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  • A and B , An untreated girl with the non–salt-losing form of congenital adrenal hyperplasia. Androgens caused disproportionate acceleration of bone maturation compared with stature. C , Virilized adult female with non–salt-losing adrenal hyperplasia. The patient had a deep voice, shaved daily, and wore a toupee for baldness. After treatment with cortisone, her 17-ketosteroid levels fell to normal values, her breasts enlarged, she underwent a normal menarche, and hair regrew on her head. Note short stature and short extremities. D , Female pseudohermaphroditism caused by maternal ingestion of an oral progestational compound from the 8th to 12th week of pregnancy. Labioscrotal fusion is sufficient to obscure the vaginal orifice and create a urogenital sinus. Clitoris is enlarged. There is no progressive virilizing tendency. (C, from Wilkins L. The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, 3rd ed. Springfield, IL, Charles C Thomas, 1965.)
  • Because testosterone production never significant, brain imprinting not a factor in gender assignment.
  • At least one Y and two X to be Klinefelter’s. ICIS  intracytoplasmic sperm injection
  • A 19-year-old phenotypic male with chromatin-positive seminiferous tubule dysgenesis (Klinefelter's syndrome). The karyotype was 47,XXY, gonadotropin levels were elevated, and testosterone levels were low normal. Note normal virilization with long legs and gynecomastia (B, C) . The testes were small and firm and measured 1.8 × 0.9 cm. Testicular biopsy revealed a severe degree of hyalinization of the seminiferous tubules and clumping of Leydig cells. D , A 48-year-old male with 47,XXY Klinefelter's syndrome with severe leg varicosities.
  • Characterized by … Patients typically present for evaluation of gynecomastia. Androgen replacement and reduction mamoplasty in selected pts. Lack of germ cell elements obviates testicular biopsy & ICSI (intracytoplasmic sperm injection)
  • Three patients with 45,X/46,XY sex chromosome mosaicism who illustrate the highly variable phenotype in this variant of the syndrome of gonadal dysgenesis. (Numbers of the patients refer to designation in Table 22-13 .) A , Patient 1, a phenotypic female, was age 15 years, 4 months. She had short stature (-3.1 SD), an increased number of pigmented nevi, puffiness over the dorsa of fingers, and broad and short hands, and she was sexually infantile (breast development seen in photograph followed estrogen therapy) except for sparse pubic and axillary hair. The urinary gonadotropins were markedly elevated. B , Patient 3, aged 3 years, 1 month, had ambiguous external genitalia, perineal hypospadias, and undescended gonads. He was of average height and had a broad chest and a duplication of the left kidney. C , Patient 9, aged 8 years, 1 month, was a phenotypic male with a penile urethra and unilateral undescended gonad, average height, cubitus valgus, short fourth metacarpals, and puffiness of dorsa of fingers. By age 15, male secondary sexual characteristics were well advanced and a left scrotal testis, which was normal in histologic appearance, measured 4.0 × 2.4 cm.
  • Closely related to Turner’s syndrome In contrast to Turner’s growth hormone here is normal.
  • Elevated LH  likely responsible for androgen production  clitoromegaly
  • The syndrome entails the presence of testes that "vanish" during embryogenesis and is distinguished from pure gonadal dysgenesis, in which there is no evidence of testicular function in utero. Possible etiology  genetic mutation, teratogen, bilateral torsion. At puberty males get androgens and females get estrogen supplementation.
  • 75% raised male; hypospadius and chordee in about 80%. Virtually all have UG sinus present and most have uterus present. 2/3 are 46,XX karyotype but 46,XY and mosaics occur less commonly. Fallopian tubes present on the side of ovary and vas deferens present adjacent to testis. A 17-year-old true hermaphrodite with bilateral scrotal ovotestes and a 46,XX sex chromosome constitution in cultures of peripheral blood and skin, perineal hypospadias (partially repaired in photograph), moderate bilateral gynecomastia and pubic hair (recently shaved in picture), sparse axillary hair, a high-pitched voice, and absent facial hair. Height was 168 cm. Urinary 17-ketosteroid level was 1.3 mg/day; urinary gonadotropin levels were elevated. A male type of urethra, bilateral scrotal fallopian tubes and ovotestes, and rudimentary bicornuate uterus and vagina attached to the posterior urethra were seen at operation. The photomicrographs show histopathology of the ovarian and testicular portion of one ovotestis. B , Immature seminiferous tubules lined with Sertoli cells and spermatogonia and Leydig cells. C , Ova and follicles. (From Grumbach MM, Barr ML. Cytologic tests of chromosomal sex in relation to sexual anomalies in man. Recent Prog Horm Res 1958; 14:255–334.)
  • Partial gonadectomy possible in female but stimulate the bHCG post op to ensure all testicular tissue removed.
  • Presence of one or two gonads on exam rules out female pseudohermaphroditism Because ovaries do not descend…
  • Diagnostic algorhythm for newborn with ambiguous genitalia based on gonadal palpability, presence or absence of mullerian structures, 17, hydroxyprogesterone concentration, and karyotype If no testes check for elevated LH or stimulate with hCG to demonstrate testicular tissue.
  • Study by Kaefer and associates 1999, studied incidence of intersex in pts with chriptorchidism and hypospadius without ambiguous genitalia. Karyotype usually takes 2-3 days, but can get rapid analysis with FISH (fouorescent in situ hybridizaiton)  few hrs.
