1 / 60

Chpter 9 Normal and Abnormal Sexual Development

CLINICAL GYNECOLOIC ENDOCRINOLOGY AND INFERTILITY. Chpter 9 Normal and Abnormal Sexual Development. OBGY R1 Lee Eun Suk. Normal Sex Differentiation. Gender identity the result of the following determinants Genetic sex Gonadal sex Internal & external genitalia

johannes
Download Presentation

Chpter 9 Normal and Abnormal Sexual Development

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. CLINICAL GYNECOLOIC ENDOCRINOLOGY AND INFERTILITY Chpter 9 Normal and Abnormal Sexual Development OBGY R1 Lee Eun Suk

  2. Normal Sex Differentiation • Gender identity the result of the following determinants • Genetic sex • Gonadal sex • Internal & external genitalia • The secondary sexual characteristics that appear at puberty • The role assigned by society • Four major steps which constitute normal sexual differentiation • Fertilization and determination of genetic sex • Formation of organs common to both sexes • Gonadal differentiation • Differentiation of the internal ducts and external genitalia

  3. Fertilization and Determination of Genetic Sex • Step 1 in sex differentiation:Determination of genetic sex Egg (23,X) + Sperm (23,X)=46,XX genetic female OR Egg (23,X) + Sperm (23, Y)=46, XY genetic male karyotype

  4. Formation of Organs Common to Both Sexes • The fertilized egg multiplies to form a large number of cells Differentiation of the sex organs in this development ; At that stage, both 46,XX & 46,XY fetuses have similar sex organs, specifically • Gonadal ridges • Internal ducts • External genitalia

  5. Internal reproductive organs

  6. Gonadal Differentiation • The important event in gonadal differentiation is of the gonadal ridge to become either an ovary or a testis • In males, the gonadal ridge develops into testes as a result of a product from a gene located on the Y chromosome “Testis determining factor" (TDF) : Gonadal medullary resion -> Sertoli cell “Sex determining region of the Y chromosome" (SRY) • In females, the absence of SRY, due to the absence of a Y chromosome, permits the expression of other genes which will trigger the gonadal ridge to develop into ovaries

  7. Gonadal Differentiation • Pseudoautosomal region • The distal ends of the short arms of the X and Y chromosomes • During meiosis the homologous distal short arms of the X and Y chromosomes pairs, and interchange of genetic material occurs in autosomes • Gene deletions in this area of the X chromosome (Xp22.3) are associated with various conditions short stature , mental retardation, X- linked ichthyosis, Kallmann’s sydrome

  8. Gonadal Differentiation • Subsequent sexual differentiation requires direction by various genes with TDF • SRY: The Y chromosome sex determinants region • SOX9: An autosomal testis-determining gene • DAX1: A potential testis-suppressing gene on X-chromosome • SF1: The link between SRY and the male development pathway • WT1: necessary for normal renal and gonadal development • WNT4: A potential ovary-determining gene on an autosome

  9. Gonadal Differentiation • SRY • Sex determining region of the Y chromosome • Locate on the short arm of the Y chromosome • Transcription factor contains HMG (high-mobility group) box - a DNA binding domain => conrol of gene transcrition • Investigations of the DNA-binding properties of the protein of SRY in the promoter P450 aromatase (conversion of testosterone to estradiol that is down-regulated in the embryo) & anti-mullerian hormone (responsible for regression of the mullerian ducts) • The expression of SRY in the tissue destined to become a gonad directs the cells of this gonadal primordium to differentiate as Sertoli cell

  10. Gonadal Differentiation • SOX9 :An autosomal testis-determining gene (SRY-like box) genes are similar in sequence to SRY : an extra copy of SOX9 developes males, even if they have no SRY gene – XX mice made transgenic for SOX9 develop testes • SF1 ;Steroidogenic factor, necessary to make the bipotential gonad Collaboration with SOX9  elevate levels of AMH transcription • Wnt4 :Activate DAX1 expression Lack the Wnt4 gene  Ovary fail to form properly, express testis specific markers

  11. Postulated cascades leading to the formation of the sexual phenotypes

  12. Summary of key genetic events in early sex determination • Migration of primordial germ cells to the urogenital ridge • Differentiation of the bipotential gonadal tissue under the direction of WT-1 and SF-1 • SRY activation of male-specific genes, especially SOX9, to produce the testes by cell proliferation, differentiation, migration and vascularization • Ovarian differentiation by suppression of SOX9 through the activity of DAX1 and Wnt4

  13. Summary of the genetics of gonadal dysgenesis • Gonadal streaks without germ cells in XX or XY (female phenotype) : • Deficiencies inWT-1 or SF-1 • Lack of testicular development in XY individuals pure gonadal dysgenesis (female phenotype) : • Deficiencies in SRY or SOX9 • Male phenotype in a 46,XX individual : • Presence of SRY • Mixed gonadal dysgenesis in mosaics (varying phenotype) : • Excess DAX1

