Pubertal Testosterone Research Articles

Variations in volume; Breast size in trans women in relation to timing of testosterone suppression.

Breast development is an important outcome for trans women receiving gender affirming hormone therapy (GAHT). Limited breast development has been reported, possibly because of testosterone exposure during puberty. The impact of puberty suppression (PS) on breast development is unclear. To investigate the impact of PS and timing of PS prior to GAHT on breast volume and satisfaction. Cross-sectional study. Tertiary gender identity clinic. 60 trans women (aged 17-57 years) after 4.5±1.7 years of GAHT were included of whom 23 initiated PS early in puberty (Tanner stage G2-3), 17 late in puberty (Tanner stage G4-5), and 20 started GAHT in adulthood without prior PS. Breast volume measured with a 3D scanner and breast satisfaction measured with a questionnaire. Comparisons of breast volumes were adjusted for fat percentage. Median breast volume was 115ml (IQR 68; 203), i.e. bra cup-size <A. Breast volume was 47ml (95%CI -9; 104) larger in the late PS group compared to early PS but this difference was only 4ml (95%CI -67; 75) after correction for fat percentage. Breast volume in the adult group was comparable to the early and late PS groups (adult vs. early PS 27 ml (95% CI -28; 83) and adult vs. late PS -20 ml (95% CI -80; 40)). In total, 68% of subjects were satisfied with breast size (57% of early PS, 76% of late PS and 70% of adult group). Early start of PS was not associated with larger breast volume, suggesting that pubertal testosterone exposure does not affect breast volume after subsequent GAHT. Despite limited breast size, most trans women were satisfied with their breast development.

Identification of a Novel IGSF1 Variant in Two Malaysian Male Siblings with Central Hypothyroidism and Macroorchidism.

IGSF1 mutation is the commonest cause of mild to moderate isolated central congenital hypothyroidism and has an X-linked recessive inheritance, primarily affecting males. Other notable clinical features are macroorchidism with delayed pubertal testosterone rise, large birth weight, increased body mass index, low prolactin, transient growth hormone deficiency and low prolactin. Two male siblings with central hypothyroidism were found to have a novel IGSF1 c.3467T>A variant that was likely pathogenic based on the family segregation study. The proband, aged 3 years presented at 18 days old with prolonged jaundice while his 16-year-old brother was only detected to have central hypothyroidism after the proband's genetic analysis result was known. Both siblings were obese, had large birth weights, macroorchidism and low prolactin. The proband's brother had intellectual disability while the proband had normal development. This case study highlights the importance of evaluation for the IGSF1 variant in patients with unexplained central hypothyroidism, especially when accompanied by X-linked inheritance and macroorchidism. Family segregation analysis allows detection of other affected family members or carriers who may also benefit from thyroxine treatment.

Understanding Covid-19: Digit ratios and duration of oxygen therapy in hospitalized Covid-19 patients

BackgroundCovid-19 severity shows a sex difference (males>females) and progressive hypoxia among the most seriously affected. Digit ratios are sexually dimorphic and may be negatively-related to prenatal (2nd-to-4th digits' ratio; 2D:4D) and pubertal (3rd-to-5th digits' ratio; 3D:5D) testosterone. Oxygen therapy is important in Covid-19 treatment and low 2D:4D is linked to efficient oxygen metabolism. We consider relationships between digit ratios and duration of oxygen treatment in hospitalized Covid-19 patients. MethodsDigit lengths were measured from photographs of the patient's hands. Age, Sex, BMI, vaccination status and number of days of O2 treatment, were recorded. ResultsThere were 100 (58 women) patients. Sex differences (males<females) were present in 2D:4D ratios (Dr-l 2D:4D; ǀDr-l 2D:4Dǀ) but not in 3D:5D. Positive relationships were found between 2D:4D variables (left 2D:4D, women and men; Dr-l 2D:4D women), 3D:5D (male left 3D:5D) and duration of oxygen therapy. After removal of the influence of age, BMI, vaccination status and sex there were positive relationships between 2D:4D (right and left) and duration of oxygen therapy but no such associations for 3D:5D. In addition to 2D:4D there was evidence for a positive relationship between BMI and oxygen therapy. ConclusionWe have found that high (feminized) 2D:4D of males and females is positively related to duration of oxygen therapy. This adds to the evidence for links between severity of Covid-19 and national and individual level variation in foetal androgen (as measured by 2D:4D). We discuss our finding in the light of the “low-androgen-driven COVID-19 pandemic theory”.

