The Indian Journal of Pediatrics

, Volume 84, Issue 9, pp 700–708 | Cite as

Controversies of Sex Re-assignment in Genetic Males with Congenital Inadequacy of the Penis

Review Article

Abstract

Sex assignment in 46XY genetic male children with congenital inadequacy of the penis (CIP) is controversial. Traditionally, children with penile length less than 2 cm at birth are considered unsuitable to be raised as males. They are typically re-assigned to female-sex and feminizing genitoplasty is usually done in infancy. However, the concept of cerebral androgen imprinting has caused paradigm shift in the philosophy of sex re-assignment. Masculinization of the brain, rather than length of the penis, is the modern criterion of sex re-assignment in CIP. This review summarizes the current understanding of the complex issue. In 46XY children with CIP, male-sex assignment appears appropriate in non-hormonal conditions such as idiopathic micropenis, aphallia and exstrophy. Female-sex re-assignment appears acceptable in complete androgen insensitivity (CAIS), while partial androgen insensitivity syndrome (PAIS) patients are highly dissatisfied with the assignment of either sex. Children with 5-alpha reductase deficiency are likely to have spontaneous penile lengthening at puberty. Hence, they are better raised as males. Although female assignment is common in pure gonadal dysgenesis, long-term results are not known to justify the decision.

Keywords

Disorders of sex development Ambiguous genitalia Androgen insensitivity syndrome Sex re-assignment Penile length Micropenis Aphallia Penile agenesis Exstrophy Sexual function Intersex disorders 

Introduction

Among the dual functions of the penis, micturition is independent of its morphometry while coital function is dependent on its physical dimensions and erectile capacity. It is estimated that a minimum erect penile length of 5 to 8 cm is essential for satisfactory sexual intercourse and successful insemination [1]. Biologically, maleness of an organism is defined by its ability to produce and transfer sperms. Therefore, an adequate penis is essential not only for reproductive function but also for the very identity of the individual.

Approximately 1 in 15,000 male children are born with congenital inadequacy of the penis (CIP) such as aphallia, exstrophy, micropenis and intersex disorders [2]. It is a pertinent question whether they should be raised as boys if they will not be able to fulfill the expected biological role of a male. Based on this philosophy, they are traditionally re-assigned to female-sex on diagnosis [3, 4, 5]. Opponents of this approach point out that procreation is just one of the many functions of an organism and they question if it is appropriate to treat an individual from the perspectives of a single biological function [6, 7]. Consequently, they recommend that a genetic male with 46XY should be raised as a male irrespective of his penile length and ability to perform penetrative intercourse.

The controversy of sex assignment in CIP is vexatious not only to the patient and the caring pediatric specialists but also to the family members, ethicists, social activists, and juries. Dissatisfaction with assigned sex has often prompted patients and social activists to sue caring doctors accusing them of negligence or misadventure [8]. Educated parents gather a lot of information from the internet and ask several fundamental questions to the counseling physician. It is therefore essential for the practicing pediatricians to be familiar with the principles of sex re-assignment in CIP. This descriptive review is intended to summarize the current philosophy and recent advances in the management of CIP.

Nature versus Nurture

Traditionally, boys with CIP are re-assigned to female sex [9, 10, 11]. This approach was based on several assumptions. Firstly, femaleness is the default sex of nature. All human embryos are destined to become females unless influenced to differentiate as male by the SRY gene of Y chromosome. It was, therefore, assumed that compliance with the Nature would make male-to-female conversion easier than vice versa. Secondly, boys and girls are known not to differ in their social behavior during the first few years of life. This observation has prompted the hypothesis of gender neutrality at birth [12, 13]. It was argued that males and females do not differ in their physical or mental function at birth and any such difference noted in adult life is the result of childhood conditioning by the society [14]. It was theorized that boys, if castrated early in infancy, would behave like typical females in their adult life. Thirdly, surgeons favored feminizing genitoplasty over phalloplasty because of technical reasons. It was assumed that fabricating a receptive vagina (passive function) will be easier than reconstructing a penis with erectile capacity (active function). Consequently, several baby boys with CIP underwent bilateral orchidectomy and excision of the penis early in their life.