  • High quality data regarding long-term psychosocial outcomes of gender assignment are lacking at this point but longitudinal studies are being persued. 46, XX Normal ovaries, mullerian ducts, and reproductive potential. 46, XY if complete androgen insensitivity then female appropriate gender, whereas 5a-reductase deficiency more appropriately male. Most frequent abnormal karyotype is 45X/46XY mosaicism  variable phenotypic pattern. Ultimately this is a challenging and humbling process to say the least

Intersex ppt by arch Intersex ppt by arch Presentation Transcript

  • Prof. M.C.Bansal MBBS,MS,MICOG,FICOG Professor OBGY Ex-Principal & Controller Jhalawar Medical College & HospitalMahatma Gandhi Medical College, Jaipur.
  • Defining Sex and GenderGender identity (Psychological sex)Inner sense of owns maleness / femaleness. Sex of rearing Gender roleSexual identity (Organic sex)The biologic sexual differentiation Chromosomal sex Gonadal sex Internal genital sex External genital sex Hormonal sex
  • Human sexual differentiation Chromosomal sex Gonadal sexInternal genital sex External genital sex SEX ASSIGNMENT Sex of rearing Gender identity and role
  • Gonadal development SRY-gene (TDF) Short arm of Y chromosome Present Absent Bipotential Gonad Receptors 2 X chromosomesFor H -Y antigen TESTES OVARY
  • Male development TESTIS Leydig Sertoli cells cells Testosterone Mullerian inhibiting factorWollfian duct 5a-reductase DHT Regrsession of Muuleian ducts Urogenital sinusMale internalGenital organs Male external genitalia
  • Female development Neutral Development OVARY Urogenital sinus Mullerian ductsFemale external genitalia Female internal genital. Lower part of vagina Organs . Most of upper vaginaAbsence of androgen exposure . Cervix and uterus . Fallopian tubes
  • Summary of Normal Sex Differentiation genetic sex is determined at fertilization. testes develop in XY fetus, ovaries develop in XX fetus. XY fetus produces MIS and androgens and XX fetus does not. XY fetus develops Wolffian ducts and XX fetus develops Mullerian ducts. XY fetus masculinizes the female genitalia to make it male and the XX fetus retains female genitalia.
  • 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
  • CLASSIFICATION OF INTERSEXUALITYDisorders of fetal Endocrinology
  • CLASSIFICATION OF INTERSEXUALITY Primary gonadal defect – Swyer syndrome
  • 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
  • FEMALE PSEUDOHERMAPHRODITISMEXCESS FETAL EXCESS MATERNAL ANDROGENS ANDROGENSCongenital adrenal hyperplasia 21 -hydrxylase deficiency  Maternal androgen secreting tumors (ovary, adrenal) 11-hydroxylase deficiency 3ß-hydroxysteroid  Maternal ingestion of dehydrogenase deficiency androgenic drugs
  • Congenital Adrenal Hyperplasia It is a familial disorder of adrenal steroid biosynthesis with autosomal recessive mode of inheritance. The defect is expressed as adrenal enzyme deficiency. 5 major Enzymes deficiency are clinically important  21-Hydroxylase  11-b-Hydroxylase  17-a-Hydroxylase  3-b-Hsteroid hydrogenese  20,22 Desmolase deficiency
  • CAH The most frequent is steroid 21- hydroxylase deficiency, accounting for more than 90 percent of cases. The enzyme deficiency causes reduction in end-products, accumulation of hormone precursors & increased ACTH production. The clinical picture reflects the effects of inadequate production of cortisol & aldosterone and the increased production of androgens & steroid metabolites.
  • Biochemistry Steroid 21-hydroxylase (CYP21, also termed CYP21A2 and P450c21) is a cytochrome P-450 enzyme located in the endoplasmic reticulum. Itcatalyzes the conversion of 17- hydroxyprogesterone to 11-deoxycortisol, a precursor of cortisol, and the conversion of progesterone to deoxycorticosterone, a precursor of aldosterone. Owing to this loss of enzyme function, patients with 21-hydroxylase deficiency cannot synthesize cortisol efficiently, and as a result, the adrenal cortex is stimulated by corticotropin and overproduces cortisol precursors.
  • Contd… Cortisol is an adrenal steroid hormone that is required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of ACTH, which in turn induces overgrowth (hyperplasia) and overactivity of the steroid -producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e., present at birth)
  • Contd… Some of these precursors are diverted to the biosynthesis of sex hormones, which may cause signs of androgen excess, including ambiguous genitalia in newborn girls and rapid postnatal growth in both sexes. Concomitant aldosterone deficiency may lead to salt wasting with consequent failure to thrive, hypovolemia, and shock.
  • 21-hydrxylase deficiency congenital adrenal hyperplasia Cholesterol Pituitary Pregnenolone Progesterone ACTH 17-OH progesterone Adrenal cortex21-hydroxylase  Cortisol Androgens Cortisol Androgens
  • 21-hydrxylase deficiency congenital adrenal hyperplasia Most common type, accounts for >80% of cases. Incidence is 1:5000 to 1:15000 live birth. Gene is located on the short arm of chromosome 6 near the C4 locus in close association with HLA genes. Heterozygous carriers can be detected by ACTH stimulation test.
  • Contd.. It is characterized by reduced production of cortisol and aldosterone and increased production of progesterone; 17-OH-progesterone, and sex steroids. The urinary steroid metabolites (17-ketosteroids and pregnanetriol) are elevated above normal levels.
  • Contd.. Decreased secretion of aldosterone results in salt loss with hyponatremia and hyperkalemia; plasma renin activity is therefore elevated. In partial enzyme deficiencies, the aldosterone deficiency is not expressed, and patients remain normonatremic and normokalemic. The excess androgens causes virilization of girls & ambiguous genitalia & dark scrotum in boys.