The development of sensorimotor cortical oscillations is mediated by pubertal testosterone

Puberty is a period of substantial hormonal fluctuations, and pubertal hormones can modulate structural and functional changes in the developing brain. Many previous studies have characterized the neural oscillatory responses serving movement, which include a beta event-related desynchronization (ERD) preceding movement onset, gamma and theta responses coinciding with movement execution, and a post-movement beta-rebound (PMBR) response following movement offset. While a few studies have investigated the developmental trajectories of these neural oscillations serving motor control, the impact of pubertal hormone levels on the maturation of these dynamics has not yet been examined. Since the timing and tempo of puberty varies greatly between individuals, pubertal hormones may uniquely impact the maturation of motor cortical oscillations distinct from other developmental metrics, such as age. In the current study we quantified these oscillations using magnetoencephalography (MEG) and utilized chronological age and measures of endogenous testosterone as indices of development during the transition from childhood to adolescence in 69 youths. Mediation analyses revealed complex maturation patterns for the beta ERD, in which testosterone predicted both spontaneous baseline and ERD power through direct and indirect effects. Age, but not pubertal hormones, predicted motor-related theta, and no relationships between oscillatory responses and developmental metrics were found for gamma or PMBR responses. These findings provide novel insight into how pubertal hormones affect motor-related oscillations, and highlight the continued development of motor cortical dynamics throughout the pubertal period.

Pubertal Testosterone and Brain Response to Faces in Young Adulthood: An Interplay between Organizational and Activational Effects in Young Men.

According to the organizational-activational hypothesis, the organizational effects of testosterone during (prenatal) brain development moderate the activational effects of adult testosterone on behavior. Accumulating evidence supports the notion that adolescence is another period during which sex hormones organize the nervous system. Here we investigate how pubertal sex hormones moderate the activational effects of adult sex hormones on social cognition in humans. To do so, we recruited a sample of young men (n = 507; age, ∼19 years) from a longitudinal birth cohort and investigated whether testosterone exposure during adolescence (from 9 to 17 years of age) moderates the relation between current testosterone and brain response to faces in young adulthood, as assessed with functional magnetic resonance imaging (fMRI). Our results showed that the cumulative exposure to testosterone during adolescence moderated the relation between adult testosterone and both the mean fMRI response and functional connectivity (i.e., node strength). Specifically, in participants with low exposure to testosterone during puberty, we observed a positive relationship between current testosterone and the brain response to faces; this was not the case for participants with medium and high pubertal testosterone. Furthermore, we observed a stronger relationship between the brain response and current testosterone in parts of the angry-face network associated with (vs without) motion in the eye region of an observed (angry) face. We speculate that pubertal testosterone modulates the relationship between current testosterone and brain response to social cues carried by the eyes and signaling a potential threat.SIGNIFICANCE STATEMENT Accumulating evidence supports the organizational effects of pubertal testosterone, but the body of literature examining these effects on social cognition in humans is in its infancy. With a sample of young men from a longitudinal birth cohort, we showed that the cumulative exposure to testosterone during adolescence moderated the relation between adult testosterone and both the mean BOLD signal change and functional connectivity. Specifically, we observed a positive relationship between adult testosterone and the brain response to faces in participants with low exposure to testosterone during puberty, but not in participants with medium and high pubertal testosterone. Results of further analysis suggest that sensitivity to cues carried by the eyes might underlie the relationship between testosterone and brain response to faces, especially in the context of a potential threat.

Pubertal Testosterone and the Structure of the Cerebral Cortex in Young Men.

