Presentation on theme: "Disorders of Sexual Differentiation"— Presentation transcript:
1 Disorders of Sexual Differentiation Vincenzo Galati, D.O.Stephen Confer, MDBen O. Donovan, MDBrad Kropp, MDDominic Frimberger, MDUniversity of OklahomaDepartment of UrologySection of Pediatric Urology
2 Normal Sexual Differentiation Jost paradigm:Establishment of chromosomal sex at fertilizationDevelopment of the undifferentiated gonads into testes or ovariesDifferentiation of the internal ducts and external genitaliaSexual differentiation is a very complex process which normally proceeds sequentially through complex genetic and hormonal interactions. According to the Jost paradigm 3 steps must occur: establishment of chromosomal sex at fertilization, which determines development of the undifferentiated gonads into testes or ovaries, and subsequent differentiation of the internal ducts and external genitalia as a result of endocrine functions associated with the type of gonad present.
3 Chromosomal SexTDF was mapped to the most distal aspect of the Y-unique region of the short arm of the Y chromosome, adjacent to the pseudoautosomal boundarySry is localized to the smallest region of the Y chromosome capable of inducing testicular differentiation in humans and in miceSry appears to be capable of recognizing specific sites on DNA, and, by binding and producing bending of the DNA, it is able to activate downstream gene expressionNow, we’ve known since the 1950’s that the Y chromosome possesses genetic material which determines the destiny of the bipotential gonad.This is a genetic map of the short arm of the human Y chromosome. SRY is an evoultionarily conserved gene on the Y chromosome of mammals.In 1991 Koopman and coworkers introduced the Sry gene into XX mouse embryos and demonstrated it was capable of giving rise to testicular development in the transgenic mice. Genetic and molecular data have established that SRY can be equated to the TDF
4 TDF candidatesZFY (zinc finger gene on Y chromosome) was excluded with certainty as a candidate for TDF when four individuals with testicular development were found to have inherited a fragment of the Y chromosome that did not include ZFYH-Y gene: A number of women with 45,X gonadal dysgenesis were found to be H-Y antigen positive
5 Other Important GenesWT-1 : originally isolated in experiments that identified an oncogene on chromosome 11 as being involved in the etiology of Wilms' tumor. Research on WT-1 in the mouse suggests that it exerts its effects upstream of SRY and is likely to be necessary for commitment and maintenance of gonadal tissueSF-1: a nuclear receptor, is expressed in all steroidogenic tissue and appears to be a regulator of müllerian inhibiting substance (MIS)SOX-9 gene: identified in patients with camptomelic dysplasia, a congenital disease of bone and cartilage formation that is often associated with XY sex reversalSOX-9 HMG-box amino acid sequence has 71% similarity to that of SRY.Expression of the gene in adults is greatest in the testes and is thought to be involved in gonadal differentiationHMG high mobility group
6 Other Important GenesDSS (DAX-1) (dosage-sensitive sex reversal). Found in XY females with duplication of this geneSuggests duplicated X chromosome causes XY sex reversal by expressing a double dose of the gene normally subject to X inactivation. Screening of XY females with a normal Sry gene detected a submicroscopic duplication designated DSSImplicated in adrenal hypoplasia congenitaWNT4 (factor in ovarian pathway)Thought to repress the biosynthesis of gonadal androgen in female mammals, therefore is suppresses male sexual differentiation (Hughes, NEJM, 351(8), Aug 19, )
7 Gonadal Stage of Differentiation During the first 6 weeks of embryonic development structures are bipotential in both 46,XY and 46,XX embryosMigration of the germ cells begins in the 5th week of gestation through the mesentery to the medial ventral aspect of the urogenital ridgeSRY initiates the switch that induces the indifferent gonad toward testicular organogenesisIn the absence of SRY, ovarian organogenesis resultsThe differentiation of Sertoli cells is associated with the production of MIS, a glycoprotein encoded by a gene on the short arm of chromosome 19Primordial cells of steroidogenic mesenchyme remain among the testicular cords and represent future Leydig cells, which differentiate at 8 to 9 weeksPrimordial germ cells recognized in the 3rd week migrate in 5th week.In males a second line of primordial cells of steroidogenic mesenchyme…
8 Gonadal Stage of Differentiation Duplicate copies of at least one X chromosomal locus is likely necessary for normal oviarian organogenesisDysgenetic ovaries in Turner's syndrome patientsIn embryonal ovaries, germ cells undergo intense mitotic proliferation and in the process exhaust their entire mitotic potential prenatallya maximum endowment of 20 million cells by 20 weeks gestationThis presumably explains the dysgenetic ovaries in Turner’s syndrome
9 Gonadal FunctionThe initial endocrine function of the fetal testes is the secretion of MIS by the Sertoli cells at 7 to 8 weeks' gestationTestosterone secretion by the fetal testes is detectable shortly after the formation of Leydig cells in the interstitium at approximately 9 weeks' gestationtestosterone peaks at 13 weeks and then declinestestosterone enters target tissues by passive diffusionDHT binds to the androgen receptor with greater affinity and stability than does testosteronethe gene encoding the androgen receptor has been cloned and mapped to the X chromosome between the centromere and q13Estrogen synthesis is detectable in the female embryo just after 8 weeks of gestationTestosterone enters androgen target tissue and either binds to androgen receptor in cell nuclei or is converted by 5a-reductase to DHT.The local source of androgen is important for wolffian duct development, which does not occur if testosterone is supplied only via the peripheral circulation. In some cells like those in the UG sinus, testosterone is converted to dihydrotestosterone intracellular 5a-reductase.Remember estrogens are not required for normal female differentiation of the reproductive tract but they can interfere with male differentiation.