  • Contd… There are 3 forms: 1. classic early virilization type with or without salt-losing crisis(typically identified at birth because of genital ambiguity) 2.Salt wasting (in which there is impairment of mineralocorticoid as well as glucocorticoid secretion), 3. non-classic type with late-onset virilization(in which heterosexual development occurs at the expected age of
  • Contd… Male babies with non salt-losing non- classic type remains asymptomatic till late childhood when they may show signs of sexual precocity. Because members of the same family may have classic, non-classic & asymptomatic forms, the disorder may be due to allelic variations of the same enzyme. Massneonatal screening using filter paper blood sample for 17-OH-
  • CLINICAL MANIFESTATIONS1. In classic form(girls are born with ambiguous genitalia) having enlarged clitoris fusion of the labioscrotal folds and the urogenital sinus. The internal female organs (including the uterus, fallopian tubes, and ovaries) develop normally because they are not affected by the increased androgen levels. early pubic hair and rapid growth in childhood precocious puberty or failure of puberty to occur ( sexual infantilism: absent or delayed puberty) excessive facial hair Virilization menstrual irregularity in adolescence infertility due to anovulation shallow vagina
  • clitoromegalylabioscrotal fusion Marked virilization with hypospadiac-appearing phallus
  • 2. In salt wasting 21hydroxylase deficiency hyponatremia hyperkalemia hypotensionCLASSICAL CAH
  • Contd… During childhood, untreated girls with either the classic or salt wasting form grow rapidly but have advanced bone ages, enter puberty early, experience early closure of their epiphyses, and ultimately are short in stature as adults. CAH, with appropriate therapy, is the only inherited disorder of sexual differentiation in which normal pregnancy and childbearing are possible. Boys : -no overt signs of the disease except variable and subtle hyperpigmentation and penile en-largement
  • BOYS WITH CAH Are unrecognized at birth because their genitalia are normal. They are not diagnosed until later, often with a salt wasting crisis resulting in dehydration, hypotension, hyponatremia and hyperkalemia or later in childhood with early pubic hair & phallic enlargement accompanied by accelerated linear growth and advancement of skeletal maturation. High blood pressure & hypokalemia may occur in those with 11-b-hydroxylase deficiency and 17-a- hydroxylase deficiency due to the accumulation of the mineralocorticoid desoxycorticosterone
  • )Williams Textbook of Endocrinology, 10th ed, 2003(
  • 11-hydroxylase (P450c11) deficiency Accounts for 5-10% of cases of CAH. Gene is located on the long arm of chromosome 8. caused by mutations in the CYP11B1 gene. It is characterized by low plasma renin activity & elevation of serum 11-Deoxycortisol and 11- deoxycorticosterone. Because of the strong mineralocorticoid activity of deoxycorticosterone, the condition is characterized by salt retention, hypertension & hypokalemic alkalosis. The elevated plasma androgens may cause virilization of the female fetus.
  • 3ß-hydroxysteroid dehydrogenase deficiency This is a very rare disorder that results in accumulation of DHEA, which is converted to testosterone in peripheral tissues. Enzyme defects in adrenal and ovary in autosomal – recessive fashion Caused by mutations in the HSD3B2 gene encoding the 3 ß- HSDII enzyme affects the synthesis of glucocorticoids, mineralocorticoids, and sex steroids. Cortisol ↓ & aldosterone ↓ Dehydroepiandrosterone ↑↑  the external genitalia ambiguity It can cause virilization of female fetus and leads to ambiguous genitalia in the newborn. 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
  • 17-hydroxylase deficiency  Genetic def ect is on chromosome 10.  Corticosterone, 11- deoxycorticosterone ↑  Presents with similar f eatures of those of 11- Hydroxylase def iciency except that Androgens are low, so no virilization in girls & genitalia is ambiguous in boys.  Hypertension (due to hypernatremia and hypervolemia), hypokalemia  Inf antile f emale external genitalia & primary amenorrhea
  • ESSENTIALS OF DIAGNOSIS Increased linear growth with advanced bone age and eventual short stature Pseudohermaphorditism in girls due to androgen virilizing effect Isosexual precocity in boys with small infantile testes. Adrenal crisis with salt-loss & metabolic acidosis or Hypertension & hypokalemic alkalosis. Low cortisol with high androgens, ACTH and steroid precursors e.g. 17-OH-Progest. or 11-Deoxycortisol. Diagnosis is confirmed by measurement of ACTH, Cortisol, Aldosterone, 17-OH-progesterone, Testosterone & urinary 17-ketosteroids. Needs alertness for the possibility in all babies with Diarrhea & Vomiting, hypoglycemia or ↑ BP.
  • Diagnosis Classic 21-hydroxylase deficiency is characterized by markedly elevated serum levels of 17- hydroxyprogesterone, the main substrate for the enzyme. The gold standard for differentiating 21-hydroxylase deficiency from other steroidogenic enzyme defects is the corticotropin (cosyntropin) stimulation test,measuring base-line and stimulated levels of 17-hydroxyprogesterone. corticotropin (cosyntropin) stimulation test : The most commonly used stimulatory test involves measurement of 17-hydroxyprogesterone 30 minutes after administration of a bolus of 250 mg of synthetic cosyntropin (Cortrosyn).
  • Contd… In normal women - this value seldom exceeds 400 ng/dL. Patients with classic 21-hydroxylase deficiency - achieve peak levels of 3,000 ng/dL or higher. Patients with nonclassic 21-hydroxylase deficiency-achieve levels of 1,500 ng/dL or more. Heterozygous carriers - achieve peak levels up to about 1,000 ng/dL.In hirsute women with hypertension, 11-deoxycortisol levels can be determined during the test. If both 11-deoxycortisol and 17- hydroxyprogesterone levels are increased, the rare 11-hydroxylase deficiency is present. Only measurements of several steroid precursors after corticotropin stimulation can identify individuals with nonclassic forms of 3-HSD deficiency.The elevated levels of 17-hydroxyprogesterone present in all forms of 21- hydroxylase deficiency are rapidly suppressed by administration of exogenous corticoids. Even a single dose of a glucocorticoid such as dexamethasone will suppress 17-hydroxyprogesterone in CAH but not in virilizing ovarian and adrenal neoplasms.
