Disorders of Sexual Differentiation

Disorders of Sexual Differentiation
Vincenzo Galati, D.O. Stephen Confer, MD Ben O. Donovan, MD Brad Kropp, MD Dominic Frimberger, MD University of Oklahoma Department of Urology Section of Pediatric Urology

Normal Sexual Differentiation
Jost paradigm: Establishment of chromosomal sex at fertilization Development of the undifferentiated gonads into testes or ovaries Differentiation of the internal ducts and external genitalia Sexual 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.

Chromosomal Sex TDF was mapped to the most distal aspect of the Y-unique region of the short arm of the Y chromosome, adjacent to the pseudoautosomal boundary Sry is localized to the smallest region of the Y chromosome capable of inducing testicular differentiation in humans and in mice Sry 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 expression Now, 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

TDF candidates ZFY (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 ZFY H-Y gene: A number of women with 45,X gonadal dysgenesis were found to be H-Y antigen positive

Other Important Genes WT-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 tissue SF-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 reversal SOX-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 differentiation HMG  high mobility group

Other Important Genes DSS (DAX-1) (dosage-sensitive sex reversal). Found in XY females with duplication of this gene Suggests 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 DSS Implicated in adrenal hypoplasia congenita WNT4 (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, )

Gonadal Stage of Differentiation
During the first 6 weeks of embryonic development structures are bipotential in both 46,XY and 46,XX embryos Migration of the germ cells begins in the 5th week of gestation through the mesentery to the medial ventral aspect of the urogenital ridge SRY initiates the switch that induces the indifferent gonad toward testicular organogenesis In the absence of SRY, ovarian organogenesis results The differentiation of Sertoli cells is associated with the production of MIS, a glycoprotein encoded by a gene on the short arm of chromosome 19 Primordial cells of steroidogenic mesenchyme remain among the testicular cords and represent future Leydig cells, which differentiate at 8 to 9 weeks Primordial germ cells recognized in the 3rd week migrate in 5th week. In males a second line of primordial cells of steroidogenic mesenchyme…

Gonadal Stage of Differentiation
Duplicate copies of at least one X chromosomal locus is likely necessary for normal oviarian organogenesis Dysgenetic ovaries in Turner's syndrome patients In embryonal ovaries, germ cells undergo intense mitotic proliferation and in the process exhaust their entire mitotic potential prenatally a maximum endowment of 20 million cells by 20 weeks gestation This presumably explains the dysgenetic ovaries in Turner’s syndrome

Gonadal Function The initial endocrine function of the fetal testes is the secretion of MIS by the Sertoli cells at 7 to 8 weeks' gestation Testosterone secretion by the fetal testes is detectable shortly after the formation of Leydig cells in the interstitium at approximately 9 weeks' gestation testosterone peaks at 13 weeks and then declines testosterone enters target tissues by passive diffusion DHT binds to the androgen receptor with greater affinity and stability than does testosterone the gene encoding the androgen receptor has been cloned and mapped to the X chromosome between the centromere and q13 Estrogen synthesis is detectable in the female embryo just after 8 weeks of gestation Testosterone 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.

Undifferentiated Urogenital Tract
8 wks Differentiation 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 wks Undifferentiated External genitalia

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.

Psychosexual Differentiation
gender identity: the identification of self as either male or female gender role: aspects of behavior in which males and females appear to differ gender orientation: choice of sexual partner (heterosexual, homosexual, or bisexual) cognitive differences

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 milieu strong evidence has accumulated for the impact of prenatal hormonal influences on sexually dimorphic behavior or gender role previously 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 differentiation A 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.

Disorders of Gonadal Differentiation and Development

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)

Seminiferous Tubule Dysgenesis (Klinefelter's 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 At least one Y and two X to be Klinefelter’s. ICIS intracytoplasmic sperm injection

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 Klinefelter's 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 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)

Turner’s Syndrome (45,XO)
No oocytes remain in the ovaries, which become streaks Fertility = 60% pregnancy rate w/ART Ovum donation for those with bilateral streaks 1 in 2500 live births 60% are 45,XO and 40% are mosaics Y chromosomal material masculinization & gonadoblastoma (30%) 33% - 60% have structural or positional abnormalities of the kidney horseshoe kidney = 10%, duplication or renal agenesis= 20% malrotation= 15% multiple renal arteries = 90% Four classic features: female phenotype short stature lack of secondary sexual characteristics a variety of somatic abnormalities: Webbed neck Wide spaced nipples Broad chest (shield) Cubitus valgus Short stature Rapid 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

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 Closely related to Turner’s syndrome In contrast to Turner’s growth hormone here is normal.

