sexual disorders. classification of anomalous sexual development a.seminiferous tubule dysgenesis...

Sexual DisordersSexual Disorders

Classification of Anomalous Classification of Anomalous Sexual DevelopmentSexual Development

A.A. Seminiferous tubule dysgenesis Seminiferous tubule dysgenesis (Klinefelter’s syndrome)(Klinefelter’s syndrome)

B.B. Syndrome of gonadal dysgenesis & its Syndrome of gonadal dysgenesis & its variants (Turner’s syndrome)variants (Turner’s syndrome)

C.C. Complete & incomplete forms of XX & XY Complete & incomplete forms of XX & XY gonadal dysgenesisgonadal dysgenesis

D.D. True hemaphroditismTrue hemaphroditism

Disorders of Gonadal differentiationDisorders of Gonadal differentiation::


A.A. Congenital virilizing adrenal hyperplasiaCongenital virilizing adrenal hyperplasia

B.B. Androgens & synthetic progestins Androgens & synthetic progestins transferred from maternal circulationtransferred from maternal circulation

C.C. Malformations of intestine & urinary tract Malformations of intestine & urinary tract (nonadrenal (nonadrenal femalepseudohermaphroditism.)femalepseudohermaphroditism.)

D.D. Other tetralogic factorsOther tetralogic factors

Female PseudohermaphroditismFemale Pseudohermaphroditism::

Cholesterol

Pregnelonone Progesterone DOC Corticosterone 180H Corticosterone

Aldosterone

170H Pregnenolone

170H Progesterone

11 Deoxycortisol Cortisol

DHEA Androstenedione Testosterone Estradiol

P450sccP450c213(B)HSD P450c11 P450c11 P450c11

P450c17 P450c17

3(B)HSD

P450c21 P450c113(B)HSD

17(B)HSD P450aro


A.A. Testicular unresponsiveness to hCG & LH Testicular unresponsiveness to hCG & LH (Leydig cell agensis or hypoplasia).(Leydig cell agensis or hypoplasia).

B.B. Inborn errors of testosterone biosynthesis:Inborn errors of testosterone biosynthesis:1.1. Enzyme defects affecting synthesis of both Enzyme defects affecting synthesis of both

corticosteroids & testosterone (variants of corticosteroids & testosterone (variants of congenital adrenal hyperplasiacongenital adrenal hyperplasia

i.i. P-450 scc (Cholesterol side-chain cleavage) deficiency P-450 scc (Cholesterol side-chain cleavage) deficiency (Congenital lipoid adrenal hyperplasia)(Congenital lipoid adrenal hyperplasia)

ii.ii. 3(B)-hydrooxysteroid dehydrogenase 5 isomerase 3(B)-hydrooxysteroid dehydrogenase 5 isomerase deficiencydeficiency

iii.iii. P-450c17 (17(a)-hydroxylase) deficiency.P-450c17 (17(a)-hydroxylase) deficiency.

Male Pseudohermaphroditism:Male Pseudohermaphroditism:

Classification of Anomalous Sexual DevelopmentClassification of Anomalous Sexual Development

C.C. Defects in androgen-dependent target tissue:Defects in androgen-dependent target tissue:1.1. End-organ resistance to androgenic hormones End-organ resistance to androgenic hormones

(androgens receptor & postreceptor defects).(androgens receptor & postreceptor defects).A.A. Syndrome of complete androgens resistance & its Syndrome of complete androgens resistance & its

variants (testicular feminization & its variant forms)variants (testicular feminization & its variant forms)

B.B. Syndrome of incomplete androgen resistance & its Syndrome of incomplete androgen resistance & its variants (Reifenstein’s syndrome)variants (Reifenstein’s syndrome)

C.C. Androgen resistance in phenotypically normal malesAndrogen resistance in phenotypically normal males

2.2. Defects in testosterone metabolism by peripheral Defects in testosterone metabolism by peripheral tissues; 5(a)-reductance deficiency (pseudovaginal tissues; 5(a)-reductance deficiency (pseudovaginal perineoscrotal hypospadias).perineoscrotal hypospadias).