  • 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 iN adult , raNdom 17-hydroxyprogesteroNe (17-ohp) : baseliNe - 200Ng/dl ↓ levels greater 200Ng/dl, but less thaN 800 Ng/dl -> corticotropiN stimulatioN test
  • Lab Findings Demonstration of inadequate production of cortisol and/or aldosterone in the presence of accumulation of excess concentrations of precursor hormones is diagnostic. In 21-hydroxylase deficiency, very high serum 17- hydroxyprogesterone is characteristic together with very high urinary pregnanetriol (metabolite of 17-hydroxyprogesterone). Both are accompanied by elevated 24-hour urinary 17- ketosteroids, the urinary metabolites of adrenal androgens.
  • Other tests Salt wasting forms of adrenal hyperplasia are accompanied by low serum aldosterone, hyponatremia, hyperkalemia and elevated plasma renin activity indicating hypovolemia. In contrast hypertensive forms of adrenal hyperplasia (11-β-hydroxylase deficiency and 17- α-hydroxylase deficiency) are associated with suppressed plasma renin activity and hypokalemia A karyotype is essential in the evaluation of the infant with ambiguous genitalia in order to establish the chromosomal sex. Prenatal diagnosis of adrenal hyperplasia is possible through biochemical and genetic tests.
  • Imaging Studies A pelvic ultrasound : in the infant with ambiguous genitalia to demonstrate the presence or absence of a uterus or associated renal anomalies A urogenitogram is often helpful to define the anatomy of the internal genitalia. A CT scan of the adrenal gland to R/O bilateral adrenal hemorrhage in the patient with signs of acute adrenal failure A bone age study is useful in the evaluation of the child who develops precocious pubic hair, clitoromegaly, or accelerated linear growth.
  • CONGENITAL ADRENAL HYPERPLASIA – Management GOALS  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  Classic 21-OH def -> glucocorticoid : adrenal androgen secretion ↓ -> mineralocorticoid : electrolytes & plasma renin activity
  • MODE OF TREATMENT Steroid replacement Supportive therapy when needed Treatment is life-long Plastic surgery for ambiguous genitalia at early age Genetic counseling Psychological support
  • Treatment(1)-Glucocorticoids Patients with classic 21-hydroxylase deficiency require long-term glucocorticoid treatment to inhibit excessive secretion of corticotropin- releasing hormone and corticotropin by the hypothalamus and pituitary, respectively, and to reduce elevated levels of adrenal sex steroids. In children, the preferred drug is hydrocortisone (i.e., cortisol itself ) in maintenance doses of 10 to 20 mg per square meter of body-surface area per day in three divided doses.
  • Treatment(2)-Glucocorticoids Doses of up to 100 mg per square meter per day are given during adrenal crises and life-threatening situations. Even these maintenance doses exceed physiologic cortisol secretion (7 to 9 mg per square meter per day in neonates and 6 to 8 mg per square meter per day in children and adolescents). The efficacy of treatment is best monitored by measuring 17-hydroxyprogesterone and androstenedione levels at a consistent time in relation to the administration of medication.
  • Treatment(3)-Glucocorticoids The therapeutic goal is to use the lowest dose of glucocorticoid that adequately suppresses adrenal androgens and maintains normal growth and weight gain. Children should also undergo radiography annually to determine bone age, and their linear growth should be carefully monitored. Older adolescents and adults may be treated with prednisone (e.g., 5 to 7.5 mg daily in two divided doses) or dexamethasone (total, 0.25 to 0.5 mg given in one or two doses per day).
  • Treatment(1)-Mineralocorticois  Infants with the salt-wasting form of 21- hydroxylase deficiency require supplemental mineralocorticoid (usually 0.1 to 0.2 mg of fludrocortisone daily) and sodium chloride (1 to 2 g or 17 to 34 mmol of sodium chloride chloride daily in addition to glucocorticoid treatment).  Older infants and children usually do not require sodium chloride supplements, and they often have reduced requirements for fludrocortisone.
  • Treatment(2)-Mineralocorticoids Plasma renin activity levels or direct renin immunoassays may be used to monitor the adequacy of mineralocorticoid and sodium replacement, taking into account the age-specific reference ranges for each laboratory. Hypotension, hyperkalemia, and elevated renin levels suggest the need for an increase in the dose, whereas hypertension, edema, tachycardia, and suppressed plasma renin activity signify overtreatment with mineralocorticoids.
  • NEW TRENDS OF T/T A New approach therapy is the combined use of 4 drugs: glucocorticoid (to suppress ACTH and adrenal androgen production), mineralocorticoid (to reduce angiotensin II concentrations), aromatase inhibitor (to slow skeletal maturation), flutamide (an androgen blocker to reduce virilization)
  • Management of AmbiguousGenitalia Improvements in the surgical correction of genital anomalies over the past two decades have led to earlier use of single-stage surgery — between two and six months of life in girls with 21-hydroxylase deficiency, a time when the tissues are maximally pliable and psychological trauma to the child is minimized. The long-term outcomes of the newer surgical procedures have yet to be evaluated.
  • SURGICAL T/T Infants with CAH may require surgical evaluation and, if needed, corrective surgery. Traditional approach is clitroplasty early in life, followed by vaginoplasty after puberty. Some female infants with adrenal hyperplasia are only mildly virilized and may not require corrective surgery if they receive adequate medical therapy to prevent further virilization.
