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2018-10-10

Gender identity in patients with 5-alpha reductase deficiency raised as females.

J Pediatr Urol. 2018 Sep 5. pii: S1477-5131(18)30499-6. doi: 10.1016/j.jpurol.2018.08.021. [Epub ahead of print]

Gender identity in patients with 5-alpha reductase deficiency raised as females.

Nascimento RLP1, de Andrade Mesquita IM1, Gondim R1, Dos Apóstolos RAAC1, Toralles MB1, de Oliveira LB1, Canguçu-Campinho AK1, Barroso U Jr2.

Author information ブラジル

Abstract

BACKGROUND AND OBJECTIVE:

5-Alpha reductase type 2 deficiency (5-ARD) is a rare disorder of sex development. The lack of 5-alpha reductase, an enzyme that converts testosterone into dihydrotestosterone, results in external genitalia that may appear female, or predominantly male, albeit undervirilized, or, more often, ambiguous.

METHODS:

This study describes a series of patients with 5-ARD raised as female, focusing on aspects related to gender identity. Following a retrospective chart review, patients with 5-ARD were invited to return to the clinic to enable their gender identity to be assessed using an 11-item structured in-house questionnaire. The Golombok-Rust Inventory of Sexual Satisfaction was applied to patients who had initiated their sexual life.

RESULTS:

Six patients aged >15 years with 5-ARD and raised as female were included. Most patients were diagnosed late: two before and four after puberty. The mean length of the phallus was 2.8 cm (0.5-5.0). Reasons for seeing a doctor included genital appearance (n = 3), amenorrhea/absence of breast development (n = 2), and changes in gender role attitudes (n = 1). According to the gender identity assessment, 4 patients identified as female, 1 as male, and 1 as both genders. Only the patient identified as male requested gender re-assignment. Of the two patients who had initiated their sexual life, sexual satisfaction was found to be good in one and poor in the other due to vaginal discomfort during intercourse.

CONCLUSION:

In the present series, the majority of undervirilized patients with a diagnosis of 5-ARD raised as female were in complete conformation with being female and described themselves as heterosexual. The more virilized patients were those least in conformity with their female-assigned gender.

Copyright © 2018. Published by Elsevier Ltd.


KEYWORDS:
5-Alpha reductase deficiency; Ambiguous genitali; Disorder of sex development; Gender; Gender identity; Intersex

2018-08-22

Childhood Sex-Typed Behavior and Gender Change in Individuals with 46,XY and 46,XX Disorders of Sex Development: An Iranian Multicenter Study.

Arch Sex Behav. 2018 Aug 20. doi: 10.1007/s10508-018-1281-9. [Epub ahead of print]

Childhood Sex-Typed Behavior and Gender Change in Individuals with 46,XY and 46,XX Disorders of Sex Development: An Iranian Multicenter Study.

Khorashad BS1, Roshan GM2, Reid AG3, Aghili Z2, Moghadam MD4, Khazai B2, Hiradfar M5, Afkhamizadeh M6, Ghaemi N4, Talaei A2, Abbaszadegan MR7, Aarabi A7, Dastmalchi S8, Van de Grift TC9,10.

Author information イラン・オランダ


Abstract

Disorders of sex development (DSD) are congenital conditions in which the typical genetic and hormonal profiles are affected and thereby the usual process of sexual differentiation. Most of these studies, however, have been conducted in Western countries. In the present study, preschool sex-typed activities of Iranian individuals with DSD and their age-matched non-affected male and female relatives were assessed using the Pre-School Activities Inventory (PSAI) modified for retrospective self-report. A total of 192 individuals participated in our study, including 33 46,XX individuals with congenital adrenal hyperplasia (CAH; M age = 10.36, SD = 5.52), 15 46,XY individuals with complete androgen insensitivity syndrome (CAIS; M age = 19.8, SD = 7.14), and 16 46,XY individuals with 5-alpha reductase deficiency type-2 (5α-RD-2; M age = 17.31, SD = 7.28), as well as one age-matched non-affected male and female relative for each patient. With regard to PSAI scores, male-identifying participants with 5α-RD-2 and male controls reported similar levels of male-typical childhood play. Female-identifying participants with 5α-RD-2 and CAH showed comparable scores: significantly less masculine and more feminine than male controls, but significantly more masculine and less feminine than females with CAIS and female controls. These findings support the role of androgens in the development of sex-typical childhood play behavior, with those being exposed to higher levels of fetal functional androgens expressing more masculine behavior at preschool ages.