  14. Internal reproductive organs - Embryonic development • Urinary and genital tract • Closely related, anatomically and embryologically • Embryologic urinary system -> important inductive influence on developing genital system • Anomalies in one system are often mirrored by anomalies in another system • Urinary system, internal reproductive organs & external genitalia • Develop synchronously at an early embryologic age

  15. Kidney, renal collecting system & ureters from nephrogenic cord

  16. Mesonephric (Wolffian) duct • Singular importance for the following reasons • Grows caudally in developing embryo to open an excretory channel into the primitive cloaca and outside world • Serves as starting point for development of the metanephros which becomes definitive kidney • Differentiates into the sexual duct system in male • Although regressing in female fetuses, inductive role in development of the paramesonephric or mullerian duct

  17. Mullerian duct • Paramesonephric or mullerian ducts - development • Form lateral to mesonephric ducts • Grow caudally and then medially to fuse in midline • Contact urogenital sinus in region of the post. urethra at slight thickening known as sinusal tubercle

  18. Duct System Differentiation - Male • TDF • Results in degeneration of gonadal cortex and differentiation of the medullary region of the gonad into Sertoli cells • Sertoli cells • Secrete glycoprotein known as anti-mullerian hormone(AMH) • Regression of paramesonephric duct system in male embryo • Signal for differentiation of Leydig cells from the surrounding mesenchyme

  19. Duct System Differentiation - Female fetus • In the absence of TDF, medulla regresses and cortical sex cords break up into isolated cell clusters (-> primordial follicles) • In the absence of AMH & testosterone • Mesonephric duct system degenerates • Then, paramesonephric duct system develops • Inf. fused portion • Uterovaginal canal -> uterus and upper vagina • Cranial unfused portions • Open into celomic cavity (future peritoneal cavity) • Fallopian tubes

  20. Anti-Müllerian Hormone • A member of the transforming growth factor-ß family • Regression of Müllerian duct system in male embryo • AMH has an inhibitory effect on oocyte meiosis • Plays a role in the descent of the testes • Inhibits surfactant accumulation in the lungs • Proteolytic cleavage of AMH produces fragments that have the ability to inhibit growth of various tumor ( a potential therapeutic application)

  21. Duct System Differentiation • Leydig cells • Produce testosterone & dihydrotestosterone with 5a-reductase • Testosterone • Responsible for evolution of mesonephric duct system into vas deferens, epididymis, ejaculatory duct & seminal vesicle • At puberty, leads to spermatogenesis & changes in primary and secondary sex characteristics • DHT(dihydrotestosterone) • Results in development of the male external genitalia , prostate and bulbourethral glands

  22. External Genitalia Differentiation • In the female, absence of androgens permits the external genitalia to remain feminine • The genital tubercle becomes the clitoris • The labioscrotal swellings → the labia majora • The urogenital folds → the labia minora • In the male, fetal androgens from the testes masculinize the external genitalia • The genital tubercle grows to become the penis • The labioscrotal swellings fuse to form the scrotum

  23. External Genitalia

  24. Abnormal Sexual Development

  25. CLASSIFICATION OF INTERSEXUALITY Disorders of fetal Endocrinology

  26. CLASSIFICATION OF INTERSEXUALITY Primary gonadal defect – Swyer syndrome

  27. 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

  28. EXCESS FETAL ANDROGENS Congenital adrenal hyperplasia 21 -hydrxylase deficiency 11-hydroxylase deficiency 3ß-hydroxysteroid dehydrogenase deficiency EXCESS MATERNAL ADROGEN Maternal androgen secreting tumours (ovary, adrenal) Maternal ingestion of androgenic drugs FEMALE PSEUDOHERMAPHRODITISM

  29. 21-hydrxylase deficiencycongenital adrenal hyperplasia Cholesterol Pituitary Pregnenolone Progesterone ACTH 17-OH progesterone Adrenal cortex 21-hydroxylase  Androgens Cortisol Cortisol Androgens

  30. Masculinized females CONGENITAL ADRENAL HYPERPLASIA • There are several different forms of CAH, each related to one of the enzymes necessary to transform cholesterol to cortisol (hydrocortisone) • StAR / 20,22-hydroxylase, 3 -hydroxysteroid-dehydrogenase / 17-hydroxylase / 21-hydroxylase and 11 -hydroxylase • When one of these enzymes is deficient, this leads to a hyperfunction and increased size (hyperplasia) of the adrenals • 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

  31. Masculinized females CONGENITAL ADRENAL HYPERPLASIA - Biochemistry • Steroid 21 hyrdoxylase is a cytochrome p-450 enzyme located in ER • Catalyzed the conversion of 17-hydoxyprogesterone to 11-hydroxycortisol :precursor of cortisol • Conversion of progesterone to deoxycortisterone :precursor of aldosterone • This enzyme deficiency -> adrenal cortex is stimulated & over production of cortisol precursor