Adolescence is a period of brain maturation that may involve a second wave of organizational effects of sex steroids on the brain. Rodent studies suggest that, overall, organizational effects of gonadal steroid hormones decrease from the prenatal/perinatal period to adulthood. Here we used multimodal magnetic resonance imaging to investigate whether 1) testosterone exposure during adolescence (9-17years) correlates with the structure of cerebral cortex in young men (n = 216, 19years of age); 2) this relationship is modulated by the timing of testosterone surge during puberty. Our results showed that pubertal testosterone correlates with structural properties of the cerebral cortex, as captured by principal component analysis of T1 and T2 relaxation times, myelin water fraction, magnetization transfer ratio, fractional anisotropy and mean diffusivity. Many of the correlations between pubertal testosterone and the cortical structure were stronger in individuals with earlier (vs. later) testosterone surge. We also demonstrated that the strength of the relationship between pubertal testosterone and cortical structure across the cerebral cortex varies as a function of inter-regional profiles of gene expression specific to dendrites, axonal cytoskeleton, and myelin. This finding suggests that the cellular substrate underlying the relationships between pubertal testosterone and cerebral cortex involves both dendritic arbor and axon.

SAT-057 A Novel IGSF1 Variant in a Boy with Central Hypothyroidism and Epiphyseal Dysplasia

Background: IGSF1 deficiency syndrome, also known as X-linked central hypothyroidism and testicular enlargement (CHTE) syndrome, is caused by mutations in the immunoglobulin superfamily, member 1 gene. Recently recognized as the most common genetic cause of isolated central hypothyroidism (CH), its cardinal features include CH and adult macroorchidism. We describe a boy with CH and epiphyseal dysplasia found to have a novel IGSF1 variant.Clinical case: A male with attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, obsessive compulsive disorder and obesity was evaluated at age 9y for high total and LDL cholesterol and low T4 with normal TSH. He had short stature for family, high BMI, high sitting height ratio, and short arm span. Laboratory investigation revealed persistently mildly high total and LDL cholesterol, low T4, normal cortisol response to low-dose Cortrosyn stimulation, and normal IGF-1 and IGF-BP3. Bone age at 9y1m chronological age was 8y0m. Skeletal survey showed abnormal epiphyses of the femoral heads, knees, and humeral capitella suggesting primary epiphyseal dysplasia; he was referred to genetics. Growth improved after starting levothyroxine for CH. Multiple epiphyseal dysplasia gene panel (with reflex to clinical exome) did not find any variants known to be pathogenic for his condition. He was found to be a carrier of autosomal recessive Bartter syndrome. Heterozygous variants of unknown significance were found in RMRP, FGFR1, CDT1 and APOB. Whole exome sequencing showed hemizygosity for the p.Q743X (c.2227C>T) variant in IGSF1.Discussion: The p.Q743X IGSF1 variant has not been reported in the literature and is not present in population databases. It is predicted to cause loss of normal protein function and is considered pathogenic. CH is found in all males with IGSF1 deficiency syndrome. Macroorchidism, another defining feature, develops in adulthood; age of testicular growth onset is normal, but pubertal testosterone rise is delayed. Our patient remains prepubertal at age 11y. Other features sometimes present include hypoprolactinemia (which was found in this child) and transient partial GHD (not seen in this case). Overweight and the metabolic syndrome are common; this child’s cholesterol abnormalities may be due to weight and/or APOB variant found on genetic testing. ADHD has been seen in some patients with this syndrome; this child also has extensive psychiatric/behavioral problems, which have not been described. The skeletal findings in this case have not been previously noted in IGSF1 deficiency syndrome; whether this is a rare feature of IGSF1 deficiency syndrome or a separate entity is unclear. This case adds to the growing list of disease-causing variants in IGSF1. Endocrinologists should consider IGSF1 deficiency syndrome when diagnosing isolated CH in boys, as the characteristic macroorchidism is not present in childhood.