  • Prenatal diagnosis and t/t Done by chorionic villus sampling at 8-12 wk & amniocentesis at 18-20 wk. HLA typing in combination with measurement of 17- OH-progesterone & androstenedion in amniotic fluid is used for antenatal diagnosis. Prenatal treatment of 21-hydroxylase deficiency prevents intrauterine virilization of female fetuses. According to the protocol proposed by Carlson et al, the mother is treated with dexamethasone (20 µ/kg/d in 3 divided doses) as soon as the pregnancy is recognized to suppress fetal ACTH secretion & prevent the fetal adrenal gland from overproducing adrenal androgens.
  • Incompletely Masculized Males
  • Male pseudohermaphroditism (XY- FEMALE)Failure to utilize Failure to producetestosterone testosterone  Defects in testicular Androgen receptor deficiency steroidogenesis * Complete androgen  Gonadotropin-resistant Insensitivity (TFS) testes (LH receptor mutation) * Incomplete androgen  Congenital lipoid adrenal Insensitivity hyperplasia 5-alpha reductase deficiency  Defective synthesis, secretion, or response to anti-mullerian hormone
  • 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 1. CAIS (completely insensitive to AR gene) -External female genitalia -Lacking female internal organs 2. PAIS (partially sensitive-varying degrees) -External genitalia appearance on a spectrum (male to female) 3. MAIS (mildly sensitive, rare) -Impaired sperm development and/or impaired masculinization Also called Testicular Feminization
  • Normal Sexual Development MALE Sex Chromosome = XY Gonads = Testes External Genitalia = MaleFEMALE Sex Chromosome = XX Gonads = Ovaries External Genitalia = Female Normally chromosome sex determines gonad sex which determines phenotypic sex ?WHAT HAPPENS IN AIS
  • 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
  • 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
  • AIS Fetus Development• Each fetus has non-specific genitalia for the first 8 weeks after conception• When a Y-bearing sperm fertilizes an egg an XY embryo is produced and the male reproductive system begins to develop • Normally the testes will develop first and the Mullerian ducts will be suppressed and testosterone will be produced• Due to the inefficient AR gene cells do not respond to testosterone and female genitalia begin to form The amount of external feminization depends on the severity of the androgen receptor defect  CAIS: complete female external genitalia  PAIS: partial female external genitalia  MAIS: Mild female external genitalia, essentially male
  • 46-XY/SRY Testicular feminization TESTIS  MIF syndrome Testosterone 5-∝-reductase DHT Absent androgen receptors Female Male External Internal Genitalia GenitaliaIncomplete form  Ambiguous genitalia
  • Complete Androgen InsensitivityTesticular Feminization SD (female phenotype) – female-appearing external genitalia, and absence of müllerian derivatives  Blind ending vagina, reduced pubic hair1 in 20-60,000 males, X-linked traitIn utero loss of androgen, & MIS secretion means loss ofinternal genitalia2% of males with an inguinal hernia have Complete androgensensitivity so vaginoscopy prudenUsuallydiagnosed amenorrhea, absence of pubic hair orhormonal profileGonadectomy and Oestrogen replacement therapy
  • Incomplete Androgen Insensitivity (Reifenstein’s Syndrome) Incomplete male pseudohermaphroditismAmbiguous genitalia to varying degrees  male with perineoscrotal hypospadias, cryptorchidism, rudimentary Wolffian duct structures, gynecomastia, and infertility  the phenotypic spectrum can range from hypospadias and a pseudovagina to gynecomastia and azoospermia etiology:  (1) a reduced number of normally functioning androgen receptors  (2) a normal receptor number but decreased binding affinity Gender assignment is often dictated by phenotype and degree of virilization Normal testosterone, LH and testosterone/DHT ratioAll intermediate type of androgen insensitivity
  •  Infertile male syndrome – normal male phenotype but are azoospermic or severely oligospermic – normal to elevated serum testosterone – normal to elevated LH – decreased androgen receptor binding to DHT in genital skin fibroblasts
  • Testing for AIS Tests – During Pregnancy  Chorionic Villus Sampling (9-12 weeks)  Ultrasound and Amniocentesis (after 16 weeks) – After Birth  Presence of XY Chromosomes – Buccal Mouth Smear – Blood Test  Pelvic Ultrasound  Histological Examination of Testes
  • Biochemical Testing forCarriers Tests – 1960-70s: Skin biopsies-evaluate androgen binding capacity  Carries: 50% androgen binding  Problem: some cases skipped because mutation did not always take place in the binding region of the gene – 1990s: DNA Testing  blood or mouth cavity smears – Now:  Measure length of base pair repeat region in first exon of gene and compare it to a female relative’s repeat region to determine if they are a carrier
  • Non-Biochemical Testing Maternal relatives affected by AIS In an XX female – Delayed puberty – Reduced pubic-auxiliary hair – Asymmetric pubic-auxiliary hair – Reduced bone density
  • Treatments Surgery – Orchidectomy or gonadectomy  Removal of the testes – Vaginal lengthening – Genital plastic surgery  Reconstructive surgery on the female genitalia if masculinization occurs  Phalloplasty  Vaginoplasty – Pressure dilation  Clitorectomy Debate – What age? – Who decides?
