Neuroendocrine Influences on Human Sexuality
Abstract and Keywords
While prenatal sex hormones guide the development of sex-typical reproductive structures, they also act on the developing brain, resulting in sex differences in brain and behavior in animal models. Stemming from this literature is the prominent hypothesis that prenatal neuroendocrine factors underlie sex differences in human sexual orientation, to explain why most males have a preference for female sexual partners (gynephilia), whereas most females display a preference for male sexual partners (androphilia). Convergent evidence from experiments of nature and indirect markers of prenatal hormones strongly support a role for prenatal androgens in same-same sexual orientations in women, although this finding is specific to a subset of lesbians who are also gender nonconforming (“butch”). More gender-conforming lesbians (“femmes”) do not show evidence of increased prenatal androgens. The literature has been more mixed for male sexual orientation: some report evidence of low prenatal androgen exposure, while others report evidence of high androgen levels and many other studies find no support for a role of prenatal androgen exposure in the development of androphilia in males. Recent evidence suggests there may be subgroups of gay men who owe their sexual orientation to distinct biodevelopmental mechanisms, which could account for these mixed findings. Although this research is young, it is similar to findings from lesbian populations, because gay men who are more gender nonconforming, and report a preference for receptive anal sex, differ on markers of prenatal development from gay men who are more gender conforming and report a preference for insertive anal sex. This chapter concludes with future research avenues including assessing whether multiple biodevelopmental pathways underlie sexual orientation and whether neuroendocrine factors and other biological mechanisms (e.g., immunology, genetics) interact to promote a same-sex sexual orientation.
A central mystery of human sexuality is sexual orientation: the persistent preference for either opposite- or same-sex sexual partners. As such, sexual orientation is inherently intertwined with sex, both of the individual and of potential partners (reviewed in van Anders, 2015). Sex is usually defined at birth by the appearance of the genitalia; however, biological sex is multifaceted, and can be defined not only by phenotypic sex (genitalia) but also chromosomal sex (XY = male; XX = female), gonadal sex (ovaries; testes; ovotestes), and sex hormones (e.g., higher androgens levels in males than females). Furthermore, in humans biological sex is often intertwined with gender identity—while gender refers to the socially constructed roles and behaviors that can vary cross-culturally, gender development is influenced by the same biological processes that affect sex development. Generally, there is consistency across categorizations of sex and gender identity because chromosomal sex typically mediates gonadal sex and the gonads produce sex hormones, which guide genitalia development—these biological events also mediate gender development both directly by affecting neural development and indirectly due to sociocultural upbringing, which is profoundly influenced by phenotypic sex. However, there are exceptions to the consistency between chromosomal, gonadal, endocrine, and phenotypic sex, and gender, as discussed throughout this chapter. While biological processes guide sex development in utero, these processes are also known to exert effects on the developing brain in animal models, resulting in sex differences in the brain and behavior. Stemming from this research is one of the primary theories for the basis of sexual orientation: that developmental mechanisms underlying biological sex also mediate sex differences in sexual orientation (i.e., male sexual attraction to females and female sexual attraction to males). However, in humans it is difficult to assess whether heterosexuality is due to cultural expectations or biology. To evaluate whether there is a biological influence on in sexual orientation in humans, individuals who do not follow the traditional trajectory of sexual development are often studied, surmising that some event or process must have intervened for them to defy cultural expectations. For example, some individuals are born with conditions in which hormone exposure or sensitivity is altered, in which case one may ask whether this altered neuroendocrine environment affected sexuality in adulthood (“natural experiments”; see “Androgen Insensitivity in Males” and “Girls Exposed to High Levels of Prenatal Androgens”). Alternatively, many adults report a same-sex sexual orientation, in which case a retrospective approach is appropriate, looking for differences in biological development that may have shifted sexual preferences. The literature evaluating the role neuroendocrinology plays in the development of sex and human sexual orientation will be reviewed in this article.
Understanding Sexual Differentiation in Non-Human Animals Informs Research in Human Sexuality
Most of what is known about neuroendocrine influences on human sexuality stems from work conducted in other mammalian species, where a traditional view of sexual differentiation has been established. During prenatal mammalian development, chromosomal sex (XX = female; XY = male) typically determines gonadal sex: specifically, testes development is determine by the presence of a gene located on the Y chromosome called the sex-determining region of the Y chromosome (SRY) (reviewed in Morris, Jordan, & Breedlove, 2004; Negri-Cesi, Colciago, Celotti& Motta, 2004). In the absence of SRY, ovaries develop, producing little hormone during early development; typically, it is not until puberty that ovaries produce sex steroids such as estrogens, progesterone, and, to a lesser extent, androgens. In the event that testes develop, they produce relatively high androgen levels and anti-Müllerian hormone (AMH). In prenatal development, androgens promote male-typical growth of genitalia and internal reproductive organs, and AMH inhibits the development of female-typical reproductive structures. In the absence of testes and/or a male-typical range of both androgens and AMH, female-typical genitalia and internal reproductive organs develop. During this time in development, sex hormones also act on the central nervous system (CNS) organizing its structure and thus affecting behavior into adulthood—these long-lasting effects of hormones during critical periods in development are referred to as organizational effects (reviewed in Morris et al., 2004). After these early organizational periods, the gonads produce low levels of hormones until the onset of puberty, after which hormones remain in relatively high production throughout reproductive years. In adulthood these hormones can exert transient effects on neural structures that activate behavior—referred to as activational effects. Although this traditional view of sexual differentiation can, by and large, account for experimental findings in the literature, it should be noted that sex chromosomes also contribute to sexual differentiation of CNS (reviewed in McCarthy & Arnold, 2011) and female sexual differentiation may not be entirely passive (e.g., estrogen receptors are required for the full extent of female-typical neural development; Bakker & Brock, 2010).