10 Undifferentiated Urogenital Tract 8 wksDifferentiation of the wolffian and mullerian duct and UG sinus in male and female.Schematic diagram of external genitalia in the indifferentiated period.Before the 8th week of gestation the UG tract is identical ini the two sexes. In the male fetus, sertoli cells produce MIS, which acts locally and unilaterally to suppress the mullerian ducts, and leydig cells produce testosterone, which permits local development of the wolffian structures.By 10 weeks gestation, degeneration of the mullerian ducts is almost complete in the male and the wolffian ducts have become more prominent. In the female the absence of testosterone regression of wolffian ducts.10 wksUndifferentiated External genitalia
11 Differentiation Timeline Timetable of normal sexual differentiation.By weeks gestation, the genitalia of the male fetus is completed with closure of the elongated UG cleft.In female in absence of testosterone the external genetalia are maintained at the 6 week gestational age.
12 Psychosexual Differentiation gender identity: the identification of self as either male or femalegender role: aspects of behavior in which males and females appear to differgender orientation: choice of sexual partner (heterosexual, homosexual, or bisexual)cognitive differences
13 Psychosexual Differentiation Experience in patients with congenital adrenal hyperplasia (CAH) who were exposed prenatally to androgen and in patients reared in a sex opposite to their chromosomal or gonadal sex have provided evidence to indicate that gender identity is not merely a function of chromosomal complement or prenatal endocrine milieustrong evidence has accumulated for the impact of prenatal hormonal influences on sexually dimorphic behavior or gender rolepreviously accepted dogma that children are psychosexually neutral at birth and capable of being environmentally oriented has been seriously challenged by those who support the concept of prenatal psychosexual differentiationA national task force has been organized to study larger numbers of affected patients in hopes of improving our understanding of the “nurture vs nature” controversy, and will likely prove very important in optimizing our management of patients with intersex disorder.
14 Disorders of Gonadal Differentiation and Development
15 Klinefelter's syndrome 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.(Williams Textbook of Endocrinology, 10th ed, 2003)
16 Seminiferous Tubule Dysgenesis (Klinefelter's syndrome) Syndrome characterized by eunuchoidism, gynecomastia, azoospermia, increased gonadotropin levels, and small, firm testes, 47,XXY karyotypenondisjunction during meiosis1 of 1000 liveborn malesassociated with 48,XXYY; 49,XXXYY; 48,XXXY; 49,XXXXY; 46,XY/47XXYGynecomastia can be quite marked at pubertal development8 X risk for breast carcinoma compared with normal malesSeminiferous tubules degenerate and are replaced with hyalineFertility, with the benefit of ICSI, has been reported in one patientdecreased androgens prevents normal secondary sexual developmentpoor 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 legsPredisposed to malignant neoplasms of extragonadal germ cell origin.Androgen supplementation to improve libido & reduction mammoplastysurveillance for breast carcinomaAt least one Y and two X to be Klinefelter’s.ICIS intracytoplasmic sperm injection
17 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 infertile80% are Sry positive and rest are Sry negativeSry -positive group rarely have genital abnormalities, but they have phenotypic features of Klinefelter's syndromeShorter (mean height, 168 cm) and have more normal skeletal proportions than Klinefelter’s patientsDue to translocation of Y chromosomal material, including SRY, to the X chromosomeInfertile lack of germ cell elementsCharacterized 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)
18 Turner’s Syndrome (45,XO) No oocytes remain in the ovaries, which become streaksFertility = 60% pregnancy rate w/ARTOvum donation for those with bilateral streaks1 in 2500 live births60% are 45,XO and 40% are mosaicsY chromosomal material masculinization & gonadoblastoma (30%)33% - 60% have structural or positional abnormalities of the kidneyhorseshoe kidney = 10%,duplication or renal agenesis= 20%malrotation= 15%multiple renal arteries = 90%Four classic features:female phenotypeshort staturelack of secondary sexual characteristicsa variety of somatic abnormalities:Webbed neckWide spaced nipplesBroad chest (shield)Cubitus valgusShort statureRapid attrition rate of oocytes thought due to inadequate protective layer of follicular cells which usually surround the germ cells; streaks typically located in broad ligament.Both estrogen and androgens are decreased and LH and FSH are increased.Dx. Frequently made because of amenorrhea.Y chromosome predisposes to masculinization and gonadoblastoma, therefore timely excision of streaks in Y mosaic is advised.Human growth hormone between yrs, and exogenous hormone therapy to induce puberty and to maintain normal female endocrine status is begun.Pregnancy is realistic possibility with current assisted reproductive technology.peripheral edema at birth, short 4th metacarpal, hypoplastic nails, multiple pigmented nevi, coarctation of the aorta, and renal anomalies
19 46,XX pure gonadal dysgenesis Features:normal female external genitalianormal müllerian ducts with absence of wolffian duct structuresa normal heightbilateral streak gonadssexual infantilismnormal 46,XX karyotypestreak gonads elevated serum gonadotropinsManagement of 46,XX "pure" gonadal dysgenesis:cyclic hormone replacement with estrogen and progesterone.growth is basically normal so GH is not neededpossibly autosomal recessive traitClosely related to Turner’s syndromeIn contrast to Turner’s growth hormone here is normal.