  • Treatments Hormone Replacement Therapy (HRT) – Types  Female: Estrogen – Progesterone (sometimes take to reduce risk of breast or uterine cancer) – postorchidectomy  Male: Testosterone and DHT – Form  Oral, transdermal, implant, injection, vaginally – Prevents osteoporosis (age 10 or 11)  Body responds as if it is post-menopausal, thus body density decreases and osteoporosis occurs
  • The Androgen Insensitivity Syndromes 5α-redutase Complete Incomplete Reifenstein Infertile Inheritance Autosomal X-linked X-linked X-linked X-linked recessive recessive recessive recessive recessiveSpermatogenesis Decreased Absent Absent Absent Decreased Mullerian Absent Absent Absent Absent Absent Wolffian Male Absent Male Male Male External Female Female Female Male Male Clitomegaly Hypospadia Breasts Male Female Female Gynecomastia Gynecomastia
  • 5-alpha reductase deficiency Secondary to mutations in the type II gene Phenotype may vary from penoscrotal hypospadias to, more commonly, markedly ambiguous genitalia 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
  • 5-alpha-reductase 46-XY/SRY Testis  MIF deficiency Testosterone 5-∝-rductase DHT Female or Male Internal Ambiguous Genitaliaexternal Genitalia
  • Male Pseudohermaphroditism Disorders of Testosterone Biosynthesis – Defect in any of the five enzymes  incomplete (or absent) virilization of the male fetus during embryogenesis – Inheritance is autosomal recessive Cholesterol Side Chain Cleavage Deficiency (StAR Deficiency) – a defect in cholesterol transport prevents conversion of cholesterol to pregnenolone – 46,XY individuals have female or ambiguous external genitalia  a blind-ending vaginal pouch  intra-abdominal, inguinal, or labial testes  absence of müllerian structures & Wolffian ducts are present but rudimentary  severe adrenal insufficiency and salt wasting – suspect this if nonvirilized female external genitalia with:  cortisol and aldosterone deficiency  hyponatremia, hyperkalemia, and metabolic acidosis. – Abdominal CT scanning demonstrates large, lipid-laden adrenal glands
  • Testosterone Biosynthesis 5 enzymes involved in the conversion of cholesterol to testosterone–3 in the adrenal & testis Cholesterol side change cleavage 3β O steroid Dehydrogenase H 17α Hydroxylase–2 in the testis only 17,20 Lyase Deficiency 17β O steroid Dehydrogenase H
  • Testicular enzymatic 46-XY/SRY failure Testis  MIF Autosomal recessive enzyme(defects in testosterone deficiency : Synthesis) -20-22 desmolase -3-ß-ol- dehydrogenase testosterone precursors -17- ∝ -hydroxylaseDHT -17,20-desmolase -17-ß –OH steroid dehydrogenaseAmbiguous MaleExternal InternalGenitalia Genitalia
  • Leydig Cell hypoplasia /LH receptor mutation-46,XY male karyotype, normal-appearing female phenotype– Palpable testes but ↑LH and ↓Testosterone– No stimulation of testosterone with HCG–spectrum  absent Leydig cells to Leydig cells with abnormal LH receptor–autosomal recessive trait– No Mullerian structures / short vagina–DDx = androgen insensitivity syndrome or a terminal defect in androgensynthesis.–Testis histology = absent of Leydig cells in intratubular spaces, normalSertoli cells
  • Leydig-cell agenesis 46-XY/SRY TESTIS  MIF ( partial/ complete absence Of leydig-cells) No or  testosterone No or  DHTFemale or ± Maleambiguous Internalexternal GenitaliaGenitalia
  • 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
  • Diagnosis of XY Female Testosterone concentration Low Normal Male level Concentration ofTestosterone precurcers DHT High Low Low NormalTesticular Absent testes or 5 ∝-reductase Testicular enzyme Absent leydig- Deficiency Feminization Failure cell Syndrome Surgical exploration
  • Seminiferous Tubule Dysgenesis(Klinefelters syndrome) Syndrome characterized by eunuchoidism, gynecomastia, azoospermia, increased gonadotropin levels, and small, firm testes, 47,XXY karyotype – nondisjunction during meiosis – 1 of 1000 liveborn males – associated with 48,XXYY; 49,XXXYY; 48,XXXY; 49,XXXXY; 46,XY/47XXY Gynecomastia can be quite marked at pubertal development – 8 X risk for breast carcinoma compared with normal males Seminiferous tubules degenerate and are replaced with hyaline – Fertility, with the benefit of ICSI, has been reported in one patient – decreased androgens prevents normal secondary sexual development  poor muscle development, the fat distribution is more female than male.  Normal amounts of pubic and axillary hair, but facial hair is sparse.  Patients tend to be taller than average, due to disproportionately long legs Predisposed to malignant neoplasms of extragonadal germ cell origin. Androgen supplementation to improve libido & reduction mammoplasty – surveillance for breast carcinoma
  • Klinefelters syndrome )Williams Textbook of Endocrinology, 10th ed, 2003(
  • 46,XX maleness Occurs in 1 of every 20,000 males Testicular development in subjects who have two X chromosomes and lack a normal Y chromosome. Most of these subjects have normal male external genitalia, but 10% have hypospadias and all are infertile – 80% are Sry positive and rest are Sry negative – Sry -positive group rarely have genital abnormalities, but they have phenotypic features of Klinefelters syndrome Shorter (mean height, 168 cm) and have more normal skeletal proportions than Klinefelter’s patients Due to translocation of Y chromosomal material, including SRY, to the X chromosome Infertile  lack of germ cell elements
  • Disorders of Gonadal Development
  • Gonadal Dysgenesis Features:Turners Syndrome (45 X0) 1. Female Phenotype 2. Short Stature 3. No Secondary Sexual Characteristics 4. Somatic Abnormalities Occult Y Ch. Material: - Webbed Neck Predisposed to Virilisation - Broad Chest and Gonadoblastoma (30%) - Short Ring finger and other GCT (50%).–Presence of one functioning X Chromosome–1 in 2500 females. Mosaicism 45 X/46 XX (10%) or 45 X/46 XY (3%)–Oocytes degenerate leaving streak gonads (in broad lig.) at birth–Reduced Oestrogen, Raised FSH/LH. No pubertal development Renal Anomalies:–Management includes: 90% Multiple Renal Arteries 20% Renal agenesis/Duplication Growth Hormone to Children & estrogens at puberty 15% Malrotation 10% Horseshoe kidney Up to one third may have functioning ovaries - so pregnancy is possible Remove Streak gonads in Mosaic patients Alternative Names:Bonnevie-Ullrich syndrome; Gonadaldysgenesis; Monosomy X