The seminal paper by Phoenix and colleagues (1959) highlighted two principles that continue to guide research in neuroendocrinology and sexuality: 1) androgens are the primary hormone responsible for sex differences in sexual behavior, and 2) early exposure to hormones can organize the developing brain and thus can have lasting effects on brain and behavior. Phoenix and colleagues based these conclusions on experiments in which pregnant guinea pigs were given high doses of androgen. Female offspring were then assessed in adulthood for sexual behaviors. These androgenized females displayed male-typical motor-patterns of sexual behavior such as mounting, while female-typical behaviors like lordosis were decreased, even when primed with activational hormones (i.e., estradiol and progesterone) that typically induce sexual receptivity in females. Since this paper, a plethora of research has supported the role of androgens for male-typical sexual behavior and preferences in laboratory mice and rats (Morris et al., 2004; Swift-Gallant & Monks, 2017; Zuloaga, Puts, Jordan, & Breedlove, 2008). Research since this seminal paper has supported the theory put forth by Phoenix and colleagues: androgens can have lasting organizing effects on neural development and behavior by acting during critical periods in development including prenatally, and during early neonatal development and puberty, and hormones can also have activational (transient) effects throughout adulthood (reviewed in Schulz & Sisk, 2016). The mechanism of androgen action is complicated by the fact that testosterone can metabolize into other steroids, including estrogens, and thus can exert its effect via both androgen receptors (AR) and estrogen receptors (ER; reviewed in Roselli, Liu, & Hurn, 2009). ER and AR are found in abundance in the CNS, especially in brain regions that are sexually dimorphic in volume, cell number, cell size and/or gene expression (reviewed in Handa et al., 1994; Segovia & Guillamón, 1993; Simerly, Swanson, Chang, & Muramatsu, 1990).
These sexually dimorphic brain regions also exhibit sex differences in function; for example, male odors elicit increased neural activity in the accessory olfactory pathway in females, whereas in males, the same neural regions show increased neural activity in response to female sexual stimuli (e.g., Bodo & Rissman, 2007; Paredes, Lopez, & Baum, 1998; Swift-Gallant, Coome, Srinivasan, & Monks, 2016). Other hormones, such as progesterone and the neuropeptides dopamine, oxytocin, and vasopressin also influence sexual behavior and preferences, and interact with the traditional sex hormones (e.g., De Vries & Panzinca, 2006; Hull, Muschamp, & Sato, 2004; Insel, Winslow, Wang, & Young, 1998). Furthermore, immune and epigenetic mechanisms contribute to brain and sexual behavior and interact with endocrine mechanisms (Forger, 2018; McCarthy, Nugent, & Lenz, 2017). Researchers continue to unravel the complex interactions between sex hormones, the site(s) of action (tissue/cell types), and the timing (organizational/activational effects) of neuroendocrine actions that underlie sexual behavior in rodents (McEwen & Milner, 2017; Swift-Gallant & Monks, 2017). However, almost 60 years after the publication of Phoenix et al., the field of behavioral neuroendocrinology is only beginning to elucidate whether hormones similarly affect human sexuality.
Experiments of Nature
Humans are unique in the degree to which sociocultural environment contributes to behavior. As a consequence, it is often difficult to parse out the effects of sociocultural factors versus biology. One explanation of sexual orientation and gender identity in humans is that the sociocultural environment guides children with male genitalia to be male-typical, whereas children with female-typical genitalia are raised to be female-typical in their behavior. However, over the last several decades, researchers have found substantive evidence for a “biological” influence on human sexual orientation and gender, in part through experiments of nature (Bailey et al., 2016).
Raising Boys as Girls
It was once the opinion of the medical community that in circumstances in which the phallus of a newborn was ablated or otherwise presented as abnormal (e.g., accidental penile ablation during circumcision or abnormal penis development due to cloacal exstrophy), the boy would be “better off” raised as a girl due to possible socio-interpersonal ramifications associated with having abnormal genitalia. As a consequence, several boys were surgically altered to appear female-typical (e.g., castration/ vaginoplasty), and parents were instructed to raise their child as a girl. This form of experimentation did not work as the doctors intended: in a key study, six out of seven genetic males raised as girls reverted to a male gender identity in adulthood, and all seven reported sexual attraction to females (Bailey et al., 2016). While this experiment of nature has limitations (e.g., small sample sizes, potential bias of families), the pattern of results strongly suggests that prenatal factors affect human sexuality, predisposing typically developing males to be attracted to females in adulthood.
