Genital ambiguity is caused by a defect in the process of foetal sexual differentiation. Normal sexual differentiation follows a sequential pattern from fertilisation to gestation. Each subsequent step depends on the preceding one and any aberration along the way results in disorder of sexual development.
Genetic sex/Genotype:
Egg 23X
Sperm 23X or 23Y
Male genotype 46XY
Female genotype 46XX
Genital ridge becomes testis or ovary.
Germ cells populate undifferentiated gonads.
Two sets of internal sex ducts appear: Mullerian/Paramesonephric duct and Wolffian/Mesonephric duct.
Bipotential external genitalia.
The presence of TDF (Testis determining factor) encoded by the SRY (Sex determining region located on short arm of Y chromosome) gene provides the signal for testicular development and the primitive gonad/genital ridge differentiates into:
Sertoli cells at approximately 6 weeks, which secrete MIS/MIF (Mullerian inhibiting substance/factor)
Leydig cells after 7 weeks, which produce testosterone
The absence of the Y chromosome results in the differentiation of the gonads into ovaries at around 11-13 weeks. The ovarian hormone is thought to play no role in phenotypic sexual differentiation.
This involves 2 major structures: the development of internal sex ducts (Mullerian/Paramesonephric duct and Wolfian/Mesonephric) and external genitalia.
Male Phenotype
In the male, MIS/MIF, a peptide hormone encoded by a gene at the tip of the short arm of chromosome 19, is produced first by the foetal testis (primitive sertoli cells). This induces an almost complete regression of the Mullerian duct (remnant - appendix testis, prostrate utricle). The second substance, testosterone, is produced by the Leydig cells of the foetal testis under the influence of placental/maternal hCG.
Testosterone works:
a) within the testis to promote maturation of spermatogonia
b) beyond the testis, to regulate development of the male phenotype by paracrine and endocrine actions.
Paracrine action influences the wolfian/mesonephric duct to differentiate into the epididymis, vas, ejaculatory duct and seminal vesicles. In the absence of testosterone the mesonephric duct involutes.
Endocrine action allows testosterone to enter the cells of target organs where it is converted to dihydrotestosterone (DHT) by the enzyme 5-alpha reductase.
DHT binds with androgen receptors to form the DHT-Receptor complex. This complex induces the final effect for the male phenotype, in particular virilization of external genitalia and urogenital sinus (male urethra). The androgen receptor gene is located near the centromere on the long arm of the X chromosome.
Virilization is complete by the 12th week. In the following two trimesters a 10-fold increase in the size of the penis occurs and the testes descend. Testicular descent occurs in two phases, the first prompted by MIS and the second under the stimulus of testosterone. Both influences are mediated via the gubernaculum.
Female Phenotype
In the absence of MIS the mullerian/paramesonephric duct persists and develops into the ovarian/fallopian tube, uterus, cervix and upper vagina. In the absence of testosterone, the wolfian duct involutes and the urogenital sinus and external genitalia develop into bladder, urethra, lower portion of vagine and clitoris.
Secondary sexual characteristics entirely depend on post-natal endocrine influence.
The most comprehensive and widely recognised classification was proposed by Allen (1976):
| Ovary only |
- Female pseudohermaphrodite |
| Testis only |
- Male pseudohermaphrodite |
| Ovary + Testis |
- True hermaphrodite |
| Testis + Streak gonad |
- Mixed gonadal dysgenesis |
| Streak + Streak gonad |
- Pure gonadal dysgenesis |
This is the most common type and forms 60-70% of all intersex cases presenting during the neonatal period.
| Genotype/Karyotype: |
46XX, SRY/TDF gene negative |
| Phenotype/Genitalia: |
Ambiguous, from minimal clitoral enlargement to apparent complete virilization/masculinization |
| Prognosis: |
Excellent when raised as female
Attainment of normal female characterisitics
Sexual activity and reproductive capability |
| Cause: |
Exposure to endogenous or exogenous androgens
1) Congenital adrenal hyperplasia
2) Transplacental androgens (rare) |
Congenital adrenal hyperplasia/Adreno-genital Syndrome
Autosomal recessive inheritance, 1:10000 live birth.
