Intersex Prepared by Professor Dr Lilyan Sersam Definition

Intersex Prepared by Professor Dr. Lilyan Sersam

Definition • Intersex is defined as mix or blend of the physically defining features associated with males or females.

Incidence The incidence is unknown, but has an estimated prevalence of 1 in 2000.

Presentation • • • Adolescence/adulthood: Pelvic mass with gonadal tumour. Primary amenorrhoea. Delay in puberty. Sexual dysfunction. Infertility.

Investigations • • • Karyotyping LH FSH Testosterone 17 -hydroxyprogesterone Oestradiol Androstenedione HCG stimulation test Synacthen test Ultrasound (Pelvic, Renal) MRI

Management • An early and correct diagnosis is paramount. • Involvement of a multidisciplinary team, this team should consist of an endocrinologist, psychologist, gynaecologist and surgeon. • Consideration of sex of rearing and of cosmetic genital surgery are assigned where appropriate.

Clinical Disorders

Congenital adrenal hyperplasia (CAH) (46 XX)

Congenital adrenal hyperplasia • This is the most common cause of female intersex, with an incidence ~ 1: 14 000 births. • It is an autosomal-recessive condition of enzyme defects in the adrenal steroidogenesis pathways. Ninety-five % is due to deficiency of 21 -hydroxylase in the adrenal gland, with 5% being caused by 11ß-hydroxylase deficiency.

The enzymatic defects in the adrenal steroidogenesis pathways lead to: • Cortisol deficiency. • ↑ACTH secretion with build up of cortisol precursors. • ↑androgen production. • If severe, aldosterone production is also affected leading to salt wasting

Clinical features of CAH • There is wide spectrum of presentation including: • Neonatal salt wasting crisis and hypoglycaemia. • The commonest cause of ambiguous genitalia at birth, responsible for up to 50% cases (ranges from mild clitoral enlargement to a near normal male appearance. • Childhood virilization, accelerated growth with early epiphyseal closure → restricted final height. • Late-onset with hirsutism and oligomenorrhoea.

Congenital adrenal hyperplasia Diagnosis • Karyotyping • Measurement of 17αhydroxyprogesterone in blood, which will be elevated in 21 -hydroxylase deficiency. • Estimation of electrolytes to check the possibility of a salt-losing syndrome, and if saltlosing state is present, sodium and chloride may be low and potassium is raised. • Pelvic ultrasound to discover the presence of a uterus and vagina.

Diagnosis • Is made by detection of elevated plasma 17 -hydroxyprogesterone levels and 24 hour urinary steroid analysis.

Investigations for ambiguous genitalia at birth: • Full assessment looking for evidence of lifethreatening salt-losing crisis including hypovolaemia and hypoglycaemia. • Urea and Electrolytes should be sent urgently. • Urgent serum 17 -hydroxyprogesterone. • 24 hour urine collection for steroid analysis. • Karyotyping. • Ultrasound to locate gonads and presence of a uterus. • Further investigations as deemed appropriate.

Management • A multidisciplinary approach by paediatric urologists, endocrinologists, psychologists, and gynaecologists is required. • Treatment: Replacement glucocorticoid to suppress ACTH and decrease excess androgen production. • Salt-losing CAH requires fludrocortisones to replace aldosterone. • Antiandrogens may be used to combat the effects of raised androgens with lower doses of glucocorticoids

Management • Surgery for ambiguous genitalia (feminizing genitoplasty). • Clitoral surgery is deferred until puberty especially in mild or moderate cliteromegaly.

Turner Syndrome

Turner Syndrome • Complete or partial absence of one X chromosome (45 XO). • occurring in 1 in 2, 500 live female births. • The gonads are called ‘streak gonads’ and do not function to produce oestrogen or oocytes. • A mosaic karyotype is not uncommon, leading to a variable presentation.

Clinical features of Turners syndrome

Turner Syndrome • Usually, the diagnosis is made at birth from the clinical appearance of the baby or in early childhood due to short stature. • In about 10% of women, the diagnosis is not made until adolescence with presentation of delayed puberty. • The ovaries do not produce oestrogen, so the normal physical changes of puberty cannot happen. • In childhood, treatment is focused on growth, but in adolescence it focuses on induction of puberty. • Pregnancy is only possible with ovum donation. Psychological input and support is important. • In girls with mosaicism the clinical picture can vary and normal puberty and menstruation can occur, with early cessation of periods.