Clinico-social experiment of John Money and its follow-up report by Milton Diamond were the game changers in the management of CIP [15]. One Reimer, who was born male, lost his penis at the age of 7 mo consequent to circumcision accident. Money, who had then been developing the concept of ‘gender neutrality’ [16] advised sex re-assignment of Reimer. Money believed that social nurturing is more influential than the biological nature of sexes. Accordingly, Reimer was transformed into female at the age of 22 mo and he underwent bilateral orchidectomy and vulvoplasty. Money, after a decade of follow-up, claimed that the sex conversion was successful and he cited this case as proof of gender neutrality theory. However, the truth surfaced several years later when Milton Diamond published long-term follow-up details of the case [17]. Reimer, in his adolescence increasingly felt uncomfortable to be identified as a female. In late adolescence, when he came to know the truth of his sex re-assignment, he opted to become a male once again. Thus the Nature is shown to prevail over nurture.

Androgen Imprinting of Brain

The mechanism by which the Nature supersedes nurture was discovered against much opposition and pressure from feminist groups. Contrary to the claims of neurofeminists, the story of Reimer strongly suggested that male and female brains biologically differ in their basic characteristics [18]. Boys always identify themselves as boys irrespective of the physical or social disguise and its analogue is also true of girls. Money named this phenomenon as ‘gender identity’ (GI) and distinguished it from ‘gender role-play’ (GRP) [12]. The latter is a social phenomenon which includes adherence to gender specific play, dress, job, manners and sexual relationships. Money emphasized that GI and GRP are usually, but not necessarily, be congruent in a given individual.

While GRP is influence by parental rearing, GI appears to be biologically determined by androgen imprinting of the cerebral cortex [19]. In boys, serum testosterone reaches peak levels twice before actual puberty: The first surge occurs at around 12 wk of gestation, when testicular formation is completed. The second surge, which is also called mini-puberty, occurs between 1 to 6 mo of postnatal life. It is not clear as to which of the two surges cause androgen imprinting of the brain. Probably, postnatal surge reinforces the cortical impression made by fetal surge. Androgen imprinting of the brain leads to permanent male GI. Therefore, if a male infant is decided to be raised as female, bilateral orchidectomy before 12 wk of age was recommended to avoid postnatal androgen imprinting [20]. Even then, prenatal androgen surge, which is beyond human control, may still cause variable degree of male GI. This proviso has to be borne in mind while re-assigning the sex of a genetic male.

Estrogen imprinting, the analogue of androgen imprinting in females, does not appear to exist. There is very little data on the mechanism of female GI development. Drawing analogies from sex determination of embryos, it is assumed that all brains are basically feminine unless imprinted differently by androgens. In other words female GI is caused not by the presence of estrogens but by the absence of androgens [21]. Thus, in androgen insensitivity syndrome (AIS) where cerebral tissues are deficient in androgen receptors, the individual is likely to develop female GI irrespective of serum testosterone levels.

Phalloplasty and Assisted Reproductive Techniques

Advances in reconstructive surgery, assisted reproduction techniques and implant technology occurred simultaneously with the development of androgen imprinting concept. Reconstruction of erectable phallus was previously considered a formidable task. Experience with trans-sexual patients enabled surgeons to perfect the technique of penile reconstruction using various skin flaps such as radial forearm free flap, pedicled groin flap, anterolateral thigh flap, myocutaneous lattissimus dorsi flap and fibular osteocutaneous flap, scrotal skin flap, bird-wing abdominal flap and De Castro flap [22, 23] (Fig. 1). Artificial erection of the neo-phallus is made feasible by the introduction of inflatable penile prostheses and semi-malleable penile implants. Anastomosis of ileo-inguinal nerve to the neural stump of phallic flap is claimed to regain even erogenous sensation of the neo-phallus and orgasm [23]. In addition to fabrication of a new phallus (neo-phalloplasty), girth and length of existing penis can also be improved by augmentation phalloplasty.
Fig. 1

Penile agenesis (Aphallia) (a) clinical appearance of intact scrotum with rugosity and absence of penis; (b) same patient after RAM flap neo-phalloplasty. The phallus is reconstructed from rectus abdominis myocutaneous (RAM) flap

Development of assisted reproduction techniques (ART) has diminished the indispensability of the penis in human reproductive function. Techniques such as percutaneous sperm aspiration, testicular sperm extraction, intracytoplasmic sperm injection and in vitro fertilization have rendered the penis more and more an organ of pleasure rather than that of reproductive importance. It is now possible for men with CIP to father children by ART if their gonads had not been removed in childhood [24].

Paradigm Shift and Fresh Problems

With advancements in knowledge and techniques, the criterion of sex re-assignment in CIP has shifted from length of the penis to androgen imprinting status of the brain [25]. Strong androgen imprinting supports rearing as male, while weak or absent imprinting probably calls for re-assignment to female sex [4]. However, the greatest hurdle at present is our inability to measure the degree of cerebral androgen imprinting in a given individual. There is no laboratory or imaging investigation to ascertain masculinity of the brain. The surest way is to directly ask the child about his GI and sexual preferences. Unfortunately, one has to wait for decades to obtain this unambiguous answer. Until then, raising the boy with gender uncertainty is neither practical nor advisable.

