31.13 Gonadal Dysgenesis

•A high ratio of serum testosterone to DHT

•There is a spectrum of 5-alpha-reductase deficiency

•The fetus is born with minimally virilized external genitalia (pseudovaginal perineoscrotal hypospadias)

•The striking feature is the extreme virilization at puberty

•Many recommend that all patients with 5-alpha reductase deficiency should be raised as males.

•Others recommend that only the most extremely virilized infant should be raised as males.

•Many authors recommend gonadectomy and feminizing genitoplasty in these patients.

–During the first 60 days of life, infants experience a surge of LH that obviates the need to carry out HCG stimulation, which may be useful to exaggerate the testoster- one-to-DHT ratio characteristic of this syndrome.

–The normal testosterone-to-DHT ratio is 8–16:1, while patients with 5-alpha- reductase deficiency characteristically have a ratio greater than 35:1.

–Urinary metabolites of testosterone and DHT can be used to establish the diagnosis.

–Cultured skin fibroblasts will demonstrate decreased 5-alpha-reductase activity.

•Gender assignment and management:

–Gender assignment is difficult in these patients because of the major virilization that occurs at puberty.

–Many recommend that all patients with 5-alpha reductase deficiency should be raised as males.

–Others recommend that only the most extremely virilized infant should be raised as males.

–The surgical results of a masculinizing operation in a mildly virilized infant are poor, and the burden to the child of growing up with inadequate genitalia hardly seems justified.

–Many authors recommend gonadectomy and feminizing genitoplasty in these patients.

31.13 Gonadal Dysgenesis

•Gonadal dysgenesis refers to a variety of congenital developmental disorders in which the development of the indifferent embryonic gonads to differentiated gonads is inhibited.

•The gonads are usually hypoplastic and dysfunctional with a complete germ cell deficiency.

•This loss leads to extremely hypoplastic (underdeveloped) and dysfunctioning gonads mainly composed of fibrous tissue, hence the name streak gonads—i.e., a form of aplasia in which the ovary is replaced by functionless tissue.

•The accompanying hormonal failure also prevents the development of secondary sex characteristics in either sex, resulting in a sexually infantile female appearance and infertility.

•The group of gonadal dysgenesis disorders includes:

–Pure gonadal dysgenesis (46,XX or 46,XY = Swyer syndrome)

–Mixed gonadal dysgenesis (mosaic 45,X0/46,XY etc.)

–Partial gonadal dysgenesis

–Turner syndrome

–Dysgenetic male pseudohermaphroditism (DMP)

–XX gonadal dysgenesis

–Perrault syndrome

•A streak gonad:

–A gonads only consisting of fibrous tissue and with no histological evidence of germ cells.

•A dysgenetic testis:

–A dysgenetic testis histologically demonstrates immature and hypoplastic testicular

tubules in a stroma characteristic of ovarian tissue but that lacks oocytes.

–This stroma has the appearance of that seen in streak gonads and may help to explain the similarities of these syndromes.

–Dysgenetic testes have a high risk for malignancy and can develop into malignant germ cell tumors such as dysgerminomas or gonadoblastomas.

–In contrast, dysgenetic ovaries do not seem to comprise an increased risk for malignancy, as the existence of the GBY region on the Y chromosome as well as the testes specific protein gene (TSPY) on the Y chromosome predispose for a malignant transformation

•Embryology and pathogenesis:

–The genetic sex is determined by the karyotype, which is either XX or XY.

–The Y chromosome contains the SRY (sex determining region of the Y chromosome), which induces male sex development during embryogenesis (The development of the testes).

–In the absence of the SRY or in the presence of a second X chromosome, ovaries develop.

–This then determines the gonadal sex.

–The testes produce testosterone as well as the anti-müllerian hormone (AMH), which suppresses the development of the müllerian ducts, precursors of the fallopian tubes, the uterus and the upper vagina.

–The ovaries produce estrogens.

–As a response to this hormone production of the testes or ovaries, the phenotypic sex develops.

–As a result, if a gonad cannot express its sexual identity via its hormones—as in gonadal dysgenesis—then the affected person, no matter whether their chromosomes are XY or XX, will develop external female genitalia. Internal female genitalia, primarily the uterus, may or may not be present depending on the etiology of the disorder.

–In both sexes, the commencement and progression of puberty require functional gonads that will work in harmony with the

hypothalamic and pituitary glands to produce adequate hormones.