Classification of Anomalous Sexual DevelopmentClassification of Anomalous Sexual Development

D.D. Dysgenetic male pseudohermaphroditism:Dysgenetic male pseudohermaphroditism:1.1. X chromatin-negative variants of the syndrome of gonadal X chromatin-negative variants of the syndrome of gonadal

dysgenesis (eg. XO/XY,XYp-).dysgenesis (eg. XO/XY,XYp-).

2.2. Incomplete form of XY gonadal dysgenesis.Incomplete form of XY gonadal dysgenesis.

3.3. Associated with degenerative renal disease (Wilms’ tumor-Associated with degenerative renal disease (Wilms’ tumor-aniridia-gonadoblastoma-mental retardation syndrome).aniridia-gonadoblastoma-mental retardation syndrome).

4.4. ““Vanishing testes” (embryonic testicular regression XY agonadismVanishing testes” (embryonic testicular regression XY agonadismXY gonadal agenesisXY gonadal agenesis rudimentary testes rudimentary testes

anorchia).anorchia).

E.E. Defects in synthesis, secretion, or response to mulleran Defects in synthesis, secretion, or response to mulleran duct inhibitory factor: female genital ducts in otherwise duct inhibitory factor: female genital ducts in otherwise normal men – “ uteri herniae inguinale”; persistent normal men – “ uteri herniae inguinale”; persistent mullerian duct syndrome.mullerian duct syndrome.


Unclassified Forms of Abnormal Unclassified Forms of Abnormal Sexual DevelopmentSexual Development

A.A. In malesIn males1.1. HypospadiasHypospadias

2.2. Ambiguous external genitalia in XY males with Ambiguous external genitalia in XY males with multiple congenital anomalies.multiple congenital anomalies.

B.B. In Females:In Females:1.1. Absence or anomalous development of the Absence or anomalous development of the

vagina, uterus, & uterine tubes (Rokitansky-vagina, uterus, & uterine tubes (Rokitansky-Kuster syndrome).Kuster syndrome).

Disorders of Gonadal differentiationDisorders of Gonadal differentiation::


The adrenal androgens serve no essential The adrenal androgens serve no essential physiological role but mediate some physiological role but mediate some secondary sexual characters in females secondary sexual characters in females and their overproduction may result in and their overproduction may result in virilism.virilism.

These steroids are synthesized from These steroids are synthesized from cholesterol by a complex series of cholesterol by a complex series of enzymatic conversions.enzymatic conversions.

Congenital Adrenal HyperplasiaCongenital Adrenal Hyperplasia

Cholesterol

Pregnelonone Progesterone DOC Corticosterone 180H Corticosterone

Aldosterone

170H Pregnenolone

170H Progesterone

11 Deoxycortisol Cortisol

DHEA Androstenedione Testosterone Estradiol

P450sccP450c213(B)HSD P450c11 P450c11 P450c11

P450c17 P450c17

3(B)HSD

P450c21 P450c113(B)HSD

17(B)HSD P450aro


Congenital adrenal hyperplasia can be Congenital adrenal hyperplasia can be caused by a disorder in any of the steps in caused by a disorder in any of the steps in steroid hormone synthesis.steroid hormone synthesis.There are 6 major types of congenital There are 6 major types of congenital adrenal hyperplasia (CAH) all transmitted adrenal hyperplasia (CAH) all transmitted as autosomal recessive disorders. as autosomal recessive disorders. The The common denominator in all the 6 types is a common denominator in all the 6 types is a defect in the synthesis of cortisol that result defect in the synthesis of cortisol that result in an increase in ACTH production and then in an increase in ACTH production and then in adrenal hyperplasia.in adrenal hyperplasia.



Type IType I P-450c21 hydroxylase deficiency P-450c21 hydroxylase deficiency with virilization.with virilization.

Type IIType II P-450c21 hydroxylase deficiency P-450c21 hydroxylase deficiency with virilization & salt loss.with virilization & salt loss.

Type IIIType III P-450c21 hydroxylase deficiency P-450c21 hydroxylase deficiency with virilization & hypertenstion.with virilization & hypertenstion.

