JOURNAL PRESENTATION UROLOGY UNIT DEPT.

OF SURGERY ABUTH, ZARIA

PRESENTER: DR TELLA A.O. MODERATOR: PROF. MBIBU

CURRENT VIEWS ON EVALUATION, MANAGEMENT, AND GENDER ASSIGNMENT OF THE INTERSEX INFANT

AUTHORS: 1) CALEB P. NELSON (Fellow) 2) JOHN P. GEARHART (Professor)

Paediatric Urology Division, Brady Urological Institute, Johns Hopkins Hospital, Baltimore.

OUTLINE
INTRODUCTION INTERSEX CONDITIONS EVALUATION AND DIAGNOSIS GENDER ASSIGNMENT CURRENT MANAGEMENT OF INTERSEX LONG-TERM OUTCOME DATA FUTURE RESEARCH DIRECTIONS CONCLUSIONS

INTRODUCTION
Management of intersex is complicated by psychological, social, sexual & medical concerns. Historically, the priority has been to assign a gender quickly, and to surgically establish the gender both physically & functionally. These practices have been challenged recently by medical & ethical concerns. There is both promise & limitations of medical science in the management of these children.

INTERSEX CONDITIONS
The article focused on the most common & clinically significant intersex conditions, which can arise at the chromosomal, gonadal, hormonal, or end-organ levels.

Chromosomal and gonadal disorders

These include xsomal abnormalities like: - XXY (Klinefelters synd.) - XYY/XX males (sex reversal synd.) - XO females (Turners synd.) - Mosaic conditions (45XO/46XY), which are commonly seen with MGD These pxs often have persistent mullerian structures internally owing to absence of MIS.

 These pxs have streak gonads on one or both sides with asymmetric & ambiguous genitalia. True hermaphrodites have both ovarian & testicular gonadal tissue, with variable genitalia.

46 XY males: Incomplete masculinization

Occurs as a result of failure of virilization giving rise to male pseudohermaphrodites This can occur anywhere along the phenotypic spectrum from female to male.

 Defects of testosterone biosynthesis - Leydig cell agenesis or hypoplasia - Defects in enzymes needed to synthesize testosterone from cholesterol Impaired androgen metabolism or response - 5 -reductase def. - Complete androgen insensitivity synd. (CAIS) - Partial androgen insensitivity synd. (PAIS)

46 XX females with excessive masculinization

CAH is the most common cause of female virilization. Enzyme deficiency diverts steroid precursors into androgen synthesis, elevating fetal androgen levels. CAH causes intersex in >80% of affected genetic females.

 CAH can be due to 21-hydroxylase def. (90%); 11 -hydroxylase; 3 -hydroxysteroid DH & P450 aromatase. Other causes of androgen exposure in utero are: *maternal CAH; *androgen-producing tumour; *ingestion of exogenous androgen as medication e.g. danazol. CAH pxs can have severe disturbances in electrolyte due to low glucocorticoid & mineralocorticoid levels.

EVALUATION AND DIAGNOSIS

The intersex infant needs to be stabilized medically as some variant of CAH (salt-wasting variant) represent medical emergency. Diagnostic evaluation must be prompt and thorough in these pxs. The complex issues of gender & gender assignment should be approached more deliberately once px is stabilized. Approach to management is multidisciplinary.

CLINICAL EVALUATION
HISTORY TAKING: - Maternal & obstetric history, should focus on exposure to drugs e.g. phenobarbital. - Family history , should focus on ambiguity or abnormal puberty; sudden infant death or infertility. PHYSICAL EXAMINATION: - Fluid status shoul be evaluated including the B/P. - The external genitalia should be examined.

 - Palpation for the presence of gonads should be done. - Note the size of phalus (Normal is at least 2 cm) - Female with adrenal def. have hyperpigmented & fused labia. - The vaginal orifice should be identified & separation from the urethral meatus confirmed. Examination of the newborns in the presence of parents is advocated.

LABORATORY TESTING
The cornerstone of intersex diagnosis. Serum electrolytes should be assessed immediately. Steroid precursors ( 17-hydoxyprogesterone & pregnenolone) should be tested on 3rd or 4th day after birth. Karyotyping is recommended for the following cases: - Any infant with ambiguous genitalia - Boys with hypospadias & cryptorchidism, b/c of high incidence of MGD in affected infants.

 A range of more specific molecular & genetic tests are becoming available. These tests detect mutations in the following: - Androgen receptor; - MIS; - LH receptor; - Testosterone synthesis enz.; - 5 -red. type 2 enz.; - steroidogenesis enz. & testicular dev. genes. These tests will be central to the diagnosis of male pseudohermaphrodites.