–For this reason, in gonadal dysgenesis the accompanying hormonal failure also prevents the development of secondary sex characteristics in either sex, resulting in a sexually infantile female appearance and infertility.

–Dysgenetic testes do not produce a sufficient amount of testosterone in order to achieve a complete masculinization of the genitals.

–Furthermore, AMH, which suppresses the female anlage of the genitals is not produced.

–The clinical picture is heterogeneous.

•Depending on the expression, the phenotype can be female or, in milder cases, the genitals can be male or only present with hypospadias.

–Gonadal dysgenesis will occur if there is an absence of both Müllerian inhibiting factor and testosterone.

•The absence of testosterone will result in regression of the Wolffian ducts; normal male internal reproductive tracts will not develop.

•The absence of Müllerian inhibiting factor will allow the Müllerian ducts to differentiate into the oviducts and uterus.

•The affected person will possess femalelike internal and external reproductive characteristics, lacking secondary sex characteristics.

•The genotype may be either 45,XO, 46,XX or 46,XY.

•The gonads are usually asymmetrical:

–A dysgenetic testis on one side composed of disordered tubules, often sparse and abundant stroma

–A streak gonad on the other side, composed of ovarian stroma but with no oocytes.

•The degree of virilization is variable but all patients have a vagina and a uterus, and most have a fallopian tube, at least on the side of the streak gonad.

•Fertility has not been reported in patients with MGD.

•Mixed gonadal dysgenesis (MGD):

–Mixed gonadal dysgenesis (MGD) is the second most common cause of ambiguous genitalia in a newborn.

–It is characterized by unusual and asymmetrical gonadal development.

•A streak gonad is usually present on one side and a testis (usually dysgenetic) on the opposite side.

–A number of chromosomal karyotypes have been reported but most patients with MGD have a mosaic karyotype, 45XO/46XY or 46,XX/46,XY.

–It is assumed that the 45,X0 cell line causes the development of the streak gonads and the 46,XY cell line is associated with the differentiated testis.

–In MGD, 25% of gonads, including streak gonads, can be expected to undergo malignant change, most commonly to gonadoblastoma.

–In addition to gonadoblastomas, seminomas and embryonal cell carcinomas may develop.

–Gender assignment for patients with MGD remains controversial.

–The clinical picture of mixed gonadal dysgenesis is heterogeneous.

•The external genitals can have a phenotype ranging from female to male.

•In most cases, the genitals are intersexual with a hypertrophy of the clitoris or hypospadias.

•As the AMH secretion is also affected to different degrees, variable constellations of the müllerian duct derivatives are possible.

•In most cases, the gonads have developed asymmetrically (a streak gonads on one side and normal or dysgenetic testes on the other side). The testis is usually intra-abdominal or inguinal.

•In some cases, the streak gonads are bilateral.

•The testes have a normal histological appearance before puberty. Sertoli and Leydig cells are present but germ cells are missing.

–As in all gonadal dysgeneses with Y-chromosomes, there is a certain risk for malignancy, which is why gonadectomy is indicated as early as possible.

•Dysgenetic male pseudohermaphroditism (DMP):

–This term is used to describe patients with bilaterally dysgenetic testes and incomplete virilization of the internal sex ducts and external genitalia.

•XX gonadal dysgenesis:

–This is a type of female hypogonadism in which no functional ovaries are present to induce puberty in an otherwise normal girl whose karyotype is found to be 46,XX.

–The presence of nonfunctional streak ovaries is associated with low estrogen levels (hypoestrogenic) and high levels of FSH and LH.

–Estrogen and progesterone therapy is the recommended treatment.

•Perrault syndrome:

–In 1951, Perrault reported the association of gonadal dysgenesis and sensorineural hearing loss.

•Management:

–Early gonadectomy is recommended in these patients.

–The gender assignment for patients with DMP and MGD remains controversial.

–There are those who recommend a male gender assignment for those patients who are sufficiently virilized.

–Others recommend a female gender assignment for patients with MGD because a uterus and vagina are present always and half of these patients have inadequate external virilization.

–Patients who are raised as females require estrogen supplements.

–If the uterus remains in place, the unopposed estrogen can increase the incidence of endometrial carcinoma and these patients should receive a combination of estrogen and a progestational agents.

•Pure gonadal dysgenesis:

–Pure gonadal dysgenesis is defined as the absence of differentiated gonads, but with

normally developed internal and external genitalia.

–The karyotype is either 46,XX or 46,XY.

