SEXUAL DIFFERENTIATION

Sexual differentiation begins with the sex difference of the chromosomes established at conception (see Chapter 118). In humans, it was traditionally believed that the combination of chromosomes present in all cells of the body had no direct effect on erotosexual status. Rather, the influence was presumed to be derivative through determination of the nature of the embryonic gonadal anlagen and their hormonal products, but this view is changing. Genetic factors play a role in sex-dimorphic traits.^4,5

BRAIN SEXUAL DIFFERENTIATION

In the early 1900s, it became clear from animal experimentation that the process of sexual differentiation is not completed with formation of the external genitalia, but that the brain, as the substrate of sexual and nonsexual behavior, also undergoes sexual differentiation consistent with the other characteristics of sex. In lower animals, evidence has accumulated that the same hormonal organizing principles of sexual dimorphic differentiation account for both the genitalia and the brain,^6,7 though presently, genetic factors are increasingly recognized.⁸ The hormonal action of testosterone has been termed organizational, and it is exerted during a rather circumscribed, so-called critical period of prenatal or early postnatal development. In lower mammals, part of this action is mediated in part by estrogens through aromatization of testosterone,⁹ but this has not been convincingly demonstrated in the human.¹⁰ The main regions of the mammalian brain undergoing sexual differentiation are the hypothalamus, the septum, the bed nucleus of the stria terminalis, the preoptic area, and the amygdala.^9,11

The sexual dimorphic differentiation of the human brain is less well documented, but a number of sexual dimorphic nuclei have been found (sexual dimorphic nucleus [SDN] and the bed nucleus of the stria terminalis).¹² The morphologic sex difference in the SDN is not established until the first postnatal years, and the development of sexual dimorphism of the bed nucleus of the stria terminalis may extend into adulthood.¹³ During childhood, there are no significant sex differences in circulating sex steroids. Whereas sexual differentiation in laboratory animals is clearly induced by gonadal steroids⁹ and genetic factors,⁸ in humans the mechanism and the clinical relevance of brain sexual dimorphism are not yet certain. In humans this information has been deduced from “experiments of nature”: genetic and endocrine disorders that spontaneously occur in the fetus or result from exposure to exogenous hormones such as estrogenic drugs during pregnancy.^3,14 Clinical observations support the hypothesis that in human prenatal development, sexual brain differentiation is subject to effects of androgens, but these are not of the hormonal-robot type found in subprimate mammals, in which sex steroids typically exert a simple on/off effect on sexual behavior.^3,14

DISORDERS OF SEXUAL DIFFERENTIATION

Human sexual differentiation is a multistep, sequentially interrelated process in which genetic information is translated into the phenotype of a person who subsequently establishes a male or female identity and an awareness of sexual orientation.^1,3,15,16 The human embryo is initially bipotential with respect to gonadal and genital development, and consequently, disorders in any of these steps can result in ambiguity of the gonads/genitalia. A child born with ambiguous genitalia constitutes a psychosocial emergency in which sex assignment must take place without delay, in days rather than weeks (see Chapter 119).^17,18 Western society demands two clearly defined sexes, with an absolute distinction between male and female. Modern techniques such as karyotyping, molecular biology, and imaging techniques allow a rather precise diagnosis of the condition, but decisions regarding sex assignment are still based on very limited empirical data.¹⁷

Most experts would agree that biological characteristics (such as chromosomal pattern, nature of the gonad, and so on) are not sufficient to provide reliable indicators for determining a person’s “true” sex status as a man or woman.^3,17–19 Though relevant, they do not fully govern the decision to assign a particular sex to a newborn with ambiguous genitalia. A widely adopted policy is to arrive at a prognosis on the “optimal sex” for the newborn, the elements of which are an overall sex-appropriate appearance with stable gender identity, good sexual function (preferably combined with reproductive function if attainable), minimal medical/surgical procedures, and a reasonably fulfilling life hampered as little as possible by the condition.^17–20

