Disorders of Sexual Development

 

Disorders of sexual development (DSD)

 

Human sex development is divided into three parts:

1. Chr Chromo omosom somal al sex sex — the the presen presence ce of X and/ and/or or Y chromosomes 2. Go Gonad nadal al sex sex — develo developme pment nt of the the gonad gonad into into either testis or ovary 3. Phen Phenotyp otypic ic or or anatomi anatomic c sex sex — the appe appearan arance ce of of the internal and external genitalia.

 

Disorders of sex development (DSD) conditions are divided into:

Occur due to either a genetic or environmentall disruption of the environmenta fetal sexual development pathway.

1. Se Sex x ch chro romo moso some me DS DSD D 2. 46XX DSD 3. 46XY DSD

Disruptions to: ● ● ●

Gonadal differentiation or development Sex steroid production Sex steroid conversion

●

Tissue Tiss ue utilisation of sex steroids

 

DSD may be diagnosed: 1. at birth birth with with ambigu ambiguou ous s or abnorm abnormal al genit genitali alia a 2. at puberty puberty in girls girls who presen presentt with primary primary amenorr amenorrhoea hoea or or increasin increasing g virilization.

 

Most common cause of

Sex chromosome DSD

primary amenorrhoea

● ● Chromosomal mosaicism: 45X/46XY and 45XX/46XY chimerism

●

High FSH and LH levels. Bilateral streaked gonads. Treatment: HRT

 

46XX/46XY DSD ● Defined by the presence of both ovarian tissue and testicular tissue in the one person. ● Present with ambiguous genitalia. ● The gonads can be any mix of ovary, testes and ovotestes, and the aetiology is unknown.

 

46XX DSD 46XX with:

●  Abnormal Müllerian tract tract development ● Disorder of gonadal development leading to virilisation ●  Androgen excess

 

Müllerian anomalies (Mayer-Rokitansky-Kuster-Hauser Syndrome) ●  Abnormal embryological development development of the Müllerian ducts and/or persistence of Wolffian structures: failure of fusion of the two Müllerian ducts, failure of one or both ducts to develop, or failure of resorption of the adjoining areas of Müllerian duct fusion. ● ●

1 in 200 women (subfertile or infertile women having a greater incidence) Causes: Largely unknown, genetic errors, teratogenic events, or combinations of these may contribute.

Second common cause of primary amenorrhoea

 

Normal secondary sexual characteristics: Breast and sexual hair 

Investigations: ● Ultrasound, MRI and hysterosalpingogram, laparoscopy and hysteroscopy hysteroscopy.. ● Imaging of the renal tract (e.g. by ultrasound) ul trasound) is always indicated, as 30% of women with Müllerian tract anomalies also have urogenital anomalies.. anomalies

 

(depends on the type of anomaly and the Management (depends t he presenting features): ●  Asymptomatic anomalies require no no treatment. ● Surgery is indicated for symptomatic uterine and longitudinal vaginal septa. ● Treatment : Vaginal creation (Dilatation VS Vaginoplasty) ●  Any form of menstrual obstruction requires requires surgical decompression, which will also prevent pain and endometriosis.

 

Congenital adrenal hyperplasia Occurs in an XX XX fetus  fetus due to an enzyme deficiency (usually 21 hydroxylase) in the adrenal gland. High circulating androgen levels lead to masculinising effects on the external genitalia, ambiguous genitalia, or normal looking male looking male genitalia at birth. CAH is the only DSD condition that can be lifethreatening, as unrecognised cortisol deficiency can lead to a salt-wasting crisis in the neonate.

 

46XY DSD 46XY DSD encompasses:

● Gonadal development ● Disorders of androgen synthesis or action.

 

 Androgen insensitivity syndrome (testicular feminization) ●  An XY XY fetus  fetus initially proceeding down the pathway of male fetal sexual determination with testicular development, and both AMH (ensures regression of the Müllerian duct) duct) and testosterone produced normally normally.. ● Disruption of the androgen receptor gene, inability of the body to respond to androgens, female external genitalia develop because some cells are insensitive to androgens. ● This insensitivity may be complete (CAIS), or partial (PAIS).

 

In CAIS:  An XY female with:

In PAIS (some response to androgens occur):

● Absent Müllerian structures ● Normal female genitalia ● variable vaginal hypoplasia

● Presentation is a spectrum from a normal male phenotype with infertility to ambiguous

● Absent or sparse pubic and axillary hair  ● Normal breast development ● Normal female behaviour and gender identity ● Intra-abdominal testes that produce high levels of

genitalia. ● In some cases the diagnosis is not made until puberty, when virilisation occurs.

circulating testosterone.  testosterone.  ● Treatment Treatment : gonadectomy after

 

ubert + HR HRT

Gonadal dysgenesis (Swyers syndrome) ● Disruption at the very start of the male sex determination pathway that causes an XY fetus to divert to the female the female development pathway. ● The result is dysgenetic (abnormally formed) streak gonads. ●  As these gonads produce neither neither AMH nor testosterone, the external genital development is female and the Müllerian ducts develop into the vagina, uterus and cervix.

 

 Androgen biosynthetic biosynthetic defects Present with genital ambiguity at birth. The most common are 5 alpha reductase type 2 deficiency and 17 beta hydroxysteroid dehydrogenase type 3 deficiency that are involved in androgen synthesis, leading to a variant of female external genital development. Both are autosomal recessive conditions in which an XY  fetus initially starts down XY fetus the male development pathway with normal testicular t esticular development.