tract symptoms (LUTS). METHODS: From May 2018 to January 2020, 220 subjects: 110 men with BPH-related LUTS (BPH-LUTS group) and 110 men without any urination complaints (control group) were selected. Clinical questionnaires, detailed physical examinations, including AGDas (distance between the anus and posterior base of the scrotum) and AGDap (distance between the anus and upper penis) measurements, and blood tests were all assessed. RESULTS: The two groups were similar in terms of basic features (P > 0.05). The AGDap and AGDas in the control group were significantly shorter than the BPH-LUTS group (P < 0.001). Adjusted multivariate analyses showed that AGDas was significantly related to International Prostate Symptom Score (IPSS), post-voiding residual volume (PVR), total prostate volume (TPV) and maximum urine flow rate (Qmax) (P = 0.002, P = 0.009, P = 0.001, P = 0.028, respectively). However, the associations between AGDap and IPSS score, PVR, TPV, Qmax and total testosterone (TT) were all negligible (P > 0.05 for all). The associations between TT and BPH-LUTS related evaluations were also negligible (P > 0.05 for all). Furthermore, the study revealed that the AGDas cut-off values for mild, moderate, and severe symptom (based on IPSS score) in BPH-LUTS cases were 27.4 mm and 46.8 mm [area under curve (AUC): 0.802 and AUC: 0.779, respectively], respectively. CONCLUSION: Longer AGDas was related to more severe BPH related symptoms. It may be useful to consider AGD as a marker for BPH-LUTS. Further well-designed studies are remained to be done to explore the intriguing problem.

2D:4D Digit Ratios in Adults with Gender Dysphoria: A Comparison to Their Unaffected Same-Sex Heterosexual Siblings, Cisgender Heterosexual Men, and Cisgender Heterosexual Women.

We compared gender dysphoria (GD) patients and their same-sex siblings in terms of their 2D:4D ratios, which may reflect prenatal exposure to androgen, one of the possible etiological mechanisms underlying GD. Sixty-eight GD patients (46 Female-to-Male [FtM]; 22 Male-to-Female [MtF]), 68 siblings (46 sisters of FtMs; 22 brothers of MtFs), and 118 heterosexual controls (62 female; 56 male) were included in the study. FtMs were gynephilic and MtFs were androphilic. We found that 2D:4D ratios in the both right hand (p < .001) and the left hand (p = .003) were lower in male controls than in female controls. Regarding right hands, FtM GD patients had lower 2D:4D ratios than female controls (p < .001) but their ratios did not differ from those of their sisters or male controls. FtM GD patients had no significant difference in their left-hand 2D:4D ratios compared to their sisters or female and male controls. While there was no significant difference in right hands between FtM's sisters and male controls, left-hand 2D:4D ratios were significantly higher in FtM's sisters (p = .017). MtF GD patients had lower right-hand 2D:4D ratios than female controls (p <.001), but their right-hand ratios did not differ from those of their brothers and male controls. There was no significant difference in left-hand 2D:4D ratios between MtF GD patients, and their brothers, or female and male controls. FtM GD patients showed significantly masculinized right-hand 2D:4D ratios, while there was no evidence of feminization in MtF GD patients.

Testing the twin testosterone transfer hypothesis-intergenerational analysis of 317 dizygotic twins born in Aberdeen, Scotland.

STUDY QUESTION: Does having a male co-twin influence the female twin's reproductive outcomes? SUMMARY ANSWER: Women with a male co-twin had the same chances of being pregnant and having children compared to same-sex twin pairs. WHAT IS KNOWN ALREADY: According to the twin testosterone transfer (TTT) hypothesis, in an opposite-sex twin pregnancy, testosterone transfer from the male to the female co-twin occurs. A large body of literature supports the negative impact of prenatal testosterone exposure on female's reproductive health in animal models; however, evidence from human studies remains controversial. STUDY DESIGN, SIZE, DURATION: This cohort study included all dizygotic female twins in the Aberdeen Maternity and Neonatal Databank (Scotland) born before 1 January 1979. The 317 eligible women were followed up for 40 years for any pregnancies and the outcome of those pregnancies recorded in the same database. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fertility outcomes (number of pregnancies, number of livebirths and age at first pregnancy) were compared between women with a male co-twin (exposed group, n = 151) and those with a female co-twin (unexposed group, n = 166). Population averaged models were used to estimate odds ratios (OR) and 95% CI for all outcomes with adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: There were no differences in chances of having pregnancies (adj. OR 1.33; 95% CI 0.72, 2.45) and livebirths (adj. OR 1.22; 95% CI 0.68, 2.18) between women from same-sex and opposite-sex twin pairs. Women with a male co-twin were more likely to smoke during pregnancy and, in the unadjusted model, were younger at their first pregnancy (OR 2.13; 95% CI 1.21, 3.75). After adjusting for confounding variables (year of birth and smoking status) the latter finding was no longer significant (OR 1.67; 95% CI 0.90, 3.20). LIMITATIONS, REASONS FOR CAUTION: The dataset was relatively small. For women without a pregnancy recorded in the databank, we assumed that they had not been pregnant. WIDER IMPLICATIONS OF THE FINDINGS: Despite the evidence from animal studies concerning the adverse effects of prenatal testosterone exposure on female health, our results do not support the TTT hypothesis. The finding that women with a male co-twin are more likely to smoke during pregnancy highlights the importance of considering post-socialisation and social effects in twin studies. STUDY FUNDING/COMPETING INTEREST(S): European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie project PROTECTED (grant agreement No. 722634) and FREIA project (grant agreement No. 825100). No competing interests. TRIAL REGISTRATION NUMBER: N/A.