This policy has been called into question. While it is reasonable to assume that a neural substrate corresponding to traits and self-concepts of being male or female will eventually be present in a person’s life, the factors that determine these self-concepts remain a matter of debate. Assignment of a newborn with ambiguous genitalia to one sex or the other on the basis of a prognosticated best future functioning as male or female presupposes psychosexual neutrality of children at that stage of their lives. In other words, the clinical and scientific question is whether at the time of birth a (biologically determined) “neural bias” is already present with regard to future gender identity/role and sexual orientation. Are the latter shaped (exclusively) by postnatal factors in the course of rearing a child as boy or girl, or is this development wholly or partially determined by prenatal factors such as the hormonal milieu?^16,17,21

Brain research, mostly performed on lower mammals, demonstrates a significant role of prenatal and perinatal sex hormones in the sexual differentiation of brain and behavior.^9,12 Several reports provide evidence that such hormonal effects are present in humans, but the association is not absolute, and the information is too preliminary to constitute solid guidelines for sex assignment of children with ambiguous genitalia.^3,16,17

The clinical syndromes that allow assessment of prenatal androgen effects on future gender identity/role, sexual orientation, and other behaviors are 46,XX subjects with congenital adrenal hyperplasia (CAH),^22–26 46,XY subjects with hypoandrogenism,^27–33 such as (partial) androgen insensitivity ([P]AIS), and children with nonhormonally induced severe genital malformations such as cloacal exstrophy and penile agenesis/ablation who have been assigned to the female sex but whose prenatal androgen production/exposure has been similar to other males.^33–36 Available data allow the preliminary conclusion that effective prenatal exposure to androgens is indeed associated with masculinization of gender role behavior. Girls with CAH, particularly the more severe salt-wasting form, exhibit a spectrum of masculinized gender role behavior, though this is often but not always compatible with a core female gender identity. The likelihood of a gender change later in life in such females correlates with the presumed degree of prenatal androgen exposure,²⁶ but the association is not very strong.

Naturally, the degree of prenatal and postnatal androgen exposure also determines the extent of genital ambiguity; together with the postnatal experience and considerations of quality of life, this may also be a factor in a change of gender.^35,37 Predictors of gender change are stigmatization, gonadectomy, and/or feminizing surgery after the age of 3 years.³⁸ A relative absence of gender dysphoria in childhood does not preclude a gender change later in life.³⁸

The majority of 46,XY disorders of sexual development (DSD), such as in AIS, seem to develop an identity commensurate with the assigned gender and do not change their gender later.^{27,30–32,37} Childhood gender identity will in most cases continue into adolescence and adulthood. Patient-initiated gender change in intersex patients does seem to happen more often in adolescence and adulthood than in childhood. More female-assigned 46,XY patients initiate a gender change to male than male-assigned 46,XY patients to female, possibly indicating the prenatal effects of androgens.^{27,30,31,37,39}

Boys born with a cloacal exstrophy have normal testes and have had a presumed normal prenatal exposure to androgens. About 50% of those assigned to the female sex report dissatisfaction with this assignment and change to male, but these data are still rather preliminary.^35,39,40 In a series of 18 children born with a micropenis, all subjects were satisfied with their sex of rearing in adulthood, though both men and women expressed dissatisfaction with their genital status.³⁴ In summary, the evidence available to date permits only tentative policy-relevant conclusions: (1) the organizational effects of prenatal androgens are more noticeable in gender role behavior than in gender identity; (2) gender identity can develop as female or male over wide variations of gender role behavior; and (3) there is suggestive but not conclusive evidence that a male gender identity/role is more frequent in patients with a history of fully male-typical prenatal androgenization. There is, at this stage of research, no unambiguous evidence for or against female gender assignment of 46,XY patients, even in the prenatally most androgenized conditions.