‘Toy preference’ has been proposed as an indirect method of predicting androgen imprinting status in toddlers [26]. Boys always prefer a certain type of toys which are very different from what the girls choose. This difference was hypothetically related to androgen imprinting status of the brain. It is criticized that the observed difference in toy preference could be due to social stereotype of child rearing rather than hormonal influence [27]. Nonetheless, observation of similar phenomenon in wild monkeys invalidates any criticism against hormonal origin of toy preference [28]. But, it is not clear if toy preference simply correlates with GRP rather than GI. The alternate way of inferring cerebral androgenization is to analyse the long-term results of those who had had their sex re-assigned in infancy. Unfortunately, such clinical data with robust statistical power hardly exist in medical literature. Relative rarity of CIP, psychosocial embarrassment associated with it, poor understanding of the GI concept, practical difficulty of prolonged follow-up for decades and interference by feminist and activist groups could be the reason for such deficiency. Therefore, we are left with the only option of making informed guess based on anecdotal reports and clinical observations.

Classification of Congenital Inadequacy of the Penis (CIP)

Classification of CIP will facilitate our understanding of androgen imprinting status and sex re-assignment. Penis is considered abnormally short if its stretch length is 2 standard deviations below the mean expected length of a given age group. This is usually less than 2 cm in newborn. It is important to recognize and exclude conditions such as buried penis, webbed penis, hypospadias and obesity wherein even a penis of normal length may appear deceptively small (pseudo-CIP). Similarly the ‘small penis’ of 46XX or mosaic karyotype is in fact enlarged clitoris and such conditions are excluded from further analysis. True CIP can be either hormonal or non-hormonal. Hormonal CIP may in turn be either central or peripheral. The latter is further divided into defective gonad formation (gonadal dysgenesis), impaired androgen synthesis (enzyme deficiency) and ineffective target response (receptor insensitivity).

Non-hormonal CIP

Local insult to the developing genital tubercle appears to be the cause of all non-hormonal CIP. Aphallia (agenesis of penis), exstrophy (splayed out bladder, pelvis and penis) (Fig. 2) and idiopathic micropenis are included under this category. Normal testicular function despite CIP is characteristic of this group. Strong androgen imprinting of the brain, development of male-type secondary sexual characters at puberty and adequate sperm production are expected in all non-hormonal CIP. Therefore, 73% of pediatric urologists think that it is appropriate to raise these children as males [29]. Correctness of this opinion is confirmed by several clinical observations.
Fig. 2

Exstrophy of bladder with intact scrotum and stump like penis (arrow). Huge bulge on either side is associated inguinal hernia

Approximately two-third of aphallic boys raised as females identified themselves as males in adult life while all those who were raised as males did not have gender dysphoria [9]. As many as 80% of micropenis patients were dissatisfied with female sex assignment [30]. Contrarily, 100% of the micropenis males reported good to fair erection and 77% maintained heterosexual relationships [30]. Similarly, among the male exstrophy patients who were raised as females, almost all had interests and attitudes typical of males and more than 50% of them opted to become male once again [10, 31]. Contrarily, none of 46XY exstrophy patients who were raised as males had gender dysphoria [11]. Despite CIP, 92% of male exstrophy patients enjoyed masturbation, 36% could perform penetrative intercourse and 72% achieved ejaculation at orgasm [32]. By comparison, male-to-female exstrophy patients scored poorly on sexual functions. About 73% of the male exstrophy patients were in stable relationship, 32% had married and 14% had fathered children [33]. These data support male sex assignment in non-hormonal CIP.

Rearing non-hormonal CIP children as males is not without problems. Prevalence of erectile dysfunction (58%), oligospermia (71%) and infertility (27%) are very high among them [33, 34, 35]. As many as 66% were dissatisfied with their genital appearance [30]. Despite these disadvantages assignment of male sex is preferred over female sex in non-hormonal CIP because gender dysphoria is unlikely to occur in adulthood (Table 1). Further, in the social context of developing countries it is easier to live as an inadequate male than as a sexually handicapped female [36]. It is easy for the former to find a job, experiment openly with his sexuality, remain independent and even marry.
Table 1

