Male sex diffrentiation • Choromosomal sex • Gonadal sex • Sexual phenotype Gonadal sex Urogenital ridge →Primitive gonad 4-5 wk Testis determination Testis determination occurs at about six weeks of gestation Testis determination The SRY gene initiates the process of testis determination. Internal urogenital tract Wolffian and mullerian ducts are present in both sexs Anti mullerian hormone Sertoli cells→:AMH (7wk) Regression of mullerian duct Fetal Leydig cells and androgen production Fetal Leydig cells → androgens by 8 to 9 wk Fetal Leydig cells and androgen production Testosterone Wolffian duct: Epididymides Vasa deferentia Seminal vesicles Ejaculatory ducts Sexual phenotype DHT:androgenization of the external genitalia and urogenital sinus Sexual phenotype Genital swelling→ Scrotum Genital folds → Shaft of the penis Genital tubercle →Glans penis Testis descenting Testicular descent : at around 12 weeks • Complete by the middle of the third trimester. • Ambiguous or female external genitalia DEFINITION Incomplete intrauterine masculinisation with or without the presence of Mullerian structures Classification 1-ABNORMALITIES OF GONADAL DEVELOPMENT Complete or partial gonadal dysgenesis Testis regression syndrome Ovotesticular 46,XY DSD 2-Testosterone synthesis defects LH receptor mutations Smith-Lemli-Opitz syndrome Steroidogenic acute regulatory protein mutations Cholesterol side chain cleavage (CYP11A1) defects Classification 3-β-HSD 2 deficiency 17α-hydroxylase/17,20-lyase deficiency POR deficiency 17-βHSD 3 deficiency 5α-reductase 2 deficiency 3-DEFECTS IN ANDROGEN ACTION AIS 4-other Persistence of Müllerian ducts syndrome Case 1 دختر 14سال و 2ماهه ای به علت تا خیر بلو غ مراجعه کرده است.وزن بیمار kg 52و قد وی 167سانتیمتر می باشد. در معاینه باید به چه نکاتی دقت کرد؟ P/E معاینه از نظر مرحله بلوغ (سینه ها –موهای تناسلی) معاینه ژنیتالیا معاینه شکم از نظر توده عالئم حیاتی با تاکید بر فشار خون case1 Breast=II, Pubic hair=I Genitalia:clitoromegaly,blind vaginal pouch BP=110/70 Other examination:normal Lab evaluation از نظر پاراکلینیک چه ارزیابی هایی درخواست می کنید؟ Lab evaluation1 سونوگرافی شکم و لگن Lab evaluation1 در سونوگرافی رحم و تخمدان ندارد.دو توده با اکوی مشابه بیضه در اینگوینال Lab evaluation1 تشخیص احتمالی؟ بررسی بعدی ؟ Lab evaluation1 LH FSH Testosterone DHT Estradiol 17OHP AD Lab evaluation 1 : آزمایشات 17OHP=normal Testosterone :High ↑Estradiol )for male( ↑↑LH FSH=Nl Lab evaluation 1 HCG test Lab evaluation 1 T/DHT=7 ) NL( Lab evaluation 1 Karyotype Diagnosis اگر کاریوتیپ بیمار 46 XYباشد چه تشخیصی مطرح می شود؟ Diagnosis Androgen insensitivity syndrome Loss of function mutations of the gene that encodes the androgen-receptor X-linked recessive CAIS ,PAIS Female external genitalia Ambiguous Hypospadias Vagina is either absent or short and blind-ending Testes may be located in the abdomen, the inguinal canals, or the labia majora 1-2% girls with inguinal hernia Androgen insensitivity syndrome The urogenital tract :absence or near absence of müllerian structures Breast development is that of a normal woman, but has not had her menarche Axillary and pubic hair are markedly decreased or absent. Androgen insensitivity syndrome These patients are taller (average height 172 cm) and heavier than normal women AIS:Lab Data ↑ LH and testosterone levels ↑Estradiol (for male reference range) FSH levels often normal or slightly increased AIS:Treatment Gonadectomy should be performed because of the increased risk of testicular tumors, especially after puberty. Possibility of AIS Girls with inguinal hernias or labial masses Women with primary amenorrhea Adolescent girls who become virilized and develop clitoromegaly Adult men with undervirilization or with infertility associated with azoospermia or severe oligospermia Case 2 نوزاد 16روزه ای با بی حالی و لتارژی ارجاع شده است .