Gonadal Dysgenesis and Its Variants

Gonadal Dysgenesis and Its Variants

Symposium on Pediatric and Adolescent Gynecology Gonadal Dysgenesis and Its Variants Phung Thi Tho, M.D.* and Paul G. McDonough, M.D. t Gonadal deve...

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Symposium on Pediatric and Adolescent Gynecology

Gonadal Dysgenesis and Its Variants Phung Thi Tho, M.D.* and Paul G. McDonough, M.D. t

Gonadal developmental failure occurs in phenotypic females and in rare individuals with sexual ambiguity. The associated cytogenetic constitutions range from the typical monosomic 45,X to the normal 46,XX or 46,XY complements through variable structural anomalies of the X or Y chromosome and numerous X or Y mosaicisms. The morphology of the gonad in gonadal dysgenesis varies from the typical bilateral white bands of fibrous tissue devoid of follicular apparatus to rudimentary streaks with some residual follicles, and finally to a unilateral fibrous streak associated with a contralateral dysgenetic testis. 21 In the nineteenth century, several authors reported cases of congenital "ovarian aplasia" and short stature in otherwise proportionate females. In 1938, Turner described a group of seven girls, 15 to 23 years of age, with short stature, sexual infantilism, and webbed neck. He believed their sexual infantilism w:as of pituitary origin. Later, the demonstration of increased urinary gonadotropins made it evident that the condition was due to a primary ovarian deficiency. The ovaries in these patients were invariably replaced by thin white streaks of ovarian stroma without follicles. Individuals with the Turner's phenotype were discovered in 1954 to have negative sex chromatin and in 1959 to have a 45,X constitution with one of the X chromosomes missing. 7 Since this important cytogenetic discovery, a wide spectrum of chromosome karyotypes has been described over the past two decades in association with the rudimentary gonad. Most patients with sex chromosome privations present with short stature and some somatic anomalies. The Turner phenotype is well known to the pediatrician. The easy availability of serum gonadotropin determinations over the past decade has expanded the spectrum of patients with streak gonad to include phenotypically and cytogenetically normal females. Since 1973, X chromosome inactivation has been studied on somatic20 and germ cells 10 by utilization of differential glucose-6-phosphate dehydrogenase (G6PD) electrophoretic patterns. By this technique human oocytes have been demonstrated to have two genetically active X chromosomes. *Department of Obstetrics and Gynecology, Research Fellow, Reproductive Endocrine Division, Medical College of Georgia, Augusta, Georgia fProfessor, Department of Obstetrics and Gynecology; Chief, Reproductive Endocrine Division, Medical College of Georgia, Augusta, Georgia

Pediatric Clinics of North America- Vol. 28, No. 2, May 1981

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Jirasek in 1977 correlated his observations of a deficient follicular layer around the primary follicles in 45,X fetuses to the X material privation suggesting the requirement of two intact active X chromosomes for final development of the adult ovary. 15 Since 1975 H-Y antigen identification and quantitation in Swyer's gonadal dysgenesis and variants with abnormal X or Y mosaicism have provided for localization of H-Y genes and also for understanding ofH-Y antigen function. Radioimmunoassay of gonadotropins in the basal and dynamic states in children and adolescents with gonadal dysgenesis has given interesting information concerning the ontogeny of the hypothalamic pituitary ovarian axis. The purpose of this presentation is to bring into focus our current knowledge in the gonadal morphogenetic, cytogenetic, and clinical aspects of this entity as well as diagnostic aids for an appropriate approach to management.