Comparison of sex assignment in 46XY male children with non-hormonal CIP

Concerns

Male-sex assignment

Female-sex re-assignment

Gender dysphoria in adulthood

Very unlikely

Highly probable

Social acceptance in developing countries

Fairly Good

Poor

Fertility (natural or assisted)

Possible as testes produce sperms (one-third father children)

Early orchidectomy leads to absolute infertility

Secondary sexual characters*

Typical of male

Mild to moderate phenotypical incongruence possible even after infantile orchidectomy

Surgical reconstruction of genitalia

Technically challenging

Relatively easier †

Need for hormone replacement

No

May require estrogen injections at puberty

Autoerotic activities§

92% masturbate

Only 50% masturbate

Self satisfaction with sexual activity

Probably good because the glans is retained

Probably very poor due to surgical excision of the glans

Sexual satisfaction of partner after appropriate genitoplasty

Probably impaired

Probably fair to good †

CIP Congenital inadequacy of penis

*Secondary sexual characters include pattern of body hair, pitch of voice and development of breasts

† These are the only advantages of female-sex re-assignment in 46XY male with non-hormonal CIP

§ Reference: Park et al. (2015) [32]

Hormonal CIP

Androgen imprinting of the brain is variable and complex in different forms of hormonal CIP. Therefore, each of the entities should be considered separately on their own merits. Micropenis of hypopituitary hypogonadism is easily differentiated from other hormonal CIP by the presence of hypoplastic and/or undescended testes, intact (fully fused) scrotum and absence of hypospadias. Variable degrees of bifid scrotum, hypospadiac urethral meatus and testes of adequate volume are characteristic of peripheral hormonal CIP such as androgenogenic enzyme deficiency syndromes and androgen receptor insensitivity syndromes (AIS). Clinical features of various peripheral hormonal CIP are often indistinguishable and their differential diagnosis depends upon laboratory evaluation (Table 2).
Table 2

Differential diagnosis of congenitally inadequate penis in a 46XY genetic male

Features

Idiopathic micropenis

Hypopituitary micropenis

Aphallia

Exstrophy

5α-RD

17β-HSD deficiency

CAIS

PAIS

Pure gonadal dysgenesis

Location of urethral meatus

Penile tip

Penile tip

Anorectum

Suprapubic (with open bladder)

Hypospadias (Moderate)

Hypospadias (Moderate)

Hypospadias (Severe)

Hypospadias (Variable)

Hypospadias (Severe)

Testicular size

Normal

Hypoplastic

Normal

Normal

Normal

Normal

Normal

Normal / Hypoplastic

Streak gonads

Testicular location

Scrotal

Scrotal or undescended

Scrotal

Scrotal

Scrotal or undescended

Scrotal or undescended

Labial * or undescended

Labial * or undescended

Streak gonads

Scrotal sac

Intact

Intact but hypoplastic

Intact

Intact

Intact or partially bifid

Intact or partially bifid

Completely bifid

Completely or partially bifid

Completely or partially bifid

Scrotal rugosity

Yes

Faint

Yes

Yes

Yes

Yes

No

Yes

Variable

Serum testosterone

Normal

Decreased

Normal

Normal

Increased

Decreased

Normal

Normal

Decreased

Serum DHT

Normal

Decreased

Normal

Normal

Reduced

Decreased

Normal

Normal

Decreased

Serum DHEA

Normal

Decreased

Normal

Normal

Normal

Increased

Normal

Normal

Decreased

Gonadotrophin

Normal

Decreased

Normal

Normal

Normal or slightly elevated

Elevated

Normal or elevated

Normal or elevated

Elevated, very high

HCG stimulation test

Good response

Poor response

Good response

Good response

Good response

Poor response

Good response

Variable response

No response

5α-RD 5α- reductase enzyme deficiency syndrome; 17β-HSD - 17β-Hydroxysteroid dehydrogenase; CAIS Complete androgen insensitivity syndrome; PAIS Partial androgen insensitivity syndrome; DHT Dihydro testosterone; DHEA Dehydro-epiandrosterone; HCG Human chorionic gonadotrophin

“Normal” means values within mean ± 2SD appropriate for a given age group; Good response with HCG stimulation test means increased levels of serum testosterone after HCG injection; poor response means no change or minimal elevation in testosterone levels after HCG challenge.

*As the scrotal folds are not fused, they are referred to as “labia majora”

Micropenis of Hypopituitary Hypogonadism

In this condition, testosterone synthesis is greatly decreased due to anterior pituitary failure. Consequently, virilization of external genitalia is inadequate [37]. Notwithstanding impaired synthesis of testosterone, receptors capable of responding to androgens are invariably present [38]. Testosterone supplements are shown to increase the mean penile length from 1 cm in infancy to 10 cm in adolescence [39]. All the patients developed male GI and 75% of them were sexually active [39, 40]. Therefore, male sex assignment is appropriate in micropenis of hypopituitary hypogonadism [40].