KEYWORDS:
Childhood play behavior; Disorders of sex development; Sex chromosome; Sex differences; Testosterone

2018-02-09

Prenatal testosterone and theory of mind development: Findings from disorders of sex development.

Prenatal testosterone and theory of mind development: Findings from disorders of sex development.

Psychoneuroendocrinology. 2017 Dec 14;:

Authors: Khorashad BS, Khazai B, Roshan GM, Hiradfar M, Afkhamizadeh M, van de Grift TC

Highlights

•Studies factors theory of mind (ToM) development in individuals with Disorders of Sex Development (DSD).
•Based on sexual dimorphism seen in ToM performance of females and males through Reading the Mind in the Eyes Test (RMET).
•ToM development is significantly affected by prenatal androgen exposure.

Abstract

Women on average perform better than men on the "Reading the Mind in the Eyes" test (RMET) which is a measure of Theory of Mind (ToM). The aim of this study was to assess whether these sex differences are influenced by differences in prenatal testosterone levels through a study on individuals with Disorders of Sex Development and matched controls. ToM performance was examined using the RMET in female-assigned-at-birth individuals with increased prenatal testosterone exposure (Congenital Adrenal Hyperplasia (CAH) and 5-alpha Reductase type-2 Deficiency (5α-RD-2)), female-assigned-at-birth individuals with testosterone insensitivity (Complete Androgen Insensitivity Syndrome (CAIS)), and their age-matched unaffected male and female relatives. A total number of 158 individuals participated in the study; 19 with 5α-RD-2, 17 with CAH, 18 women with CAIS, 52 matched unaffected men and 52 matched unaffected women. All subgroups were around 20 years of age. Women with CAH scored significantly lower on RMET than control women and CAIS individuals. CAIS individuals scored significantly higher than control men and participants with 5α-RD. Statistically, CAIS individuals' performance on RMET was similar to control women's, women with CAH did not differ significantly from control men and 5α-RD-2 individuals scored significantly lower than control men. These results, which are in line with previous theories, illustrate that performance on the RMET, as an index of ToM, may be influenced by variations in prenatal androgens levels.

2015-01-29

Phenotypical, biological, and molecular heterogeneity of 5alpha-reductase deficiency: an extensive international experience of 55 patients

Phenotypical, biological, and molecular heterogeneity of 5alpha-reductase deficiency: an extensive international experience of 55 patients

Maimoun L, Philibert P, Cammas B, Audran F, Servant N, Lubroso S, Paris F, Sultan C. J Clin Endocrinol Metab. 2011 Feb; 96:296-307

DOI: 10.1210/jc.2010-1024

Abstract

CONTEXT:
In 46,XY disorders of sex development, 5α-reductase deficiency is rare and is not usually the first-intention diagnosis in newborn ambiguous genitalia, contrary to partial androgen insensitivity syndrome. Yet the cause of ambiguous genitalia may guide sex assignment, and rapid, precise diagnosis of 5α-reductase deficiency is essential.

OBJECTIVE:

The aim of the study was to describe relevant data for clinical diagnosis, biological investigation, and molecular determination from 55 patients with srd5A2 mutations identified in our laboratory over 20 yr to improve early diagnosis.
SETTING:
The study was performed at Montpellier University Hospital.

PATIENTS:
We studied a cohort of 55 patients with srd5A2 gene mutations.

MAIN OUTCOME MEASURE(S):
Genetic analysis of srd5A2 was conducted.

RESULTS:
Clitoromegaly (49.1%) and microphallus with various degrees of hypospadias (32.7%) were frequent phenotypes. Female external genitalia (7.3%) and isolated micropenis (3.6%) were rare. Seventy-two percent of patients were initially assigned to female gender; five of them (12.5%) switched to male sex in peripuberty. Over 72% of patients were considered for 5α-reductase deficiency diagnosis when the testosterone/dihydrotestosterone cutoff was 10. In 55 patients (with 20 having a history of consanguinity), we identified 33 different mutations. Five have never been reported: p.G32S, p.Y91H, p.G104E, p.F223S, and c.461delT. Homozygous mutations were present in 69.1% of cases, compound heterozygous mutations in 25.5%, and compound heterozygous mutations alone with the V89L polymorphism in 5.4%. Exons 1 and 4 were most affected, with 35.8 and 21.7% mutant alleles per exon, respectively.