The Male Warrior Hypothesis: Testosterone-related Cooperation and Aggression in the Context of Intergroup Conflict

The Male Warrior Hypothesis (MWH) establishes that men’s psychology has been shaped by inter-group competition to acquire and protect reproductive resources. In this context, sex-specific selective pressures would have favored cooperation with the members of one’s group in combination with hostility towards outsiders. We investigate the role of developmental testosterone, as measured indirectly through static markers of prenatal testosterone (2D:4D digit ratio) and pubertal testosterone (body musculature and facial masculinity), on both cooperation and aggressive behavior in the context of intergroup conflict among men. Supporting the MWH, our results show that the intergroup conflict scenario promotes cooperation within group members and aggression toward outgroup members. Regarding the hormonal underpinnings of this phenomenon, we find that body musculature is positively associated with aggression and cooperation, but only for cooperation when context (inter-group competition) is taken into account. Finally, we did not find evidence that the formidability of the group affected individual rates of aggression or cooperation, controlling for individual characteristics.

Pubertal testosterone correlates with adolescent impatience and dorsal striatal activity

Recent self-report and behavioral studies have demonstrated that pubertal testosterone is related to an increase in risky and impulsive behavior. Yet, the mechanisms underlying such a relationship are poorly understood. Findings from both human and rodent studies point towards distinct striatal pathways including the ventral and dorsal striatum as key target regions for pubertal hormones. In this study we investigated task-related impatience of boys between 10 and 15 years of age (N = 75), using an intertemporal choice task combined with measures of functional magnetic resonance imaging and hormonal assessment. Increased levels of testosterone were associated with a greater response bias towards choosing the smaller sooner option. Furthermore, our results show that testosterone specifically modulates the dorsal, not ventral, striatal pathway. These results provide novel insights into our understanding of adolescent impulsive and risky behaviors and how pubertal hormones are related to neural processes.

Disruptive effects of neonatal gonadectomy on adult sexual partner preference and brain dimorphism in male rats: partial restoration with pubertal testosterone

According to the organizational-activational hypothesis, testosterone or its metabolite estradiol, can organize the brain in a male direction (permanently or for long periods) if exposure occurs during a critical (sensitive) time of brain development like the prenatal period. Male rodents with insufficient levels of testosterone during such critical period would irreversibly fail to display sexual partner preference for receptive females in adulthood. However, exposure to testosterone during puberty is believed to function as a second critical period for organization of brain and behavior. Thus, in the present study we explored the effects of neonatal gonadectomy at postnatal day 1 (GNX) on the partner preference of adult males and the size of some sexually dimorphic regions in the brain like the SDN-MPOA, SCN, MeApd and VMH; and challenged its irreversibility by providing exogenous testosterone during puberty. Our results indicated that neonatal GNX impaired partner preference for females and reduced the size of SDN-MPOA, MeApd and VMH, but not SCN. GNX males restored with testosterone in PD30-PD59 (GNX + T) expressed partner preference for sexually receptive females and increased the size of SDN-MPOA and VMH, but not MeApd in adulthood. We conclude that neonatal castration and the lack of testosterone during the first month of life alters sexual behavior and brain dimorphism in adult male rats, but pubertal testosterone reverses the effects on behavior and brain dimorphism to some extent.

Pubertal Testosterone Programs Adult Behavioral Adaptations to Sexual Experience through Infralimbic Cortex ΔFosB.