Androgen insensitivity syndrome (AIS) (46 XY DSD)

Androgen insensitivity syndrome • Previously known as testicular feminization syndrome. The condition is caused by mutation in the androgen receptor gene causing resistance to androgens in the target tissues: • In the embryo the testis develops normally but the testosterone-dependent Wolffian structures do not. • AMH is still secreted by the fetal testis, so regression of the Müllerian structures also occurs.

Androgen insensitivity syndrome • It is an X-linked recessive pattern in 2/3 of cases. • It can be complete (CAIS) or partial (PAIS) depending on the amount of residual receptor function. • It is the commonest form of undermasculinization in an XY individual.

Androgen insensitivity syndrome • → Clinical features of AIS: (46 XY but appear female) • • Phenotypically appear female. Normal female external genitalia. Blind-ending vagina. Absent uterus, cervix and fallopian tube. Scant to absent pubic and axillary hair. Testes may be located in the abdomen or inguinal region. Normal to large female breast development: Tanner stage II, areola are often pale and underdeveloped.

Diagnosis: • Prenatally fetal karyotype XY does not match female ultrasound findings. • After birth inguinal hernias or labial swellings are found to contain testis. • At puberty breast development is normal, pubic and axillary hair are scanty or absent, and menstruation fail to occur. • Testosterone levels are in the normal male range and oestrogen levels are where normal male and female levels overlap. • Imaging: US, CT and MRI may help to identify location of testes and uterine absence.

Management: • Lifetime risk for developing testicular cancer is thought to be about 2% and there is no need for immediate gonadectomy • If CAIS is diagnosed before puberty the testes may be left in to allow natural puberty without the need for HRT in a child. • After puberty: gonadectomy should be considered, HRT with oestrogens should be implemented, BMD should be checked, once sexual activity is anticipated vaginal lengthening with the use of dilators and if dilators fail to help then consider vaginoplasty.

End-organ insensitivity (5 -Alpha-reductase deficiency) (46 XY)

End-organ insensitivity (46 XY) • This is an autosomal-recessive condition results in the development of normal Wolffian structures and regression of Müllerian structures due to normal production of MIS. Testosterone is converted to dihydrotestosterone via the enzyme 5α-reductase and it is thought that a deficiency in this enzyme leads to endorgan insensitivity. Poor masculinisation of genital organs is present at birth.

• Initially, these patients are assigned as a female, however after puberty high levels of testosterone lead to virilisation to an extent that the patient may wish to change their gender. Even the penis size tends to remain barely adequate. • Early diagnosis and gender assignment in individual cases is the management of choice. • h. CG stimulation of the gonad for 3 days followed by a measurement of testosterone levels will confirm the diagnosis.

46 XY gonadal dysgenesis

46 XY gonadal dysgenesis • In the absence of activation of the sexdetermining region of the Y chromosome, testicular development is halted and the result is female development in the male. The resulting gonad is dysgenetic and is streaked. • In bsence of anti-Müllerian hormone (AMH), the Müllerian structures do not regress and the uterus, vagina and Fallopian tubes develop normally.

• These patients will develop a normal uterus and hair growth, but will present with primary amenorrhoea and poor breast development. • The biochemical picture will reveal raised gonadotrophins with low testosterone and oestrogen. • Gonadectomy is recommended due to high risk of malignancy and hormone replacement therapy with oestrogen and progesterone will lead to menstruation. • Donor oocytes can lead to pregnancy.

True hermaphroditism (Ovotesticular DSD)

True hermaphroditism • Rare in Europe and USA, a higher prevalence is seen in Africa. The gonads may be a varying mix of testis and ovary. They present with differing degrees of sexual ambiguity. The degree of masculinisation is thought to be due to the proportion of testicular tissue.

True hermaphroditism • The karyotype is commonly 46 XX, with some having a mosaic XX/XY and fewer having 46 XY. Gender assignment may be difficult and should be ascertained on an individual basis. Sex of rearing is determined on the functional capability of the external genitalia, after which inappropriate organs are removed. Eighty percent have female organs and are potentially fertile.