 The adrenal-gonadal axis can be evaluated by measuring serum gonadotrophin, testosterone & DHT levels. Equivocal results can be evaluated by: -hcg & ACTH stimulation tests, which should generate a testosterone surge in infants with functional testicular tissue. MIS assay has been recently reported to be extremely sensitive indicator of functional testicular tissue. MIS is normally remains high in newborn males .

DIAGNOSTIC IMAGING
Imaging studies are used to assess internal genital anatomy & mullerian duct structures. USS is most sensitive soon after birth as the ovaries & uterus of newborns are enlarged. MRI can also identify mullerian duct structures but not 100% accurate. Retrograde genitograms can reveal the anatomy of the urogenital sinus Laparoscopy and biopsy are additional useful investigations that can be done.

GENDER ASSIGNMENT
This is a key aspect of care of intersex infants. It used to be a paradigm described as the optimal gender policy. - Based on the principle that a newborn infant can be raised in either gender following surgical reconstruction based on genital appearance & penis size. - Infant surgery was guided by technical capabilities, largely dependent on sufficient penis size. - Undervirilized males were assigned as females and underwent gonadectomy & genitoplasty. - Virilized females were maintained as females and underwent clitoral reduction & vaginoplasty.

 In recent times, some clinicians, researchers, and patient advocacy groups have argued against genital surgery on newborns. - They believe that surgery is a violation of patient autonomy, and should be postponed until the patient can consent to the procedure - This stand raises a lot of psychological issues for the parents concerned. The primary considerations in gender assignment should include: - potential fertility; - sexual function; - hormonal function; - cosmetic appearance; & psychosexual/psychological well-being.

CURRENT MANAGEMENT OF INTERSEX

Due to the serious questions which have been raised regarding the traditional management paradigm, and availability of a few data to support an alternative approach, the management strategies for some of the more common intersex conditions were thus discussed.

 MIXED GONADAL DYSGENESIS: - Most common gonadal disorder. - Genital function & gender identity are 1 considerations as fertility is unachievable. - Most pxs are raised as females & the dysgenetic gonads are removed. - More masculinized infants might be raised as males, the gonads here are managed in light of their malignant potential (probability is 40%). The options are: 1) Gonadectomy & hormone supplementation. 2) Orchidopexy & surveillance with USS + physical examination.

 46XX INFANTS: - Most are affected by CAH, and gender assignment will usually be female. - Early genital surgery in these pxs is debatable but many authorities feel that feminizing genitoplasty could be indicated for severely masculinized pxs. 46XY INFANTS: - Are affected by a broad range of conditions.

 5 -reductase deficiency: - Mgt is influenced by cultural & social factors. - Pxs are raised as females in the US & Europe. - In other places ( Dom. Rep. & Turkey), infants are routinely raised as males from birth or as females during childhood with conversion to male gender at puberty. - This mgt model may become more prevalent with the availability of topical DHT. Patients with PAIS have varying virilization, so gender assignment is based on criteria earlier outlined. Some intersex conditions like CAIS or persistent mullerian duct syndrome, present later, and gender identity is usually wellestablished at that time.

 Long-term follow up by a multidisciplinary team of Paediatric endocrinologists, surgeons, psychologists & social workers is essential. Communication about intersex conditions btw clinicians, parents, & pxs has been deficient in the past, and may still be sub-optimal. Inclusion of young intersex pxs in frank discussions, when appropriate (on the basis of age & psychosocial dev.) may help prevent anger & frustration expressed by pxs at being excluded from the decision-making process.

LONG-TERM OUTCOME DATA

High-quality clinical data on intersex outcomes are lacking. Patient-reported data have become available recently though are weakened by absence of validated instruments & participation bias. Certain guarded conclusions can be drawn from them nontheless.

GENDER IDENTITY
Some intersex pxs are dissatisfied with their sex of rearing (gender dysphoria), some have bisexual /homosexual preferences, and some convert gender spontaneously. Scober reported on 10 selected pxs from an intersex advocacy group. - Of the 8 raised as females, all preferred female sexual partners & 2 converted to male gender. Hines et al. found that adult females with CAH were less likely to express heterosexual interest or be satisfied with their gender compared with normal controls. Male-typical behaviour is more common among girls aged 5-12 yrs with CAH.

 Reiner and Gearhart reported a high rate of conversion back to male gender among fourteen 46XY pxs with cloacal exstrophy who were raised as females- indicating an important role for the androgen-exposed brain in gender identity. Adult intersex pxs commonly consider themselves to be either male or female; few support the concept of a third gender. In a group of adult 46XY with intersex: - 85% were satisfied with their sex of rearing; - 15% supported the concept of third gender - 33% believed that genital surgery for intersex should be delayed until adolescence or adulthood. Of the females with CAIS surveyed, 81% did not believe that intersex children should be raised in a third gender, and all considered themselves to be females.