Six types of CAH exist, but only types I - IV are virilising causing female pseudohermaphrodites.
| Type I |
21-Hydroxylase deficiency in zona fasciculata
Increased production of 17-hydroxy-progesterone
Block in cortisole production |
| Type II |
21-Hydroxylase deficiency in zona fasciculata & granulosa resulting in a deficiency of aldosterone causing salt & water loss |
| Type III |
11-Hydroxylase deficiency. There will be an accumulation of androgens, 17-hydroxy-progesterone and 11-deoxy-corticosterone (potent mineralcorticoid action). The result is salt & water retention/hypertension. |
| Type IV |
3-Hydroxy-steroid dehydrogenase deficiency. Survival is rare due to more proximal enzymatic block. Virilization is not sever due to accumulation of weak androgen Dehydro-epi-androsterone (DHEA). |
All CAH patients require cortisole treatment - 50mg/m2 Hydrocortisone I.V. as bolus followed by maintenance treatment. Regular monitoring of BP/electrolytes is also needed.
Trans-placental androgen exposure/maternal androgen exposure
This is rare and may occur in babies of mothers with virilizing ovarian or adrenal tumour. In the past progestational agents with androgenic side effects were given to pregnant women to prevent abortion. These are not given anymore.
This is the most diverse type.
| Genotype/Karyotype |
46XY with testis exclusively |
| Phenotype/Genitalia |
Caused by defective virilization
Variable degree of feminisation
Male - Ambiguous - Female |
Aetiology
Inborn errors of testosterone biosynthesis
3-beta Hydroxy-steroid dehydrogenase (3 beta HSD) deficiency
17-Hyroxylase (17OH) deficiency
17,20-Desmolase deficiency
17-beta Hydroxy-steroid dehydrogenase (17 beta HSD) deficiency
Leydig cell aplasia/hypoplasia - LH Receptor defect
5-alpha Reductase deficiency
Due to autosomal recessive inheritance. DHT is mandatory for virilization of external genitalia. There can be severe perineo-scrotal hypospadias in the new-born. At puberty there is some virilization due to low affinity of receptor for testosterone. The diagnosis is based on the ratio of testosterone to DHT.
Androgen-insensitivity syndrome - androgen resistance at the receptor to complete androgen resistance and complete testicular feminisation. Also known as Morris syndrome.
It occurs in 1:20000 to 1:64000 male births. At birth the child shows normal female external genitalia, but there is a blind vaginal pouch and no uterus. At puberty there are normal breasts with scanty or no pubic axillary hair. Presentation is usually at puberty with primary amenorrhoea or undescended testis as inguinal hernia. The assigned gender is female after vaginoplasty and orchidectomy.
Incomplete androgen resistance - incomplete testicular feminisation
Also known as Reifenstein syndrome and it occurs in 1 in 10 of the complete form (Morris syndrome). It has an X-linked pattern of inheritance.
| Genotype/Karyotype: |
46XY with exclucsively testis (undescended) |
| External genitalia: |
Ambiguous as lesser defect of virilization.
Small phallus
Variable labio-scrotal fusion |
| Puberty: |
Some virilization, some feminisation
Normal pubic/axillary hair
Gynaecomastia |
| Assigned gender: |
Depends on degree of genital ambiguity
May be growth response to androgen stimulation in time
Usually in favour of female gender assignment |
Isolated MIS/MIF activity deficiency - persistent mullerian structures
Hernia uteri inguinalis (uterus and fallopian tubes in inguinal hernia)
| Genotype/Karyotype: |
46XY with testis (usually undescended) |
| Phenotype: |
Male
Potentially fertile |
This type forms less than 10% of intersex states.
| Genotype/Karyotype: |
46XX (60-70%)
46XY
46XX/XY (mosaic) |
| Phenotype/genitalia: |
Variable
Female with clitoromegaly to male with hypospadias, bifid scrotum |
| Gonads: |
Ovary + testis 30%
Ovary + ovotestis 30%
Bilateral ovotestis 20%
Ovotestis + testis 10%
Unilateral ovotestis 10%
Uterus is almost always present - may be hypoplastic/unicornuate |
| Gender assignment: |
If diagnosed in the infant - according to anatomical finging.
If diagnosed in older patient - where gender is establised contradictory gonads should be removed (risk of tumour).
More emphasis now on underlying genetic make-up. |
This type is the second most common intersexuality in neonates.
| Genotype/Karyotype: |
46XY/45XO mosaic |
| Phenotype: |
Variable - ambiguous or female |
| Gonads: |
Testis - both sertoli and leydig cells, no germinal cells
Streak gonad |
| Gender assignment: |
Female - requiring gonadectomy, clitoroplasty, vaginoplasty |
There is a 15-25% risk of malignancy of streak gonad - Gonadoblastoma, Dysgerminoma
There is no sexual ambiguity neonatally
| Genotype/Karyotype: |
Variable
46XX, 46XY - present with primary amenorrhoea an delayed secondary sex characters
45XO - with typical Turner syndrome appearance |
| Phenotype/Genitalia: |
Female - sometimes clitoral hypertrophy
Sexual infantilism during adolescent/puberty |
| Gonads: |
Bilateral undescended streak gonads and underdeveloped mullerian derivatives
46XY - high gonadal cancer risk |
Klinefelter syndrome
Male with small firm testis, impaired sexual maturation, azoospermia, gynaecomastia (in 50%) and elevated levels of urinary gonadotrophins.