Acquisition of social proficiency entails behavioral adaptations to social experience, including both behavioral flexibility and inhibition of behaviors inappropriate in specific social contexts. Here, we investigated the contributions of testosterone and ΔFosB, a transcription factor linked to experience-dependent neural plasticity, to the adolescent maturation of social proficiency in male-female social interactions. To determine whether pubertal testosterone organizes circuits underlying social proficiency, we first compared behavioral adaptations to sexual experience in male Syrian hamsters that were deprived of testosterone during puberty (prepubertal castration; NoT@P) to those of males deprived of testosterone for an equivalent period of time in adulthood (postpubertal castration; T@P). All males were given testosterone replacement in adulthood for two weeks before sexual behavior testing, where males were allowed to interact with a receptive female once per week for five consecutive weeks. T@P males showed the expected decrease in ectopic (mis-directed) mounts with sexual experience, whereas NoT@P males did not. In addition, sexual experience induced FosB gene products expression in the infralimbic cortex (IL) in T@P, but not NoT@P, males. Overexpression of ΔFosB via an adeno-associated viral (AAV) vector in the IL of NoT@P males prior to sexual behavior testing was sufficient to produce a behavioral phenotype similar to that of experienced T@P males. Finally, overexpression of ΔFosB in IL increased the density of immature spines on IL dendrites. Our findings provide evidence that social proficiency acquired through sexual experience is organized by pubertal testosterone through the regulation of ΔFosB in the IL, possibly through increasing synaptic lability.

Temporal Expression Patterns of Genes Related to Sex Steroid Action in Sexually Dimorphic Nuclei During Puberty.

Sex steroids play a major role in sexually dimorphic brain development during not only the perinatal period but also the pubertal period. We previously showed that, in male mice, the estrogen receptor-α (Esr1) and aromatase (Cyp19a1) genes are essential to the sexually dimorphic formation of the anteroventral periventricular nucleus (AVPV) and the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), but the estrogen receptor-β (Esr2) gene is not necessary. We also showed that the androgen receptor (Ar) gene is essential to the sexually dimorphic formation of the BNSTp. These genes are expressed in the AVPV and BNSTp of perinatal mice. However, it remains unknown whether these genes are expressed in the AVPV and BNSTp during puberty, and whether the expression, if any, differs by sex, age, and brain region. Here, we dissected the AVPV and BNSTp from Nissl-stained brain sections of male and female mice on postnatal day (PD) 20 (prepuberty), PD30 (puberty onset in females), PD40 (puberty onset in males), and PD60 (young adult) using a laser microdissection system. We then examined the mRNA levels of Esr1, Esr2, Cyp19a1, and Ar in these brain regions. In the AVPV, Esr1 mRNA levels were greater in females than males during PD20–60. Esr2 and Ar mRNA expressions did not differ between sexes. Ar mRNA levels were higher at PD30 than PD20. Cyp19a1 mRNA was not detected in the AVPV at PD20–60. In the BNSTp, Esr1 and Esr2 mRNA levels were higher in females than in males during PD20–60, although the mRNA levels of Cyp19a1 and Ar did not differ between sexes. Additionally, we revealed that orchiectomy at PD20 induced a failure of normal formation of the male BNSTp and testosterone replacement in the prepubertal period rescued the effect of orchiectomy at PD20. Taken together, it is suggested that pubertal testosterone transported to the AVPV is not converted to estradiol there and does not act via ESR1 and ESR2. By contrast, the formation of the male BNSTp may be affected by testicular testosterone during puberty via AR and/or via ESR1 after conversion to estradiol by CYP19A1.

Prenatal and pubertal testosterone affect brain lateralization

After decades of research, the influence of prenatal testosterone on brain lateralization is still elusive, whereas the influence of pubertal testosterone on functional brain lateralization has not been investigated, although there is increasing evidence that testosterone affects the brain in puberty. We performed a longitudinal study, investigating the relationship between prenatal testosterone concentrations in amniotic fluid, pubertal testosterone concentrations in saliva, and brain lateralization (measured with functional Transcranial Doppler ultrasonography (fTCD)) of the Mental Rotation, Chimeric Faces and Word Generation tasks. Thirty boys and 30 girls participated in this study at the age of 15 years. For boys, we found a significant interaction effect between prenatal and pubertal testosterone on lateralization of Mental Rotation and Chimeric Faces. In the boys with low prenatal testosterone levels, pubertal testosterone was positively related to the strength of lateralization in the right hemisphere, while in the boys with high prenatal testosterone levels, pubertal testosterone was negatively related to the strength of lateralization. For Word Generation, pubertal testosterone was negatively related to the strength of lateralization in the left hemisphere in boys. For girls, we did not find any significant effects, possibly because their pubertal testosterone levels were in many cases below quantification limit. To conclude, prenatal and pubertal testosterone affect lateralization in a task-specific way. Our findings cannot be explained by simple models of prenatal testosterone affecting brain lateralization in a similar way for all tasks. We discuss alternative models involving age dependent effects of testosterone, with a role for androgen receptor distribution and efficiency.