Obviously, the policy of sex assignment of intersexed newborns is based on a number of insufficiently substantiated presuppositions, but this must also be weighed against the consequences of allowing infants to grow up intersexed until they are old enough to make their own choices. Not intervening can be a complicated decision as well, with the risk of not taking adequate account of the two-sexed world in which the children have to live and the depth of feeling of parents who might find it difficult to cope with their child’s sexual ambiguity.¹⁷

A rigorous policy of early sex assignment has been criticized by interest groups of intersexed people, who advocate a safe space for the development of identities as intersexuals, as occurs in some societies (http://www.isna.org). Some of these individuals, having undergone hormonal and surgical sex assignment treatment, are unable to identify themselves as belonging to either sex. This group believes that surgical therapy should be limited to instances necessary for physical health and comfort. In particular, it opposes clitorectomy or substantial reduction of the clitoris and poor surgical repair of penile abnormalities, both of which reduce the prospects for later pleasurable sexual activity (http://www.isna.org). These views deserve serious attention.

COMPLETE ANDROGEN INSENSITIVITY

Children afflicted with the androgen insensitivity syndrome (AIS) have a 46,XY karyotype and testes as gonads.^41–43 An abbreviated blind vaginal pouch is present but no uterus or fallopian tubes. Because the external genitalia have a normal female appearance, the disorder of these patients is often unnoticed at birth. Surgical repair of an inguinal hernia containing a testis may reveal the condition. Without intervention, hormonal puberty is feminizing due to the aromatization of endogenous androgens to estrogens. In cases of complete AIS, sex assignment and rearing are almost invariably female. The differentiation of gender identity/role is feminine.^{27,29–33,41–45} This fact is theoretically important in showing that the nature of the chromosomes and gonads per se does not dictate gender identity and role. And further, that the virtual absence of androgen exposure is associated with a female gender identity and a sexual orientation towards men. Another theoretically important aspect of this condition is the high circulating levels of estradiol derived from elevated levels of testosterone production (to which these subjects are insensitive). In lower mammals, prenatal estrogen exposure has behaviorally a defeminizing effect, but in the human, this apparently is not the case, as is also true for nonhuman primates.⁴⁶

In adulthood, gender identity/role and sexuality conform to typical heterosexual feminine expectations.

PARTIAL ANDROGEN RESISTANCE SYNDROMES

The spectrum of phenotypes in 46,XY may include individuals with almost female external genitalia, children with ambiguous genitalia (perineoscrotal hypospadias, a microphallus, and cryptorchidism), and a normal male phenotype.^{27,28,30–32} There may be some relation between the nature of the androgen receptor defect and the phenotype.^28,45 At puberty, because of the androgen insensitivity, the development of male secondary sex characteristics is sluggish. Gynecomastia develops, usually as a result of an imbalance in androgen-estrogen action. Less severe cases may have either hypospadias or a normal male phenotype and normal male development at puberty, with impaired spermatogenesis. There is considerable variability in expression of PAIS.^27–32 Minor deviations may go unnoticed or may be repaired by surgery (e.g., hypospadias). In more severe cases, the child has ambiguous genitalia. In these children, the problem of sex assignment has arisen.

In practice, the chances for relatively normal development have been better in a female direction.^{27,28,30–32} If a male sex of rearing has been chosen, reconstructive surgery of the genitalia has usually been performed in childhood, with later surgical correction of pubertal gynecomastia. The majority of 46,XY intersex patients with partial androgen insensitivity seem to develop an identity commensurate with the assigned gender and only rarely change their gender later.^17,33 A recent review found an approximately 10% self-initiated sex reassignment.³³

5α-REDUCTASE DEFICIENCY

5α-Dihydrotestosterone (DHT), the most potent natural androgen, is formed exclusively through 5α-reduction of testosterone by the enzyme 5α-reductase.^47,48 Affected people are born with labioscrotal folds and a clitoridean penis. At puberty they become moderately virilized or remain eunuchoid, with enlargement of the clitoridean penis. No breast development is seen.