Enzyme Deficiency Syndromes

In androgen synthesis pathway, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) and 5α-reductase are three important enzymes necessary for the bio-conversion of dehydro-epiandrosterone (DHEA), androstenedione and testosterone respectively to dihydro testosterone (DHT) (Fig. 3). DHEA, androstenedione, testosterone and DHT are increasingly potent androgens in that order. When these enzymes are congenitally deficient, synthesis of DHT is impaired leading to accumulation of weaker androgens. Consequently, virilization is inadequate during childhood. However, rising levels of testosterone at the start of puberty effectively compensate the deficiency of DHT. Therefore, these children spontaneously develop full virilization during adolescence [41]. In Dominican Republic, where this enzyme deficiency is very common, affected boys with female-like genitalia are raised with the designation ‘Guevedoces’ (meaning “penis at twelve”) or ‘Machihembras’ (meaning “first a woman, then a man”) [42]. Strong androgen imprinting, invariable development of male GI at adolescence [43], adequate lengthening of the penis at puberty and good chances of fertility [44] discourages childhood sex re-assignment or feminizing genitoplasty in enzyme deficient CIP.
Fig. 3

Pathway of androgen bio-synthesis and important enzymes involved in it. 3βHSD 3β-Hydroxysteroid dehydrogenase; 17βHSD 17β- Hydroxysteroid dehydrogenase

Even those children, in whom orchidectomy had been done with a mistaken diagnosis or philosophy, can still be raised as males by giving DHT or testosterone supplements at puberty. However, a group of Iranian clinicians have claimed that 50% of those who had been raised as females by mistake continued to accept the assigned gender if parents adopt benevolent sexism in rearing them [45]. It is not known if they simply accepted or enjoyed their assigned gender.

Androgen Insensitivity Syndromes

In inherited disorders with absent or unresponsive androgen receptors, circulating testosterones - even if the levels are normal - cannot produce virilization. Approximately 1 in 20,000 “female children” born is actually a male with complete androgen insensitivity syndrome (CAIS) [2]. In normal females, traces of androgen secreted from adrenals will effect minimal masculinization such as hairy legs and acne. But individuals with CAIS will be fully feminized with typical female phenotype sans uterus and vagina (Fig. 4). They even develop attractive breasts at puberty by peripheral metabolization of testosterone into estrogen [46]. As cerebral receptors will also be absent, androgen imprinting does not appear to happen in most of them and hence they develop unambiguous female GI [47]. Therefore, it is appropriate to raise CAIS boys as girls. Vaginoplasty and perhaps orchidectomy may be postponed until late adolescence. Retaining native testes obviates the need of estrogen replacement (for breast development) at puberty. As the long-term risk of malignancy is high, orchidectomy is eventually required.
Fig. 4

Partial androgen insensitivity syndrome. Bifid scrotum with rugosity is characteristic of this condition. (Note: Rugosity will be absent in complete androgen insensitivity syndrome)

Long-term psychosexual outcome of CAIS is generally favorable. None of the CAIS females had gender dysphoria. All of them were satisfied with assigned sex, body image and sexual activities [48, 49]. CAIS and healthy control women did not differ significantly in their sexual satisfaction [50]. However, raising CAIS boys as females is not without problems. Approximately 90% of the CAIS women had difficulty in penetrative intercourse and lack of sexual confidence [51, 52]. As this is attributed to hypoplastic vagina, adequate neo-vaginoplasty may satisfactorily address this issue.

Partial androgen insensitivity syndrome (PAIS) is more difficult to manage than CAIS. Distribution of androgen receptors and the degree of their responsiveness greatly varies not only between individuals but also in various organs of the same individual. Therefore, academic predictions frequently fail in PAIS. High degree of dissatisfaction with either male- or female- sex assignment is not uncommon [53]. Recently, mutation of androgen receptor gene (ARG) has been shown to assist rational sex-assignment in PAIS. In the presence of this mutation, 100% of the patients developed gynecomastia as against 9% in those without the mutation. Presence of ARG mutation is also associated with lesser score of masculinization and more number of surgeries to correct hypospadias [54]. It appears that PAIS patients with ARG mutation will benefit from female-sex reassignment, while those without it may be raised as males. Long-term follow-up results are needed to confirm this theoretical proposal.

