2Classification of Anomalous Sexual Development Disorders of Gonadal differentiation:Seminiferous tubule dysgenesis (Klinefelter’s syndrome)Syndrome of gonadal dysgenesis & its variants (Turner’s syndrome)Complete & incomplete forms of XX & XY gonadal dysgenesisTrue hemaphroditism
3Classification of Anomalous Sexual Development Female Pseudohermaphroditism:Congenital virilizing adrenal hyperplasiaAndrogens & synthetic progestins transferred from maternal circulationMalformations of intestine & urinary tract (nonadrenal femalepseudohermaphroditism.)Other tetralogic factors
5Classification of Anomalous Sexual Development Male Pseudohermaphroditism:Testicular unresponsiveness to hCG & LH (Leydig cell agensis or hypoplasia).Inborn errors of testosterone biosynthesis:Enzyme defects affecting synthesis of both corticosteroids & testosterone (variants of congenital adrenal hyperplasiaP-450 scc (Cholesterol side-chain cleavage) deficiency (Congenital lipoid adrenal hyperplasia)3(B)-hydrooxysteroid dehydrogenase 5 isomerase deficiencyP-450c17 (17(a)-hydroxylase) deficiency.
6Classification of Anomalous Sexual Development Male Pseudohermaphroditism:Defects in androgen-dependent target tissue:End-organ resistance to androgenic hormones (androgens receptor & postreceptor defects).Syndrome of complete androgens resistance & its variants (testicular feminization & its variant forms)Syndrome of incomplete androgen resistance & its variants (Reifenstein’s syndrome)Androgen resistance in phenotypically normal malesDefects in testosterone metabolism by peripheral tissues; 5(a)-reductance deficiency (pseudovaginal perineoscrotal hypospadias).
7Classification of Anomalous Sexual Development Male Pseudohermaphroditism:Dysgenetic male pseudohermaphroditism:X chromatin-negative variants of the syndrome of gonadal dysgenesis (eg. XO/XY,XYp-).Incomplete form of XY gonadal dysgenesis.Associated with degenerative renal disease (Wilms’ tumor-aniridia-gonadoblastoma-mental retardation syndrome).“Vanishing testes” (embryonic testicular regression XY agonadism XY gonadal agenesis rudimentary testes anorchia).Defects in synthesis, secretion, or response to mulleran duct inhibitory factor: female genital ducts in otherwise normal men – “ uteri herniae inguinale”; persistent mullerian duct syndrome.
8Unclassified Forms of Abnormal Sexual Development Disorders of Gonadal differentiation:In malesHypospadiasAmbiguous external genitalia in XY males with multiple congenital anomalies.In Females:Absence or anomalous development of the vagina, uterus, & uterine tubes (Rokitansky-Kuster syndrome).
9Sexual Disorders Congenital Adrenal Hyperplasia The adrenal androgens serve no essential physiological role but mediate some secondary sexual characters in females and their overproduction may result in virilism.These steroids are synthesized from cholesterol by a complex series of enzymatic conversions.
11Sexual Disorders Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia can be caused by a disorder in any of the steps in steroid hormone synthesis.There are 6 major types of congenital adrenal hyperplasia (CAH) all transmitted as autosomal recessive disorders. The common denominator in all the 6 types is a defect in the synthesis of cortisol that result in an increase in ACTH production and then in adrenal hyperplasia.
12Sexual Disorders Types of Congenital Adrenal Hyperplasia Type I P-450c21 hydroxylase deficiency with virilization.Type II P-450c21 hydroxylase deficiency with virilization & salt loss.Type III P-450c21 hydroxylase deficiency with virilization & hypertenstion.
13Sexual Disorders Types of Congenital Adrenal Hyperplasia Type IV 3B hydroxy steorid dehydrogenase deficiency with adrenal insufficiencyType V P-450c17 deficiency with sexual infantilism, hypertension & hypokalaemic alkalosis.Type VI P-450cc side-chain cleavage deficiency with sexual infantilism & adrenal insufficiency.
14Sexual Disorders Congenital Adrenal Hyperplasia The most common type of congenital adrenal hyperplasia is the P-450c21 hydroxylase deficiency.Prevalence is 1:14,000 live birth in caucasions.The defect in the enzyme activity results in impaired cortisol synthesis, increased ACTH levels & increased adrenal androgen & androgen precursors production.