CONCLUSIONS:
In the largest cohort to date, we demonstrate a wide spectrum of phenotypes and biological profiles in patients with 5α-reductase deficiency, whatever their geographical or ethnic origins.

_ _ _ _ _ _ _ _ _ _ _ _ _ _

Summary

This report underscores the wide variability in the genital phenotype associated with alterations in the 5alpha-reductase type 2 gene (SRD5A2) responsible for syndrome of 5alpha-reductase deficiency (5ARD), a disorder of sex development (DSD). Because of the limited sensitivity of biochemical testing, the authors strongly encourage clinicians to consider genetic testing. This study potentially also represents a major challenge to the notion that the majority of affected persons with 5ARD, assigned as girls at birth, choose to reassign themselves as boys — in this study, this transition occurred in only 12.5% of cases.Maimoun and colleagues make a substantial contribution to our understanding of genotype-phenotype relationships in 5ARD. In this international series of 55 patients with incomplete genital masculinization and alteration in the SRD5A2 gene, the investigators reported a wide variability in genotype/genital phenotype associations. The study shows that SRD5A2 alterations are occasionally observed in the presence of a normal testosterone (T)/dihydrostestosterone (DHT) ratio (i.e. <10), a common biochemical screening test for 5ARD. Accordingly, reliance on a negative biochemical test in an affected child could result in a diagnostic odyssey assuming 5ARD had been ruled out. This limitation of the biochemical diagnosis should encourage clinicians to consider genetic testing as the primary route to diagnosis in 5ARD.Although this study makes a strong case for genetic testing as the primary route to diagnosing 5ARD, it does not follow that an accurate diagnosis implies a gender assignment recommendation, as suggested in the final sentence of the paper. The observed failure to detect genotype-phenotype correlations directly challenges this expectation. Mutations of the SRD5A2 gene are associated with a genital phenotype ranging from female external genitalia with clitoromegaly to microphallus with hypospadias of varying degrees. Although rarer as outcomes, both normal female genital appearance and isolated micropenis were observed. In one salient example of this, the genital appearance of two siblings in this series with the same compound heterozygous mutation diverged substantially enough (one with a normal clitoris and the other with microphallus and hypospadias) in that one was reared as a girl and the other as a boy.

A startling finding of this study is that only five of 40 patients assigned as female (12.5%) subsequently changed their gender to male. This proportion is remarkably lower than the 63% reported in a recent systematic review {1}. Unfortunately, gaps in the details provided, in particular the age of patients at the time of recording gender assignment, make it difficult to reconcile these highly discrepant observations. Accurate diagnosis is always of value, even if it does not solve the question of optimal gender assignment. Parents, and later the affected person, will want to know even if management is unaffected. The consensus statement on the management of DSD {2} notes that gender assignment recommendations must take into account factors other than diagnosis, including genital appearance, surgical options, need for hormonal therapy, fertility and family and cultural perspectives.

References

1. Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta hydroxysteroid dehydrogenase-3 deficiency. Cohen-Kettenis PT Arch Sex Behav 2005 Aug; 4(34):399-410 PMID: 16010463

2. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Lee PA, Houk CP, Ahmed SF, Hughes IA, International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology Pediatrics 2006 Aug; 2(118):e488-500 PMID: 16882788

Recommendation Citation:

Sandberg D: F1000Prime Recommendation of [Maimoun L et al., J Clin Endocrinol Metab 2011, 96:296-307]. In F1000Prime, 30 Aug 2011; DOI: 10.3410/f.12909960.14201055. F1000Prime.com/12909960#eval14201055

2013-11-15

Prenatal endocrine influences on sexual orientation and on sexually differentiated childhood behavior

Prenatal endocrine influences on sexual orientation and on sexually differentiated childhood behavior

Melissa Hines
Department of Social and Developmental Psychology, University of Cambridge


Abstract
Both sexual orientation and sex-typical childhood behaviors, such as toy, playmate and activity preferences, show substantial sex differences, as well as substantial variability within each sex. In other species, behaviors that show sex differences are typically influenced by exposure to gonadal steroids, particularly testosterone and its metabolites, during early development (prenatally or neonatally). This article reviews the evidence regarding prenatal influences of gonadal steroids on human sexual orientation, as well as sex-typed childhood behaviors that predict subsequent sexual orientation. The evidence supports a role for prenatal testosterone exposure in the development of sex-typed interests in childhood, as well as in sexual orientation in later life, at least for some individuals. It appears, however, that other factors, in addition to hormones, play an important role in determining sexual orientation. These factors have not been well-characterized, but possibilities include direct genetic effects, and effects of maternal factors during pregnancy. Although a role for hormones during early development has been established, it also appears that there may be multiple pathways to a given sexual orientation outcome and some of these pathways may not involve hormones.