In the first reports, it was claimed that these people were reared as girls during childhood, but after pubertal physical changes, took up life as men.^47,49 The interpretation offered was that the pubertal surge of testosterone apparently induces a reversal of gender identity and role and generates a “male” sex drive.^47,49 Later studies show that this interpretation probably needs modification.^48,50 Local people are usually aware of the genital disorder of these neonates and of their potential future male pubertal development. In a study from Brazil,⁴⁸ 25 of 26 affected with 5α-reductase type 2 deficiency were assigned at birth to the female sex and raised as girls. Thirteen changed to the male sex after puberty. This was associated with some virilization of the external genitalia. There was no straightforward relationship between the severity of the condition and change of gender.^48,50 It is of note that both testosterone itself and 5α-dihydrotestosterone are capable of masculinizing the brain in nonhuman primates,⁴⁶ so prenatally there has been potentially a fair amount of brain masculinization in subjects with this condition.

17β-HYDROXYSTEROID DEHYDROGENASE DEFICIENCY

17β-Hydroxysteroid dehydrogenase 3 is involved in the terminal step in the synthesis of testosterone in the Leydig cell and of estradiol in the ovarian granulosa cell.⁵¹ Subjects affected with 17β-hydroxysteroid dehydrogenase 3 deficiency who have an XY chromosomal pattern and testes have more or less female external genitalia owing to lack of an effective androgenic stimulus at the time of the differentiation of the external genitalia.^51–53 Such children are usually assigned to the female sex at birth and raised as girls.⁵³ A particular feature of this disorder is that the testosterone production increases with time (due to a higher LH drive and alternative pathways of testosterone production), and subjects may have near-normal testosterone levels at the time of puberty, inducing substantial virilization. There are several reports of affected individuals raised as females who have changed their gender role behavior from female to male at the time of expected puberty.^49,53 This is not universally the case but appears to happen in approximately 50% of the reported cases in the literature.^49–5153 Subjects with 5α-reductase deficiency and 17β-hydroxysteroid dehydrogenase deficiency, with a less than normal prenatal androgen exposure and a much stronger androgen exposure following puberty, pose the theoretically interesting question whether androgen exposure in puberty and the ensuing physical virilization are factors in sex reassignment.

CONGENITAL ADRENAL (VIRILIZING) HYPERPLASIA

Congenital adrenal hyperplasia (CAH) is a disorder occurring in both sexes involving undue/untimely exposure to androgens. Early reports indicated an overriding influence of the sex of assignment and rearing on the gender identity of CAH girls.^1,54 If CAH subjects were assigned as girls, they turned out to have a female gender identity but tomboyish behavior in play and activity and high energy expenditure—a marked masculine shift on the scale of sex dimorphic behavior, likely due to prenatal and possibly postnatal androgen exposure.^22,54,55

These observations also extend to childhood and later indices of maternal interest. This is truer for the salt-wasting form of CAH than for the simple virilizing forms which show a large variability in masculinized gender role behavior, although this is intrapersonally often compatible with a core female gender identity.⁵⁵ Some are less contented with life as women without having an explicit gender identity disorder (GID).^22,55 In a report of older CAH subjects reared as girls, 37% rated themselves as homosexual or bisexual, or they had fewer heterosexual experiences than the comparison group.²² This finding has been further corroborated.^55,56 An earlier study was less affirmative in this regard.⁵⁴ Nevertheless, retrospective studies indicate that there may be a decreased sexual interest and below-average engagement in heterosexual relationships. This may also result from anatomical inadequacies of the genitalia.^{22,55,57–59} Further, hirsutism may be a disruptive factor. The likelihood of a bisexual or homosexual orientation correlates with the supposed degree of prenatal androgen exposure,⁵⁶ which applies also to the likelihood of a gender change later in life, though the association is not very strong. Naturally, the degree of prenatal and postnatal androgen exposure also determines the extent of genital ambiguity, which together with the postnatal biography and considerations of quality of life may also be factors in a change of gender. Predictors of gender change are stigmatization, gonadectomy, and/or feminizing surgery after the age of 3 years. A relative absence of gender dysphoria in childhood does not preclude a gender change later in life.