20 (Williams Textbook of Endocrinology, 10th ed, 2003) Gonadal dysgenesisThree 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 ) 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.(Williams Textbook of Endocrinology, 10th ed, 2003)
21 Mixed gonadal dysgenesis (MGD) Characterized by a unilateral testis, often intra-abdominalContralateral streak gonadPersistent müllerian structures with varying inadequate masculinizationMost are 45,XO/46,XY, the most common form of Y chromosome mosaicismSecond most common cause of ambiguous genitalia after CAHDysgenetic or streak gonad is associated with ipsilateral müllerian derivatives (uterus, fallopian tube)Well-differentiated testis with functional Sertoli and Leydig cells will have ipsilateral wolffian but no müllerian ductsno germ cells so infertility is the ruleIncreased risk of developing gonadoblastoma or dysgerminoma of 15% to 20%Also increased risk for Wilm’s tumor and association with Denys-DrashEndocrine function of testis is normal post-pubertallyfetal testis dysfunction may account for ambiguous genitalia90% to 95% of 45,X/46,XY mosaicism have normal-appearing male genitaliaPhenotypic spectrum with XO/XY extends from females with Turners (25%), to those with ambiguous genetalia, to, rarely those appearing as normal males.Denys-Drash syndrome nephropathy, HTN, and progressive renal failure.
22 Dysgenetic Male Pseudohermaphroditism Two dysgenetic testes rather than one dysgenetic testis and a streak gonad as in MGDTypically are 45,X/46,XY or 46,XYPresent with a spectrum of external genital abnormalitiesDysgenetic testis is composed of immature hypoplastic seminiferous tubules and persistent stroma resembling that seen in the streak gonadIncidence of gonadoblastoma or dysgerminoma is 46% by 40 yearsAt risk for Denys-DrashAs wit MGD karyotype similar.Mullerian structures present depending on amount of MIS secreted by dysgenetic testes.Histologically dysgenetic testes …They may present with a spectrum of external genital abnormalities, depending on the capability of the dysgenetic gonads to produce testosterone. Similarly, persistent müllerian structures are typically present, but to varying degrees depending upon MIS secretion by the dysgenetic gonads.
23 46,XY Complete Gonadal Dysgenesis Characterized by :normal female genitaliawell-developed müllerian structuresbilateral streak gonadsnonmosaic karyotypeAmbiguity of genitalia is not an issueSexual infantilism is the primary clinical problempresent in their teens with delayed pubertyAn abnormality of the Sry gene function, or loss of another gene downstream from Sry that is necessary for SRY protein actionLH elevated clitoromegaly30% risk of germ cell tumor development by age 30 yearsgonadoblastoma is most commonembryonal carcinoma, endodermal sinus tumor, choriocarcinoma, and immature teratoma have also been reportedManagement removal of both streak gonads and proper cyclic hormone replacement with estrogen and progesteroneElevated LH likely responsible for androgen production clitoromegaly
24 Embryonic Testicular Regression and Bilateral 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 uteroDiagnosis can be made on the basis of a 46,XY karyotype and castrate levels of testosterone despite persistently elevated serum LH and FSHbilateral vanishing testes syndrome, agonadal XY phenotypic males with fully developed wolffian structures, but an empty scrotum, absent prostate, and microphallusintermediate point presentation is the 46,XY patient with absent gonads and internal ductal structures but with ambiguous genitalia incomplete elaboration of androgenmost severe form, agonadism is discovered in a 46,XY phenotypic female with no internal genital structures; the testis has elaborated MIS but vanishes at days before elaboration of androgenThe 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.Spectrum of presentation
25 (Williams Textbook of Endocrinology, 10th ed, 2003) True HermaphroditismIndividuals 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 display gradations between male and female75% 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.)(Williams Textbook of Endocrinology, 10th ed, 2003)
26 True HermaphroditismIn most patients, the external genitalia are ambiguous but masculinized to variable degrees, and 75% are raised as maleInternal ductal development are influenced by ipsilateral gonadFallopian tubes are consistently present on the side of the ovarya vas deferens is always present adjacent to a testisFallopian tube is present with 66% of ovotestes, vas or both in 33%Most have urogenital sinus and and uterus80% of those raised as male have hypospadias and chordeeOvaries usually on left in normal position, testis usually on right and located anywhere along path of descent60% of gonads palpable in canal or labia are ovotestes
27 True HermaphroditismOvarian portion of the ovotestis is frequently normal, whereas the testicular portion is typically dysgenetic66% of patients are 46 XXGonadal tumors is approximately 10% in 46,XY true hermaphroditism and 4% in 46,XX true hermaphroditismMost important aspect of management in true hermaphroditism is gender assignmentSex 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 structuresMales, remove ovaries and/or ovotestis and mullerian duct structures consider gonadectomyFemales remove all testicular and wolffian structuresPartial gonadectomy possible in female but stimulate the bHCG post op to ensure all testicular tissue removed.