Sources of information on prenatal hormones and sexual differentiation of human behavior

Although the adult hormone environment does not seem to influence sexual orientation, this does not mean that the early hormone environment is also without effect. Studying possible influences of the prenatal or neonatal hormone environment on human behavior is challenging. It would be unethical to administer hormones experimentally to pregnant women to test for influences on sexual orientation. However, some disorders of sex development (DSD) [75] involve alterations in the hormone environment, beginning prenatally. In addition, women have sometimes been prescribed hormones during pregnancy. Both of these types of situations provide information on the consequences of dramatic alterations in hormones prenatally for human behavioral development, including the development of sexual orientation. Information also has come from studies where hormones have been measured during early development, for example in the amniotic fluid or in the maternal blood, and related to later behavior. Some studies also have related physical characteristics that are thought to relate to prenatal androgen exposure, particularly finger ratios, to behavioral outcomes, using these physical characteristics as bioassays of prenatal androgen exposure. Finally, some evidence has come from studies of the impact of stress, which causes changes in adrenal hormones, including androgens, during gestation on sexual orientation of offspring. Each of these types of influences will be described in more detail in subsequent sections.

Congenital adrenal hyperplasia (CAH) and sexual orientation

The most extensively studied DSD in regard to sexual differentiation of behavior is congenital adrenal hyperplasia (CAH). CAH is an autosomal, recessive disorder that occurs in approximately 1 in 5,000 to 1 in 15,000 births in Europe and North America [110]. In about 95% of cases, the disorder results from mutations in the CYP21A2 gene that encodes the enzyme, 21-hydroxylase (21-OH). The deficiency in 21-OH impedes cortisol production, and results in shunting of cortisol precursors into the androgen pathway and therefore overproduction of adrenal androgens. Androgen levels in female fetuses with classical CAH,
the form of the disorder known to involve prenatal androgen elevation, are raised dramatically [114;152], and, as a consequence, girls with classical CAH are born with some degree of genital virilization. In rare cases, the virilization is sufficiently severe that they are mistaken for boys at birth [108]. Usually, however, the genital ambiguity leads to prompt diagnosis and postnatal treatment to regulate hormone levels, and assignment and rearing as girls, with surgical genital feminization typically in infancy.

At least 10 studies have been published in the English language on sexual orientation in girls and women with CAH in comparison to female controls [29;44;45;67;82;88;95;103;109;155]. The overwhelming conclusion from these studies is that women with CAH are less likely to be exclusively or almost exclusively heterosexual than are other women. The studies have used varied methodologies to assess sexual orientation and have looked at different age ranges, and these differences appear to influence the results obtained. Reduced heterosexual orientation is more likely to be observed in studies assessing erotic imagery, as well as, or rather than solely, the sex of actual sexual
partners [103]. In addition, reduced heterosexual orientation is more likely to be found in studies that are restricted to individuals 16 years of age or older, than in studies that include children. For instance, in one study that reported data for various age groups [29], 20% of females with CAH in the age range 11 to 41 years indicated that they had “had or wished to have a long term/ steady relationship with a female partner”, whereas the comparable figure for those over 16 years of age was 26%, and for those over 21, it was 44%. This age related difference may occur because individuals become more aware of, and comfortable with, their sexual orientation as they develop from early adolescence into adulthood.