(Williams Textbook of Endocrinology, 10th ed, 2003)
Gonadal dysgenesis 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 ) 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)

Mixed gonadal dysgenesis (MGD)
Characterized by a unilateral testis, often intra-abdominal Contralateral streak gonad Persistent müllerian structures with varying inadequate masculinization Most are 45,XO/46,XY, the most common form of Y chromosome mosaicism Second most common cause of ambiguous genitalia after CAH Dysgenetic 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 ducts no germ cells so infertility is the rule Increased risk of developing gonadoblastoma or dysgerminoma of 15% to 20% Also increased risk for Wilm’s tumor and association with Denys-Drash Endocrine function of testis is normal post-pubertally fetal testis dysfunction may account for ambiguous genitalia 90% to 95% of 45,X/46,XY mosaicism have normal-appearing male genitalia Phenotypic 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.

Dysgenetic Male Pseudohermaphroditism
Two dysgenetic testes rather than one dysgenetic testis and a streak gonad as in MGD Typically are 45,X/46,XY or 46,XY Present with a spectrum of external genital abnormalities Dysgenetic testis is composed of immature hypoplastic seminiferous tubules and persistent stroma resembling that seen in the streak gonad Incidence of gonadoblastoma or dysgerminoma is 46% by 40 years At risk for Denys-Drash As 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.

46,XY Complete Gonadal Dysgenesis
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 Elevated LH  likely responsible for androgen production  clitoromegaly

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 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 microphallus 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 days before elaboration of androgen 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. Spectrum of presentation

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 display gradations between male and female 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.) (Williams Textbook of Endocrinology, 10th ed, 2003)

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 Partial gonadectomy possible in female but stimulate the bHCG post op to ensure all testicular tissue removed.

Female Pseudohermaphroditism
clitoromegaly 46,XX individuals with ovaries have a partially masculinized phenotype and ambiguous genitalia CAH is most common cause Uncommon etiologies: Maternal ingestion of androgens Virilizing tumors in the mother labioscrotal fusion Marked virilization with hypospadiac-appearing phallus WNT4 also may be cause

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)

Congenital Adrenal Hyperplasia
Error in cortisol biosynthesis pathway The 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 CAH 21-hydroxylase is responsible for 95% of cases of CAH Incidence 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 Eskimo Inborn error of metabolism

Inborn error of metabolism Any of the 5 enzymes that lead to cortisol synthesis can be affected.

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 pattern Mutations 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 cases Gene deletions are responsible for 10% to 35% of the remainder of mutations that produce 21-hydroxylase deficiency 75% present with salt wasting and 25% with simple virilization Clinically pts are divided into 3 categories Detection much greater since now screening in newborn period In 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.

Prader Classification of Virilization
Developed in 1958 but in my experience not used much in clinical practice until recently

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 dehydration In severely affected infants, adrenal crises occur within the first 10 to 21 days of life Vomiting 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 shock Masculinization of the untreated female; pubic and axillary hair develop prematurely, acne appears, and the voice deepens Isosexual 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.

CAH: Diagnosis of 21-Hydroxylase Deficiency
Plasma levels of progesterone and 17-hydroxyprogesterone are markedly elevated Urinary 17-ketosteroids and pregnanetriol are elevated. The diagnosis may be made biochemically with the use of radioimmunoassay of plasma 17-hydroxyprogesterone Replaced the more cumbersome 24-hour urine collection of metabolites (e.g., pregnanetriol). A pelvic ultrasound study demonstrating the presence of müllerian tissues is confirmatory.

CAH: 11 b-Hydroxylase Deficiency
Accounts for about 5% of cases mutations in the CYP-11B1 gene Hypertension is common in patients with this type of CAH due 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

CAH: 3b Hydroxysteroid Dehydrogenase (3b-HSD) Deficiency
Affects the early steroid biosynthesis in adrenals and gonads inability to convert 3β-hydroxysteroids to 3-ketosteroids females exhibit mild clitoromegaly and labial fusion with symptoms of aldosterone and cortisol deficiency Autosomal recessive inheritance pattern Increased serum levels of 17-hydroxypregnenolone and dehydroepiandrosterone (DHEA) are diagnostic Treatment is similar to that of patients with 21-hydroxylase deficiency

Inborn error of metabolism Any of the 5 enzymes that lead to cortisol synthesis can be affected.