28 Female Pseudohermaphroditism clitoromegaly46,XX individuals with ovaries have a partially masculinized phenotype and ambiguous genitaliaCAH is most common causeUncommon etiologies:Maternal ingestion of androgensVirilizing tumors in the motherlabioscrotal fusionMarked virilization with hypospadiac-appearing phallusWNT4 also may be cause
29 (Williams Textbook of Endocrinology, 10th ed, 2003) 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.)(Williams Textbook of Endocrinology, 10th ed, 2003)
30 Congenital Adrenal Hyperplasia Error in cortisol biosynthesis pathwayThe most commonly recognized syndromes result from a deficiency of one of the terminal two enzymes of glucocorticoid synthesis (21-hydroxylase or 11-hydroxylase)Formation of hydrocortisone is impaired, causing a compensatory increase in the secretion ACTH enhances formation of adrenal steroids proximal to the enzymatic defect and a secondary increase in the formation of testosterone, the active androgen in CAH21-hydroxylase is responsible for 95% of cases of CAHIncidence is 1 in 5,000 to 1 in 15,000 in the United States and Europe. The highest incidence, 1 in 490, in the Alaskan EskimoInborn error of metabolism
31 Congenital Adrenal Hyperplasia Inborn error of metabolismAny of the 5 enzymes that lead to cortisol synthesis can be affected.
32 CAH: 21-Hydroxylase Deficiency Three categories:(1) salt wasters (patients with virilization and aldosterone deficiency),(2) simple virilizers (patients with virilization, but without salt wasting),(3) nonclassic patients (those without evidence of virilization or salt wasting).21-hydroxylase gene ( CYP-21 ) is located on chromosome 6p,transmitted in an autosomal recessive patternMutations leading to conversion of the active CYP-21 gene into the inactive gene occur in 65% to 90% of cases of classic 21-hydroxylase deficiency (i.e., salt wasting and simple virilizing forms) and in all nonclassic casesGene deletions are responsible for 10% to 35% of the remainder of mutations that produce 21-hydroxylase deficiency75% present with salt wasting and 25% with simple virilizationClinically pts are divided into 3 categoriesDetection much greater since now screening in newborn periodIn female with simple virilization female pseudohermaphroditism results and vagina and urethra open into common UG sinus.Nonclassic present late with hirsuitsm, oligomenorrhea, male pattern baldness, and polycystic ovaries.
33 Prader Classification of Virilization Developed in 1958 but in my experience not used much in clinical practice until recently
34 CAH: 21-Hydroxylase Deficiency Salt-losing variant of CAH symptoms begin within the first few weeks after birth, with failure to regain birth weight, progressive weight loss, and dehydrationIn severely affected infants, adrenal crises occur within the first 10 to 21 days of lifeVomiting is prominent and can be so extreme that a mistaken diagnosis of pyloric stenosis is made, particularly in the male.Death ensues from hyperkalemia, dehydration, and shockMasculinization of the untreated female; pubic and axillary hair develop prematurely, acne appears, and the voice deepensIsosexual precocity (2-3 yo) is hallmark for non-salt wasting males “little Hercules”Little Hercules testes normal size, but enlargement of penis, scrotum, prostate and appearance of pubic hair, acne and deepening of voice.Often unrecognized in non-salt-wasting males until signs of androgen excess occur.
35 CAH: Diagnosis of 21-Hydroxylase Deficiency Plasma levels of progesterone and 17-hydroxyprogesterone are markedly elevatedUrinary 17-ketosteroids and pregnanetriol are elevated.The diagnosis may be made biochemically with the use of radioimmunoassay of plasma 17-hydroxyprogesteroneReplaced the more cumbersome 24-hour urine collection of metabolites (e.g., pregnanetriol).A pelvic ultrasound study demonstrating the presence of müllerian tissues is confirmatory.
36 CAH: 11 b-Hydroxylase Deficiency Accounts for about 5% of casesmutations in the CYP-11B1 geneHypertension is common in patients with this type of CAHdue to increased serum levels of deoxycorticosterone (DOC).The diagnosis can be confirmed by increased plasma levels of 11-deoxycortisol and 11-DOC.Urinary 17-ketosteroids and 17-hydroxycorticoids are increased.The treatment with glucocorticoid is identical to that of patients with 21-hydroxylase deficiency
37 CAH: 3b Hydroxysteroid Dehydrogenase (3b-HSD) Deficiency Affects the early steroid biosynthesis in adrenals and gonadsinability to convert 3β-hydroxysteroids to 3-ketosteroidsfemales exhibit mild clitoromegaly and labial fusion with symptoms of aldosterone and cortisol deficiencyAutosomal recessive inheritance patternIncreased serum levels of 17-hydroxypregnenolone and dehydroepiandrosterone (DHEA) are diagnosticTreatment is similar to that of patients with 21-hydroxylase deficiency
38 Congenital Adrenal Hyperplasia Inborn error of metabolismAny of the 5 enzymes that lead to cortisol synthesis can be affected.
39 CAH: TreatmentEarly diagnosis could prompt prenatal treatment to prevent virilizationPrenatal diagnosis is made by amniotic fluid 17-hydroxyprogesteroneDiagnosed by chorionic villous cells at 8-10 weeks or amniotic cells at weeks.BUT treatment should be instituted at 5-6 weeks of gestationCurrently, it is not possible to confirm the diagnosis before therapy is initiatedTreat mother with dexamethasone which crosses placenta to prevent virilizationBUT the long-term effects of dexamethasone on unaffected fetuses undergoing treatment prenatally remain unknownDexamethasone suppresses ACTHFertility issue supports feminizing genitoplasty in virtually all 46,XY CAH pts.