Types of Congenital Adrenal HyperplasiaTypes of Congenital Adrenal Hyperplasia


Type IVType IV 3B hydroxy steorid dehydrogenase 3B hydroxy steorid dehydrogenase deficiency with adrenal insufficiencydeficiency with adrenal insufficiency

Type VType V P-450c17 deficiency with sexual P-450c17 deficiency with sexual infantilism, hypertension & infantilism, hypertension &

hypokalaemic alkalosis.hypokalaemic alkalosis.

Type VIType VI P-450cc side-chain cleavage deficiency P-450cc side-chain cleavage deficiency with sexual infantilism & adrenal with sexual infantilism & adrenal

insufficiency.insufficiency.

Types of Congenital Adrenal HyperplasiaTypes of Congenital Adrenal Hyperplasia


The most common type of congenital The most common type of congenital adrenal hyperplasia is the P-450c21 adrenal hyperplasia is the P-450c21 hydroxylase deficiency. hydroxylase deficiency. Prevalence is 1:14,000 live birth in Prevalence is 1:14,000 live birth in caucasions.caucasions.The defect in the enzyme activity results in The defect in the enzyme activity results in impaired cortisol synthesis, increased impaired cortisol synthesis, increased ACTH levels & increased adrenal androgen ACTH levels & increased adrenal androgen & androgen precursors production.& androgen precursors production.



Prior to 12 weeks of gestation high fetal androgen Prior to 12 weeks of gestation high fetal androgen level lead to varying degree of labioscrotal fusion level lead to varying degree of labioscrotal fusion & clitorial enlargement in the female fetus& clitorial enlargement in the female fetus, , exposure to androgens after 12 weeks induces exposure to androgens after 12 weeks induces clitorimegaly only.clitorimegaly only.

In the male fetus no structural abnormalities in the In the male fetus no structural abnormalities in the external genitalia are evident at birth but the external genitalia are evident at birth but the phallus may be enlarged.phallus may be enlarged.

These patients produce sufficient amount of These patients produce sufficient amount of aldosternone to prevent the signs & symptoms of aldosternone to prevent the signs & symptoms of mineralocorticoid deficiency, virilization continues mineralocorticoid deficiency, virilization continues after birth in the untreated patients.after birth in the untreated patients.



This results in rapid growth & bone This results in rapid growth & bone maturation as well as physical signs of maturation as well as physical signs of excess androgen secretion (e.g. Acne, excess androgen secretion (e.g. Acne, seborrhoea, premature development of seborrhoea, premature development of pubic & axillary hair & phallic enlargement).pubic & axillary hair & phallic enlargement).Mild defect in the P-450c21 enzyme activity Mild defect in the P-450c21 enzyme activity can occur & patientscan occur & patients::

A.A. Can be symptomatic (late onset or acquired Can be symptomatic (late onset or acquired form).form).

B.B. Asymptomatic (cryptic form).Asymptomatic (cryptic form).These forms are more common that the These forms are more common that the classical form of the diseaseclassical form of the disease..



It has been postulated that the “non-It has been postulated that the “non-classical” P-450c21 hydroxylase deficiency classical” P-450c21 hydroxylase deficiency is the most common autosomal recessive is the most common autosomal recessive disorder affecting 1:100 persons of all the disorder affecting 1:100 persons of all the ethnic groups but having an incidence 2-3 ethnic groups but having an incidence 2-3 times higher intimes higher in



Males have normal external genitalia at Males have normal external genitalia at birth but later in childhood they may exhibit birth but later in childhood they may exhibit premature pubic & axillary hair, early premature pubic & axillary hair, early puberty & short stature due to early bone puberty & short stature due to early bone maturation & epiphyseal fusion.maturation & epiphyseal fusion.

Asymptomatic patients can be detected by Asymptomatic patients can be detected by hormonal testing in families in which there hormonal testing in families in which there is at least one member with symptoms.is at least one member with symptoms.


DiagnosisDiagnosis

In patients with this enzymatic defects the In patients with this enzymatic defects the 17-17-hydroxy progesterone values are usually very hydroxy progesterone values are usually very highhigh depending on the age of the patient & the depending on the age of the patient & the severity of the enzymatic defect.severity of the enzymatic defect.

In the late onset form the basal 17-hydroxy-In the late onset form the basal 17-hydroxy-progesterone may be borderline but can be progesterone may be borderline but can be augmented by ACTH stimulation test.augmented by ACTH stimulation test.