Pure Gonadal Dysgenesis

Congenital replacement of both testes with streak gonads leads to impaired testosterone synthesis and CIP. As the risk of malignancy is very high for dysgenetic gonads, they have to be surgically excised as early as possible. Androgen imprinting status varies depending upon the volume of functional testicular tissue left behind. Need for early orchidectomy and uncertainty of androgen imprinting status favor female-sex re-assignment in 46XY pure gonadal dysgenesis. However, paucity of scientific data on the long-term outcome prohibits any meaningful conclusion on the appropriate sex of rearing [55].

Conclusions

Assignment of sex in 46XY genetic males with CIP should no longer be based on penile length; rather it should be decided on the basis of androgen imprinting status of the brain and predicted GI. Male-sex assignment appears to be appropriate in all 46XY males with non-hormonal CIP, hypogonadal micropenis and enzyme deficient CIP. Female sex re-assignment seems to be acceptable in CAIS and pure gonadal dysgenesis. PAIS is the most difficult problem that defies intelligent prediction of GI. Testing for mutation of androgen receptor gene may be useful in the sex-assignment of PAIS.

Notes

Compliance with Ethical Standards

Conflict of Interest

None.

Source of Funding

None.

Disclaimer

Views expressed in this article reflect the author’s understanding of sex re-assignment and they do not represent any official recommendations.