Severity of the CAH disorder also relates to outcomes for sexual orientation. This has been demonstrated in a study of 143 women with CAH, ages 18 to 61 years, compared to 24 control women who were unaffected sisters or female cousins of women with CAH [103]. Sexual orientation was assessed using interviews regarding both erotic imagery and behavior. Looking at data for lifetime, overall sexual responsiveness, which combines imagery and behavior, among 38 women with the most severe, salt losing form of CAH, 41% were not excusively or almost exclusively heterosexual, whereas the comparable figure for 21 women with the less severe, simple virilizing CAH was 29% and for unaffected controls it was 5%. Figures for actual sexual experience with a partner of the same sex were lower, but showed the same pattern, with 21% of women with salt losing CAH having had experience with same sex partners, compared to 5% of simple virilizers and 0% of unaffected women. Surprisingly, 79 women with non-classical CAH, which is thought not to cause elevated androgen prenatally, showed altered lifetime, overall sexual responsiveness, with 24% not exclusively or almost exclusively heterosexual, and 4% reporting sexual experience with a partner of the same sex.

Another recent study of 62 women with CAH, ages 18 to 63 years, compared to 62 agematched controls, also found a relationship between disease severity and sexual orientation in women with CAH. This study assessed sexual orientation in terms of response to a single item on a paper and pencil questionnaire scored as “homosexual”, “bisexual” or “heterosexual” [44], and related this to CAH severity as indicated by genotype. Among women with the most severe, null mutation of the CYP21A2 gene, 50% indicated that they were bisexual or homosexual, whereas for those with the next most severe, 12splice mutation, the comparable figure was 30%. These two mutations correspond roughly to the salt losing variant of CAH, and for the two mutations together, 35% of the women reported being either bisexual or homosexual. For women with the I172N mutation, which is
associated with the simple virilizing form of CAH, 5% reported that they were not heterosexual, and for the least severe V281L mutation, associated with non-classical CAH, the same figure was 5%. This last group was very small, including only 5 women, but the result contrasts with the prior unexpected finding [103] of decreased heterosexual orientation in women with non-classical CAH.

Only one of the 10 studies [88] did not find elevated rates of non-heterosexuality in women with CAH. This study included 45 patients, many with milder forms of CAH. Only 45% had salt wasting CAH, and 17% had the non-classical form of the disorder. In addition, the assessment of sexual orientation might not have been sufficiently sensitive. The assessment procedure was not described in detail, but it appeared to involve response during an interview to a question about sexual orientation identity and perhaps a question about the sex of any co-habiting partner. In addition, women might not have felt sufficiently
comfortable to reveal their sexual orientation. In regard to outcomes for sexual orientation, the authors say “Two patients and 1 control individual stated they were lesbians and lived
with a female partner. One of the women stated in the questionnaires that she was a lesbian but denied it in the personal interview. Whether this was a sign of shyness or instability in
her decision remains unclear.” [88].

In addition to being associated with reduced heterosexual orientation, CAH is associated with reduced sexual activity and interest in general [44;155]. This may occur in part as a consequence of the genital virilization at birth and poor outcomes of surgeries to feminize the genitalia [26;27;107]. For instance, in explaining their reduced sexual activity, individual women with CAH have been reported to indicate “nobody wants someone like me”, or that they “have not dared to take that step” [44]. In regard to reduced interest, individuals have cited “looking different”, or “inability to relax when partner is not told (about the disease)”[44]. A negative impact of CAH on a person’s sex life has also been attributed to “pain and bleeding during intercourse” [44]. Based on consideration of these types of physical problems, it has been suggested that decreased heterosexual interest and activity in women with CAH might result partly from the physical consequences of CAH.


Androgen deficiency and sexual orientation in men

Some research also has investigated the influence of early androgen deficiency on sexual orientation in men. We have less information about such effects in men than about the effects of elevated androgens in women, however, perhaps because disorders causing reduced androgen exposure in males are even rarer than disorders causing increased androgen exposure in females. Relevant information has come from several DSD, however, including androgen insensitivity syndrome (AIS), and syndromes causing enzymatic deficiencies in the androgen pathway.

AIS involves deficiency in the ability of androgen receptors to respond to androgens [58]. It is transmitted as an X-linked genetic trait and so occurs almost exclusively in XY individuals. In the complete form of AIS (CAIS), the testes produce normal amounts of androgens, but the affected individual appears female at birth, because the external genital structures have been unable to respond to the androgens. These XY individuals are typically assigned and reared as girls with no suspicion of the underlying disorder or the Y chromosome. At puberty, estrogen derived from testicular androgens causes female-typical
breast development. The disorder is usually diagnosed after menstruation fails to occur, because of the lack of female internal reproductive structures. Sexual orientation in XY women with CAIS appears not to differ from that of women in general. Women with CAIS do not differ in their sexual orientation from female population norms [151] or from matched female controls [66]. These XY women also are more likely to be exclusively interested in male sexual partners than are XX women with CAH [109], suggesting that the early hormone environment plays a larger direct role than genetic information on the X or Y chromosomes in the development of sexual orientation.