  • Symptoms
  • Turner syndromeKaryotype 45,X (60%)(45,X/46,XX, structural abnormalities of X chromosome)Short stature (final height 142-147 cm)Gonadal dysgenesis - streak gonad & sexual infantilismSkletal abnormalities & dysmorphic faceCardiac and kidney malformationAutoimmune ds : Hashimoto’s thyroditis, Addison’s dsMild insulin resistance & hearing lossLymphedemaEssential hypertensionNo mental defectImpairment of cognitive function : mathematical ability↓Visual–motor coordination, spatial-temporal processing↓ H. Tuner, 1938
  • Turner syndrome – work up IVP or renal USG Echocardiography Audiometry Lipid profile & glucose metabolism (annually) Annual pelvic examination & appropriate screening for gonadal neoplasm as an adnexal mass Expert consultation to pursue further analysis with X- and Y- specific DNA probes
  • Pure Gonadal Dysgenesis All subjects with female genitalia, normal mullerian structure & streak gonads ( with either 46,XX or 46,XY karyotypes) None of Turner phenotype anomalies
  • Gonadal dysgenesis)Williams Textbook of Endocrinology, 10th ed, 2003(
  • 46,XX pure gonadal dysgenesis Features: – normal female external genitalia – normal müllerian ducts with absence of wolffian duct structures – a normal height – bilateral streak gonads – sexual infantilism – normal 46,XX karyotype streak gonads elevated serum gonadotropins Management of 46,XX "pure" gonadal dysgenesis: – cyclic hormone replacement with estrogen and progesterone. – growth is basically normal so GH is not needed possibly autosomal recessive trait
  • 46,XY Complete GonadalDysgenesis Characterized by : – normal female genitalia – well-developed müllerian structures – bilateral streak gonads – nonmosaic karyotype Ambiguity of genitalia is not an issue Sexual infantilism is the primary clinical problem – present in their teens with delayed puberty An abnormality of the Sry gene function, or loss of another gene downstream from Sry that is necessary for SRY protein action LH elevated  clitoromegaly 30% risk of germ cell tumor development by age 30 years – gonadoblastoma is most common – embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, and immature teratoma have also been reported Management  removal of both streak gonads and proper cyclic hormone replacement with estrogen and progesterone
  • Gonadal Dysgenesis Multiple X female (47,XXX) – Normal development & reproductive function – Mental retardation- frequent – Secondary amenorrhea & eunuchoidism
  • Mixed Gonadal Dysgenesis Features: Unilateral testis (undescended) Contralateral Streak Gonad Persistent Mullerian Structures Some masculinisation–Mosaicism: 45 XO/ 46 XY Mostly females with; Enlarged phallus–Second most common cause for Ambiguous Labioscrotal foldsgenitalia Uterus /vagina & tubes–Mostly phenotypic females, but entire spectrumcovered Increased risk of:–Due to lack of MIS production in unilateral Gonadoblastoma (20%) - testis > streak gonaddysgenetic Wilm’s tumor Denys-Drash Syndrome testis with ipsilateral fallopian tube - Nephropathy /CRF - Genital Abnormalities–Management includes Gender assignment (2/3 - Wilms tumourfemale), - XX/XY mosaicism May need prophylactic Appropriate gonadectomy & screen for Wilm’s bilateral nephrectomytumor
  • Mixed Gonadal Dysgenesis Karyotype 46XY / 45X0 Combined features of Turner’s SD & male pseudohermaphroditism Short stature Streak gonad on one side with a testis on the other side Unicornuate uterus & fallopian tube- side of streak gonad Considrable variation in the sexual phenotype
  • Gonadal Dysgenesis Surgical Removal of Gonadal Tissue  The gonadal tissue having any Y chromosome component in phenotypic females  removal as soon as the diagnosis is made to avoid the risk of malignant gonadal tumor (except complete androgen insensitivity) : Laparoscopy or laparotomy  The uterus and tubes should be preserved for the possibility of pregnancy with donor oocytes
  • Gonadal Dysgenesis Hormone Treatment of Patients Without Ovaries  Starting when the bone age is 12 with unopposed estrogen ( 0.3mg conjugated estrogens or 0.5mg estradiol daily)  After 2 years , a sequential program is initiated with 0.625mg conjugated estrogens or 1.0mg conjugated estrogens + 5mg medroxyprogesterone acetate for 14days (if a uterus is present)  In patients with genetic shortness in stature (e.g. Turner SD)  Estrogens treatment is not started until bone age is 12 (to avoid epiphysial closure)
  • Gonadal Dysgenesis Stimulation of Growth  Growth hormone treatment for short stature in turner syndrome : Optimal response  an early onset of Tx around age 6~7  Now that the success of GH treatment in recognized & accepted, an argument can be made for chromosomal screening by molecular analysis of all growth-retarded girls
  • Gonadal Dysgenesis The Possibility of Pregnancy  In women who have variants of gonadal dysgenesis and who menstruate, pregnancy can occur  30% incidence of congenital anomalies in the offspring  amniocentesis or chorionic villus biopsy  Donated oocytes yields excellent results  Fatal aortic events (aneurysm, dissection, or rupture) can occure during pregnancy in patients with gonadal genesis. A cardiology consultation with a echocardiogram is strongly advised
  • Swyer’s syndrome (Bilateral dysgenesis of the testes) 46, XYNo SRY OR its receptors STREAK GONADS - NO MIF (Uterus +) - NO SEX STEROIDS Female Female external Internal Genitalia Genitalia
