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Abnormal Sexual Differentiation

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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Abnormal Sexual Differentiation

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  1. Abnormal Sexual Differentiation

  2. 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: Discordance between organic sex and psychological sex components

  3. CLASSIFICATION OF INTERSEXUALITY Disorders of fetal Endocrinology

  4. CLASSIFICATION OF INTERSEXUALITY Primary gonadal defect – Swyer syndrome

  5. How many children are born with intersex conditions? • A conservative estimate is that 1 in 2000 children born will be affected by an intersex condition • 98 % of affected babies are due to congenital adrenal hyperplasia

  6. EXCESS FETAL ANDROGENS 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 PSEUDOHERMAPHRODITISM

  7. 21-hydrxylase deficiencycongenital adrenal hyperplasia Cholesterol Pituitary Pregnenolone Progesterone ACTH 17-OH progesterone Adrenal cortex 21-hydroxylase  Androgens Cortisol Cortisol Androgens

  8. Masculinized femalesCONGENITAL ADRENAL HYPERPLASIA • There are several different forms of CAH, each related to one of the enzymes necessary to transform cholesterol to cortisol (hydrocortisone) • 20,22-hydroxylase, 3 -hydroxysteroid-dehydrogenase / 17-hydroxylase / 21-hydroxylase and 11 -hydroxylase • Among the various forms of CAH, the 21-hydroxylase deficiency is by far the most frequent, representing more than 95% of all cases • Defect in cortisol biosynthesis, with or without aldosterone def, + androgen excess

  9. Ambiguous genitalia • Girls with classic 21-hydroxylase deficiency : exposed to high level of adrenal androgen level (GA 7 wks) • Girls with ambiguous genitalia: -a large clitoris -rugated and partially fused labia majora -uterus,fallopian tubes, and ovaries : normal • Boys : -no overt signs of the disease except variable and subtle hyperpigmentation and penile en-largement

  10. Masculinized females 21-hydrxylase deficiency (P450c21)- Biochemistry • 21 hyrdoxylase is a cytochrome p-450 enzyme located in endoplasmic reticulum • Catalyzed the conversion of 17-hydoxyprogesterone to 11-hydroxycortisol :precursor of cortisol • Conversion of progesterone to 11-deoxycortisterone :precursor of aldosterone • The 21-hydroxylase gene, CYP21, is located on chromosome 6 -> a variety of mutations -> this enzyme deficiency -> adrenal cortex is stimulated & over production of cortisol precursor

  11. Pathways of steroid biosynthesis in the adrenal cortex

  12. Clinical menifestation • Salt wasting type : severe form with a concurrent defect in aldosterone synthesis • Simple virilizing type : normal aldosterone biosynthesis • Both are together termed classic 21-hydroxylase deficiency • Classic 21-hydroxylase deficiency : 1 in 15,000 births • There is also a mild,nonclassic form : may be asymptomatic

  13. Classic 21-hydroxylase deficiency - salt wasting • 1/3 of patients with classic 21-hydroxylase deficiency  severely impaired 21-hydroxylation of progesterone  cannot synthesis of aldosterone • Aldosterone deficiency (esp. in infant)  hyponatremia, hyperkalemia ,acidosis, hypovolemia and shock

  14. 11-hydroxylase (P450c11) deficiency • 11-deoxycortisol, 11-deoxycorticosterone (DOC) • DOC : strong salt-retaining hormone (mineraloorticoid) • HTN, plasma volume expansion, hypokalemic alkalosis with reduced renin & aldosterone • Androgen deficiency  virilization • Tx : glucocorticoids

  15. 3ß-hydroxysteroid dehydrogenase deficiency • Enzyme defects in adrenal and ovary in autosomal –recessive fashion • Cortisol ↓ & aldosterone ↓ • Dehydroepiandrosterone ↑↑  the external genitalia ambiguity • A diagnosis based on baseline and ACTH-stimulated changes in steroid levels is not accurate ; indeed, in adult women, an apparent late-onset 3ß-hydroxysteroid dehydrogenase deficiency is almost always, if not always, a secondary response to anovulation and polycystic ovaries, accompanied by hyperinsulinemia