CURRENT CONCEPTS OF OVARIAN MORPHOGENESIS AND H-Y ANTIGEN The cytogenetic sex of an embryo is determined at conception but the ovary does not become morphologically distinct until the 6th to 8th week of intrauterine life. At approximately four weeks of embryonic development, the genital ridge develops as an external layer of coelomic epithelium covering an internal core of mesenchyme. At five weeks the indifferent gonadal anlage is formed, and the primitive germ cells are incorporated into the genital ridge. The primitive germ cells have an extragenital origin. They migrate from the entoderm of the yolk sac and the hindgut into the gonadal primordia by amoeboid movement. Migration of germ cells has been traced, using alkaline phosphatase as a marker. Their journey is complete by the fifth week and no germ cells are found in extragenital sites after eight weeks. Mitotic multiplication of the initial germ cell endowment continues in the ridge until the original number is increased to approximately 100,000. Histologic differentiation of the gonad begins promptly after the arrival of the primitive germ cells. The indifferent gonad is transformed into a testis or an ovary depending upon the genetic constitution of the germ cells. Differentiation occurs earlier in the testicular line at four to six weeks and later in the ovarian line at six to eight weeks. Testicular organization is controlled by the testis determinants localized on the active short arm of the Y chromosome. These structural Y linked genes specify the production of a male-specific, cell surface antigenic protein named H-Y (histocompatibility Y) antigen. It is postulated from experimental observations that H-Y antigen is disseminated and gonadal cells bear specific receptors for H-Y antigen. The engagement of the disseminated H-Y molecule with the receptor causes a change in the membrane receptor configuration. This configurational change signals the primordial germ cells in the medullary cords to congregate into seminiferous tubules. H-Y genes on the Y chromosome comprise a group of genes of which a critical number seems to be necessary to generate sufficient H-Y antigen to induce testis organogenesis."' Primary germ cells having an XX genotype or a rare XY genotype with missing or deleted genetically active short arm Y material congregate essentially in the cortical area to form the primitive ovarian anlage. The primordial germ cells, now termed oogonia, continue to multiply rapidly by mitosis. Active mitotic proliferation ceases by the 20th week, giving a finite fetal oogonial endowment reaching 6 to 7 millions by this time. The oogonia become primary oocytes when they enter the first meiotic division, indicating the first stage of ovarian exocrine maturation. After cessation of mitotic division the oogonium enters an interphase in which DNA synthesis occurs in preparation for the first meiotic division. This phase is called preleptotene and is followed by the leptotene stage in which chromosomes become thicker and more identifiable. In the next stage or zygotene, the germ cell chromosomes begin to pair, forming 23 homologous bivalents. Then these chromosomes arranged in

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bivalents condense and undergo spiralization in the next stage of pachytene. During this process synapsis or crossing over occurs, mediated by the chromatids which are formed by the longitudinal splitting of each of the paired chromosomes. The chromatids break and rejoin during spiralization with exchange of paternal and maternal DNA material, resulting in gene reassortment. Following this pachytene stage, the chromosomes become more diffuse and the oocyte enters a prolonged arrested quiescent state known as dictyotene. The dormant dictyotene state is terminated only if the primary oocyte is to undergo precocious maturation or be ovulated, thereby leading to atresia. Most of the primary oocytes are in the arrested prophase or dictyotene by 28 weeks of fetal life. The initial stages of this meiotic process begin in oogonia that are not surrounded by follicular cells. However, early in meiotic prophase the oocytes are quickly enveloped by a single layer of flattened granulosa cells. This '>Ocyte single layer granulosa complex constitutes the primordial follicle. Later in development, the granulosa cells surround the oocytes completely, forming the primary follicles. Oocyte survival depends in some way upon the integrity of a complete follicular ring. This mantling process takes place from the 16th week of fetal life until shortly after birth. Follicular growth begins at twenty weeks of fetal life when the primary oocyte starts to enlarge and the granulosa cells multiply. After 24 weeks the multiplication of granulosa cells results in the formation of multilayered primary follicles and a few antral follicles. These antral follicles are encapsulated by epithelioid theca interna cells which presumably are capable of some steroidogenesis. The follicle population at 24 weeks can be categorized morphologically into two pools of nonproliferating and proliferating follicles. The latter are characterized by an increase in the number of granulosa cells surrounding the oocyte. Once a follicle enters the proliferating pool, it must proceed onto maturation and ovulation or it degenerates by atresia. The oocyte and follicle population therefore declines progressively throughout the life span of the ovary. Follicular growth and atresia constitute a continuous basic biological phenomenon that starts at six months of fetal life, and continues during childhood and into the reproductive years. Complete enveloping of the oocyte by the follicular cells, essential for the survival of the oocyte, seems to require the presence of two intact X chromosomes in the oocyte. Anatomical and presumably biochemical inactivation occurs in all female somatic cells by the 50th day. 20 In the human oocyte, both X chromosomes are presumed active as evidenced by full expression of both G6PD alleles on electrophoretic patterns. 10 In the 45,X female the oocytes go through their growth with half of the normal X chromosome activity. This marked deficiency in X-linked products might affect meiosis control mechanisms and accelerate the primary follicle through the complete meiotic cycle prematurely leading to excessive follicular atresia and depletion. Jirasek suggests that X chromosome privation in germ cells is associated with an incomplete follicular mantle resulting in degeneration of the oocyte shortly after formation of the primary follicles. Whether a deficiency of X chromosome activity thwarts mantle formation leading to accelerated uncontrolled meiosis is enigmatic. Cussen recently reported his observations on the gonads of a female twin child with a 46,XY karyotype at three months and three years ten months respectively.• He found on the gonadal biopsies at the age of three .months many germ cells and occasional ova in primordial follicles and on the ovarian sections at the age of three years only ovarian stroma with no primordial follicles or testicular elements. His findings were similar to those in children with sex chromosome privation gonadal dysgenesis. These findings seem to suggest that abnormal follicular cell arrangement, premature follicular and germ cell degeneration and depletion constitute the basic pathologic process independent of the primary genetic event. In the absence or malfunction of the testis determining genes, the 46,XY gonad behaves no differently than the 45,X gonad because of the absence of the second X chromosome. However, the presence of two intact X chromosomes is not a guarantee for ensuring normal ovarian development. For example, the etiology of 46,XX familial gonadal dysgenesis is still obscure. The presence of multiple affected siblings, the increased frequency of consanguinity, and associated neuroauditory abnormalities in some instances indicate a single autosomal recessive mutant gene limited to 46,XX subjects. Whatever the primary event in these individuals the process of follicular degeneration and atresia is compressed into a brief time span rather than the first 40 to 50 years of life.

