
Abnormal Sexual Differentiation. INTERSEX. An individual in whom there is discordance between chromosomal, gonadal, internal genital, and phenotypic sex or the sex of rearing INTERSEXUALITY: Discordance between any two of the organic sex criteria TRANSSEXUALITY:
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An individual in whom there is discordance between chromosomal, gonadal, internal genital, and phenotypic sex or the sex of rearing
Discordance between any two of the organic sex criteria
Discordance between organic sex and psychological sex components
Disorders of fetal Endocrinology
Primary gonadal defect – Swyer syndrome
Congenital adrenal hyperplasia
21 -hydrxylase deficiency
11-hydroxylase deficiency
3ß-hydroxysteroid
dehydrogenase deficiency
EXCESS MATERNAL ANDROGENS
Maternal androgen secreting tumors (ovary, adrenal)
Maternal ingestion of androgenic drugs
FEMALE PSEUDOHERMAPHRODITISMCholesterol
Pituitary
Pregnenolone
Progesterone
ACTH
17-OH progesterone
Adrenal cortex
21-hydroxylase
Androgens
Cortisol
Cortisol
Androgens
exposed to high level of adrenal androgen level (GA 7 wks)
-a large clitoris
-rugated and partially fused labia majora
-uterus,fallopian tubes, and ovaries : normal
-no overt signs of the disease
except variable and subtle hyperpigmentation
and penile en-largement
-> a variety of mutations
-> this enzyme deficiency
-> adrenal cortex is stimulated
& over production of cortisol precursor
: severe form with a concurrent defect in aldosterone synthesis
severely impaired 21-hydroxylation of progesterone
cannot synthesis of aldosterone
hyponatremia, hyperkalemia ,acidosis, hypovolemia and shock
with reduced renin & aldosterone
: depends on the type of 21-hydroxylase def
: baseline - 200ng/dl ↓
-> Corticotropin stimulation test
: pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone ,
11-deoxycortisol, and testosterone
: Normal growth, B.Wt, pubertal development, optimal adult height
-> glucocorticoid : adrenal androgen secretion ↓
-> mineralocorticoid : electrolytes & plasma renin activity -> nl
: obesity, growth failure, adult short stature, striae,
osteoporosis, hyperlipidemia
: virilism, infertility of female, precocious virilisation of male,
early puberty, adult short stature
: Dexamethasone fetal pituitary adrenal axis inhibition
& affected female’s genital ambiguity↓
-> 1 of 8 fetuses requires Tx for classic CAH
: 6weeks gestation -> start Tx
: male or unaffected female -> Tx stop
: DNA analysis normal stop Dex
- Synthetic progestins
- Danocrine
- Diazoxide
- Minoxidil
- Phenetoin sodium
- Streptomycin
- Penicillamine
Drugs with Androgenic side effectsingested during pregnancytestosterone
Defects in testicular
steroidogenesis
Gonadotropin-resistant
testes (LH receptor mutation)
Congenital lipoid adrenal
hyperplasia
Defective synthesis,
secretion, or response to
anti-mullerian hormone
Male pseudohermaphroditism(XY- FEMALE)Failure to utilize
testosterone
Androgen receptor deficiency
* Complete androgen Insensitivity (TFS)
* Incomplete androgen Insensitivity
5-alpha reductase deficiency
Testicular feminization syndrome
TESTIS MIF
Testosterone
5--reductase
DHT
Absent androgen receptors
Male Internal Genitalia
Female
External
Genitalia
Incomplete form Ambiguous genitalia
indication of androgen insensitivity
46-XY/SRY
Testis MIF
Testosterone
5--rductase
DHT
Female or Ambiguous external Genitalia
Male Internal Genitalia
: testes secrete T, MIH causes Mullerian ducts to degenerate
testes descend, scrotum darkens, phallus enlarges, muscular &
deep voice
testosterone
Cholesterol side change cleavage
3β OH steroid Dehydrogenase
17α Hydroxylase
17,20 Lyase Deficiency
17β OH steroid Dehydrogenase
46-XY/SRY
Autosomal recessive enzyme deficiency : -20-22 desmolase -3-ß-ol-dehydrogenase -17- -hydroxylase -17,20-desmolase -17-ß–OH steroid dehydrogenase
Testis MIF
(defects in testosterone
Synthesis)