•The 46XX type is usually transmitted by autosomal recessive inheritance, while the 46,XY type is transmitted by X-linked inheritance.

•The 46,XY type is named after G. J. Swyer, the first person who described the syndrome (Swyer syndrome).

•A major part of the patients carries a mutation of the SRY gene which inhibits the differentiation of the testes.

•Due to the lack of testosterone and AMH, the vagina and the uterus develop.

–These patients are phenotypically females.

–They have bilateral streak gonads appearing as ovarian stroma without oocytes.

–Hypogonadism with elevated gonadotropin levels is a characteristic finding in the affected patients.

–These patients are usually not recognized in the newborn period and they present at puberty when they do not undergo normal pubertal changes.

–The secondary sex characteristics fail to develop, and or the menarche is absent (primary amenorrhea)

–Girls with Turner syndrome (45XO) may be detected earlier by noting the characteristic associated anomalies of short stature, webbing of the neck, and wide-spaced nipples.

–Swyer Syndrome (Also known as Pure Gonadal Dysgenesis or XY gonadal dysgenesis):

•This is a type of hypogonadism in a person whose karyotype is 46,XY.

•The person is phenotypically female with streak gonads, and if left untreated, will not experience puberty.

•Such gonads are typically surgically removed as they have a significant risk of developing tumors.

•These patients are treated with female hormone replacement therapy.

–Neither Turner syndrome (45XO) nor the 46XX type of pure gonadal dysgenesis

appears to be associated with increased risk of gonadal malignancy.

–Histologically, there are streak gonads composed of fibrous tissue or dysgenetic testes with Leydig and Sertoli cells but no or only few germ cells, which have a malignancy potential of 25 %.

–Patients with 46XY pure gonadal dysgenesis on the other hand carry a significant risk for malignancy. Nearly one third of patients develop a dysgerminoma or gonadoblastoma; therefore, gonadectomy should be done as soon as the diagnosis is confirmed.

–In 46,XX gonadal dysgenesis, the patient usually has a homozygote or heterozygote mutation of the FSH receptor gene.

–An FSH receptor mutation causes a female phenotype in the absence of secondary sex characteristics.

–The leading symptom is usually primary amenorrhea that results from a primary or premature ovarian insufficiency.

–A homozygote FSH receptor mutation in patients with a female karyotype always causes ovarian insufficiency and infertility, while the heterozygote or the homozygote form in patients with a male karoytype not always causes gonadal dysfunction or infertility.

–Treatment of those with pure gonadal dysgenesis is primarily limited to appropriate estrogen and progesterone replacement therapy.

–This is important for the maintenance of bone density and for the induction of female genital development.

–Pure gonadal dysgenesis syndromes can be familial and call for genetic counseling.

•Turner syndrome appears sporadically, suggesting a postzygotic error.

•The 46XX type of pure gonadal ysgenesis is transmitted as autosomal recessive.

•The 46XY type is inherited as an X-linked recessive trait

31.14Deficient Testosterone Biosynthesis

•Testosterone is produced from cholesterol.

•Production of testosterone from cholesterol involves five enzymatic steps, and defects have been identified at each step.

•Of these five enzymes, three are shared with the adrenal glands, and their deficiency leads to ambiguous genitalia and symptoms of CAH. These three enzymes are:

–20-alpha hydroxylase

–3-beta-hydroxysteroid dehydrogenase

–17-alpha hydroxylase

•The other two enzymes occur only as part of the normal testosterone biosynthesis and their defects leads to ambiguous genitalia without the symptoms of congenital adrenal hyperplasia.

•These two enzymes are:

–17, 20 desmolase.

–17-ketosteroid reductase.

•The diagnosis of these enzyme deficiencies is possible by measuring the levels of precursor

products. This however is available in specialized centers only.

•During the newborn period, these patients present as 46XY gonadal males with poor virilization and ambiguous genitalia.

•The genitalia in these patients respond to exogenously testosterone.

•This help differentiating them from 5-alpha reductase deficiency which do not respond to testosterone but will respond to dihydrotestosterone.

•It is also important to treat those with CAH manifestations with steroid and mineralocorticoid replacement.

•Genetic counseling is also important in these patients as 17-alpha hydroxylase and 3-beta- hydroxysteroid dehydrogenase deficiencies are transmitted as autosomal recessive traits.

•Other rare causes of testosterone production deficiencies include:

–Leydig cell agenesis

–Leydig cell hypoplasia

–Abnormal Leydig cell gonadotropin receptors

–Delayed receptor maturation