40 CAH: TreatmentPost-natally, after control of electrolytes and blood pressure has been achieved in the acute setting, maintenance therapy with fludrocortisone (0.05 to 2.5 mg daily) should be institutedChildren with the salt-losing form of the disease require increased salt intake and mineralocorticoid treatment in addition to hydrocortisone therapyGenitoplasty at 3 to 6 months of ageLong-term fertility in males and feminization, menstruation, and fertility in females can be anticipated in the well-treated patientDexamethasone suppresses ACTHFertility issue supports feminizing genitoplasty in virtually all 46,XX CAH pts.
41 Female Pseudohermaphroditism: Maternal Hormones & Tumors Androgen or progestational agent affects the female fetusFunction of the strength of the agent, its maternal dosage, and timing and duration of administrationMasculinization occurred in 2% of female infants whose mothers were treated with progestins during pregnancy to prevent abortion (Ishizura et al, 1962 )Rarely, maternal ovarian or adrenal tumor has virilizing effects on a female fetusarrhenoblastomahilar cell tumorlipoid cell tumorovarian stromal cell tumorluteoma of pregnancyadrenocortical carcinoma and adenomaKrukenberg's tumorManagement is confined to external genital reconstructionThe degree to which any …These are tumors that have resulted in masculinization of female fetus
42 Male Pseudohermaphroditism 46,XY individuals with differentiated testes who exhibit varying degrees of feminization phenotypically.Inadequate secretion of testosterone by the testes at the necessary period in developmentInability of target tissue to respond to androgen appropriatelyImpaired production or action of MISLeydig cell aplasia no mullerian structures
43 Male Pseudohermaphroditism Leydig Cell Aplasia (Luteinizing Hormone Receptor Abnormality)46,XY male karyotype, normal-appearing female phenotypeTypically, testes are palpable in the inguinal canals or labia majorano rise in testosterone after HCG stimulationspectrum absent Leydig cells to Leydig cells with abnormal LH receptorautosomal recessive traitDDx = androgen insensitivity syndrome or a terminal defect in androgen synthesis.testis histology = absent of Leydig cells in intratubular spaces, normal Sertoli cellsLeydig cell aplasia no mullerian structures
44 Male Pseudohermaphroditism defect in any of the five enzymes required for the conversion of cholesterol to testosterone can cause incomplete (or absent) virilization of the male fetus during embryogenesis
45 Male Pseudohermaphroditism Disorders of Testosterone BiosynthesisDefect in any of the five enzymes incomplete (or absent) virilization of the male fetus during embryogenesisInheritance is autosomal recessiveCholesterol Side Chain Cleavage Deficiency (StAR Deficiency)a defect in cholesterol transport prevents conversion of cholesterol to pregnenolone46,XY individuals have female or ambiguous external genitaliaa blind-ending vaginal pouchintra-abdominal, inguinal, or labial testesabsence of müllerian structures & Wolffian ducts are present but rudimentarysevere adrenal insufficiency and salt wastingsuspect this if nonvirilized female external genitalia with:cortisol and aldosterone deficiencyhyponatremia, hyperkalemia, and metabolic acidosis.Abdominal CT scanning demonstrates large, lipid-laden adrenal glandsBecause testosterone production never significant, brain imprinting not a factor in gender assignment.
46 Male Pseudohermaphroditism 3β-Hydroxysteroid Dehydrogenase Deficiencyincomplete masculinization with salt-wasting impaired aldosterone and cortisol synthesisa small phallus, hypospadias with labioscrotal fusion, a urogenital sinus, and a blind-ending vaginal pouch. Testes are often scrotal, and wolffian ducts develop normallydiagnosis: increased levels of 3β-hydroxysteroids (pregnenolone, 17-hydroxypregnenolone, and DHEA)17α-Hydroxylase Deficiencyconversion of pregnenolone and progesterone to 17-hydroxypregnenolone and 17-hydroxyprogesteroneimpaired cortisol production ACTH hypersecretion increased DOC, corticosterone, and 18-hydroxycorticosterone in the adrenals (check levels)These mineralocorticoids salt and water retention, HTN, and hypokalemiaFertility has not been reported and inadequate testosterone production makes androgen imprinting a less significant issue for these patientsPhenotype may dictate gender assignmentBecause testosterone production never significant, brain imprinting not a factor in gender assignment.