Urinary 17-ketosteroids & pregnanetriol are still Urinary 17-ketosteroids & pregnanetriol are still valid test in the diagnostic procedure but have valid test in the diagnostic procedure but have been replaced by the ACTH stimulation test.been replaced by the ACTH stimulation test.

DiagnosisDiagnosisThe diagnosis of P-450c21 hydroxylase The diagnosis of P-450c21 hydroxylase deficiency should always be considered in deficiency should always be considered in the following:the following:

1.1. Patients with ambiguous genitalia who have Patients with ambiguous genitalia who have 45XX Karyotype i.e. Female pseudo-45XX Karyotype i.e. Female pseudo-hemophrodite.hemophrodite.

2.2. Apparent cryptochid males.Apparent cryptochid males.

3.3. In any infant who presents with shock, In any infant who presents with shock, hypoglycemia & chemical findings compatible hypoglycemia & chemical findings compatible with adrenal insufficiency.with adrenal insufficiency.

4.4. Males & females with sign of virilization prior to Males & females with sign of virilization prior to puberty, including premature adrenarche.puberty, including premature adrenarche.

TreatmentTreatment

Replacement therapy with glucocorticoids Replacement therapy with glucocorticoids provides the body with that which it cannot provides the body with that which it cannot produce.produce.

The choice of the specific formulation of the The choice of the specific formulation of the glucocorticoids & the dose varies glucocorticoids & the dose varies depending on the age & the therauptic depending on the age & the therauptic goals in each patient.goals in each patient.

It is necessary to increase the physiological It is necessary to increase the physiological requirement (3-10 times) during period of requirement (3-10 times) during period of stress e.g. surgery, illnessstress e.g. surgery, illness..

Turner’s Syndrome & its VariantsTurner’s Syndrome & its Variants

One in 10,000 new born females has a One in 10,000 new born females has a 45, X or XO sex chromosome 45, X or XO sex chromosome constitutions & the cardinal feature of constitutions & the cardinal feature of 45, X gonadal dysgenesis are :45, X gonadal dysgenesis are :

– A variety of somatic anomaliesA variety of somatic anomalies

– Sexual infantilism at pubertySexual infantilism at puberty

– Short statureShort stature

Turner’s Syndrome & its VariantsTurner’s Syndrome & its Variants

• Lymphedema of the extremetiesLymphedema of the extremeties• Loose skin folds over the nape of the neckLoose skin folds over the nape of the neck• Typical faces include:Typical faces include:

– MicrognathiaMicrognathia– Epicanthal foldsEpicanthal folds– Prominent low-set earsProminent low-set ears– Fish like mouthFish like mouth– PtosisPtosis

• Sheild like chestSheild like chest• Short neck which is broad & webbed (40%)Short neck which is broad & webbed (40%)

Additional Anomalies Associated Additional Anomalies Associated with Turner’s Syndromewith Turner’s Syndrome

• Coarctation of the aortaCoarctation of the aorta 10%10%

• Renal abnormalitiesRenal abnormalities 50%50%

• HypertensionHypertension

• Pigmented naeviPigmented naevi

• Cabitus valgusCabitus valgus

• Tendency to keloid formationTendency to keloid formation

• Puffiness of dorsum of hand & feetPuffiness of dorsum of hand & feet

• Short fourth metacarpalShort fourth metacarpal

• Recurrent otitis mediaRecurrent otitis media

Additional Anomalies Associated Additional Anomalies Associated with Turner’s Syndromewith Turner’s Syndrome

• Coarctation of the aortaCoarctation of the aorta 10%10%

• Renal abnormalitiesRenal abnormalities 50%50%

• HypertensionHypertension

• Pigmented naeviPigmented naevi

• Cabitus valgusCabitus valgus

• Tendency to keloid formationTendency to keloid formation

• Puffiness of dorsum of hand & feetPuffiness of dorsum of hand & feet

• Short fourth metacorpalShort fourth metacorpal

• Recurrent otitis mediaRecurrent otitis media

Associated DisordersAssociated Disorders

• ObesityObesity

• OsteoporosisOsteoporosis

• Diabetes MellitusDiabetes Mellitus

• Hashimoto thyroiditisHashimoto thyroiditis

• Rheumatoid arthritisRheumatoid arthritis

• Inflammatory bowel diseaseInflammatory bowel disease

• Biscupid aortic valve & aortic dilatation with Biscupid aortic valve & aortic dilatation with aneurysm formation.aneurysm formation.