15Congenital Adrenal Hyperplasia Sexual DisordersCongenital Adrenal HyperplasiaPrior to 12 weeks of gestation high fetal androgen level lead to varying degree of labioscrotal fusion & clitorial enlargement in the female fetus, exposure to androgens after 12 weeks induces clitorimegaly only.In the male fetus no structural abnormalities in the external genitalia are evident at birth but the phallus may be enlarged.These patients produce sufficient amount of aldosternone to prevent the signs & symptoms of mineralocorticoid deficiency, virilization continues after birth in the untreated patients.
16Congenital Adrenal Hyperplasia Sexual DisordersCongenital Adrenal HyperplasiaThis results in rapid growth & bone maturation as well as physical signs of excess androgen secretion (e.g. Acne, seborrhoea, premature development of pubic & axillary hair & phallic enlargement).Mild defect in the P-450c21 enzyme activity can occur & patients:Can be symptomatic (late onset or acquired form).Asymptomatic (cryptic form).These forms are more common that the classical form of the disease.
17Congenital Adrenal Hyperplasia Sexual DisordersCongenital Adrenal HyperplasiaIt has been postulated that the “non-classical” P-450c21 hydroxylase deficiency is the most common autosomal recessive disorder affecting 1:100 persons of all the ethnic groups but having an incidence 2-3 times higher in
18Congenital Adrenal Hyperplasia Sexual DisordersCongenital Adrenal HyperplasiaMales have normal external genitalia at birth but later in childhood they may exhibit premature pubic & axillary hair, early puberty & short stature due to early bone maturation & epiphyseal fusion.Asymptomatic patients can be detected by hormonal testing in families in which there is at least one member with symptoms.
19DiagnosisIn patients with this enzymatic defects the 17-hydroxy progesterone values are usually very high depending on the age of the patient & the severity of the enzymatic defect.In the late onset form the basal 17-hydroxy-progesterone may be borderline but can be augmented by ACTH stimulation test.Urinary 17-ketosteroids & pregnanetriol are still valid test in the diagnostic procedure but have been replaced by the ACTH stimulation test.
20DiagnosisThe diagnosis of P-450c21 hydroxylase deficiency should always be considered in the following:Patients with ambiguous genitalia who have 45XX Karyotype i.e. Female pseudo-hemophrodite.Apparent cryptochid males.In any infant who presents with shock, hypoglycemia & chemical findings compatible with adrenal insufficiency.Males & females with sign of virilization prior to puberty, including premature adrenarche.
21TreatmentReplacement therapy with glucocorticoids provides the body with that which it cannot produce.The choice of the specific formulation of the glucocorticoids & the dose varies depending on the age & the therauptic goals in each patient.It is necessary to increase the physiological requirement (3-10 times) during period of stress e.g. surgery, illness.
22Turner’s Syndrome & its Variants One in 10,000 new born females has a 45, X or XO sex chromosome constitutions & the cardinal feature of 45, X gonadal dysgenesis are :A variety of somatic anomaliesSexual infantilism at pubertyShort stature
23Turner’s Syndrome & its Variants Lymphedema of the extremetiesLoose skin folds over the nape of the neckTypical faces include:MicrognathiaEpicanthal foldsProminent low-set earsFish like mouthPtosisSheild like chestShort neck which is broad & webbed (40%)
24Additional Anomalies Associated with Turner’s Syndrome Coarctation of the aorta 10%Renal abnormalities 50%HypertensionPigmented naeviCabitus valgusTendency to keloid formationPuffiness of dorsum of hand & feetShort fourth metacarpalRecurrent otitis media
25Additional Anomalies Associated with Turner’s Syndrome Coarctation of the aorta 10%Renal abnormalities 50%HypertensionPigmented naeviCabitus valgusTendency to keloid formationPuffiness of dorsum of hand & feetShort fourth metacorpalRecurrent otitis media
27Diagnosis Turner’s syndrome should be suspected in any female with : Short stature (>2.5 SD below the mean value per age).Somatic anomalies associated with the syndrome of gonadal dysgenesis.Delayed adolescence & increased plasma level of gonadotrophinsAlthough a buccal smear of sex chromatin is useful, karotype should be performed for definitive diagnosis, 45, XO
28Treatment Treatment should be directed towards: Maximizing final heightInducing secondary sexual characters at menarche.Clinical trials showed that patients treated with growth hormone plus oxandrolone had an increase in growth rate which resulted in an increase in the predicted final height after 3 years of therapy.
