Controversies of Sex Re-assignment in Genetic Males with Congenital Inadequacy of the Penis
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.
KeywordsDisorders of sex development Ambiguous genitalia Androgen insensitivity syndrome Sex re-assignment Penile length Micropenis Aphallia Penile agenesis Exstrophy Sexual function Intersex disorders
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 . 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 . 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 . 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 . 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 . 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’  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 . 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 . 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) . 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 . 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 . 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 . 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
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 .
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 . Strong androgen imprinting supports rearing as male, while weak or absent imprinting probably calls for re-assignment to female sex . 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 . 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 . Nonetheless, observation of similar phenomenon in wild monkeys invalidates any criticism against hormonal origin of toy preference . 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).
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 . As many as 80% of micropenis patients were dissatisfied with female sex assignment . Contrarily, 100% of the micropenis males reported good to fair erection and 77% maintained heterosexual relationships . 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 . Despite CIP, 92% of male exstrophy patients enjoyed masturbation, 36% could perform penetrative intercourse and 72% achieved ejaculation at orgasm . 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 . These data support male sex assignment in non-hormonal CIP.
Comparison of sex assignment in 46XY male children with non-hormonal CIP
Gender dysphoria in adulthood
Social acceptance in developing countries
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
Relatively easier †
Need for hormone replacement
May require estrogen injections at puberty
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 fair to good †
Differential diagnosis of congenitally inadequate penis in a 46XY genetic male
Pure gonadal dysgenesis
Location of urethral meatus
Suprapubic (with open bladder)
Normal / Hypoplastic
Scrotal or undescended
Scrotal or undescended
Scrotal or undescended
Labial * or undescended
Labial * or undescended
Intact but hypoplastic
Intact or partially bifid
Intact or partially bifid
Completely or partially bifid
Completely or partially bifid
Normal or slightly elevated
Normal or elevated
Normal or elevated
Elevated, very high
HCG stimulation test
Micropenis of Hypopituitary Hypogonadism
In this condition, testosterone synthesis is greatly decreased due to anterior pituitary failure. Consequently, virilization of external genitalia is inadequate . Notwithstanding impaired synthesis of testosterone, receptors capable of responding to androgens are invariably present . Testosterone supplements are shown to increase the mean penile length from 1 cm in infancy to 10 cm in adolescence . 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 .
Enzyme Deficiency Syndromes
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 . It is not known if they simply accepted or enjoyed their assigned gender.
Androgen Insensitivity Syndromes
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 . 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 . 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 . 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 .
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.
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Conflict of Interest
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Views expressed in this article reflect the author’s understanding of sex re-assignment and they do not represent any official recommendations.
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