  16. 17-hydroxylase deficiency • Corticosterone, 11-deoxycorticosterone ↑ • Hypertension (due to hypernatremia and hypervolemia), hypokalemia • Infantile female external genitalia & primary amenorrhea • Genital ambiguity – problem only in male infants

  17. CONGENITAL ADRENAL HYPERPLASIA- Prenatal Diagnosis

  18. CONGENITAL ADRENAL HYPERPLASIA - Diagnosis • Normal infant :100ng/dl (17 -hydroxyprogesterone) • Affected infants : 3,000 - 40,000ng/dl ↑ • The severity of hormonal abnormalities : depends on the type of 21-hydroxylase def • Salt wasting : 17-hydroxyprogesterone: 100000ng/dl

  19. CONGENITAL ADRENAL HYPERPLASIA- Diagnosis • In adult , random 17-hydroxyprogesterone (17-OHP) : baseline - 200ng/dl ↓ • Levels greater 200ng/dl, but less than 800 ng/dl -> Corticotropin stimulation test • To distinguish the 21-hydroxylase deficiency from the order , all of the following in addition to 17-OHP should be measured at zero & 60 minutes after ACTH stimulation : pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone , 11-deoxycortisol, and testosterone

  20. CONGENITAL ADRENAL HYPERPLASIA- Diagnosis

  21. CONGENITAL ADRENAL HYPERPLASIA – Management • According to the clinical course & hormonal level • Purpose : Normal growth, B.Wt, pubertal development, optimal adult height • Growth velocity, body Wt velocity, bone age maturation F/U • Classic 21-OH def -> glucocorticoid : adrenal androgen secretion ↓ -> mineralocorticoid : electrolytes & plasma renin activity -> nl

  22. Treatment Problems • Hypercortisolism (iatrogenic Cushing’s syndrome) -> Sn & Sx : obesity, growth failure, adult short stature, striae, osteoporosis, hyperlipidemia • Symptoms of hyperandrogenism : virilism, infertility of female, precocious virilisation of male, early puberty, adult short stature

  23. CONGENITAL ADRENAL HYPERPLASIA –Prenatal therapy • Classic CAH fetus – pregnant women : Dexamethasone fetal pituitary adrenal axis inhibition & affected female’s genital ambiguity↓ • Risk : when both parents are known carriers -> 1 of 8 fetuses requires Tx for classic CAH • Masculinisation of external genitalia : 6weeks gestation -> start Tx • Chorionic villi sampling or amniocentesis : male or unaffected female -> Tx stop : DNA analysis  normal  stop Dex

  24. Congenital adrenal hyperplasia • The commonest cause of genital ambiguity at birth • 21-Ohas deficiency is most common form • Autosomal reccessive • Salt wasting form may be lethal in neonates • SERUM 17OH-progesterone (21OHase) •  SERUM deoxycorticosterone, 11-deoxycotisol (11- OHase) • Treatment : cortisol replacement and ? Surgery

  25. -Testosterone - Synthetic progestins - Danocrine - Diazoxide - Minoxidil - Phenetoin sodium - Streptomycin - Penicillamine Drugs with Androgenic side effectsingested during pregnancy

  26. Incompletely Masculized Males

  27. Failure to produce testosterone 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

  28. 46-XY/SRY Testicular feminization syndrome TESTIS  MIF Testosterone 5--reductase DHT Absent androgen receptors Male Internal Genitalia Female External Genitalia Incomplete form  Ambiguous genitalia

  29. What is AIS? • A genetic condition where affected people have male chromosomes & male gonads with complete or partial feminization of the ext. genitals • An inherited X-linked recessive disease with a mutation in the Androgen Receptor (AR) gene resulting in: • Functioning Y sex chromosome • Abnormality on X sex chromosome • Types • CAIS (completely insensitive to AR gene)-External female genitalia -Lacking female internal organs • PAIS (partially sensitive-varying degrees)-External genitalia appearance on a spectrum (male to female) • MAIS (mildly sensitive, rare)-Impaired sperm development and/or impaired masculinization