There is also a condition, 5a-reductase deficiency, in which males are unable to metabolize testosterone to the potent androgen, dihydrotestosterone (DHT), which drives masculinization of the genitalia (Imperato-McGinley, Guerrero, Gautier, & Peterson, 1974; Imperato-McGinley, Peterson, Gautier, & Sturla, 1979). Thus, at birth they appear to be female. Then, at puberty, the surge in testosterone production is sufficient to masculinize their genitalia. Now, these individuals, raised as girls, typically begin to adopt a male gender identity, and show a preference for female partners. This condition is especially common among subpopulations in the Dominican Republic and Turkey (Imperato-McGinley & Zhu, 2002), and so, because members of these communities are generally aware of this condition, the cultures are accepting of the transition from female to male identity. Thus, although the findings support a role for neuroendocrine influences on human sexuality, it is also possible that children in these communities are raised differently to facilitate the eventual gender transition.
Androgen Insensitivity in Males
Other experiments of nature also suggest a role for androgens in both sexual orientation and gender development. Complete androgen insensitivity syndrome (AIS) affects 2–5 of every 100,000 chromosomal (XY) males (Gottlieb & Trifiro, 2017). A mutation in the androgen receptor gene (AR) renders these XY males insensitive to androgens and often indistinguishable from females at birth. Thus, parents raise these children as girls. It is often not until puberty, when menstruation fails to begin, that individuals with AIS seek medical advice and learn of their condition (Hughes et al., 2012). As adults, XY individuals with complete AIS overwhelmingly present with sexual preferences for males and continue to identify with the female gender, even after learning of their condition. Although it is possible that factors relating to being raised as a girl also contributed to their gender and sexual orientation as adults, these results suggest that prenatal androgens in humans are required for both male-typical sexual orientation and gender identity, similar to findings in other mammals.
Girls Exposed to High Levels of Prenatal Androgens
Approximately 1 in 14,000 girls are born with congenital adrenal hyperplasia (CAH); cortisol production is impaired due to an enzyme deficiency that causes the negative feedback system to overstimulate the adrenals, resulting in excessive androgen production (Yau, Nimkarn, & New, 2015). Girls with CAH are exposed to high androgen levels prenatally, resulting in genital phenotypes that range from female-typical to ambiguous. In many cases, medical professionals and parents agree upon genital surgery to construct more female-typical genitalia, whereas others are not surgically altered. Although these children are almost always raised as girls and identify as women in adulthood, gender dysphoria and same-sex sexual orientations are 2–3-fold higher than in control females (Hines, Brook, & Conway, 2004; Meyer-Bahlburg, Dolezal, Baker, & New, 2008; Pasterski et al., 2015; Yau et al., 2015). Furthermore, the degree of androgenization in early development positively correlates with same-sex attraction, suggesting higher prenatal androgen levels increase the likelihood that girls with CAH will identify as bisexual or lesbian as adults (Meyer-Bahlburg et al., 2008). These results suggest that prenatal androgens can affect the development of gender and sexual orientation in women. Note that some investigators have provided sociocultural explanations for these findings: girls with CAH often have ambiguous genitalia and female partners may be more accepting of this, and/or parents might be more likely to treat their child in a more ambiguous way (Breedlove, 2017).
While it is difficult to study prenatal neuroendocrine influences on human sexuality because of confounding factors like sociocultural upbringing, convergent evidence from many sources, such as the evidence from multiple experiments of nature summarized in this section, provide strong support for neuroendocrine influences on human gender and sexual preferences. Next, the literature of retrospective markers of prenatal neuroendocrine environment is examined to assess whether such research further supports this conclusion.
Retrospective Markers of Prenatal Androgens and Sexual Orientation
It is rarely practical or possible to extract precise measures of the neuroendocrine environment during human prenatal development, and even when precise measures are obtained of individuals prenatally, it poses further challenges to retain these participants into adulthood to assess behavioral outcomes such as sexuality. Thus, in human sexuality research, putative markers of biological processes (i.e., biomarkers) often are used to provide a rough estimate of the prenatal milieu. Research evaluating whether markers of prenatal androgens are associated with human sexuality have yielded mixed findings. These mixed findings could signal that: a) the influence of hormones on human sexuality is minimal; b) the biomarkers themselves are influenced by other factors in addition to hormones; c) the timing of biomarker and sexuality development may differ, and thus the biomarkers may not be an accurate measure of hormone levels during sexuality development per se; d) local sensitivity of hormones may vary in neural regions associated with sexuality compared to neural and non-neural sites associated with biomarkers; and/or e) there are individual differences in the factors that influence human sexuality, and thus when studying the population as a whole and/or biomarkers in isolation, researchers overlook subgroups of people who owe their sexuality to one factor vs another.