  32. Pathways of steroid biosynthesis in the adrenal cortex

  33. Hypothalamic pituitary adrenal axis Renin-angiotensin-aldosterone axis

  34. 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 • There is also a mild,nonclassic form : may be asymptomatic • Classic 21-hydroxylase deficiency : 1 in 16,000 births

  35. CONGENITAL ADRENAL HYPERPLASIA - salt wasting • 75 percent of patients with classic 21-hydroxylase deficiency  severely impaired 21-hydroxylation of progesterone  cannot synthesis of aldosterone • Elevated of 21-hydroxylase precursor: aldosterone antagonist • Aldosterone deficiency  hypovolemia and hypereninemia, and hyperkalemia (esp. in infant) • Cortisol deficiency poor cardiac contractility, poor vascular resp. to catecholamine, and GFR ↓ , antidiuretic H ↑

  36. CONGENITAL ADRENAL HYPERPLASIA - salt wasting • So together : hyponatremic dehydration and shock • Adrenal medulla : depending on the glucocorticoid in part  so salt wasting 21hyroxylase deficiency  catecholamine deficiency  exacerbating shock Identify : e, aldosterone, plasma renin (hyperkalemia and low aldosterone and hyperreninemia)

  37. 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

  38. Postnatal virilization • Exposed to the high levels of sex steroids • Rapid growth (usually androgen effect) • Advanced bone age  premature epiphyseal closure (androgen’s extragonatal aromatization of estrogen) • Pubic and axillary hair: early develop • Girl : clitorial growth • Young Boys : penile growth • Long term stimulation : central precocious puberty

  39. Linear growth • A meta-analysis of data from 18 centers showed : 1.4 SD below the population mean • Both undertreatment and overtreatment : risk for short stature • Undertreatment : causing premature epiphyseal closure induced by high levels of sex steroids • Overtreatment : glucocorticoid-induced inhibition of the growth

  40. Reproductive function • Girls : problem at the reproductive system -oligomenorrhea, amenorrhea -prenatal androgen exposure: effect to sex-role behavior • Boys : fewer problems

  41. CONGENITAL ADRENAL HYPERPLASIA - Diagnosis

  42. CONGENITAL ADRENAL HYPERPLASIA • Normal infant :100ng/dl (17 hydroxyprogesterone) • Affected infants:10000ng/dl ↑ • New born -> screening test • 10% (severe affected infant) : 17 hydroxyprogesterone level ↓ • Preterm or sick infants -> 17 hydroxyprogesterone level ↑↑ • The severity of hormonal abnormalities: depends on the type of 21-hydroxylase def • Salt wasting : 17-hydroxyprogesterone: 100000ng/dl

  43. CONGENITAL ADRENAL HYPERPLASIA • Random 17-hydroxyprogesterone(17-Ohpro) >80 ug/L or 242 nmol/L (nl : <2.95 ug/L or 9 nmol/L) • Salt losing > nonsalt loser -> corticotropin stimulation test : unneeded • Genetic analysis -> prenatal testing • Nonclassic CAH : random 17-OHpro : nl -> Screening : early morning basal 17-OHpro level >1.5 ug/L (4.5 nmol/L) in children & >2.0 ug/L(6nmol/L) in women during follicular phase of menstrual cycle -> Corticotropin ST(250ug of tetracosactide(cosyntropin) ) : any time during the day => positive : 17-OHpro >15.0 ug/L(45nmol/L)

  44. CONGENITAL ADRENAL HYPERPLASIA • Heterozygote carrier : mild elevation, 17-OHpro <10 ug/L(30nmol/L) following CST • Carrier : symptoms or signs of the disease • Premature adrenarche 1/3 : heterozygote carriers of 21-OH def (recent) • 17-OHpro :10-15 ug/L -> DDx of heterozygote carrier or homozygote affected Pt -> Genetic analysis

  45. 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 normalization

  46. 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

  47. Glucocorticoid and mineralocorticoid therapy • Hydrocortisone of physiologic dose -> corticotropin & androgen production suppression (Х): 6 mg/m2/day • Hydrocortisone 12-15mg/m2/day -> sufficient androgen suppression • 20 mg/m2/day (neonatal period) • 25 mg/m2/day -> do not use • Dose variability factor • Indivudual variation in the metabolism and sensitivity • Previous degree of hypothalamic-pituitary-adrenal axis suppression • High dose glucocorticoid short course therapy

  48. Glucocorticoid and mineralocorticoid therapy • Mineralocorticoid (fludrocortisone) : plasma renin activity ->mid normal range • Dose :100-200 ug/day • Nonsalt losing :elevated plasam renin activity • Infant with salt losing : NaCl supply ->1-2 g/day • 17mEq Na/NaCl 1g

  49. CONGENITAL ADRENAL HYPERPLASIA – Monitoring therapy • Commonly, serum 17-hydroxyprogesterone & androstenedione level • Testosterone level in female and prepubertal male • Test time : early morning(8:00 AM) • Target level of 17-OHpro : 4-12 ug/L (12-36 nmol/L)

More Related