47 Male Pseudohermaphroditism 17,20-Lyase Deficiencycortisol and ACTH secretion are normal aldosterone normal no HTNambiguous rather than totally female genitalia at birthsuspect this dx if absent müllerian derivatives and no defect in glucocorticoid or mineralocorticoid synthesis.17β-Hydroxysteroid Oxidoreductase Deficiencysimilar to 5α-reductase deficiency normal female phenotype, no significant virilizationwell-differentiated testes located intra-abdominally, inguinally, or in the labia and no müllerian structures.At puberty phallic growth and male secondary sexual characteristicsAndrostenedione increased to 10 to 15x normaltype III 17β-hydroxysteroid dehydrogenase isozyme mutationmale pseudohermaphroditism17 b HO- oxidoreductase defficiency late onset of virilization is related to pubertal increase in gonadotropin production, which may partially overcome the block in testosterone biosynthesis5 different isoenzyme types identified, type 3…The late onset of virilization is related to the pubertal increase in gonadotropin production, which may partially overcome the block in testosterone biosynthesis
48 Androgen Receptor & Post-Receptor Defects Most common definable cause of male pseudohermaphroditismAll are 46,XY karyotype and have testesThree classifications exist that describe the spectrum of phenotypesComplete androgen insensitivityfemale-appearing external genitalia, and absence of müllerian derivativesBlind ending vagina, reduced pubic hair1 in 20,000 to 1 in 60,000 males2% of female with hernia so vaginoscopy prudentX-linked trait, chromosome Xq11–12, point mutationunequivocal female gender identity androgen resistance of brain tissueNo reported female male gender conversion at pubertygonadectomy is key wait until after puberty2% to 5% risk of seminoma or gonadoblastomaTestis produces estradiol feminizationBecause the testes produce estradiol, which results in appropriate female changes, it is considered preferable to leave the testes insitu until puberty is complete.
49 Androgen Receptor & Post-Receptor Defects Partial androgen insensitivity (Reifenstein's syndrome)ambiguity of the external genitalia to varying degreesmale with perineoscrotal hypospadias, cryptorchidism, rudimentary Wolffian duct structures, gynecomastia, and infertilitythe phenotypic spectrum can range from hypospadias and a pseudovagina to gynecomastia and azoospermiaetiology:(1) a reduced number of normally functioning androgen receptors(2) a normal receptor number but decreased binding affinitygender assignment is often dictated by phenotype and degree of virilizationInfertile male syndromenormal male phenotype but are azoospermic or severely oligospermicnormal to elevated serum testosteronenormal to elevated LHdecreased androgen receptor binding to DHT in genital skin fibroblastsPartial AI X-linked; classically pts have…Mildest form Infertile male syndrome infertility in otherwise normal male may be manifestation of PAI.
50 5α-Reductase Deficiency A, A prepubertal 46,XY child with 5α-reductase-2 deficiency who was raised as a female. B, A postpubertal male with 5α-reductase-2 deficiency who has virilized and changed gender role behavior. (From Peterson RE, Imperato-McGinley J, Gautier T, et al. Male pseudohermaphroditism due to 5α-steroid deficiency. Am J Med 1977; 62:170–191.)(Williams Textbook of Endocrinology, 10th ed, 2003)
51 Androgen Receptor & Post-Receptor Defects 5a-reductase deficiencySecondary to mutations in the type II genePhenotype may vary from penoscrotal hypospadias to, more commonly, markedly ambiguous genitaliaElevated mean plasma testosterone, but low DHT levelsDHT appears to be critical for the development of normal external genitalia in uteroTestosterone alone appears sufficient for wolffian duct developmentMale gender assignment is generally favored, bearing in mind that the studies strongly supporting male gender identity in this disorderAR defect, Type II on chromosome 2, expressed in high levels in prostate and external genetalia.Vas terminate in blind ending vaginal pouch.clitoromegaly with marked labioscrotal fusion and small vaginal introitusurogenital sinus with separate urethral and vaginal openings, and posterior labioscrotal fusion
52 Androgen Receptor & Post-Receptor Defects Persistent Müllerian Duct Syndrome (PMDS)46,XY karyotype and normal male external genitalia but internal müllerian duct structuresPhenotypic males with:unilateral or bilateral undescended testesbilateral fallopian tubesuterusupper vagina draining into a prostatic utricleDiscovered when müllerian tissue is found during inguinal herniorrhaphy or orchidopexy60% to 70% with bilateral intra-abdominal testes in a position analogous to ovaries20% to 30% in which one testis is found in a hernia sac or scrotum in association with a contralateral inguinal hernia (the classic presentation of hernia uteri inguinale)10% in which both testes are located in the same hernia sac (as a result of transverse testicular ectopia) along with the fallopian tubes and uterusPMDS is believed to be etiologically important in transverse testicular ectopia, occurring in 30% to 50% of casesDecreased secretion of MIS and others have an abnormality of the MIS receptorAll patients are phenotypic males who require orchidopexyvasa deferentia are in close proximity to the uterus and proximal vagina preserve fertilitymalignancy of retained müllerian structures has not been reportedMost common testis tumor seminomaDo not remove Mullerian structures as is risk for fertility problems.