By contrast, those subjects assigned as boys because of the high degree of masculinization of their external genitalia successfully developed a male gender identity and role,⁵⁴ although patient-initiated reassignments to the female gender have been reported.^22,55

Prenatal dexamethasone treatment of pregnant mothers possibly bearing a child affected with CAH has become an option.⁶⁰ Treatment must start “blindly” by or before the sixth or seventh postmenstrual week until the diagnosis can be made by chorionic villous biopsy at week 10 or 11 or by amniocentesis at week 14 to 16. The treatment requires intensive guidance of the patient but is efficacious.⁶⁰ Of late it has been hypothesized that the condition of salt-wasting CAH or prenatal dexamethasone may affect future cognitive function.⁶¹

BOYS WITH MALFORMATIONS OF THE GENITALIA OR EXTREME MICROPENIS

Boys born with a cloacal exstrophy have normal testes and a presumed normal prenatal exposure to androgens. About 50% of those assigned to the female sex are reported to evidence dissatisfaction with this and change to male.^35,40,62,63 The interpretation is that prenatal androgen exposure underlies this change and is consistent with the notion that there is an increased probability of later patient-initiated gender reassignment to male after female assignment in infancy or early childhood in 46,XY subjects born with ambiguous genitalia.³⁹ The latter probably also plays a significant role in the change of gender observed in boys with cloacal exstrophy. It is clear that androgen exposure in XY subjects predisposes but does not assure a male gender identity, with an approximately 40% to 50% chance of development of a female gender identity if the newborn has originally been assigned to the female sex.

Some experts caution against a female sex assignment in boys with a micropenis, stressing the beneficial effects of administration of testosterone in infancy and childhood.^64–66 But in a series of 18 children born with a micropenis, of whom 5 had been assigned to female, all subjects were satisfied with their sex of rearing in adulthood, though both men and women expressed dissatisfaction with their genital status.³⁴ A later report shows similar results.³³

PRECOCIOUS AND DELAYED HORMONAL PUBERTY

Precocious puberty occurs more often in girls than boys (see Chapter 121). Affected children typically mature sexually between the ages of 6 and 8 years and sometimes earlier. Their erotosexual behavior matches their chronologic age more closely than their physical maturation.^69,70 Erections in boys are usually associated with erotic ideation and imagery corresponding to their calendar age. Signs of erotic interest may be in evidence from time to time, but they usually do not lead to sexual encounters, possibly through lack of potential partners, though these children are usually somewhat ahead of their peers in erotosexual activity at the normal time of puberty.^70,71 With this advanced physical maturation, children may seek friends close to their stage of sexual development even though they lack the age-appropriate development of these children. Outsiders may have unrealistic expectations arising from the stage of physical maturation, with the potential for sexual abuse and the risk of pregnancy in girls.⁷¹ Studies indicate that many of the behavioral problems of precocious puberty are mediated by the perception, of self and by others, of the discrepancy of physical sexual maturation and behavior appropriate for calendar age.^69,71 Both parents and the child need guidance to cope with this premature sexual development. Parents’ anxieties and concerns should be carefully addressed. They often fear premature sexual activity.⁶⁹ The gap between chronologic age and physical age may be minimized by planned acceleration in school and social life.