  • Embryonic Testicular Regression andBilateral Vanishing Testes Syndromes  46,XY karyotype and absent testes but clear evidence of testicular function during embryogenesis  "embryonic testicular regression" = loss of testicular tissue within the first trimester and is associated with ambiguity of external genitalia  "bilateral vanishing testes syndrome" refers to individuals in whom male sexual differentiation of ducts and genitalia took place but loss of testicular tissue occurred subsequently in utero  Diagnosis can be made on the basis of a 46,XY karyotype and castrate levels of testosterone despite persistently elevated serum LH and FSH – bilateral vanishing testes syndrome, agonadal XY phenotypic males with fully developed wolffian structures, but an empty scrotum, absent prostate, and microphallusSpectrum of presentation – intermediate point presentation is the 46,XY patient with absent gonads and internal ductal structures but with ambiguous genitalia  incomplete elaboration of androgen – most severe form, agonadism is discovered in a 46,XY phenotypic female with no internal genital structures;  the testis has elaborated MIS but vanishes at 60-70 days before elaboration of androgen
  • Testicular regression syndrome Congenital Anorchia 46-XY/SRY Testis  MIF (self destruction) ± testosterone ± DHT Male ± MaleInfantile InternalExternal genitaliagenitalia
  • 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
  • True Hermaphroditism Individuals who have both testicular tissue with well-developed seminiferous tubules and ovarian tissue with primordial follicles, which may take the form of one ovary and one testis or, more commonly, one or two ovotestes. External genitalia and internal duct structures of true hermaphrodites )Williams Textbook of Endocrinology, 10th ed, 2003( display gradations between male and female
  • True Hermaphroditism In most patients, the external genitalia are ambiguous but masculinized to variable degrees, and 75% are raised as male Internal ductal development are influenced by ipsilateral gonad – Fallopian tubes are consistently present on the side of the ovary – a vas deferens is always present adjacent to a testis – Fallopian tube is present with 66% of ovotestes, vas or both in 33% – Most have urogenital sinus and and uterus 80% of those raised as male have hypospadias and chordee Ovaries usually on left in normal position, testis usually on right and located anywhere along path of descent 60% of gonads palpable in canal or labia are ovotestes
  • True Hermaphroditism Ovarian portion of the ovotestis is frequently normal, whereas the testicular portion is typically dysgenetic 66% of patients are 46 XX Gonadal tumors is approximately 10% in 46,XY true hermaphroditism and 4% in 46,XX true hermaphroditism Most important aspect of management in true hermaphroditism is gender assignment Sex assignment should be based on the functional potential of external genitalia, internal ducts, and gonads, according to the findings at laparoscopy or laparotomy. Unlike patients with most other forms of gonadal dysgenesis, true hermaphrodites have the potential for fertility if raised as female with the appropriate ductal structures Males, remove ovaries and/or ovotestis and mullerian duct structures consider gonadectomy Females remove all testicular and wolffian structures
  • Noonan syndrome Both affected males and females have apparently normal chromosome complements and normal gonadal function The phenotype appearance of Turner syndrome : short stature, webbed neck, shield chest & cardiac malformations (esp, pulmonic stenosis) The trait as autosomal-dominant with variable expression
  • MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIA GENERAL GIUDELINES Medical and social emergency Avoid immediate declaration of sex Proper counselling of the parents Team management; obstetrician, neonatologist, pediatric endocrinolgist, genetist and paediatric surgeon.
  • EVALUATION AND MANAGEMENT OF THENEWBORN WITH AMBIGUOUS GENITALIA  Medical and psychosocial emergency to be handled with great sensitivity toward the family  Goals: – precise diagnosis of the intersex disorder – assign a proper sex of rearing based on the diagnosis – determine the status of the childs anatomy – delineate the functionality of genitalia and reproductive tract  Valuable history points: – infant death – infertility – amenorrhea – hirsutism – maternal medications (i.e. steroids , OCP), during pregnancy  Physical examination: the presence of one or two gonads  Distinctly palpable gonad along the pathway of descent is highly suggestive of a testis
  • MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIADIAGNOSIS History : pregnancy; family Detailed examination ; Abdomen; pelvis; external genitalia; urethral and anal openings – Are gonads palpable? – What is the phallus length? – What is the position of the urethral meatus? – To what degree are the labioscrotal folds fused? – Is there s vagina, vaginal pouch, or urogenital sinus? – Dehydration, hypotension, hyperpigmentation in adrenal hyperplasia
  • DDx Algorithm
  • EVALUATION AND MANAGEMENT OF THENEWBORN WITH AMBIGUOUS GENITALIA Posterior urethral meatal position is a strong predictor of intersex 65%, versus 5% to 8% with a midshaft to anteriorly located hypospadiac meatus Penile size should be assessed and an accurate measure of stretched penile length recorded. Precise means of assessing müllerian anatomy is by pelvic ultrasound Karyotype should be obtained Serum studies should be immediately sent to rule out a salt-wasting form of CAH. Serum electrolytes, testosterone and DHT should be measured early
  • MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIAInvestigations• 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)
  • Gender Assignment Issues related to the diagnosis-specific potential for normal sexual functioning and fertility and the risk of gonadal malignancy should be addressed In the setting of a 46,XX karyotype, gender assignment is usually appropriately female If the karyotype is 46,XY, the issue is a more complex one and includes factors such as penile length and evidence of androgen insensitivity The degree of masculinization of the external genitalia appears to vary with the amount of testicular tissue present – gender assignment depends on the functional potential of the gonadal tissue, reproductive tracts, and genitalia Parameters of Optimal Gender Policy (Meyer-Bahlberg, 1998) – Reproductive potential (if attainable at all) – Good sexual function – Minimal medical procedures – An overall gender-appropriate appearance – A stable gender identity – Psychosocial well being