53 Unclassified Ambiguous Genitalia Mayer-Rokitansky-Kuster-Hauser (MRKH) syndromeCongenital absence of the uterus and vaginaPresents primary amenorrheaUpper urinary tract anomalies occur in 33% includes renal agenesis, pelvic kidney, and horseshoe kidneyAtypical form of MRKH in 10%asymmetrical uterine remnants and/or aplasia of one or both fallopian tubesendometrial tissue or variable development of the uterus with hematometra cyclic abdominal painUltrasound and MRI may define müllerian anatomy accurately in MRKH and distinguish between typical and atypical forms of the disorderSurgical creation of a neovagina to allow for sexual function and drainage of menstrual fluid if necessary1 in every female births, are 46, XX normal appearing external genitalia and secondary sexual characteristics.Atypical form …
54 EVALUATION AND MANAGEMENT OF THE NEWBORN WITH AMBIGUOUS GENITALIA Medical and psychosocial emergency to be handled with great sensitivity toward the familyGoals:precise diagnosis of the intersex disorderassign a proper sex of rearing based on the diagnosisdetermine the status of the child's anatomydelineate the functionality of genitalia and reproductive tractValuable history points:infant deathinfertilityamenorrheahirsutismmaternal medications (i.e. steroids , OCP), during pregnancyPhysical examination: the presence of one or two gonadsDistinctly palpable gonad along the pathway of descent is highly suggestive of a testisPresence of one or two gonads on exam rules out female pseudohermaphroditismBecause ovaries do not descend…
55 EVALUATION AND MANAGEMENT OF THE NEWBORN WITH AMBIGUOUS GENITALIA Bilaterally impalpable testes or a unilaterally impalpable testis and hypospadias should be regarded as having an intersex disorder until proven otherwise, whether or not the genitalia appear ambiguousUnilateral cryptorchid testis and hypospadius, intersex 30% overall (Kaefer et al, 1999)15% if the undescended testis was palpable and 50% if it was impalpableBilateral undescended testes and hypospadias, intersexuality 32%only 16% if both gonads were palpable.If one of two undescended testes was impalpable, the incidence of intersex tripled to 47%, comparable to the rate in those with a unilateral, impalpable, cryptorchid testis.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.
56 EVALUATION AND MANAGEMENT OF THE NEWBORN 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 meatusPenile size should be assessed and an accurate measure of stretched penile length recorded.Precise means of assessing müllerian anatomy is by pelvic ultrasoundKaryotype should be obtainedSerum studies should be immediately sent to rule out a salt-wasting form of CAH.Serum electrolytes, testosterone and DHT should be measured earlyStudy 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.
57 DDx AlgorithmDiagnostic algorhythm for newborn with ambiguous genitalia based on gonadal palpability, presence or absence of mullerian structures, 17, hydroxyprogesterone concentration, and karyotypeIf no testes check for elevated LH or stimulate with hCG to demonstrate testicular tissue.
58 Gender AssignmentIssues related to the diagnosis-specific potential for normal sexual functioning and fertility and the risk of gonadal malignancy should be addressedIn the setting of a 46,XX karyotype, gender assignment is usually appropriately femaleIf the karyotype is 46,XY, the issue is a more complex one and includes factors such as penile length and evidence of androgen insensitivityThe degree of masculinization of the external genitalia appears to vary with the amount of testicular tissue presentgender assignment depends on the functional potential of the gonadal tissue, reproductive tracts, and genitaliaParameters of Optimal Gender Policy (Meyer-Bahlberg, 1998)Reproductive potential (if attainable at all)Good sexual functionMinimal medical proceduresAn overall gender-appropriate appearanceA stable gender identityPsychosocial well beingHigh 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
60 A. congenital adrenal hyperplasia B. testicular feminization During an inguinal hernia repair, a normal appearing three-year old girl is found to have a testicle in the hernia sac. Further workup will reveal:A. congenital adrenal hyperplasiaB. testicular feminizationC. Reifenstein syndromeD. hernia uterine inguinaleE. Denys-Drash syndromeB. 3% of girls with inguinal hernias have testicular feminization. A testicle found in the hernia sac and a chromosome analysis will reveal a 46 xy karotype. They should be reaise female and will need gonadectomy.
61 A. congenital adrenal hyperplasia B. testicular feminization During an inguinal hernia repair, a normal appearing three-year old girl is found to have a testicle in the hernia sac. Further workup will reveal:A. congenital adrenal hyperplasiaB. testicular feminizationC. Reifenstein syndromeD. hernia uterine inguinaleE. Denys-Drash syndromeB. 3% of girls with inguinal hernias have testicular feminization. A testicle found in the hernia sac and a chromosome analysis will reveal a 46 xy karotype. They should be reaise female and will need gonadectomy.
62 Congenital androgen resistance syndromes are usually associated with: A. reversible infertilityB. elevated serum testosteroneC. normal serum LH levelsD. normal estradiol levelsE. low serum FSH levelsB. Generally associated with infertility and elevated serum testoserone, LH, and FSH levels. The syndromes are usually associated with elevated serum estradiol levels due to increased secretion by the testes.
63 Congenital androgen resistance syndromes are usually associated with: A. reversible infertilityB. elevated serum testosteroneC. normal serum LH levelsD. normal estradiol levelsE. low serum FSH levelsB. Generally associated with infertility and elevated serum testoserone, LH, and FSH levels. The syndromes are usually associated with elevated serum estradiol levels due to increased secretion by the testes.
64 A. fetal LH B. maternal LH C. maternal hCG D. fetal GnRH E. fetal FSH Testosterone production during differentiation of the urethra is under the regulation of:A. fetal LHB. maternal LHC. maternal hCGD. fetal GnRHE. fetal FSHC. Fetal leydig cell function during the first trimester of pregnancy is under maternal hCG regulation. The fetal pituitary does not begin to secrete gonadotropins until the second trimester of gestation. Therefore, if there is a problem with fetal hypothlamic-pituitary function, this does not become evident until the second trimester of gestation. The most common cause of micropenis is probably fetal hypothalamic-pituitary dysfunction.