Next, the evidence supporting common biomarkers and present findings from each biomarker in relation to male and female sexual orientation is discussed.
One biomarker studied extensively in relation to human sexual orientation is the ratio of the length of the 2nd and 4th fingers (2D : 4D). A sex difference is reported in 2D : 4D ratio with moderate sample sizes, and substantial evidence points to a role for prenatal androgens in mediating this sex difference. For example, the sex difference in 2D : 4D is set prenatally (Galis, Ten Broek, Van Dongen, & Wijnaendts, 2010; Malas, Dogan, Evcil, & Desdicioglu, 2006). A role for prenatal androgens is supported by the observation that girls with CAH, who are exposed to high androgens prenatally, have a more masculine (lower) ratio than do controls (Brown, Hines, Fane, & Breedlove, 2002; Ökten, Kalyoncu, & Yariş, 2002; not consistent for the left hand, e.g., Buck, Williams, Hughes, & Acerini, 2003). XY individuals with AIS (Berenbaum, Bryk, Nowak, Quigley, & Moffat, 2009) present with a female-typical ratio, ruling out the possibility that sex chromosomes or AMH could be responsible for the sex difference in 2D : 4D. Interestingly, there also are sex differences in the digit ratios of rodent species, where endocrine manipulations confirm their responsiveness to prenatal androgens (Zheng & Cohn, 2011); this study also suggests that digit ratios are sensitive to estrogens as well as androgens. Together, these findings indicate that androgens play a role in determining digit ratio, although of course other factors, including genetic makeup (Gobrogge, Breedlove, & Klump, 2008), contribute to digit ratios.
2D : 4D and Male Sexual Orientation
Investigations of 2D : 4D ratio in relation to sexual orientation in men is mixed. In a 2005 meta-analysis of five studies, two of the studies indicated that 2D : 4D ratio in gay men is more male-typical than heterosexual men, two studies reported the opposite (i.e., female-typical), and one found no difference between gay and heterosexual men; the meta-analysis concluded there is no consistent difference in 2D : 4D ratio between gay and heterosexual men across geographical regions (McFadden et al., 2005). A later meta-analysis similarly concluded there were no differences in digit ratios between gay and straight men (Grimbos Dawood, Burriss, Zucker, & Puts, 2010). As a result, the conclusion of many in the field is that androphilia in men is not related to prenatal androgens (e.g., Breedlove, 2017), although there are other possibilities for the mixed findings; for example, inconsistencies in 2D:4D results may reflect variability in the biological pathways underlying male sexual orientation (Skorska & Bogaert, 2017; Swift-Gallant, Coome, Monks, & VanderLaan, 2017, 2018). In other words, there may be multiple biological factors that either act together in an additive manner to influence male sexual orientation (i.e., immunological, endocrine, genetic, etc.) or there may be multiple distinct biodevelopmental pathways; for example, if androgens influence the sexual orientation of only a subpopulation of gay men, then differences in 2D:4D may be difficult to extract when lumping together all gay men. Alternatively, finger digit ratios are determined quite early on in development, prior to neural development, and thus it is possible that androgen variation between digit growth and neural development contribute to mixed findings (i.e., androgens among some individuals may be more consistent across digit and neural development whereas others may exhibit higher degrees of variation). However, the results of studies of digit ratio in women indicate that the marker is indeed responding to androgen at the same developmental period when sexual preferences arise, as discussed next.
2D : 4D Ratio and Female Sexual Orientation
Results of comparing sexual orientation and 2D : 4D ratio are more consistent in women: lesbians, on average, present with more male-typical digit ratios than heterosexual women (see meta-analysis of 16 studies in Grimbos et al., 2010). However, there is evidence that this relationship is driven by masculinized 2D : 4D ratio of a subgroup of lesbians: Butch lesbians (e.g., Brown, Finn, Cooke, & Breedlove, 2002) and lesbians that are more gender nonconforming (e.g., Csathó et al., 2003) present with a more male-typical ratio than self-identified “femmes” or heterosexual women. The consistency of these findings, together with the “Experiments of Nature” discussed previously, strongly support a role for prenatal androgens in the development of gender and same-sex attraction in women. However, these results also suggest that femme-identified/gender conforming lesbians do not owe their sexual orientation to prenatal androgens; thus, factors other than androgens likely contribute to sexual orientation in femme/gender conforming lesbians.