DiagnosisDiagnosis

Turner’s syndrome should be suspected in Turner’s syndrome should be suspected in any female with :any female with :

– Short stature (>2.5 SD below the mean value per Short stature (>2.5 SD below the mean value per age).age).

– Somatic anomalies associated with the syndrome Somatic anomalies associated with the syndrome of gonadal dysgenesis.of gonadal dysgenesis.

– Delayed adolescence & increased plasma level Delayed adolescence & increased plasma level of gonadotrophinsof gonadotrophins

Although a buccal smear of sex chromatin is Although a buccal smear of sex chromatin is useful, karotype should be performed for useful, karotype should be performed for definitive diagnosis, 45, XOdefinitive diagnosis, 45, XO

TreatmentTreatment

Treatment should be directed towards:Treatment should be directed towards:– Maximizing final heightMaximizing final height– Inducing secondary sexual characters at Inducing secondary sexual characters at

menarche.menarche.

Clinical trials showed that patients treated Clinical trials showed that patients treated with growth hormone plus oxandrolone had with growth hormone plus oxandrolone had an increase in growth rate which resulted in an increase in growth rate which resulted in an increase in the predicted final height an increase in the predicted final height after 3 years of therapy.after 3 years of therapy.

Klinefelter’s Syndrome & its Klinefelter’s Syndrome & its VariantsVariants

Klinefelter’s sydnrome is one of the most common Klinefelter’s sydnrome is one of the most common form of form of primary hypogonadism & infertility.primary hypogonadism & infertility.

Affected patients usually have an Affected patients usually have an XXYXXY sex sex chromosome constitution & an X chromatin-chromosome constitution & an X chromatin-positive buccal smear although patients with a positive buccal smear although patients with a variety of sex chromosome constitutions including variety of sex chromosome constitutions including mosaicism, have been described.mosaicism, have been described.

Virtually all of these variants have in the common Virtually all of these variants have in the common the presence of at least two X chromosomes & a the presence of at least two X chromosomes & a Y chromosome.Y chromosome.

The incidence is about 1/1000 in new born males.The incidence is about 1/1000 in new born males.


Clinical Feature Include:Clinical Feature Include:– Male phenotypeMale phenotype

– Samll firm testes less than 3 cm in length Samll firm testes less than 3 cm in length & azospermia (invariable)& azospermia (invariable)

– Pre pubertally thereare:Pre pubertally thereare:• Disproportionately long legsDisproportionately long legs• Low verbal I.Q. scoreLow verbal I.Q. score• Small testesSmall testes


Clinical Feature Include:Clinical Feature Include:– Delay in the onset of adolescenceDelay in the onset of adolescence– Signs of androgen deficiency such as:Signs of androgen deficiency such as:

• GynacomastiaGynacomastia• Diminished facial & body hairDiminished facial & body hair• Small phallusSmall phallus• Poor muscular developmentPoor muscular development• Eunuchoid body habitus post pubertallyEunuchoid body habitus post pubertally• Psycho-social abnornalitiesPsycho-social abnornalities• Impotence & infertilityImpotence & infertility


Associated disorders:Associated disorders:– Primary hypothyroidismPrimary hypothyroidism– Mild diatetes mellitusMild diatetes mellitus– Varicose veinsVaricose veins– Chronic pulmonary diseaseChronic pulmonary disease– Carcinoma of breast (20% more then normal Carcinoma of breast (20% more then normal

men).men).– They are at greater risk of developing They are at greater risk of developing

malignant extragonadal germ cell tumors malignant extragonadal germ cell tumors including CNS germinomaincluding CNS germinoma


Associated disorders:Associated disorders:The testicular lesion appear to be progressive The testicular lesion appear to be progressive & gonadotrophin dependent.& gonadotrophin dependent.