References

  1. 1.
    van der Zwan YG, Callens N, van Kuppenveld J, et al. Dutch study group on DSD. Long-term outcomes in males with disorders of sex development. J Urol. 2013;190:1038–42.CrossRefPubMedGoogle Scholar
  2. 2.
    Berglund A, Johannsen TH, Stochholm K, et al. Incidence, prevalence, diagnostic delay, and clinical presentation of female 46,XY disorders of sex development. J Clin Endocrinol Metab. 2016;101:4532–40.CrossRefPubMedGoogle Scholar
  3. 3.
    Gordetsky J, Joseph DB. Cloacal exstrophy: a history of gender reassignment. Urology. 2015;86:1087–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Fisher AD, Ristori J, Fanni E, Castellini G, Forti G, Maggi M. Gender identity, gender assignment and reassignment in individuals with disorders of sex development: a major of dilemma. J Endocrinol Investig. 2016;39:1207–24.CrossRefGoogle Scholar
  5. 5.
    Meyer-Bahlburg HF. Gender assignment and reassignment in 46,XY pseudohermaphroditism and related conditions. J Clin Endocrinol Metab 1999;84:3455–3458.Google Scholar
  6. 6.
    Kraus C. Am I my brain or my genitals? A nature-culture controversy in the hermaphrodite debate from the mid-1960s to the late 1990s. Gesnerus. 2011;68:80–106.PubMedGoogle Scholar
  7. 7.
    Meyer-Bahlburg HF. Gender assignment and reassignment in intersexuality: controversies, data, and guidelines for research. Adv Exp Med Biol. 2002;511:199–223.CrossRefPubMedGoogle Scholar
  8. 8.
    Sudai M. Changing ethical and legal norms in the management of differences of sex development Lancet Diabetes Endocrinol. 2017. [Epub ahead of print]; doi:10.1016/S2213-8587(17)30043-8.
  9. 9.
    Meyer-Bahlburg HF. Gender identity outcome in female-raised 46,XY persons with penile agenesis, cloacal exstrophy of the bladder, or penile ablation. Arch Sex Behav. 2005;34:423–38.CrossRefPubMedGoogle Scholar
  10. 10.
    Reiner WG. Psychosexual development in genetic males assigned female: the cloacal exstrophy experience. Child Adolesc Psychiatr Clin N Am. 2004;13:657–74.CrossRefPubMedGoogle Scholar
  11. 11.
    Reiner WG, Gearhart JP. Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med. 2004;350:333–41.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Money J. Gender: history, theory and usage of the term in sexology and its relationship to nature/nurture. J Sex Marital Ther. 1985;11:71–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Money J. The concept of gender identity disorder in childhood and adolescence after 39 years. J Sex Marital Ther. 1994;20:163–77.CrossRefPubMedGoogle Scholar
  14. 14.
    Wallen K. Nature needs nurture: the interaction of hormonal and social influences on the development of behavioral sex differences in rhesus monkeys. Horm Behav. 1996;30:364–78.CrossRefPubMedGoogle Scholar
  15. 15.
    Colapinto J. As nature made him: the boy who was raised as a girl. New York: Harper Collins; 2001.Google Scholar
  16. 16.
    Goldi T. The man who invented gender: engaging the ideas of John Money. Vancouver: UBC Press; 2014.Google Scholar
  17. 17.
    Diamond M. Sexual identity, monozygotic twins reared in discordant sex roles and a BBC follow-up. Arch Sex Behav. 1982;11:181–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Saraswat A, Weinand JD, Safer JD. Evidence supporting the biologic nature of gender identity. Endocr Pract. 2015;21:199–204.CrossRefPubMedGoogle Scholar
  19. 19.
    Hines M, Pasterski V, Spencer D, et al. Prenatal androgen exposure alters girls' responses to information indicating gender-appropriate behaviour. Philos Trans R Soc Lond Ser B Biol Sci. 2016;371:20150125.CrossRefGoogle Scholar
  20. 20.
    Hrabovszky Z, Hutson JM. Androgen imprinting of the brain in animal models and humans with intersex disorders: review and recommendations. J Urol. 2002;168:2142–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Hines M. Prenatal testosterone and gender-related behaviour. Eur J Endocrinol. 2006;155:S115–21.CrossRefPubMedGoogle Scholar
  22. 22.
    Oliveira DE, da Cruz ML, Liguori R, et al. Neophalloplasty in boys with aphallia: a systematic review. J Pediatr Urol. 2016;12:19–24.CrossRefPubMedGoogle Scholar
  23. 23.
    Bluebond-Langner R, Redett RJ. Phalloplasty in complete aphallia and ambiguous genitalia. Semin Plast Surg. 2011;25:196–205.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    D'Hauwers KW, Feitz WF, Kremer JA. Bladder exstrophy and male fertility: pregnancies after ICSI with ejaculated or epididymal sperm. Fertil Steril. 2008;89:387–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Reiner WG. Gender identity and sex-of-rearing in children with disorders of sexual differentiation. J Pediatr Endocrinol Metab. 2005;18:549–53.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Nordenström A, Servin A, Bohlin G, Larsson A, Wedell A. Sex-typed toy play behavior correlates with the degree of prenatal androgen exposure assessed by CYP21 genotype in girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2002;87:5119–24.CrossRefPubMedGoogle Scholar
  27. 27.
    Pasterski VL, Geffner ME, Brain C, Hindmarsh P, Brook C, Hines M. Prenatal hormones and postnatal socialization by parents as determinants of male-typical toy play in girls with congenital adrenal hyperplasia. Child Dev. 2005;76:264–78.CrossRefPubMedGoogle Scholar
  28. 28.
    Hassett JM, Siebert ER, Wallen K. Sex differences in rhesus monkey toy preferences parallel those of children. Horm Behav. 2008;54:359–64.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Diamond DA, Burns JP, Huang L, Rosoklija I, Retik AB. Gender assignment for newborns with 46XY cloacal exstrophy: a 6-year follow-up survey of pediatric urologists. J Urol. 2011;186:1642–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Wisniewski AB, Migeon CJ, Gearhart JP, et al. Congenital micropenis: long-term medical, surgical and psychosexual follow-up of individuals raised male or female. Horm Res. 2001;56:3–11.PubMedGoogle Scholar