| Karyotype: |
47XXY
46XX/XXY or other variation of additional X make up
Chromatin as well as H-Y antigen positive |
| Gonads: |
Testis - normal histology at birth
Drastic germ cell loss during adolescence |
| Presentation: |
Infertility, sexual infantilism, primary hypogonadism |
XX Sex reversal/male reversal - rare
| Karyotype: |
46XX |
| Phenotype: |
Male with hypospadias, gynaecomastia
Some similarity with Klinefelter patient |
| Gonads: |
Exclusively testicular tissue, small testis and normal Wolffian duct derivatives |
A fragment of DNA from the short arm of the Y chromosome is detected in the distal end of the short arm of the X chromosome.
Rapidity of evaluation and determination of gender for rearing is important to allay the anxiety of parents.
| History: |
Family H/O neonatal death - clue for CAH
Maternal H/O of androgen exposure |
| Physical examination: |
Examination of genitalia important - phallus, urethral meatus & gonads
Approx. 53% of intersex conditions are associated with hypospadias and undescended testis (Raifer et al. J. Urol. 1976). |
| Karyotype: |
Within 48 hours with activated T-lymphocyte
To determine 'mosaics' a repeat study on multiple tissues may be necessary. |
| Ultrasound/contrast radiological studies: |
USS of pelvis for uterus, gonads (biopsy needed for gonadal type)
Retrograde genitogram to visualise urogenital anatomy. |
| Surgical exploration/laparoscopy/endoscopy: |
For observation of mullerian and wolffian structures, gonadal biopsy.
Endoscopy of urogenital sinus is sometimes helpful. |
| Biochemical studies of blood and urine: |
Very useful for the diagnosis of congenital adrenal hyperplasia.
21-Hydroxylase deficiency results in high 17-Hydroxy progesterone (17 OHP) - more than 2000 ng/dl
11-Hydroxyllase deficiency results in high Deoxycortisol (DOC)
Biochemical measurement of various precursors can help in identifying the exact block in male and female pseudohermaphrodites.
Testosterone/DHT ratio = 4.9. In normal neonates it is 2.8 and remains unchanged after hCG stimulation. The ratio is elevated in 5-alpha reductase deficiency. |
The karyotype has no direct bearing on the gender assignment. Instead the decision should be based mainly on:
- appearance of external genitalia (phallic size, time-growth response to androgen stimulation)
- likely pattern of secondary sexual development at puberty
- fertility potential, some potential in female pseudohermaphrodites and true hermaphrodite
- gonadal cancer risk, risk in streak gonad that is higher in XY than in XX
- family wish
A female pseudohermaphrodite should definitely be raised as female. It is difficult to get a good functional result with masculinizing genitoplasty and it usually requires several reconstructive procedures.
| Exploratory - for diagnostic purpose: |
Proper biopsy of gonads
Genital skin biopsy for fibroblast culture in androgen insensitivity |
| Excision of: |
Inapropriate tissue - opposite to chosen gender
Oncological reasons - dysplastic gonads
Excessive mammary tissue - gynaecomastia after puberty. |
| Reconstructive: |
Masulinising genitoplasty
Feminising genitoplasty - clitoroplasty, vaginoplasty |
Masulinising genitoplasty
Very difficult to get a functional result, only cosmetic. It sometimes requires several procedures. Penile reconstruction is done using myo-cutaneous flaps.
Feminising genitoplasty
Carried out for both functional and cosmetic reasons - a wide, supple and properly placed vaginal opening for free menstrual drainage (vaginoplasty) and clitoral sensation (clitoroplasty), and phallic reduction and adjustment of the labia.
Vaginoplasty - exact anatomical evaluation of urogenital sinus and the level of branching of urethro-vaginal confluence is mandatory (vaginogram)
- Fortunoff flap
- Pull-through procedure
- Vaginal enlargement, dilatation of prostatic utricle in male pseudohermaphrodite
- Total reconstruction for vaginal agenesis, after puberty using colon.
Clitoroplasty - this is done by sub-total resection of the corpora with protection of the dorsal nerve to maintain clitoral sensation. |