Sex Differences in Binge Eating: Gonadal Hormone Effects Across Development.

Eating disorders are highly sexually differentiated disorders that exhibit a female predominance in risk. Most theories focus on psychosocial explanations to the exclusion of biological/genetic influences. The purpose of this descriptive review is to evaluate evidence from animal and human studies in support of gonadal hormone effects on sex differences in binge eating. Although research is in its nascent stages, findings suggest that increased prenatal testosterone exposure in males appears to protect against binge eating. Although pubertal testosterone may exert additional protective effects, the prenatal period is likely critical for the decreased risk observed in males. By contrast, studies indicate that, in females, it is the lack of prenatal testosterone coupled with the organizational effects of pubertal ovarian hormones that may lead to increased binge eating. Finally, twin data suggest that changes in genetic risk may underlie these hormone influences on sex differences across development.

Spermatogenesis parameters and testosterone production at puberty as predictors of testicular functional activity in mice (Mus musculus)

The aim of this study was to investigate fertility-associated parameters of spermatogenesis and androgenic status in male laboratory mice at puberty and to assess their prognostic significance in the realization of the definitive testicular function. In three inbred murine strains, BALB/cLac, CBA/Lac and PT, the serum testosterone level, its testicular concentration, epididymal sperm count (sperm reserve) and portion of sperm with abnormal head morphology were evaluated on days 45 (puberty) and 90 (adulthood) of postnatal development. CBA/Lac males were characterized by a lower epididymal sperm count vs. other strains at both ages indicative of poorer spermatogenesis. At the same time, CBA/Lac males had a lower portion of sperm with abnormal head morphology, and this could be considered as a compensatory reaction aimed at improving sperm fertility. Distinct inter-strain differences in the portion of sperm with morphologically abnormal heads were established at both ages, while the inter-strain ratio remained invariable (BALB/cLac > PT > CBA/Lac). Thus, the level of abnormal spermatogenesis in the pubertal period may have a predictive significance for the definitive testicular activity in adult mice. No inter-strain and age-dependent changes were found in serum and testicular testosterone levels except for the PT strain, in which both testosterone levels rose from puberty to adulthood, suggesting a shift of the pubertal testosterone peak towards later times. Our data show that in male laboratory mice the genetic peculiarities of the testicular function manifest themselves during puberty and persist until adulthood.

Pubertal pair-housing facilitates adult sexual behavior in male rats.

This study examined the effects of pubertal testosterone (T) and social housing manipulations on male sexual behavior in adult rats. Prepubertal rats were castrated at 21 days of age (P21) and implanted with either blank or T-releasing pellets. At the onset of puberty, P28, half the rats in each treatment group were either single- or pair-housed with a male of the same hormone condition through P56, at which time pellets were removed and all rats were single-housed. In adulthood (P84), all rats received T replacement and were tested for sexual behavior. Rats pair-housed during adolescence showed more sexual behavior and greater improvement of sexual performance over repeated tests than single-housed rats, regardless of pubertal T status. Pubertal T, however, did facilitate the frequency of anogenital investigation. Thus, in male rats, social interactions during adolescence are more important than exposure to pubertal T in enhancing adult sexual behavior.

