Normal and abnormal sexual development

كلية الطب ? جامعة بابل المرحلة الخامسة
د-نسرين مالك

Gynaecology

Normal and abnormal sexual development

Sexual differentiation and normal subsequent development are fundamental to continuation of human species .
Following fertilization, the human embryo will differentiate into a male (XY) or a female (XX) fetus, and subsequent development is genetically controlled.

The sexually undifferentiated embryo contains both Wolffian and Mullerian ducts. The Wolffian ducts have the potential to develop into the internal organs of the male , and the Mullerian ducts into the internal organs of the female. If the testis produces Mullerian inhibitor, the Mullerian ducts regress.

The testis differentiates into two cell types Leydig cells and sertoli cells. The sertoli cells responsible for the production of Mullerian inhibitor , which leads to Mullerian regression. The Lydig cells produce testosterone, which promotes the development of the Wolffian duct , leading to the development of the vas deferens, the epididymis and the seminal vesicle.






Testosterone by itself dose not have a different effect on the cloaca; in order to exert its androgenic effects, it needs to be converted by the cloacal cells through the enzyme 5-alfa-reductase to dihydrotestosterone. These androgenic effects lead to the development of penis and the scrotum.

The absence of a Y chromosome and the presence of two X chromosomes mean that Mullerian inhibitor is not created, and the Mullerian ducts persist in the female. The absence of testosterone means that th Wolffian ducts regress, and failure of androgen to affect the cloaca leads to an external female phenotype.
So the factors that determine sex are :-
1- Chromosomes:- (XX or XY) The embryo differentiation is controlled by sex chromosome.
The short arm of Y chromosome contains SRY gene (sex-determining region on Y) the protein product of this gen called testis determining factor ( TDF), will induce the development of testes .
if SRY-gene is deficient, then there will be no testicular formation.

2- Testicular formation:- Once the testes are formed, androgen will be produced, the testosterone is important for the development of the male internal genital organs(Wolffian duct) , and male external genitalia. Androgens are secreted by the effect of enzymes at 16-20 weeks of gestation, if not, there will be regression of the Wolffian, and formation of female external genitalia (genetically male but phenotypically female), the testis has anti-Mullerian factors, and this will cause degeneration of Mullerian system.
3- End- organ response:-Failure of receptors or insensitivity of end organs may cause the phallus to be small, and there will be failure of scrotal development .
As failure occurs ,we may see a phenotypically female with XY chromosomes (genetically male), also fails to produce seminal fluid or sperms (no spermatogenesis).
Pseudohermaphrodite:- Is an individual with the genetic constitution and gonads of one sex and the genitalia of the other.
Female pseudohermaphrodite :- An individual with XX chromosomes, ovaries ,and has male external genitalia.
Male pseudohermaphrodite :- An individual with XY chromosomes, testes ,and has female external genitalia.
True hermaphrodite:-The condition in which the individual has both ovaries and testes, is probably due due to XX/XY mosaicism and related mosaic patterns. and varying degrees of virilization of the external genit genitalia.
Intersex :-
An individual with ambiguous genitalia( neither a male , nor a female).

Intersex disorders either:-

A- Early presented (child with ambiguous genitalia ).

B- Late onset presentation (at puberty).