Another biomarker of prenatal androgens is handedness. The tendency to use the right or left hand for various activities is determined prenatally; for example, hand preference can be reliably assessed via ultrasound in fetuses between 10 and 15 weeks of age (Hepper, 2013; Hepper, Shahidullah, & White, 1991). Interestingly, there is a consistent sex difference in handedness; men tend to have a higher left-hand preference than women (see meta-analysis Lalumière, Blanchard, & Zucker, 2000). Due to this sex difference in handedness, it has been hypothesized that processes underlying sexual differentiation, such as prenatal androgen exposure, affect hand preference. Indeed, there is evidence of a role for prenatal androgens in mediating hand preference, although these findings have been mixed. These mixed findings could reflect other biological mechanisms interacting with endocrine factors to affect handedness. For example, genetic variation in sensitivity to androgens via AR, in addition to circulating androgens, could contribute to sex differences in hand preference (Arning et al., 2015). Specifically, CAG repeats in the gene Ar are related to the efficacy of the receptor (i.e., longer repeats are associated with less efficacy; Tut, Ghadessy, Trifiro, Pinsky, & Yong, 1997), and CAG repeats have been associated with ambidextrous hand preference (Arning et al., 2015; Hampson & Sankar, 2012; Medland et al., 2005). These findings suggest that handedness is affected by androgenic signaling, although it is also possible that other genetic contributions and/or other factors (e.g., epigenetic, immunological) interact with endocrine influences. For example, although few studies have identified candidate genes linked to handedness (e.g., Somers et al., 2015) studies of DNA methylation have identified epigenetic modifications related to handedness (Schmitz, Kumsta, Moser, Güntürkün, & Ocklenburg, 2018). Together, the evidence suggests that handedness is affected by a multitude of factors, but that androgens play a role in determining hand preference either through circulating androgens and/or via the efficiency of AR.
Handedness and Male Sexual Orientation
Male sexual orientation has been associated with handedness in many studies (Lalumière et al., 2000): Gay men tend to have a greater left-hand preference than heterosexual men. Interestingly, this finding indicates a more male-typical pattern of results in gay men. However, there are inconsistencies in the literature. Two factors in particular could account for the mixed findings: 1) handedness has been found to interact with other biomarkers related to immunology (i.e., fraternal birth order effect; e.g., Blanchard, Cantor, Bogaert, Breedlove, & Ellis, 2006; Blanchard & Lippa, 2007; Kishida & Rahman, 2015; Xu & Zheng, 2017), and 2) differences in handedness present in a subgroup of gay men based on anal sex role (Swift-Gallant et al., 2017).
The fraternal birth order effect (FBOE) refers to the well-established finding that gay men present with a greater proportion of older brothers than heterosexual men. The maternal immune hypothesis is the most prominent explanation for the FBOE. Specifically, it is hypothesized that with every male birth there is a greater chance that male material from the newborn will enter the maternal bloodstream and increase the odds of maternal antibody development against male-specific antigens. These maternal antibodies could affect future pregnancies with male fetuses. Recently, this maternal immune hypothesis was supported by the finding of higher quantities of candidate antibodies in mothers of gay male children than mothers without gay male children (Bogaert et al., 2017). This finding is of interest for the handedness literature, because the FBOE seems to affect only males who are right-handed, suggesting that the increase in left-handedness among gay men is specific to a separate subgroup of gay men to those affected by FBOE. Thus the biological processes underlying handedness and FBOE likely affect the development of sexual orientation in at least two distinct subgroups of gay men. Recently, Swift-Gallant et al., (2017) asked whether handedness was associated with subgroups of gay men delineated by anal sex role (i.e., “bottom” [receptive], “top” [insertive], or “versatile” [both insertive and receptive] anal sex role preference and behavior). Variation in gender conformity is tied to prenatal biological factors, including androgens (e.g., see section on “Gender Nonconformity”), thus it was hypothesized that anal sex role groups that differ in gender expression (i.e., bottoms report greater gender nonconformity than tops), may differ in the developmental biology for which they owe their sexual orientation. Swift-Gallant et al. (2017) found that only gay men who typically take on a receptive anal sex role differed in handedness (i.e., increased use of their left hand) from straight men, whereas gay men with a top anal sex role did not differ from heterosexual men. Together, these findings suggest that the processes that underlie handedness affect the development of androphilic attraction in a subgroup of gay men delineated by anal sex role.
Handedness findings also might be mixed in the literature due to a nonlinear relationship between handedness and markers of androgens, and between markers of androgens and androphilic attraction. Often researchers look for linear relationships in their data, and thus could overlook curvilinear or quadratic effects. For example, Ellis, Skorska, and Bogaert (2017), found that markers of prenatal androgens are associated with handedness, but the relationship is curvilinear, especially for women. In men, a linear relationship between these variables was found such that high androgens were associated with right-handedness, although the authors suggest the relationship also appears curvilinear for men, although it did not reach significance. Ellis and colleagues also reported that, for both men and women, ambidexterity is related to same-sex attraction. Together, these findings suggest that handedness and androgen markers are related to same-sex attraction in men and women, although this relationship is not always linear, which could account for the mixed findings in the literature.