CAH: Treatment Early diagnosis could prompt prenatal treatment to prevent virilization Prenatal diagnosis is made by amniotic fluid 17-hydroxyprogesterone Diagnosed by chorionic villous cells at 8-10 weeks or amniotic cells at weeks. BUT treatment should be instituted at 5-6 weeks of gestation Currently, it is not possible to confirm the diagnosis before therapy is initiated Treat mother with dexamethasone which crosses placenta to prevent virilization BUT the long-term effects of dexamethasone on unaffected fetuses undergoing treatment prenatally remain unknown Dexamethasone suppresses ACTH Fertility issue supports feminizing genitoplasty in virtually all 46,XY CAH pts.

CAH: Treatment Post-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 instituted Children with the salt-losing form of the disease require increased salt intake and mineralocorticoid treatment in addition to hydrocortisone therapy Genitoplasty at 3 to 6 months of age Long-term fertility in males and feminization, menstruation, and fertility in females can be anticipated in the well-treated patient Dexamethasone suppresses ACTH Fertility issue supports feminizing genitoplasty in virtually all 46,XX CAH pts.

Female Pseudohermaphroditism: Maternal Hormones & Tumors
Androgen or progestational agent affects the female fetus Function of the strength of the agent, its maternal dosage, and timing and duration of administration Masculinization 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 fetus arrhenoblastoma hilar cell tumor lipoid cell tumor ovarian stromal cell tumor luteoma of pregnancy adrenocortical carcinoma and adenoma Krukenberg's tumor Management is confined to external genital reconstruction The degree to which any … These are tumors that have resulted in masculinization of female fetus

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 development Inability of target tissue to respond to androgen appropriately Impaired production or action of MIS Leydig cell aplasia  no mullerian structures

Leydig Cell Aplasia (Luteinizing Hormone Receptor Abnormality) 46,XY male karyotype, normal-appearing female phenotype Typically, testes are palpable in the inguinal canals or labia majora no rise in testosterone after HCG stimulation spectrum  absent Leydig cells to Leydig cells with abnormal LH receptor autosomal recessive trait DDx = androgen insensitivity syndrome or a terminal defect in androgen synthesis. testis histology = absent of Leydig cells in intratubular spaces, normal Sertoli cells Leydig cell aplasia  no mullerian structures

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

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 Because testosterone production never significant, brain imprinting not a factor in gender assignment.

3β-Hydroxysteroid Dehydrogenase Deficiency incomplete masculinization with salt-wasting  impaired aldosterone and cortisol synthesis a small phallus, hypospadias with labioscrotal fusion, a urogenital sinus, and a blind-ending vaginal pouch. Testes are often scrotal, and wolffian ducts develop normally diagnosis: increased levels of 3β-hydroxysteroids (pregnenolone, 17-hydroxypregnenolone, and DHEA) 17α-Hydroxylase Deficiency conversion of pregnenolone and progesterone to 17-hydroxypregnenolone and 17-hydroxyprogesterone impaired cortisol production ACTH hypersecretion  increased DOC, corticosterone, and 18-hydroxycorticosterone in the adrenals (check levels) These mineralocorticoids  salt and water retention, HTN, and hypokalemia Fertility has not been reported and inadequate testosterone production makes androgen imprinting a less significant issue for these patients Phenotype may dictate gender assignment Because testosterone production never significant, brain imprinting not a factor in gender assignment.

17,20-Lyase Deficiency cortisol and ACTH secretion are normal aldosterone normal  no HTN ambiguous rather than totally female genitalia at birth suspect this dx if absent müllerian derivatives and no defect in glucocorticoid or mineralocorticoid synthesis. 17β-Hydroxysteroid Oxidoreductase Deficiency similar to 5α-reductase deficiency  normal female phenotype, no significant virilization well-differentiated testes located intra-abdominally, inguinally, or in the labia and no müllerian structures. At puberty phallic growth and male secondary sexual characteristics Androstenedione  increased to 10 to 15x normal type III 17β-hydroxysteroid dehydrogenase isozyme mutationmale pseudohermaphroditism 17 b HO- oxidoreductase defficiency late onset of virilization is related to pubertal increase in gonadotropin production, which may partially overcome the block in testosterone biosynthesis 5 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

Androgen Receptor & Post-Receptor Defects
Most common definable cause of male pseudohermaphroditism All are 46,XY karyotype and have testes Three classifications exist that describe the spectrum of phenotypes Complete androgen insensitivity female-appearing external genitalia, and absence of müllerian derivatives Blind ending vagina, reduced pubic hair 1 in 20,000 to 1 in 60,000 males 2% of female with hernia  so vaginoscopy prudent X-linked trait, chromosome Xq11–12, point mutation unequivocal female gender identity androgen resistance of brain tissue No reported female  male gender conversion at puberty gonadectomy is key  wait until after puberty 2% to 5% risk of seminoma or gonadoblastoma Testis produces estradiol  feminization Because the testes produce estradiol, which results in appropriate female changes, it is considered preferable to leave the testes insitu until puberty is complete.