SEXUAL FUNCTION
Phallus size is not the sole determinant of satisfactory sexual function or gender identity in males. Sexual satisfaction scores of 46XY adults born with intersex & severe penoscrotal hypospadias were equivalent irrespective of the gender of rearing, despite mean penile length of only 8.8cm (2.5 SD < the mean). Of a group of adult pxs with congenital micropenis raised as males: - 50% were satisfied with their genitalia in terms of their sexual function. - Reilly and Woodhouse found that 75% of adult males with micropenis were sexually active, with high grade sexual function and satisfaction and all considered themselves to be males.

 Some women who underwent clitoral reduction surgery & vaginoplasty as children before 1990 are sexually dysfunctional, and have reduced clitoral sensation and/or unacceptable cosmetic appearance. The long-term functional sexual outcomes of procedures performed since 1990 are not yet available. Clitoral T, vibration, & light touch sensation were sed in 6 adult females with CAH who underwent clitoral reduction surgery as children. Those who were sexually active reported difficulty with orgasm and intercourse.

 Of 44 adolescents who underwent feminizing genitoplasty as infants: - 41% were dissatisfied with the cosmetic appearance of their genitals and required further genital procedures. Minto and colleagues also found higher rates of sexual dysfunction & anorgasmia among intersex females who had undergone previous clitoral surgery compared with those with no surgical history. Sexual dysfunction is common among certain groups of intersex pxs, in the absence of previous genital surgery. - Among adult females with CAIS, 90% had at least one sexual problem. - Sexual function scores were similar regardless of whether pxs had undergone treatment for vaginal hypoplasia. - Another study of similar pxs found that 29% were dissatisfied with their overall sexual function.

FUTURE RESEARCH DIRECTIONS

Clinical research on intersex is difficult b/c: - The conditions are rare. - Outcomes take decades to manifest. - Stigma assoc. with disorders of gender & sexual identity that may limit participation. Ideally, multi-center randomized controlled trials will determine the optimal mgt strategies. - Ex; nonoperative mgt of severely virilized female infants could be compared with traditional feminizing genitoplasty. Long-term outcome measures could include urinary & sexual function, issues relating to gender identity and behaviour, as well as the quality of life.

 In the absence of randomized trials, much can be done to improve the quality of research: - Data need to be collected prospectively over the long term and, - Approaches must be developed to ensure persistent high levels of participation. Such prospective, well-documented cohorts would be invaluable in determining the natural history of intersex conditions. Outcome evaluation should be through patientreported, validated instruments. Such instruments must be developed, if not available.

CONCLUSIONS
Intense discussion regarding mgt of intersex conditions are ongoing but few data are available to direct changes in mgt. Further work is needed to identify the determinants of gender identity, measure the outcome of medical & surgical mgt, and determine optimal treatment strategies for the various intersex conditions. Until these are available, clinicians can only do their best to be truthful, empathic, and forthright in the care of these pxs.

OBSERVATIONS
Changes in nomenclature and definitions. - The term disorders of sex development (DSD) has been proposed in place of terms such as intersex, pseudohermaphroditism, hermaphroditism & sex reversal. - It is defined as congenital conditions in which the development of chromosomal, gonadal & anatomical sex is atypical.

Gonadal development
SRY-gene (TDF) Short arm of Y chromosome Present Absent

Bipotential Gonad
2 X chromosomes

Receptors For H -Y antigen

OVARY TESTES

Male development
Leydig cells Testosterone Sertoli cells Mullerian inhibiting factor 5a-reductase DHT Regression of Mullerian ducts Urogenital sinus Male internal Genital organs Male external genitalia

Wollfian duct

Female development

Urogenital sinus

Mullerian ducts

Female external genitalia . Lower part of vagina

Absence of androgen exposure

Female internal genital Organs . Most of upper vagina . Cervix and uterus . Fallopian tubes

Leydig-cell agenesis
46-XY/SRY TESTIS D MIF ( partial/ complete absence Of leydig-cells)

No or testosterone No or DHT
Female or ambiguous external Genitalia Male Internal Genitalia

46-XY/SRY Testis D MIF Testosterone 5-w-rductase DHT

Female or Ambiguous external Genitalia

5-alpha-reductase alphadeficiency

Male Internal Genitalia

46-XY/SRY TESTIS B MIF Testosterone

5-w-reductase DHT

Androgen insensitivity syndrome

Absent androgen receptors

Female External Genitalia Male Internal Genitalia

Incomplete form D Ambigious genitalia

Swyers syndrome
46, XY No SRY OR its receptors
STREAK GONADS - NO MIF (Uterus +) - NO SEX STEROIDS

Female external Genitalia

Female Internal Genitalia

GENITOGRAM

Congenital Adrenal Hyperplasia

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