Delayed puberty is the converse of precocious puberty. Similar to precocious puberty, behavioral problems may arise from the perception, of self and by others, of the discrepancy between calendar age and physical sexual maturation.⁷²

In most cases, the delay of puberty is constitutional, but it may also be based on disturbances in gonadotropin and sex-steroid production. The problems of being out of step with peers in sexual maturation are underrated by many parents and medical professionals. Pubertal delay may lead to shyness and withdrawal from group activities (sports, heterosexual social activities, flirtation, and erotic overtures) because of shame about physique.⁷³

TURNER’S SYNDROME

In Turner’s syndrome, with a 45,X0 or related mosaic chromosomal disorder, the gonads fail to produce hormones. The genitalia are normally female, and gender identity/role is typically feminine.⁷⁴ Awareness of infertility and the lifelong short stature typical of this syndrome do not interfere with a desire for marriage and motherhood. Secondary sexual characteristics must be induced by estrogen administration.⁷⁴ This is often delayed until the late teenage years, sexual development being temporarily sacrificed for statural growth, for which synthetic growth hormone is often added.⁷⁵ Psychological problems may arise when estrogen therapy is initiated later than (approximately) the age of 13 years. As a result of delay in sexual maturation, there may be relative romantic and erotic inertia.⁷⁶ The absence of ovarian androgen production may also be relevant. Girls with Turner’s syndrome have a specific cognitive deficit that does not affect verbal intelligence, though speech may be delayed, but it does affect nonverbal intelligence and is manifested as a handicap in visuospatial capacity (direction sense, map reading), mathematics, and a motor deficit.^74,76

KLINEFELTER SYNDROME

Klinefelter syndrome (47,XXY and its mosaics) is not infrequent. A recent study found an incidence ratio of 1 : 600 male births.⁷⁷ The condition is often not diagnosed until the age of puberty because, until teenage years, affected boys are only moderately different from control subjects. Patients may be taller or have undescended testes or relatively small external genitalia, but these features are not always present. Puberty may progress slowly, with permanently weak virilization and often gynecomastia. Patients usually receive treatment with testosterone to increase virilization and promote synchrony with the development of chronologic-age peers.

The intelligence quotient (IQ) of most 47,XXY males is usually average or somewhat lower.⁷⁸ Verbal IQ is usually more affected than nonverbal or performance IQ and is manifested in infancy as a developmental delay in speech.⁷⁹

Executive skills (such as concept formation, problem solving, switching tasks, and initiating rapid and fluent response) may be also be impaired.⁸⁰ If Klinefelter syndrome is diagnosed early, remedial teaching may help improve educational performance.⁸⁰ In sexological counseling, attention is given as needed to surgical correction of gynecomastia, cosmetic prosthetic testes, and coping with impaired fertility. With regard to erotosexuality, no systematic epidemiologic statistics are available to permit a statement about the prevalence of paraphilias or gender transpositions in the 47,XXY population versus the 46,XY population. The dominant trend is for 47,XXY men to be timid and hyposexual. The sexuality of Klinefelter patients in infertility clinics is indistinguishable from a comparison group.⁸¹

ABNORMAL BODY SHAPE AND IMAGE

Hormones have a profound impact on body shape and consequently on body self-image. Patients with conditions that affect appearance, such as disorders of sexual differentiation, gynecomastia, precocious/delayed puberty, small/tall stature, hirsutism, Klinefelter syndrome, Turner’s syndrome, obesity, and the like, may suffer from a negative body image.⁷³

In particular, adolescents often view themselves through the eyes of their peers and constantly compare themselves with them. Any deviation in appearance may evoke peer ridicule and can result in low self-esteem and feelings of inadequacy, shame, and stress; this combination may lead to withdrawal from social activities and poor academic performance and may impair healthy erotic and sexual interaction and development.⁷³

Therefore, body image dissatisfaction must be addressed when treating the aforementioned conditions, even though the complaints may lack technical medical significance. Reassurance based on medical examination that pathology has been ruled out and that no relevant medical problems are present may not be sufficient. Alternatively, it may even be counterproductive if the patient believes that the absence of disease leaves no room for discussing body-image problems. It may be up to the physician to initiate discussion of these issues. Inquiries such as “Other people with the same condition often experience discomfort with their bodies. How is this condition affecting your life?” may pave the way for an assessment of how patients experience their deviation from the norm. The physician may offer the information that joining a patient self-help group is sometimes helpful.