It is characterized in the adults by extensive It is characterized in the adults by extensive seminiferous tubular hyalinization & fibrosis, seminiferous tubular hyalinization & fibrosis, absent or severely deficient spermatogenesis, absent or severely deficient spermatogenesis, & pseudoadenomatous dumping of the leyding & pseudoadenomatous dumping of the leyding cells.cells.

Spermatogenesis is rarely found except in the Spermatogenesis is rarely found except in the XY/XXY mosaics & therefore they are infertile.XY/XXY mosaics & therefore they are infertile.

DiagnosisDiagnosisIt is suggested by the classical phenotype & It is suggested by the classical phenotype & hormonal changes & is confirmed by the findings hormonal changes & is confirmed by the findings of X chromatin-positive buccal smear & of X chromatin-positive buccal smear & demonstration of XXY karotype in blood.demonstration of XXY karotype in blood.After puberty levels of serum gonadotrophin After puberty levels of serum gonadotrophin especially FSH are raised.especially FSH are raised.The testosterone production rate, the total & free The testosterone production rate, the total & free levels of testosterone & metabolic clearance rate levels of testosterone & metabolic clearance rate of testosterone & estradiol tend to be low while of testosterone & estradiol tend to be low while plasma estradiol levels are normal or high & plasma estradiol levels are normal or high & relatively high estradiol:testosterone ratio is relatively high estradiol:testosterone ratio is responsible for the variable degrees of responsible for the variable degrees of feminization & gynaecomastia.feminization & gynaecomastia.Testicular biopsy reveals the classical findings.Testicular biopsy reveals the classical findings.

Differential DiagnosisDifferential DiagnosisKilnefelter’s syndrome should be Kilnefelter’s syndrome should be distinguished from other causes of distinguished from other causes of hypogonadism. Small firm tested should hypogonadism. Small firm tested should suggests the diagnosis.suggests the diagnosis.Hypothalamic-pituitary hypogonadism may Hypothalamic-pituitary hypogonadism may be associated with rubbery testes if puberty be associated with rubbery testes if puberty has not occurred & atrophic testes if normal has not occurred & atrophic testes if normal puberty has occurred & the gonadotrophin puberty has occurred & the gonadotrophin levels are usually low.levels are usually low.The consistency of the testes in the The consistency of the testes in the klinefelter’s syndrome is also different from klinefelter’s syndrome is also different from that noted in acquired forms of adult that noted in acquired forms of adult seminiferous tubular damage.seminiferous tubular damage.

TreatmentTreatmentTreatment is directed towards androgen Treatment is directed towards androgen replacement especially patients with replacement especially patients with delayed puberty or failure of progression in delayed puberty or failure of progression in those with subnormal testosterone levels those with subnormal testosterone levels for age & development.for age & development.Testosterone therapy also may enhance Testosterone therapy also may enhance secondary sexual characteristics & sexual secondary sexual characteristics & sexual performance prevent osteoporosis & performance prevent osteoporosis & improve general well being in most patients.improve general well being in most patients.Personally defects do not improve & most Personally defects do not improve & most patients require long term psychiatric patients require long term psychiatric counselling.counselling.

HistoryPhysical ExaminationBone ageSerum FSH, LH: GNRH test testosterone, oestradiol

FSH LH FSH LH

Karyotype+ gonad biopsy

Detailed steroid analysis

Sense of smell

Obesity

Skull radiograph & coronal CT Scan

Pituitary function tests

Follow up 6-monthly intervals

Gonadotrophin stimulation

HistoryPhysical ExaminationBone ageSerum FSH, LH: GNRH test testosterone, oestradiol

Klinefelter’s syndromeGonadal dysgenesisMale pseudohermaphroditismMixed gonadal dysgenesisTrue hermaphroditism

Congenital anorchiaResistant ovary syndromeGonadal damage

Inborn error of sex steroid synthesis

Kallmann’s syndrome

Pradder-Willi syndromeLaurence-Moon-Beidl syndrome

CNS tumor

Hypopituitarism

Constituional delayHypogonadotrophic hypogonadism

sexual disorders. classification of anomalous sexual development a.seminiferous tubule dysgenesis...

Documents

syndrome of gonadal

anomalous development

sexual disorders

variants turners syndrome

xy gonadal dysgenesis

bhsd p450aro slide

adrenal androgens

xy males