در معاینه دهیدره بوده و رفلکس های نوزادی کاهش یافته است.در معاینه چه نکاتی اهمیت دارد؟ Case 2 چک عالئم حیاتی معاینه ژنیتالیا چک فشار خون Case 2 در معاینه ژنیتالیا اسکروتوم دو شاخه-میکروپنیس و هیپوسپدیاز دارد بیضه ها در اسکروتوم می باشد تا کی کارد بوده و فشار خون پائین است Case 2 بررسی بعدی؟ Case 2 ارسال آزمایشات اولیه Blood gas Na/K BS Sepsis W/UP Case 2 Blood gas:PH=7.15 Hco3=5 Na=123 K=7.5 BS=50 Case 2 آزمایشات تکمیلی؟ Case 2 17 OHP DHEAS Testosterone Cortisol Case 2 ↑17 OHP ↑DHEAS ↓Testosterone ↓Cortisol Case 2 تشخیص؟ درمان ؟ 3β-Hydroxysteroid Dehydrogenase type II Deficiency 3β-HSD is essential for the biosynthesis of mineralocorticoids, glucocorticoids and sex steroids It affects both adrenal and gonadal AR Ambiguous external genitalia, (micropenis,perineal hypospadias,bifid scrotum and a blind vaginal pouch) With or without salt loss 3β-HSD II Deficiency(Lab) ↑17-OHPreg either basally or after ACTH stimulation 17-OHP and AD may also be elevated Most of the patients were raised as males Adrenal crisis Tx Serum N/S :10-20 cc/kg Serum DW5% with saline 0.9 without kcl Stress dose of hydrocortisone(50-100 mg/m2) 0-3 yr :25 mg /IV 3-12 yr:50 mg /IV > 12 yr:100 mg /IV Hydrocortisone :50-100 mg/m2/day q6 hr Adrenal crisis Tx Hypoglycemia:2-4 cc/kg DW10% Treat and monitor electrolyte abnormalities 3β-HSD II Deficiency)Tx) Glucocorticoid 15-20 mg/m2 /day in 3 doses Mineralocorticoids ( salt-losing form):0.05-0.2 mg/day Nacl:4 -8 meq/kg/day At puberty variable necessity for testesterone replacement Case 3 دختر 15ساله ای به علت عدم رشد سینه ها ارجاع شده است. قد 170سانتیمتر و وزن 58کیلو گرم دارد. در معاینه باید به چه نکاتی دقت کرد؟ P/E معاینه از نظر مرحله بلوغ (سینه ها –موهای تناسلی) معاینه ژنیتالیا معاینه شکم از نظر توده عالئم حیاتی با تاکید بر فشار خون Case 3 Breast =I Pubic hair=III Genitalia:clitoromegaly(recently enlarge) Blind vaginal pouch BP=110/80 Other examination:normal Lab evaluation3 از نظر پاراکلینیک چه ارزیابی هایی درخواست می کنید؟ Lab evaluation3 سونوگرافی شکم و لگن Lab evaluation 3 در سونوگرافی رحم و تخمدان ندارد.دو توده در ناحیه اینگوینال دیده می شود. Lab evaluation 3 تشخیص احتمالی؟ بررسی بعدی ؟ Lab evaluation3 LH FSH Testosterone DHT Estradiol 17OHP AD Lab evaluation 3 : آزمایشات 17OHP=normal Testosterone ,Estradiol=NL(for male) LH=NL FSH=Nl AD=NL Lab evaluation 3 سن استخوانی Lab evaluation 3 سال14= سن استخوانی Lab evaluation 3 HCG test Lab evaluation 3 T/DHT=32↑ Lab evaluation 3 Karyotype Diagnosis اگر کاریوتیپ بیمار 46 XYباشد چه تشخیصی مطرح می شود؟ Diagnosis Steroid 5-alpha-reductase 2 deficiency Autosomal recessive Inadequate conversion of T→DHT Ambiguous external genitalia Micropenis Hypospedias Blind vaginal pouch Normal internal male genitalia Prostate hypoplasia No müllerian structures are present. The testes are usually located in the inguinal region Steroid 5-alpha-reductase 2 deficiency Virilization and deep voice appear at puberty, along with penile enlargement, and muscle mass development These patients present scarce facial and body hair and absence of temporal male baldness, acne and prostate enlargement 5-alpha-reductase 2 deficiency :Lab Data Concentrations of serum testosterone and estrogens are similar to those in normal men. LH is normal or slightly elevated Measurement of basal serum concentrations of T and DHT is not sufficient for diagnosis before the expected age of puberty Steroid 5-alpha-reductase 2 deficiency T and DHT should be measured before and after multiple injections of hCG. Steroid 5-alpha-reductase 2 deficiency The ratio(T/DHT) generally exceeds 30:1(20:1) Steroid 5-alpha-reductase 2 deficiency out come ≥50 percent of 46,XY patients with this disorder undergo change in gender role from female to male after the time of expected puberty