The organizational effects of pubertal testosterone on sexual proficiency in adult male Syrian hamsters

Social proficiency requires making appropriate behavioral adaptations as a result of social experience. For example, male rodents become sexually proficient with experience as demonstrated by a reduction in ectopic (misdirected) mounts, mount-to-intromission ratio, and latency to ejaculation. We previously found that over a series of timed tests with a receptive female, male hamsters deprived of testosterone specifically during puberty (NoT@P) have overall lower levels of sexual behavior and continue to display high levels of ectopic mounts, compared with males that experienced endogenous testosterone during puberty (T@P). These results suggested that pubertal testosterone programs sexual proficiency in adulthood, but because NoT@P males engaged in less sexual behavior than T@P males in these tests, the amount of sexual experience may have been insufficient to improve sexual proficiency. To more rigorously test the hypothesis that pubertal testosterone is necessary for social proficiency in adulthood, the present study compared the behavior of NoT@P and T@P males in a series of 4 trials with a 48-h interval between each trial. Sexual experience was equated by limiting each trial to 5 intromissions. Sexually-naïve males were either gonadectomized prepubertally (NoT@P) or in adulthood (T@P) and received subcutaneous testosterone capsules four weeks later. Two weeks after testosterone replacement, these groups and a group of adult gonad-intact controls began sexual behavior testing. We found that NoT@P males had more ectopic mounts/min across all four tests compared to gonad-intact and T@P males. Moreover, both gonad-intact and T@P males, but not NoT@P males, showed an increase in the number of mounts and intromissions/min between trials 1 and 3. Unexpectedly, both gonad-intact and T@P, but not NoT@P, males showed a decrease in sexual behaviors during trial 4. Thus, T@P males display multiple behavioral adaptations to sexual experience that are not observed in NoT@P males: a reduction in ectopic mounts after repeated encounters with a receptive female and an inverted U-shape pattern in mounts and intromissions when these encounters do not lead to ejaculations. These results support the hypothesis that pubertal testosterone organizes neural circuits underlying behavioral flexibility and adaptability to promote sexual proficiency in adulthood.

Facial Width-To-Height Ratio (fWHR) Is Not Associated with Adolescent Testosterone Levels

Facial width-to-height ratio (fWHR) has been proposed as a sexually dimorphic signal in humans that develops under the influence of pubertal testosterone (T); however, no studies have examined the association between fWHR and T during the phase in which facial growth is canalized—adolescence. In a sample of adolescent Tsimane males, we evaluate the relationship between T, known T-derived traits (i.e. strength and voice pitch), and craniofacial measurements. If fWHR variation derives from T’s effect on craniofacial growth during adolescence, several predictions should be supported: 1) fWHR should increase with age as T increases, 2) fWHR should reflect adolescent T (rather than adult T per se), 3) fWHR should exhibit velocity changes during adolescence in parallel with the pubertal spurt in T, 4) fWHR should correlate with T after controlling for age and other potential confounds, and 5) fWHR should show strong associations with other T-derived traits. Only prediction 4 was observed. Additionally, we examined three alternative facial masculinity ratios: facial width/lower face height, cheekbone prominence, and facial width/full face height. In contrast to fWHR, all three alternative measures show a strong age-related trend and are associated with both T and T-dependent traits. Overall, our results question the status of fWHR as a sexually-selected signal of pubertal T and T-linked traits.

Does the facial width-to-height ratio map onto variability in men's testosterone concentrations?

Variation in the facial width-to-height ratio (fWHR) maps onto a number of behavioral and psychological traits among men (e.g., aggression, unethical behavior, negotiation performance). Importantly, observer judgments of many of these traits also correlate strongly with the fWHR, suggesting that it may represent an honest cue to dominance and status. It has been speculated that the relationship between fWHR and these behavioral traits is due to pubertal testosterone concurrently shaping facial structure and traits linked to social dominance. Others, however, have provided some initial, although inconsistent, evidence that circulating testosterone levels in adulthood may underlie associations between the fWHR and behavioral displays. Here, we provide a more powerful test of the second model by examining the relationship between fWHR, baseline testosterone, and competition-induced testosterone reactivity, across seven diverse samples of men (total N=780). We also report a further analysis including data published previously, for a total sample of 1041 men. Analysis of our individual samples, in addition to an internal meta-analysis, demonstrated no significant positive relationship between fWHR and baseline testosterone, or fWHR and three measures of competition-induced testosterone reactivity. We discuss potential reasons for previous discrepancies, and suggest avenues for future research.

IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.

Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.