Handedness and Female Sexual Orientation
Handedness also has been associated with sexual orientation in women: lesbian and bisexual women tend to have a greater left-hand preference (i.e., male-typical) than heterosexual women (see Blanchard & Lippa, 2007; meta-analysis Lalumière et al., 2000; Lippa, 2003; Mustanski, Bailey, & Kaspar, 2002; but see Gladue & Bailey, 1995). There also is a relationship between gender traits and handedness: women who report using their left-hand more often are more male-typical (Lippa, 2003). Together, these results suggest that the processes underlying handedness are related to the development of same-sex sexual orientation in women. Given the findings that ambidexterity, rather than left-handedness, is related to CAG-repeats in the gene AR, and the finding that ambidexterity is associated with same-sex attraction in women, it would be interesting for future studies to evaluate whether these findings dovetail (i.e., does variation in CAG-repeats mediate handedness and sexual orientation?).
Otoacoustic emissions (OAEs) refer to the sounds generated by the cochlea. OAEs are stronger in females than males from birth (Berninger, 2007; Burns, 1992; Morlet, Lapillonne et al., 1995, Morlet, Perrin et al., 1996; Strickland & Burns, 1985; Thornton, Marotta& Kennedy, 2003) and this sex difference continues into adulthood (Bilger, Matthies, Hammel, & Demorest, 1990; McFadden & Mishra, 1993; Talmadge, Long, Murphy, & Tubis 1993). Growing evidence suggest that prenatal androgens organize (e.g., McFadden, Pasanen, Valero, Roberts, & Lee, 2009) and adult circulating hormones further activate this sex difference (e.g., McFadden, 2000; McFadden Pasanen, Raper, Lange, & Wallen, 2006). OAEs also have been associated with other prenatal markers of androgen such as 2D : 4D (McFadden & Shubel, 2003) and sexually differentiated traits like gender, sexual activity, physical measures (i.e., height, weight) and spatial abilities (Loehlin & McFadden, 2003). As with the digit ratio literature, sexual orientation effects in OAEs are consistent in females but not males. Specifically, OAEs of lesbian and bisexual women were found to be more masculine (weaker and fewer) than those of heterosexual women (McFadden & Pasanen, 1998, 1999; reviewed in Breedlove, 2017).
Pubertal Onset and Associated Somatic Traits
The timing of pubertal onset differs between males and females, such that boys tend to undergo puberty later than girls (reviewed in Underwood & Wyk, 1992). Thus, it has been argued that later pubertal onset is male-typical (e.g., Bogaert, 2010). However, the neuroendocrine mechanisms underlying pubertal onset are very different in the two sexes: males exhibit increases in androgens whereas females exhibit increases in estrogens and progesterone. Thus, it is not clear that directly comparing pubertal onset between males and females is instructive. Indeed, much of the available evidence suggests the opposite is true: an earlier pubertal onset in males may be related to higher androgen levels and more masculine traits (Rey, Campo, Ropelato, & Bergadá, 2016; Yousefi et al., 2013). Still, it is useful to compare pubertal measures within members of the same sex as it indicates differences in their neuroendocrinology. The mean age for sexual attraction onset is age 10 for both males and females, prior to puberty (McClintock & Herdt, 1996), thus it is unlikely that the neuroendocrine factors at puberty directly mediate sexual orientation, but rather reflect organizational effects of early androgen exposure on pubertal onset.
Measures associated with puberty, such as height, weight, body hair and pubertal onset have been associated with sexual orientation, although findings are mixed for both males and females. Gay men report an earlier pubertal onset, shorter stature and lower body weight than heterosexual men (Bogaert, 2010; Bogaert & Blanchard, 1996; Bogaert, Friesen, & Klentrou, 2002; Skorska & Bogaert, 2017). These findings generally suggest lower androgens in gay men (at some point in prenatal development). However, other studies report null or the opposite finding (Bogaert & Friesen, 2002; Savin-Williams & Ream, 2006). Furthermore, other measures related to puberty, like penis size, have been reported to be more masculinized among gay men (Bogaert & Hershberger, 1999; Nedoma & Freund, 1961).
Lesbians have been reported to be taller and heavier than heterosexual women, although age of menarche does not differ according to sexual orientation (Bogaert, 1998; Bogaert & Friesen, 2002). However, multiple studies were not able to replicate the height and weight differences between lesbian and heterosexual women (Bogaert, 2010; Bogaert et al., 2002; Tenhula & Bailey, 1998). These mixed findings could reflect differences in neuroendocrine environment between butch and femme lesbians (Bogaert et al., 2002). Future research could evaluate whether mixed findings on these measures reflect difference in subgroups of gay men and lesbians that differ in pubertal onset and associated somatic measures.