Partial androgen insensitivity (Reifenstein's syndrome) ambiguity of the external 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 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 Partial AI  X-linked; classically pts have… Mildest form Infertile male syndrome  infertility in otherwise normal male may be manifestation of PAI.

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)

5a-reductase deficiency Secondary to mutations in the type II gene Phenotype may vary from penoscrotal hypospadias to, more commonly, markedly ambiguous genitalia Elevated mean plasma testosterone, but low DHT levels DHT appears to be critical for the development of normal external genitalia in utero Testosterone alone appears sufficient for wolffian duct development Male gender assignment is generally favored, bearing in mind that the studies strongly supporting male gender identity in this disorder AR 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 introitus urogenital sinus with separate urethral and vaginal openings, and posterior labioscrotal fusion

Persistent Müllerian Duct Syndrome (PMDS) 46,XY karyotype and normal male external genitalia but internal müllerian duct structures Phenotypic males with: unilateral or bilateral undescended testes bilateral fallopian tubes uterus upper vagina draining into a prostatic utricle Discovered when müllerian tissue is found during inguinal herniorrhaphy or orchidopexy 60% to 70% with bilateral intra-abdominal testes in a position analogous to ovaries 20% 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 uterus PMDS is believed to be etiologically important in transverse testicular ectopia, occurring in 30% to 50% of cases Decreased secretion of MIS and others have an abnormality of the MIS receptor All patients are phenotypic males who require orchidopexy vasa deferentia are in close proximity to the uterus and proximal vagina preserve fertility malignancy of retained müllerian structures has not been reported Most common testis tumor seminoma Do not remove Mullerian structures as is risk for fertility problems.

Unclassified Ambiguous Genitalia
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome Congenital absence of the uterus and vagina Presents primary amenorrhea Upper urinary tract anomalies occur in 33% includes renal agenesis, pelvic kidney, and horseshoe kidney Atypical form of MRKH in 10% asymmetrical uterine remnants and/or aplasia of one or both fallopian tubes endometrial tissue or variable development of the uterus with hematometra  cyclic abdominal pain Ultrasound and MRI may define müllerian anatomy accurately in MRKH and distinguish between typical and atypical forms of the disorder Surgical creation of a neovagina to allow for sexual function and drainage of menstrual fluid if necessary 1 in every female births, are 46, XX  normal appearing external genitalia and secondary sexual characteristics. Atypical form …

EVALUATION AND MANAGEMENT OF THE NEWBORN 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 child's 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 Presence of one or two gonads on exam rules out female pseudohermaphroditism Because ovaries do not descend…

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 ambiguous Unilateral cryptorchid testis and hypospadius, intersex  30% overall (Kaefer et al, 1999) 15% if the undescended testis was palpable and 50% if it was impalpable Bilateral 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.

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 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.

DDx Algorithm 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.

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 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

The End

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 hyperplasia B. testicular feminization C. Reifenstein syndrome D. hernia uterine inguinale E. Denys-Drash syndrome B. 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.

Congenital androgen resistance syndromes are usually associated with:
A. reversible infertility B. elevated serum testosterone C. normal serum LH levels D. normal estradiol levels E. low serum FSH levels B. 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.

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 LH B. maternal LH C. maternal hCG D. fetal GnRH E. fetal FSH C. 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.

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 deferense B. hypertrophy of the right testis C. absence of the left kidney D. XY/XO karyotype E. blind-ending spermatic vessels E.

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 level B. repeat semen analysis C. renal ultrasound D. X chromosome analysis E. Transrectal ultrasound B. 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.

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/XX B. XXY C. XO D. Trisomy 18 E. Trisomy 21 C 10% have horseshoe kidney

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. Ovary B. Gonadoblastoma C. Streak gonad D. Ovotestis E. Seminoma E. 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.

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 gonads B. Streak gonad and testis C. Streak gonad and ovary D. Streak gonad and ovary and dysgenetic testis E. Bilateral testes E. Over 90% of individuals with 45x/46xy have normal male genetalia.

Disorders of Sexual Differentiation

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