  30. Androgen Receptor Gene • AIS results from mutations in the androgen receptor gene, located on the long arm of the X chromosome (Xq11-q12) • The AR gene provides instructions to make the protein called androgen receptor, which allows cells to respond to androgens, such as testosterone, and directs male sexual development • Androgens also regulate hair growth and sex drive • Mutations include complete or partial gene deletions, point mutations and small insertions or deletions

  31. The Process of Sexual Development • In AIS the chromosome sex and gonad sex do not agree with the phenotypic sex • Phenotypic sex results from secretions of hormones from the testicles • The two main hormones secreted from the testicles are testosterone & mullerian duct inhibitor • Testosterone is converted into dyhydrotestosterone • Mullerian duct inhibitor suppresses the mullerian ducts & prevents the development of internal female sex organs in males • Wolffian ducts help develop the rest of the internal male reproductive system and suppress the Mullerian ducts • Defective androgen receptors cause the wolffian ducts & genitals to be unable to respond to the androgens testosterone & DHT

  32. Complete Androgen Insensitivity • Testicular Feminization SD (female phenotype) • 1 in 20-60,000 males, X-linked trait • In utero loss of androgen, & MIS secretion means loss of internal genitalia • 2% of males with an inguinal hernia have Complete androgen sensitivity • Usually diagnosed c amenorrhea, absence of pubic hair or hormonal profile • Gonadectomy and Oestrogen replacement therapy

  33. Incomplete Androgen Insensitivity(Reifenstein’s Syndrome) • Incomplete male pseudohermaphroditism • Ambiguous genitalia • Normal testosterone, LH and testosterone/DHT ratio • All intermediate type of androgen insensitivity • Azoospermia or severe oligospermic infertility indication of androgen insensitivity

  34. The Androgen Insensitivity Syndromes

  35. 5-alpha-reductase deficiency 46-XY/SRY Testis  MIF Testosterone 5--rductase DHT Female or Ambiguous external Genitalia Male Internal Genitalia

  36. 5-alpha reductase deficiency • Normal internal genitalia : testes secrete T, MIH causes Mullerian ducts to degenerate • Lack of DHT leads to inadequate masculinization of external genitalia at birth • Testes in labia or inguinal canal • Urogenital sinus: urethra & blind vagina • Prostate gland: small or absent • At puberty, lots of T  testes descend, scrotum darkens, phallus enlarges, muscular & deep voice

  37. Testosterone Biosynthesis • 5 enzymes involved in the conversion of cholesterol to testosterone • 3 in the adrenal & testis • 2 in the testis only Cholesterol side change cleavage 3β OH steroid Dehydrogenase 17α Hydroxylase 17,20 Lyase Deficiency 17β OH steroid Dehydrogenase

  38. Testicular enzymatic failure 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

  39. Pathways of steroid biosynthesis in the adrenal cortex

  40. Leydig Cell hypoplasia /LH receptor mutation • 46 XY karyotype but female phenotype • Palpable testes but ↑LH and ↓Testosterone • No stimulation of testosterone with hCG • No Mullerian structures / short vagina • Histology demonstrates no Leydig cells

  41. Leydig-cell agenesis 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

  42. Congenital Lipoid Adrenal Hyperplasia

  43. 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

  44. Hernia Uterine Inguinale(persistant mullerian structures) • Normal phallus, uterus and tubes in the inguinal hernia sac • Poor sperm and hormone production • Gonad cancer risk • Can be familial • Presumed failure of AMH function • Fertility – rarely preserved • AR pattern

  45. Diagnosis of XY Female 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. Disorders of Gonadal Development

  47. Swyer’s syndrome(Bilateral dysgenesis of the testes) 46, XY No SRY OR its receptors STREAK GONADS - NO MIF (Uterus +) - NO SEX STEROIDS Female external Genitalia Female Internal Genitalia

  48. Testicular regression syndromeCongenital Anorchia 46-XY/SRY Testis  MIF (self destruction) ± testosterone ± DHT ± Male Internal genitalia Male Infantile External genitalia

  49. TRUE HERMAPHRODITISM • 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

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