The first well-established sex difference in the rodent brain is the Sexually Dimorphic Nucleus of the Preoptic Area (SDNPOA; Gorski, Harlan, Jacobson, Shryne, & Southam, 1980). Sexual differentiation of this hypothalamic nucleus has been linked to prenatal androgens; male rats typically show a larger volume, more cells and larger cell size in this region than females, but testosterone administered on embryonic days 18–21 or to neonatal females can masculinize SDNPOA morphology in rats (Dohler et al., 1982). Similarly, the removal of androgens in neonatal males (e.g., castration) can reduce the size of the SDNPOA (Jacobson, Csernus, Shryne, & Gorski, 1981). The SDNPOA also has been linked to male-typical sexual behaviors like mounting of female partners (e.g., Arendash & Gorski, 1983). The human analogue of the SDNPOA is the interstitial nuclei of the anterior hypothalamus (INAH), one of which, INAH3, is twice as large in men as in women (Allen, Hines, Shryne, & Gorski, 1989; Swaab & Fliers, 1985). An effect of sexual orientation also has been found in INAH3; gay men show a more female-typical INAH3 size than do heterosexual men (LeVay, 1991). Skeptics initially criticized this work because analyses were done on postmortem brain tissue and it is possible that living as a gay man could alter brain morphology. A recent meta-analysis in humans reports the preoptic area of the hypothalamus is part of a neural circuit associated with sexual preferences (Poeppl, Langguth, Rupprecht, Laird, & Eickhoff, 2016), and researchers have identified a similar finding in animals. Approximately 10 % of rams show a preference for mounting other rams, even when in the presence of receptive female partners. These “gay” rams also have a more female-typical SDNPOA than control rams (Roselli, Larkin, Resko, Stellflug, & Stormshak, 2004).
Gender traits often are thought to be mediated by sociocultural factors. However, there is strong evidence that gender nonconformity, especially in childhood, is mediated by prenatal androgen exposure. Auyeung et al., 2009 found that fetal testosterone measured from amniotic fluid during gestation correlated with childhood sex-typical play behavior in both boys and girls (i.e., higher testosterone related to increased male-typical play). Hines et al. (2002) also found that maternal testosterone is positively correlated with male-typical childhood play in girls. Furthermore, girls with CAH, who were exposed to high androgen levels during gestation, also show higher male-typical play behaviors than control girls (Hines, Brook, & Conway, 2004). Adult measures, including the Bem-Sex-Role Inventory, masculine occupational preferences, and gender identity disorder, also have been associated with markers of prenatal androgen such as 2D : 4D in women (Csathó et al., 2003; Hisasue, Sasaki, Tsukamoto, & Horie, 2012; McIntyre, 2003; Wallien, Zucker, Steensma, & Cohen-Kettenis, 2008), and childhood gender nonconformity scores are positively correlated with adulthood gender traits (e.g., Rieger, Linsenmeier, Gygax, & Bailey, 2008).
Overall, gay men report higher gender nonconformity than heterosexual men on both adult measures of gender traits and recalled childhood gender nonconformity (e.g., Zucker et al., 2006). Home video analyses have corroborated findings from the retrospective recalled childhood gender nonconformity scales, such that gay men exhibited more gender nonconformity than heterosexual men (Rieger et al., 2008). Interestingly, gay men differ on these measures when grouped based on anal sex role, supporting the idea that subgroups of gay men differ in their developmental biology: bottoms and versatiles are more gender nonconforming than tops, both on adult measures of gender traits (e.g., Bem Sex-Role Inventory: Zheng, Hart, & Zheng, 2012; Occupational Preferences: Swift-Gallant et al., 2018), and recalled gender nonconformity (Swift-Gallant et al., 2017).
Consistent with a role of androgens in the development of female sexual orientation, lesbians on average are more gender nonconforming than heterosexual women. Rieger et al., (2008) found that home videos of girls who grew up to identify as lesbian displayed more gender nonconformity than girls who later identified as heterosexual. Interestingly, in line with other retrospective markers of prenatal androgen, butch lesbians are more male-typical than femme lesbians in recalled childhood gender nonconformity (Singh, Vidaurri, Zambarano, & Dabbs, 1999; Zheng & Zheng, 2016).
Adult Circulating Hormones
Sexual orientation comparisons in adult circulating testosterone are mixed. A few studies have reported elevated testosterone levels in gay men than heterosexual men (Brodie, Gartrell, Doering, & Rhue, 1974; Doerr, Pirke, Kockott, & Dittmar, 1976), but subsequent studies did not replicate this finding (Stahl, Dörner, Ahrens, & Graudenz, 1976; Rohde, Stahl, & Doërner, 1977; Gladue, 1991).
Studies more consistently indicate that lesbians have higher adult circulating testosterone levels (Gartrell, Loriaux, & Chase, 1977; but see Gladue, 1991), and in studies that did not find this effect, there was consistently a subgroup of females (approximately one-third) who presented with elevated testosterone (reviewed in Meyer-Bahlburg, 1984). Later reports suggest that this subgroup with elevated testosterone consisted of those who identify as butch (Singh et al., 1999; Pearcey, Docherty, & Dabbs, 1996).