1-Genetically female (XX) with ambiguous genitalia:-






In female , the external genitalia may be virilized , giving a masculine appearance. This is the most commonly seen in a condition known as congenital adrenal hyperplasia(CAH). In this condition, an enzyme defect in the adrenal gland usually 21-hydroxylase deficiency (which account for 90? of cases of CAH) this is result in a failure of conversion of 17?-hydroxyprogesterone to desoxycortisol, and also failure of conversion of progesterone to desoxycorticosterone. Two other enzyme deficiencies are recognized, although less common : 3?- hydroxysteroid hydrogenase deficiency , and 11? - hydroxylase deficiency. Failure of production of cortisol means that there is positive feedback mechanism on the hypothalamus leads to an elevation of adrenocorticotrophic hormone (ACTH).This in turn stimulate the adrenal gland to undergo a form of hyperplasia, and the excessive production of progesterone and its precursor (17? -hydroxyprogesterone) ,which is therefore converted to the androstenedione and subsequently to testosterone( means that the adrenal gland produces excessive amount of androgen).
This androgen enters the fetal circulation and impacts on the developing cloaca, thereby leading to virilization.
The female child is then born with a degree of phallic enlargement(clitoral enlargement and the excessive fusion of the labial folds) , and the lower part of the vagina may be obliterated by the development of a male- type perineum and hence a vaginal orifice is not apparent. This also occur if the fetus is exposed to androgen in an androgenic drugs ingested by the mother or, in many cases the virilization is idiopathic.
In some infants with CAH, a dangerous salt-losing syndrome may arise because of the associated aldosterone deficiency and the child die of wasting and vomiting within a few weeks of life if the diagnosis is not appreciated.
Congenital adrenal hyperplasia may firstly presented at puberty as increase virilization of external genitalia and /or amenorrhoea due to high androgen that cause ovulation inhibition.

2-Male (46 XY) with intersex disorders :-

















Anatomical testicular defect Testicular
enzymatic failure End organ insensitivity
Causes:-
1-True gonadal dysgenesis.

2-Atrophy of the testes due to viral infection or thrombosis (vanishing testis).

3-Mutation at site of short arm of chromosome Y lead to TDF deficiency (XY gonadal agenesis).

SO testicular absence lead to:-
No testosterone, MIS absent

This will result in :-
Wolffian duct regretion, female phenotype with tube , uterus,vagina with some masculization usually not need surgical correction.

Treatmeant:-
Remove the gonads streaks because malignancy risk is 30 per cent, estrogen and progesterone replacement at puberty for sexual characteristic development. The testes present ,but there is a defect in testosterone production.


This result in:-
1- Absence of male internal organs (Wolffian duct regression).
2-Under mascularised (ambiguous genitalia) due to incomplete testosterone deficiency.
3- MIS present so Mullerian duct regress ( no tube, uterus, or vagina)
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Sex of rearing depend on the degree of mascularization, but usually female role the chosen one. 5 alfa reductase deficiency Complete androgen insensitivity
There is failure of conversion of testosterone to dihydrotestosteron (which is biologically active), because of 5 alfa reductase deficiency

This will result in:-
Female phenotype.
But has male internal organs.(because the internal organs development depend on testosterone)

At puberty excess androgen production may lead some verillization ,and the patient may wish to change gender role ,but female role is appropriate.


Is familial condition
inherited as autosomal recessive
( inherited as autosomrecessive) There is androgen insensitivity due to absence of androgen receptors .


This will result in:-
1- Female phenotype.

2- No male internal organs(due to receptors absence)

3- MIS present ,this will lead to Mullerian duct regression ( no tube, uterus, or vagina).

4- Patient at puberty has good breast development, due to conversion of excess androgen to estrogen, there is absent or scanty axillary and pubic hair, and primary amenorrhoea.
Treatmeant:-
In child nothing done until the time of puberty when feminization occur at that time ,then remove the testes ,as the risk of malignancy after puberty is 5 per cent.