Androgen biosynthesis deficiencies result from enzymatic deficiencies transmitted as autosomal, recessive traits [77;78;120]. They include deficiency in 5-alpha-reductase and deficiency in 17-beta-dehydroxysteroid dehydrogenase. Because 5-alpha-reductase converts testosterone to dihydrotestosterone, deficiency in this enzyme results in low levels of dihydrotestosterone, despite normal to high levels of testosterone [77]. Dihydrotestosterone is necessary for prenatal virilization of the external genitalia, and so XY individuals with this deficiency are born with female-appearing or ambiguous external genitalia.

They are usually assigned and reared as girls. At puberty, however, testosterone and other androgens virilize the genitalia, deepen the voice and promote the development of male-typical musculature. A similar outcome is seen with deficiency in the enzyme, 17-betadehydroxysteroid dehydrogenase. This enzyme is needed to produce testosterone from its immediate precursor, androstenedione. Individuals with this deficiency have low levels of both testosterone and dihydrotestosterone, producing a similar physical outcome to that seen for 5-alpha-reductase deficiency. The external genitalia appear to be feminine or ambiguous at birth, the child is typically assigned and reared as a girl, but physical virilization occurs with puberty. In populations where these disorders are common, they sometimes have descriptive names, such as machihembra (first woman, then man) [79] or Turnim Man [64].

Despite their female sex of rearing, 39 to 64% of individuals with androgen biosynthesis deficiencies change to live as men following physical virilization at puberty, but this outcome does not appear to relate to the degree of genital virilization at birth [24]. Within a single family even, individuals with the same genetic mutation and the same enzymatic deficiency have been found to choose to live as different sexes, one as a man and one as a woman [148]. Information on the sexual activity of those who choose to live as men is far from complete, but in many cases they appear to form sexual partnerships with women[150;154]. Explanations of the post-pubertal gender change, in addition to the effects of the early hormone environment, include possible ambiguity in the sex of rearing, based, for instance, on knowledge that virilization will occur at puberty [64;147]. The decision to change sex also appears to relate in part to cultural factors, or to medical treatment. In the
United States and much of Europe, individuals with androgen biosynthesis deficiencies, who have been assigned and reared as girls, often have had their testes removed prior to or early
in puberty, to prevent virilization. Individuals treated in this way tend to maintain a female gender identity, and assumedly androphilic sexual orientation [150;154]. This argues against early hormonal determination of their sexual orientation outcome. In other settings, however, virilization at puberty is not prevented, and the individual is faced with a choice of continuing to live as a woman, despite having a masculine physical experience, or changing to live as a man. Added into the mix, in some cultures, there are social and practical advantages of being a male, rather than an infertile female. Thus, androgen exposure at puberty, acting either directly on the brain, or by producing a male body type, or the advantages of being a male in certain cultural groups, also are likely to contribute to some individuals choosing to live as a man, and take a female life partner.

Bio-assay of prenatal androgen exposure and sexual orientation: The 2D:4D ratio

Another approach to exploring possible prenatal hormonal influences on sexual orientation has involved correlating physical characteristics that are thought to develop as a result of
prenatal androgen exposure with variability in sexual orientation. Much of this research has focused on the ratio of the length of the second digit of the hand to the length of the fourth digit, a ratio that has been termed 2D:4D. This ratio is larger in women than in men and the sex difference is thought to develop under the control of androgenic hormones prenatally
[94]. Evidence supporting a relationship to early androgen exposure comes from two studies finding more male-typical 2D:4D in individuals exposed to high levels of androgens prenatally, because of CAH [17;113], but cf [18], and one study finding more female-typical ratios in XY females with CAIS compared to other XY individuals [12]. An initial study relating finger ratios to sexual orientation recruited 720 adults attending public street fairs in the San Francisco area, measured their 2D:4D, and asked them to indicate in an anonymous survey their sex and their sexual orientation [146]. Results showed the expected sex difference in finger ratios on the right hand, with those of 146 heterosexual women being significantly greater than those of 108 heterosexual men. In addition, right hand 2D:4D was significantly smaller (i.e., more male-typical) in 164 homosexual than in 146 heterosexual women. There was no difference, however, between the 108 heterosexual and 277 homosexual men. In addition, 2D:4D on the left hand did not differ significantly for any of the four groups.