  31. 31.
    Reiner WG, Kropp BP. A 7-year experience of genetic males with severe phallic inadequacy assigned female. J Urol. 2004;172:2395–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Park W, Zwink N, Rösch WH, et al. Sexual function in adult patients with classic bladder exstrophy: a multicenter study. J Pediatr Urol. 2015;11:125.e1–6.Google Scholar
  33. 33.
    Rubenwolf P, Thomas C, Thüroff JW, Stein R. Sexual function, social integration and paternity of males with classic bladder exstrophy following urinary diversion. J Urol. 2016;195:465–70.CrossRefPubMedGoogle Scholar
  34. 34.
    Castagnetti M, Tocco A, Capizzi A, Rigamonti W, Artibani W. Sexual function in men born with classic bladder exstrophy: a norm related study. J Urol. 2010;183:1118–22.CrossRefPubMedGoogle Scholar
  35. 35.
    Baumgartner TS, Lue KM, Sirisreetreerux P, et al. Long-term sexual health outcomes in men with classic bladder exstrophy. BJU Int. 2017; doi:10.1111/bju.13866. [Epub ahead of print]
  36. 36.
    Warne GL, Bhatia V. Cultural differences and controversies about timing of management. In: Hutson JM, Warne GL, Grover SR, editors. Disorders of sex development. Heidelberg: Springer; 2012. p. 215–30.CrossRefGoogle Scholar
  37. 37.
    Wiygul J, Palmer LS. Micropenis. ScientificWorldJournal. 2011;11:1462–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Mazur T. Gender dysphoria and gender change in androgen insensitivity or micropenis. Arch Sex Behav. 2005;34:411–21.CrossRefPubMedGoogle Scholar
  39. 39.
    Bin-Abbas B, Conte FA, Grumbach MM, Kaplan SL. Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size why sex reversal is not indicated. J Pediatr. 1999;134:579–83.CrossRefPubMedGoogle Scholar
  40. 40.
    Callens N, De Cuypere G, Van Hoecke E, et al. Sexual quality of life after hormonal and surgical treatment, including phalloplasty, in men with micropenis: a review. J Sex Med. 2013;10:2890–903.CrossRefPubMedGoogle Scholar
  41. 41.
    Cohen-Kettenis PT. Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency. Arch Sex Behav. 2005;34:399–410.CrossRefPubMedGoogle Scholar
  42. 42.
    Imperato-McGinley J, Gautier T, Peterson RE, Shackleton C. The prevalence of 5 alpha-reductase deficiency in children with ambiguous genitalia in the Dominican Republic. J Urol. 1986;136:867–73.CrossRefPubMedGoogle Scholar
  43. 43.
    Shabir I, Khurana ML, Joseph AA, Eunice M, Mehta M, Ammini AC. Phenotype, genotype and gender identity in a large cohort of patients from India with 5α-reductase 2 deficiency. Andrology. 2015;3:1132–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Kang HJ, Imperato-McGinley J, Zhu YS, Rosenwaks Z. The effect of 5α-reductase-2 deficiency on human fertility. Fertil Steril. 2014;101:310–6.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Khorashad BS, Aghili Z, Kreukels BP, et al. Psychosexual outcome among Iranian individuals with 5α-reductase deficiency type 2 and its relationship with parental sexism. J Sex Med. 2016;13:1629–41.CrossRefPubMedGoogle Scholar
  46. 46.
    Tadokoro-Cuccaro R, Hughes IA. Androgen insensitivity syndrome. Curr Opin Endocrinol Diabetes Obes. 2014;21:499–503.CrossRefPubMedGoogle Scholar
  47. 47.
    Hamann S, Stevens J, Vick JH, et al. Brain responses to sexual images in 46,XY women with complete androgen insensitivity syndrome are female-typical. Horm Behav. 2014;66:724–30.CrossRefPubMedGoogle Scholar
  48. 48.
    Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab. 2000;85:2664–9.PubMedGoogle Scholar
  49. 49.
    Hines M, Ahmed SF, Hughes IA. Psychological outcomes and gender-related development in complete androgen insensitivity syndrome. Arch Sex Behav. 2003;32:93–101.CrossRefPubMedGoogle Scholar
  50. 50.
    Wilson JM, Arnhym A, Champeau A, Ebbers M, Coakley F, Baskin L. Complete androgen insensitivity syndrome: an anatomic evaluation and sexual function questionnaire pilot study. J Pediatr Urol. 2011;7:416–21.CrossRefPubMedGoogle Scholar
  51. 51.
    Minto CL, Liao KL, Conway GS, Creighton SM. Sexual function in women with complete androgen insensitivity syndrome. Fertil Steril. 2003;80:157–64.CrossRefPubMedGoogle Scholar
  52. 52.
    Fliegner M, Krupp K, Brunner F, et al. Sexual life and sexual wellness in individuals with complete androgen insensitivity syndrome (CAIS) and Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS). J Sex Med. 2014;11:729–42.CrossRefPubMedGoogle Scholar
  53. 53.
    Bouvattier C, Mignot B, Lefèvre H, Morel Y, Bougnères P. Impaired sexual activity in male adults with partial androgen insensitivity. J Clin Endocrinol Metab. 2006;91:3310–5.CrossRefPubMedGoogle Scholar
  54. 54.
    Lucas-Herald A, Bertelloni S, Juul A, et al. The long-term outcome of boys with partial androgen insensitivity syndrome and a mutation in the androgen receptor gene. J Clin Endocrinol Metab. 2016;101:3959–67.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    McCarty BM, Migeon CJ, Meyer-Bahlburg HF, Zacur H, Wisniewski AB. Medical and psychosexual outcome in women affected by complete gonadal dysgenesis. J Pediatr Endocrinol Metab. 2006;19:873–7.CrossRefPubMedGoogle Scholar

Copyright information

© Dr. K C Chaudhuri Foundation 2017

Authors and Affiliations

  1. 1.Department of Pediatric Surgery, Sri Ramasamy Memorial (SRM) Medical CollegeSRM UniversityChennaiIndia

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