65 A. fetal LH B. maternal LH C. maternal hCG D. fetal GnRH E. fetal FSH Testosterone production during differentiation of the urethra is under the regulation of:A. fetal LHB. maternal LHC. maternal hCGD. fetal GnRHE. fetal FSHC. Fetal leydig cell function during the first trimester of pregnancy is under maternal hCG regulation. The fetal pituitary does not begin to secrete gonadotropins until the second trimester of gestation. Therefore, if there is a problem with fetal hypothlamic-pituitary function, this does not become evident until the second trimester of gestation. The most common cause of micropenis is probably fetal hypothalamic-pituitary dysfunction.
66 A. a blind ending vas deferense B. hypertrophy of the right testis An 11-year old boy has an impalpable left testis. The finding which proves left testicular absence is:A. a blind ending vas deferenseB. hypertrophy of the right testisC. absence of the left kidneyD. XY/XO karyotypeE. blind-ending spermatic vesselsE.
67 A. a blind ending vas deferense B. hypertrophy of the right testis An 11-year old boy has an impalpable left testis. The finding which proves left testicular absence is:A. a blind ending vas deferenseB. hypertrophy of the right testisC. absence of the left kidneyD. XY/XO karyotypeE. blind-ending spermatic vesselsE.
68 A. serum dihydrotestosterone level B. repeat semen analysis A 28-year old man with primary infertility has a microdeletion of the DAZ region of the Y chromosome (AZFc). One semen analysis reveals azoospermia. His wife is scheduled for in vitro fertilization. Prior to testicular sperm extraction, he should have:A. serum dihydrotestosterone levelB. repeat semen analysisC. renal ultrasoundD. X chromosome analysisE. Transrectal ultrasoundB. Y chromosome microdeletions are common in severe male infirtility. Although many men with AZFc deletions are azoospermic, occasional sperm are often found in the ejaculate and may obviate need for testicular extraction. Renal, prostatic, and X chromosome abnormalities are rarely found in associaton with Y microdeletions.
69 A. serum dihydrotestosterone level B. repeat semen analysis A 28-year old man with primary infertility has a microdeletion of the DAZ region of the Y chromosome (AZFc). One semen analysis reveals azoospermia. His wife is scheduled for in vitro fertilization. Prior to testicular sperm extraction, he should have:A. serum dihydrotestosterone levelB. repeat semen analysisC. renal ultrasoundD. X chromosome analysisE. Transrectal ultrasoundB. Y chromosome microdeletions are common in severe male infirtility. Although many men with AZFc deletions are azoospermic, occasional sperm are often found in the ejaculate and may obviate need for testicular extraction. Renal, prostatic, and X chromosome abnormalities are rarely found in associaton with Y microdeletions.
70 A. XXO/XX B. XXY C. XO D. Trisomy 18 E. Trisomy 21 A three year old girl undergoing cardiac catheterization for coarctation of the aorta is found to have a horseshoe kidney. Chromosomal studies will likely show:A. XXO/XXB. XXYC. XOD. Trisomy 18E. Trisomy 21C10% have horseshoe kidney
71 A. XXO/XX B. XXY C. XO D. Trisomy 18 E. Trisomy 21 A three year old girl undergoing cardiac catheterization for coarctation of the aorta is found to have a horseshoe kidney. Chromosomal studies will likely show:A. XXO/XXB. XXYC. XOD. Trisomy 18E. Trisomy 21C10% have horseshoe kidney
72 A. Ovary B. Gonadoblastoma C. Streak gonad D. Ovotestis E. Seminoma A 19-year old man with mixed gonadal dysgenesis undergoes surgery for an undescended right testis. A 3 cm mass is found where the testicular vessels terminate inside the inguinal ring, along the an adjacent fallopian tube. The gonadal mass is most likely:A. OvaryB. GonadoblastomaC. Streak gonadD. OvotestisE. SeminomaE. MGD 25% incidence of tumors and streak gonad should be removed when syndrome identified. Gonadoblastoma often found but seminoma sill most common in this pt population.
73 A. Ovary B. Gonadoblastoma C. Streak gonad D. Ovotestis E. Seminoma A 19-year old man with mixed gonadal dysgenesis undergoes surgery for an undescended right testis. A 3 cm mass is found where the testicular vessels terminate inside the inguinal ring, along the an adjacent fallopian tube. The gonadal mass is most likely:A. OvaryB. GonadoblastomaC. Streak gonadD. OvotestisE. SeminomaE. MGD 25% incidence of tumors and streak gonad should be removed when syndrome identified. Gonadoblastoma often found but seminoma sill most common in this pt population.
74 A. Bilateral streak gonads B. Streak gonad and testis A 38 y/o woman undergoes amniocentesis at 24 weeks gestation. The fetal karyotype is 45X/46XY. The gonads will most likely be:A. Bilateral streak gonadsB. Streak gonad and testisC. Streak gonad and ovaryD. Streak gonad and ovary and dysgenetic testisE. Bilateral testesE. Over 90% of individuals with 45x/46xy have normal male genetalia.
75 A. Bilateral streak gonads B. Streak gonad and testis A 38 y/o woman undergoes amniocentesis at 24 weeks gestation. The fetal karyotype is 45X/46XY. The gonads will most likely be:A. Bilateral streak gonadsB. Streak gonad and testisC. Streak gonad and ovaryD. Streak gonad and ovary and dysgenetic testisE. Bilateral testesE. Over 90% of individuals with 45x/46xy have normal male genetalia.
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