Other hormones have been extensively studied in gay versus heterosexual men, however the findings are variable. Doerr, Kockott, Vogt, Pirke, and Dittmar (1973), Doerr and colleagues (1976) and Newmark, Rose, Todd, Birk, and Naftolin (1979) found elevated estrogens in gay compared to heterosexual men; however, a number of other studies found no differences (Friedman, Dyrenfurth, Linkie, Tendler, & Fleiss, 1977; Futterweit, 1980; Sanders, Bain, & Langevin, 1984; Wilson & Fulford, 1979). The literature is also mixed for luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing hormone, prolactin and androstenedione (reviewed in Meyer-Bahlburg, 1984).
There is evidence that endocrine feedback mechanisms also may differ based on sexual orientation. Dörner, Rohde, Stahl, Krell, and Masius (1975) and Gladue, Green, and Hellman (1984) monitored the response of gay men, heterosexual men, and heterosexual women to a dose of estrogen. Heterosexual females exhibited an increase in luteinizing hormone, whereas heterosexual men did not; gay men exhibited an intermediate response, and testosterone was depressed longer in gay men than heterosexual men. Women have been consistently under-studied, and as a result less is known about the endocrine environment and feedback mechanisms of lesbians. However, it should be noted that circulating levels of hormones do not necessary reflect the neuroendocrine environment: hormone sensitivity (e.g., expression levels of hormone receptors) in localized neural regions as well as de novo steroid synthesis in the brain may vary between individuals and these aspects of the neuroendocrine environment are not always related to global circulating levels of hormones (for review, see Forger, Strahan & Castillo-Ruiz, 2016).
Sex-Typicality on Other Measures
The structure of the face exhibits sex differences, and processes underlying sexual differentiation are thought to underlie these differences (e.g., Burke & Sulikowski, 2010). Gay men tend to have more female-typical features, whereas lesbians have more masculine features than their heterosexual counterparts (Skorska, Geniole, Vrysen, McCormick, & Bogaert, 2015; Valentova, Kleisner, Havlíček, & Neustupa, 2014; but see, Hughes & Bremme, 2011). There is evidence that these facial differences are perceptible to observers, especially to those with a same-sex sexual orientation (reviewed in Rule, 2017).
Non-heterosexual women have shown superior performance on spatial abilities (van Anders & Hampson, 2005; for meta-analysis, see Xu, Norton, & Rahman, 2017), a cognitive task with sex differences (reviewed in Reilly, Neumann, & Andrews, 2015). Interestingly, it again appears that only lesbians who identify as butch show male-typical performance on spatial tasks, whereas femme lesbians do not differ from heterosexual women (Zheng, Wen, & Zheng, 2018). Consistent with other neuroendocrine markers, the results are variable in comparisons of gay vs heterosexual men, although a recent meta-analysis suggests that heterosexual men outperform gay men on spatial ability tasks (Xu et al., 2017).
Men typically score higher on systemizing, whereas females score higher on empathizing scales (e.g., Baron-Cohen, Knickmeyer, & Belmonte, 2005). Overall, lesbians are more male-typical on these scales, plus butch lesbians display a more male-typical pattern on these scales than femme lesbians (Zheng & Zheng, 2013; but see Zheng & Zheng, 2015). Gay men also are more female-typical on such scales than heterosexual men (Zheng & Zheng, 2015). Subgroups of gay men delineated by anal sex role show differences on these scales such that gay men with a receptive anal sex role are more female-typical than gay men with an insertive anal sex role (i.e., Zheng, Hart, & Zheng, 2015). Together these findings provide further support for increased masculinization among lesbians and increased feminization among gay men, although particularly among subgroups, suggesting multiple distinct biodevelopmental pathways within same-sex oriented groups.
In some aspects of sexuality, gay men are more male-typical and lesbians are more female-typical. For example, gay men report more sexual desires, greater numbers of partners (including while in committed relationships), and masturbate with greater frequency than heterosexual men. Conversely, lesbians, like heterosexual women, tend to have less interest in casual sex or sex outside a primary relationship, are more likely to become sexually/romantically involved with partners who were first their friends, and their sexual fantasies contain more romantic features (reviewed in Peplau, 2003).
Conclusions and Future Research
Convergent evidence from experiments of nature, biomarkers, and direct hormone analyses indicate that human sexuality is indeed influenced by neuroendocrine factors. However, the literature in this field is often mixed, likely because 1) biomarkers used to retrospectively study the prenatal neuroendocrine environment are imprecise and/or 2) the relationship is complex and there are subgroups who owe their sexual orientation to distinct biodevelopmental pathways (i.e., hormones, genetics, immunology). The field will probably continue to follow an individual-differences approach—evaluating the various biological and sociocultural factors in the same individuals, and identifying subgroups that differ in these factors and developmental pathways to their sexual orientation. This approach will allow us to understand the interactions between factors, and whether multiple distinct developmental pathways contribute to individual differences in human sexuality. Furthermore, more intensive experimental designs are required to follow prenatal, early postnatal, pubertal, and adult biology and behavior in humans. With such experiments, scientists may begin to understand the full extent of neuroendocrine influences on human sexuality.
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