True hermaphrodites :
Is the presence of testicular and ovarian tissue in the same individual .
Most of hermaphrodites are XX female 58 ?. Some are XY mosaicim 46 XX\XY
46XX\47XXY
Or other mosaics



The combination of gonads will determine the degree of virilization: the greater the testicular component, the more virilized the resulting development and the more likely the presence of Mullerian inhibitor.
Thus in the true hermaphrodites, it is possible to get co-existent Mullerian and Wolffian structures in term of internal development, and varying degrees of masculinization of the external genitalia, depending on the combination of gonads.
The initial evaluation of the child with ambiguous genitalia:-
History:-The history in a child with ambiguous genitalia should include the following information: Prenatal exposure to androgens (eg, progesterones, danazol, testosterone) or endocrine disrupters (phenytoin, aminoglutethimide), maternal virilization in pregnancy (placental aromatase deficiency, luteoma of pregnancy, in which there is solid bilateral tumor stimulating theca cells, which is potentially masculizing tumor affecting both mother and fetus) , family history of unexplained infant deaths (congenital adrenal hyperplasia), history of consanguinity or homogeneous population (recessive disorders, eg, CAH, 5-alpha-reductase deficiency)
Physical examination :-The physical examination should include careful inspection and palpation of the genitalia. Palpation of the uterus may be possible through a combination of gentle rectal examination with the examiner s fifth digit and suprapubic pressure with the examiner s other hand. The presence or absence of a uterus must be confirmed radiographically
Investigations:-
The initial evaluation of the infant with ambiguous genitalia should include assessment of anatomy, adrenal steroid secretion, and sex chromosomes.
?For assessment of the anatomy:-
A-Radiological studies:-1-Ultrasonography of the abdomen and pelvis can help to determine the presence of gonads, uterus, and/or a vagina.
2-Retrograde urethrogram may be necessary to visualize the urethral and vaginal anatomy. 3-MRI. B-Laproscopy.
?Hormonal study:- As pituitary hormones( LH, FSH, ACTH,) and the level of cortisol and testosterone.
?Chromosomal study:-
The results of the peripheral blood karyotype permit classification of the infant into one of three diagnostic categories, which determine further evaluation:-
1- XX with virilization 2- XY with undervirilization 3 -Mixed sex chromosome pattern
Fluorescence in situ hybridization (FISH) using sex determining region of Y chromosome(SRY) specific probes can be useful in clarifying the results of the karyotype.
How to deal with a patient has abnormal sexual development:-
1- The first problem is that the parents came for naming and sex of newborn.
the parents should be informed of the uncertainty about the sex their newborn, and an explanation given that baby should not be named or registered until the correct sex can be determined.
About 90 ? are known within 48 hours , and the true answer is at 6 weeks (chromosomal study).
In the first 48 hours do Barr body from the buccal smear, if Barr body is + ve then the baby is XX ,or
XY mosaicim ( 46 XX\XY, 46XX\47XXY ) ,but if it is –ve ,may be XY or XO (turner`s syndrome in which there is a complete female but there is ovarian failure , this female usually has normal female genitalia unless there is excess of androgen which lead to ambiguous genitalia).
The baby will come into one of three categories:-
? In adequate virilized genetic male like partial or complete end organ insensitivity to dihydrotestosterone or inadequate testosterone production.
? Musculinized genetic female like in congenital adrenal hyperplasia syndrome, or excess maternal androgen during pregnancy.
? True hermaphrodite.
2- If we find a virilized female ,measure serum electrolytes, serum cortisol and testosterone , and U\S to see the internal organs, to diagnose cogenital adrenal hyperplasia syndrome, which is dangerous syndrome and need immediate treatment by cortisol ( life saving).
If the condition passed ,treat the child with estrogen to stop androgenic effect , and when get older correct the anatomical defect ( if there is fused labia ).
3- Most of the patients come at the age of 5-7 years, for those patients do full investigations, and full chromosomal study by culturing lymphocytes.
We can do laproscopy to see the gonads and biopsy may need to be taken ( we may find ovotestis in which there is both types of tissues on biopsy).
After that we consult the parents and the patient properly and do estimation to which pattern the patient is nearer ( male or female ) .
If the patient has big phallus with lack of androgen ,we may help by giving androgen. If a genitalia is too small ,it difficult to make phallus, so in this patient it is easier to make a female than male ( correction not always go with the chromosomal pattern) because it is easier to make a functioning vagina than making a functioning phallus.