Anogenital distance as a measure of male competitive ability in Rwenzori Angolan colobus.

Anogenital distance (AGD) is positively correlated to fetal androgen exposure and developmental masculinization in mammals. Independent of overall body size, AGD shows a strong positive correlation with male fertility and in rodents, AGD is a good indicator of male competitive ability and is associated with female choice. We hypothesized that AGD will also predict male competitive ability in non-human primates. To test this, we measured AGD noninvasively with a parallel laser in a wild population of Angolan colobus monkeys (Colobus angolensis ruwenzorii) in Uganda and correlated to it to their social structure. C. angolensis ruwenzorii form a multilevel society with both one-male/multifemale units (OMUs) and multimale/multifemale units (MMUs). We compared AGD in males from five OMUs and six MMUs and related it to their fecal androgen metabolite concentrations, dominance rank and body size, and to the number of females in their unit. Males in OMUs had greater access to females, so were predicted to have longer AGDs, but this was not found. AGD also did not correlate overall with mean fecal androgen metabolites in MMUs. However, AGD was correlated with dominance rank in MMUs, demonstrating that higher-ranking males in these multimale units had longer AGDs. Body size did not show the same relationship with dominance rank, suggesting that male rank was not just a reflection of absolute male size. Our findings indicate that AGD predicts male competitive ability in this species and that it may be a useful correlate throughout the non-human primates. These results also support the idea that prenatal androgen exposure increases the likelihood of the expression of behaviors that maintain high dominance rank.

Digit ratio (2D:4D) in relation to substance and computer use: a meta-analysis.

Human studies have reported inconsistent associations between the length ratio of the second finger to the fourth finger (2D:4D), which is a proxy for prenatal androgen load, and substance or computer use in adolescents and adults. This meta-analysis quantifies the magnitude of this relationship and investigates the roles of sex, definition of caseness, different forms of addiction, the hand measured (right hand versus left hand), and other cohort characteristics. Univariate random-effects meta-analyses were performed, and moderators were tested with Bonferroni-corrected meta-regression analyses. The study included 18 independent samples with a total of 175,955 participants (96,316 males and 79,639 females). There was a significant difference in 2D:4D between the substance and computer-using subjects and the controls for the combined sample (Hedge's g = - 0.178 [- 0.291; - 0.064]) and for males (Hedge's g = - 0.260 [- 0.399; - 0.122]), but not for females. These effects were amplified when only analyzing studies that compared dependent versus non-dependent subjects (combined sample: g = - 0.325 [- 0.492; - 0.157]; males: g = - 0.427 [- 0.564; - 0.291]), but did not reach significance in the subgroup of studies examining other parameters of substance and computer use. When analyzing different forms of substance and computer use separately, alcohol intake and computer use revealed a significant difference in the standardized mean. Again, the effects were amplified when analyzing the subgroup of males and the subgroup of studies comparing dependent versus non-dependent subjects, with effect sizes showing Hedge's g values as many as - 0.552 [- 0.785; - 0.319] (alcohol-dependent males). Thus, this meta-analysis confirms that lower 2D:4D is associated with substance and computer dependency. Further studies are encouraged to explore the link between intrauterine hormone environment and addiction risk.

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.

Polycystic ovary syndrome: Understanding the role of the brain.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and the leading cause of anovulatory infertility. Characterised by hyperandrogenism, menstrual dysfunction and polycystic ovaries, PCOS is a broad-spectrum disorder unlikely to stem from a single common origin. Although commonly considered an ovarian disease, the brain is now a prime suspect in both the ontogeny and pathology of PCOS. We discuss here the neuroendocrine impairments present in PCOS that implicate involvement of the brain and review evidence gained from pre-clinical models of the syndrome about the specific brain circuitry involved. In particular, we focus on the impact that developmental androgen excess and adult hyperandrogenemia have in programming and regulating brain circuits important in the central regulation of fertility. The studies discussed here provide compelling support for the importance of the brain in PCOS ontogeny and pathophysiology and highlight the need for a better understanding of the underlying mechanisms involved.