Sexual differentiation:

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1 Abnormal Development of Female Genitalia Dr. Maryam Fetal development of gonads, external genitalia, Mullerian ducts and Wolffian ducts can be disrupted at a variety of points, leading to a wide range of conditions with large spectrum of clinical manifestation. Disorders of sex development (DSD) occur when w there is a disruption of either gonadal differentiation or sex steroid production or action. Disruption of embryological development leads to Mullerian & Wollfian ducts anomaly. Sexual differentiation: Differentiation of fertilized embryo into male or female fetus is controlled by the sex chromosomes. All normal fetuses have an undifferentiated gonad which has the potential to become either a test or ovary. In addition, all fetuses have both Mullerain and Wollfian ducts and the potential to develop male or female internal or external genitalia. The chromosomal complement of the zygote determines whether the indifferent goand becomes a testis or an ovary. Presence of SRY (sex determining region of the Y chromosome) causes the bi-potential gonad to begin development into testis. In the past, ovarian development was considered to be due to absence of SYR, however, recently ovarian determining genes have also been found. Development of the gonad to the testis leads to production of two hormones that is anti Mullerian hormones that suppresses development of the Mullerian ducts and testosterone that stimulates the Wollfian duct development to internal genitalia, and by its conversion to dihydrotestosteron will leads to virilization of external genitalia. Where the gonad becomes an ovary, the absence of AMH allows the Mullerian structure to develop. 1

2 Standard female pathway: The presence of the ovary is not required for regression of Wolffian duct, and it is the absence of local testosterone that causes their regression. Also the absence of testosterone leads to an absence of peripheral DHT and directs the genital tubercle, urogenital sinus, urogenital folds and labioscrotal swelling to develop into clitoris, lower vagian, labia minora and labia majora, respectively. As the AMH is not produced by fetal ovary, the Mullerian ducts continue to develop. The cranial ends of the Mullerian ducts are independent of the Wolffian duct and remain separate as the fallopian tube. At 8-10 weeks, the pelvic part has fused and subsequent breakdown of their medial walls leads to a single tube, which will become the upper vagina, cervix and the uterine epithelium and glands. At the caudal end, the fused Mullerian ducts form the Mullerian tubercle which connects to urogenital sinus that develops into the paired sinivaginal bulbs and form vaginal plate which later on canalize. Disordered sex development: DSD are conditions where the sequence of events for normal sex development will not occur. This could be at the level of: a- Chromosome. b- Gonads. c- Anatomical. 2

3 Anatomical abnormalities: Mullerian anomalies: These are common and are associated with renal tract anomalies in 30% of cases. Incidence: These occur in up to 6% of female population, the incidence is higher in sub fertile women. The most common are sepatate and bicornuate anomalies. Etiology: The cause of Mullerian anomalies is unknown; they may be due to genetic errors, teratogenic events, or a combination of theses. Only a minority of cases appear to have a family history, its assumed that there has been failure of fusion of the two Mullerian ducts, failure of one or both ducts to develop, or failure of resorption of the areas of Mullerian duct fusion. The cause of transvers vaginal septae is unknown. Mullerian obstruction: Failure of complete canalization of the Mullerian structures can lead to menstrual obstruction. The obstruction most commonly occurs at the junction of the lower third of the vagina at the level of the hymn, although more proximal obstruction can occur. Such failure will lead to the formation of vaginal septae and these may be horizontal septae, vertical septae or the vagina may be absent. 1-Transvers septae. Usually this presents with imperforated hymn, there may be primary amenorrhea with increasing cyclical abdominal pain in a girl early in adolescence, usually there is history of previous cyclical abdominal pain over the last few months. Some time the patient may present with urinary retention. The retained menstrual blood stretches the vagina causing haematocolpus. This can cause a large pelvic mass and in addition can usually be seen as a bulging membrane at the vaginal entrance. Sometime this will be presented in neonatal life as a mucocolpos. 3

4 Treatment: If obstruction is caused simply by the hymen (blood looks blue behind it) then a cruciate incision,usu. under anesthesia with drainage of blood,is all that is required. If the septum looks pink rather than blue the situation is potentially more serious and should be referred to a specialist surgeon. If the septum is in the low or midportion of the vagina, total excision and re-suturing is necessary. If the septum is high, a combined abdominal and vaginal approach may be required. Pregnancy rates are excellent with low septae, but only around 25% for those higher in the vagina. 2-Vertical septae. These may be associated with abnormal uterine development. Although presentation may be with dyspareunia or infertility, they may occasionally present in advanced labor. They can be surgically removed. 3-Vaginal atresia. This is associated with an absent, or only a rudimentary, uterus & is known as the Rokitansky syndrome (also called Mayer-Rokitansky-Hauser- syndrome). This condition is agenesis or hypoplasia of the vagina and uterus. The uterus is either absent or consist of small central rudimentary bud. The cause is unknown Presentation is at puberty with amenorrhoea (or cryptomenorrhoea) in the presence of normal secondary sexual characteristics. Investigation is as for primary amenorrhea and renal tract should be cheked because of associated 40% renal tract anomalies. Intersex should be excluding. Management: psychological support to accept the diagnosis and understand that they can establish relationship. Then intervention to help creates or enlarges the vagina by surgical vaginoplasty and self-applied vaginal dilatation therapy to improve sexual function. Uterine transplant is not studied until now fertility may be improved by surrogacy. It is possible to create a vagina with regular use of vaginal dilators, or by one of a variety of surgical techniques. Surrogacy is an option for childbearing. 4

5 Mullerian duplication or fusion anomalies: Duplication of Mullerian system can occur resulting in a wide range of anomalies, usu. of the uterus. It may be a complete duplication of the uterus, cervix & vagina. Types: a- Bicornuate uterus: if the corneal part of the uterus remains separate, it will give rise to heart-shaped appearance known as bicornuate uterus. There is no evidence that such minor degrees of this defect give rise to clinical feature or it only give rise to features of menstrual dysfunction like oligomenorrhoea, dysmenorrhoea or menorrhagia. However, the presence of a septum extending over some or all uterine cavity is likely to give rise to clinical features like recurrent miscarriage, malpresentation, persistent transverse lie in late pregnancy and preterm labor. A 'Strassman' procedure will correct the defect, but the benefits for pregnancy are unproven. A bicornuate uterus may be asymmetrical with one side hypo plastic Pregnancy in the hypo plastic horn carries a risk of rupture. b- -Unicornuate uterus. With this there is a higher miscarriage rate and risk of preterm labor. c- Uterine didelphys: complete duplication of the uterus and cervix (didelphys0, if associated with clinical problem, may prevent descent of the head in late pregnancy, or obstruct labor by the non-pregnant horn. d- Rudimentary horn: development of one horn may give rise to a very serious situation if the pregnancy is implanted there. Rapture of the horn with profound bleeding may occur as the pregnancy increase in size. The clinical picture will resemble that of ruptured ectopic pregnancy, with the difference that the amenorrhea will probably be measured in month rather than weeks. Vulval anomalies: Rarely, anomalies in the development of bowel or bladder may give rise to considerable abnormalities in the appearance of the vulva. Bladder exstrophy will give rise to bifid clitoris and anterior displacement of the vagina. Wolffian duct anomalies: Remnant of the lower part of the Wolffian duct may be evident as vaginal cysts, whereas remnants of the upper part are evident as thin-walled cysts lying within the layer of broad ligament (paraovarian cysts), they may cause dyspareunia. 5