testosterone precursors DHT
Ambiguous
External
Genitalia
Male Internal Genitalia
46-XY/SRY
TESTIS MIF
( partial/ complete absence
Of leydig-cells)
No or testosterone
No or DHT
Female or ambiguous external Genitalia
± Male
Internal
Genitalia
Steroidogenic Acute Regulatory Protein
(StAR)
CHOLESTEROL
CYP17
CYP17
PREGNENOLONE
17-HYDROXYPREGNENOLONE
DEHYDROEPIANDROSTERONE
HSD3B2
HSD3B2
HSD3B2
PROGESTERONE
17-HYDROXYPROGESTERONE
ANDROSTENEDIONE
CYP21
CYP21
DOC
11-DEOXYCORTISOL
CYP19
HSD17B3
CYP11B2
CYP11B1
ESTRONE
TESTOSTERONE
CORTICOSTERONE
CORTISOL
HSD17B1
TESTIS
CYP11B2
ADRENAL
CORTEX
ESTRADIOL
18-HYDROXYCORTICOSTERONE
OVARY
SRD5A2
CYP11B2
ALDOSTERONE
DHT
Target Cell
Testosterone concentration
Low
Normal
Male level
Concentration of
Testosterone precurcers
DHT
High
Low
Low
Normal
Testicular
Feminization
Syndrome
Testicular
enzyme
Failure
Absent testes or
Absent leydig-cell
5 -reductase
Deficiency
Surgical exploration
46, XY
No SRY OR its receptors
STREAK GONADS - NO MIF (Uterus +) - NO SEX STEROIDS
Female external
Genitalia
Female Internal Genitalia
46-XY/SRY
Testis MIF
(self destruction)
± testosterone
± DHT
± Male Internal genitalia
Male
Infantile
External
genitalia
• Gonads :
- ovary one side and testis on the other side of the abdomen
- bilateral ovotestis
• Karyotype :
46,XX most common(70%); XY and XX/XY
• Internal genitalia :
Both mullerian and wolffian derivates
• Phenotype is variable
• Gonadal biopsy is required for confirming diagnosis
Features:
1. Female Phenotype
2. Short Stature
3. No Secondary Sexual
Characteristics
4. Somatic Abnormalities
- Webbed Neck
- Broad Chest
- Short Ring finger
Occult Y Ch. Material:
Predisposed to Virilisation
and Gonadoblastoma (30%) and other GCT (50%).
- so pregnancy is possible
Renal Anomalies:
90% Multiple Renal Arteries
20% Renal agenesis/Duplication
15% Malrotation
10% Horseshoe kidney
Karyotype 45,X (60%)
(45,X/46,XX, structural abnormalities of X chromosome)
Short stature (final height 142-147 cm)
Gonadal dysgenesis - streak gonad & sexual infantilism
Skletal abnormalities & dysmorphic face
Cardiac and kidney malformation
Autoimmune ds : Hashimoto’s thyroditis, Addison’s ds
Mild insulin resistance & hearing loss
Lymphedema
Essential hypertension
No mental defect
Impairment of cognitive function : mathematical ability↓
Visual–motor coordination, spatial-temporal processing↓
H. Tuner, 1938
Most with the pure gonadal dysgenesis form without Turner SD
patients with mosaic patterns reduced risk of tumor (10%)
Features:
Unilateral testis (undescended)
Contralateral Streak Gonad
Persistent Mullerian Structures
Some masculinisation
Mostly females with;
Enlarged phallus
Labioscrotal folds
Uterus /vagina & tubes
testis with ipsilateral fallopian tube
Appropriate gonadectomy & screen for Wilm’s tumor
Increased risk of:
Gonadoblastoma (20%)
- testis > streak gonad
Wilm’s tumor
Denys-Drash Syndrome
- Nephropathy /CRF
- Genital Abnormalities
- Wilms tumour
- XX/XY mosaicism
May need prophylactic bilateral nephrectomy
(except complete androgen insensitivity)
: Laparoscopy or laparotomy
+ 5mg medroxyprogesterone acetate for 14days (if a uterus is present)
(to avoid epiphysial closure)
: Optimal response an early onset of Tx around age 6~7
amniocentesis or chorionic villus biopsy
: short stature, webbed neck, shield chest & cardiac malformations
(esp, pulmonic stenosis)
GENERAL GIUDELINES
DIAGNOSIS
; Abdomen; pelvis; external genitalia; urethral and anal openings
Investigations
•Pelvic US and sometimes MRI or Genitogram
• Karyotype
• Rule out Cong. Adrenal hyperplasia
Serum electrolytes; 17-OHP level,11-DOC & urinary levels of 17-ketosteroids
• Serum androgen (androstenedione, testosterone, DEA, DEAS)
•Laparoscopy
• Gonadal biopsy (Laparotomy)
General guidelines
•Sex assignment should be decided after detailed assessment, investigations and accurate diagnosis
• Complete gender assignment by age 18 months