ADULT MALE SEXUAL FUNCTIONING

The evidence for testosterone-induced masculinization of certain aspects of sexual behavior in men is persuasive. Most of the information has been collected from androgen withdrawal/replacement studies of hypogonadal men. It is now clear that androgens are fundamental to normal sexual behavior in men, although they do not have a simple on/off effect on sexual functions and are not the only factor involved in male sexual behavior.^82–84 When androgen production is deficient from the fetal stage, as in hypogonadotropic hypogonadism and Klinefelter syndrome, the response to androgen replacement during puberty or later may be manifestly impaired, expressing itself as relative sexual inertia. Emotional, cognitive, and social learning are also elements in adolescent and adult sexuality.^2,83

The distinction between sexual interest and erectile function and its subdivision has helped considerably in clarifying the role of androgens in male function.⁸³

Spontaneous erections, particularly those that occur during sleep and probably fantasy-induced erections, are androgen dependent, whereas erections in response to erotic (e.g., visual or tactile) stimuli are less so.⁸³ But androgens do affect penile responses to erotic stimuli with regard to the duration of response, degree of rigidity, and speed of detumescence.⁸⁵ In men, the principal target of androgen appears to be sexual interest or appetite.^82,83 Androgen might enhance the persistence of attention to eroticism, which in turn might affect sexual behavior. It has been argued that androgen influences pleasurable awareness during sexual activity, possibly by enhancing sensory (genital) function. It is not certain how androgens exert their action on the brain. They may also influence cellular activity in a nongenomic fashion by acting directly on cell membranes or by modulating other membrane receptors or secondary messenger systems.^83,84

Although it has been convincingly established that the main effect of androgens on male sexual functioning is on the central nervous system, additional evidence now suggests that they also affect nitric oxide synthase in the corpus cavernosum (nitric oxide induces smooth muscle relaxation of the penile vasculature, essential for penile erection) and that androgen administration may be helpful in men who respond poorly to treatment of erectile dysfunction with phosphodiesterase inhibitors.^85,86

The blood level of testosterone critical for normal male sexual function varies among individuals.^87,88 In most males, 60% to 70% of the reference values is sufficient.^87,88 The threshold in elderly men may be somewhat higher.⁸⁹ In contrast to hypogonadal men, in men with sexual dysfunction and normal androgen levels, additional testosterone is likely to be of no help, although a short-lived beneficial effect from additional testosterone in eugonadal men who complained of lack of sexual interest has been found.

Pubertal development is associated with a gradual though variable increase in sexual interest and activity, but it has been difficult to relate levels of androgens to the development of adolescent sexuality, probably because there is an individually different amount of socially influenced learning that impacts on this hormone-behavior relationship.⁹⁰ Physical pubertal development may be a better predictor of sexual interest and behavior than free testosterone.⁹¹ Sexual functions decline with aging. Aging is also associated with a variable decline in bioavailable testosterone levels, but levels remain mostly but not always above minimum testosterone levels for normal sexual functioning established in younger men. The hypothesis has been advanced that aging men are less sensitive to the actions of testosterone.⁸⁹

Information on the timing of onset of behavioral effects after withdrawal of androgens is limited. With both naturally occurring and pharmacologically induced hypotestosteronemia, behavioral effects and a reduction in seminal emission become clear after 2 weeks and reach a maximum after 4 weeks or longer. A sexually active partner may be a factor in prolongation of sexual activity.² In the majority of men, the ejaculatory capacity is profoundly decreased after androgen withdrawal, affecting sexual behavior in its own right.²

Restoration of testosterone effects is probably somewhat quicker, over approximately 1 to 2 weeks, and there may be a relationship with the duration of foregoing androgen deficiency.^2,82