29Klinefelter’s Syndrome & its Variants Klinefelter’s sydnrome is one of the most common form of primary hypogonadism & infertility.Affected patients usually have an XXY sex chromosome constitution & an X chromatin-positive buccal smear although patients with a variety of sex chromosome constitutions including mosaicism, have been described.Virtually all of these variants have in the common the presence of at least two X chromosomes & a Y chromosome.The incidence is about 1/1000 in new born males.
30Klinefelter’s Syndrome & its Variants Clinical Feature Include:Male phenotypeSamll firm testes less than 3 cm in length & azospermia (invariable)Pre pubertally thereare:Disproportionately long legsLow verbal I.Q. scoreSmall testes
31Klinefelter’s Syndrome & its Variants Clinical Feature Include:Delay in the onset of adolescenceSigns of androgen deficiency such as:GynacomastiaDiminished facial & body hairSmall phallusPoor muscular developmentEunuchoid body habitus post pubertallyPsycho-social abnornalitiesImpotence & infertility
32Klinefelter’s Syndrome & its Variants Associated disorders:Primary hypothyroidismMild diatetes mellitusVaricose veinsChronic pulmonary diseaseCarcinoma of breast (20% more then normal men).They are at greater risk of developing malignant extragonadal germ cell tumors including CNS germinoma
33Klinefelter’s Syndrome & its Variants Associated disorders:The testicular lesion appear to be progressive & gonadotrophin dependent.It is characterized in the adults by extensive seminiferous tubular hyalinization & fibrosis, absent or severely deficient spermatogenesis, & pseudoadenomatous dumping of the leyding cells.Spermatogenesis is rarely found except in the XY/XXY mosaics & therefore they are infertile.
34DiagnosisIt is suggested by the classical phenotype & hormonal changes & is confirmed by the findings of X chromatin-positive buccal smear & demonstration of XXY karotype in blood.After puberty levels of serum gonadotrophin especially FSH are raised.The testosterone production rate, the total & free levels of testosterone & metabolic clearance rate of testosterone & estradiol tend to be low while plasma estradiol levels are normal or high & relatively high estradiol:testosterone ratio is responsible for the variable degrees of feminization & gynaecomastia.Testicular biopsy reveals the classical findings.
35Differential Diagnosis Kilnefelter’s syndrome should be distinguished from other causes of hypogonadism. Small firm tested should suggests the diagnosis.Hypothalamic-pituitary hypogonadism may be associated with rubbery testes if puberty has not occurred & atrophic testes if normal puberty has occurred & the gonadotrophin levels are usually low.The consistency of the testes in the klinefelter’s syndrome is also different from that noted in acquired forms of adult seminiferous tubular damage.
36TreatmentTreatment is directed towards androgen replacement especially patients with delayed puberty or failure of progression in those with subnormal testosterone levels for age & development.Testosterone therapy also may enhance secondary sexual characteristics & sexual performance prevent osteoporosis & improve general well being in most patients.Personally defects do not improve & most patients require long term psychiatric counselling.
37HistoryPhysical ExaminationBone ageSerum FSH, LH: GNRH test testosterone, oestradiolHistoryPhysical ExaminationBone ageSerum FSH, LH: GNRH test testosterone, oestradiolFSH LHFSH LHKlinefelter’s syndromeGonadal dysgenesisMale pseudohermaphroditismMixed gonadal dysgenesisTrue hermaphroditismKaryotype+ gonad biopsyCongenital anorchiaResistant ovary syndromeGonadal damageGonadotrophin stimulationDetailed steroid analysisInborn error of sex steroid synthesisSense of smellKallmann’s syndromePradder-Willi syndromeLaurence-Moon-Beidl syndromeObesitySkull radiograph & coronal CT ScanCNS tumorPituitary function testsHypopituitarismFollow up 6-monthly intervalsConstituional delayHypogonadotrophic hypogonadism