Subsequent research has produced mixed outcomes for the association between 2D:4D and sexual orientation. Some individual studies have suggested that homosexual males show more feminine finger ratios than heterosexual males, but others find no differences or even the opposite result [99]. These inconsistent results may occur because studies of finger ratios are relatively easy to conduct, resulting in publication of many chance findings.

A study commissioned by the British Broadcasting Corporation (BBC) involved over 200,000 individuals who participated online, measuring their own finger lengths and completing questionnaire items about sexual orientation [25]. This study found that 2D:4D on both the right hand and the left hand was more male-typical in 102,499 heterosexual men than in 11,060 homosexual or bisexual men, but no differences were found between 84,417 heterosexual and 9,153 homosexual or bisexual women. A meta-analysis that did not include this large online study reported somewhat different findings – an association between a more male-typical finger ratio and non-heterosexual orientation in women, but no relationship in men [57]. Thus, even with very large samples, results for studies of sexual orientation in relation to finger ratios are not completely consistent.

Another type of bio-assay of prenatal androgen exposure is the size of the penis or clitoris, since enlargement of the genital tubercle depends on androgen exposure during early life.
Non-heterosexual individuals do not appear to show any obvious alteration in the external genitalia that would suggest that androgen levels were abnormal prenatally. Indeed, there is
some evidence that homosexual men have larger penises than heterosexual men [15], a finding that is in the opposite direction of what would be predicted if increasing androgen exposure promoted interest in female sexual partners.

However, although both virilization of the external genitalia and neurobehavioral virilization depend on testosterone and its metabolites, there are many ways in which they can be decoupled. For instance, the time period when androgen influences development of the external genitalia is earlier in gestation than the time when most neurobehavioral effects are seen [52]. Also, different co-factors are involved in masculinization of different neural regions [97], and similar differences in the co-factors whose action is required are likely to exist for the genitalia versus whatever neural systems are involved in hormonal influences on sexual orientation. Similarly, testosterone acts on the external genitalia largely following conversion to DHT, but may require conversion to estradiol before exerting some of its neurobehavioral effects. This last difference could even explain the apparent paradox of larger penises, suggesting greater DHT exposure, in homosexual than in heterosexual men.

If more of the testosterone these men produce is converted to DHT in the periphery, less could be available for conversion to estradiol in the brain, thus leading to greater masculinization of the external genitalia, but reduced neurobehavioral masculinization. This possibility is highly speculative, however, but the point that genital masculinization and neurobehavioral masculinization need not parallel one another, because of the varied downstream mechanisms involved in testosterone’s effects on development, is important.

The issue of differences between the processes involved in neural virilization and those involved in genital virilization also raises the question of whether estrogens play a role in human neurobehavioral masculinization, similar to that documented in rodents. In rodents, manipulations of substances that block conversion of androgens to estrogens or that block estrogen receptors have shown that activation of estrogen receptors is crucial for masculinization in some neural regions and for many sex-related behaviors. Similar manipulations are not possible in humans, and have not been conducted in non-human primates. Based in part on evidence that prenatal treatment with DHT can increase maletypical sex behavior, and reduce female-typical sex behavior, in rhesus macaques, it has been suggested that estrogens might not play a role in neurobehavioral masculinization in primates, including in humans [133]. However, in guinea pigs, DHT has similar masculinising effects to those seen in rhesus macaques [47], but the synthetic estrogen, DES does as well [71;73] Thus, either DHT or estrogens can produce male-typical behavior in guinea pigs. The situation could be similar in primates as well. No studies have reported on sexual behavior following prenatal exposure of non-human primates to DES or other estrogens. However, one study found increased male-typical rough and tumble play in female rhesus macaques exposed to DES during gestation [53]. Surprisingly, rough-andtumble play is one of the few behaviors that is thought to be masculinized by DHT, but not estrogen, in rats [100]. There appear to be species differences in the role of estrogen in sexual differentiation, and these are not yet completely understood. It appears, however, that a role for estrogen in human sexual differentiation cannot be ruled out, based on research to date.