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The ranges of ovarian function seen in individuals with gonadal dysgenesis are best comprehended when one appreciates the numerous factors contributing to normal ovarian development and function. These factors may be summarized as (1) absence of genetically active Y material and presence of two intact and genetically active X chromosomes in the germ cell line; (2) germ cell migration to the genital ridge; (3) mitotic activity of germ cells in the ridge; (4) development of granulosa cell mantle; (5) normal transformation of the oogonium into a primary ooocyte with controlled arrest of development at the dictyotene stage (arrested meiotic prophase); and (6) physiologic response of the primary follicle to fetal FSH. Interference with these normal mechanisms may result in failure of the ovaries to develop. Recent knowledge of the hypothalamic pituitary ovarian axis at different ages in both normal and agonadal individuals aids in the diagnostic evaluation of the patients in whom gonadal dysgenesis is suspected. Intrauterine diagnosis of gonadal dysgenesis is suggested by the presence of a sex chromosome privation incidentally identified during amniotic fluid karyotyping for a genetic reason. However, biochemical diagnosis of ovarian failure during fetal life is impossible since the normal fetal ovary is endocrinologically quiescent. Fetal FSH and LH are suppressed by estrogens of placental origin. During infancy and before five years of age, basal gonadotropins and gonadotropins stimulated by gonadotropin-releasing hormone (GnRH) distinguish the normal from the agonadal child because the agonadal child has increased basal and exaggerated GnRH-induced gonadotropin concentrations. These studies may not provide definite evidence of ovarian failure in the child between 5 and 11 years of age because of overlapping gonadotropin levels between normal children and children with gonadal dysgenesis at this age. 2 After puberty, the biochemical diagnosis is obvious with marked elevations in basal gonadotropin measurements.

CLINICAL CATEGORIES The multiple cytogenetic complements and the variable clinical features in association with rudimentary streak gonads may be categorized into two groups on the basis of the different mechanisms leading to defective gonadal development: (1) chromosomally incompetent gonadal dysgenesis (CIGD) with sex chromosome privation; and (2) chromosomally competent gonadal dysgenesis (CCGD): 46,XX forms and 46,XY forms.

Chromosomally Incompetent Gonadal Dysgenesis (CIGD) The cytogenetic spectrum includes essentially 45,X, 46,X,i(Xq) to 45,X/46,XX; 45,X/46,XY; 45,X/46,X,i(Xq). Analysis in 45,X monosomics of the segregation of X-linked Xg antigen showed that in 75 per cent the X chromosome is contributed by the mother and the abnormality is therefore of paternal origin owing to fertilization of a normal ovum by a nullisomic X or Y sperm. The same study related the X long arm isochromosome in 46,X,i(Xq) complement and the deleted X long arm in 46,X,del(Xq) complement to be paternal in origin. Other X chromosome structural anomalies such as ring X, isodicentric X, and X-X and X-autosome translocations have been recently

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reported. Structural aberrations of the Y chromosome associated with gonadal dysgenesis include essentially Y long arm isochromosome and ring Y. The frequency of sex chromosome mosaicism in rudimentary streak gonads suggests that the divisional error is frequently a postzygotic event. The most frequent mosaicisms are 45,X/46,XY and 45,X/46,X,i(Xq). Individuals with sex chromosome privation have somatic anomalies and rudimentary streak gonads. The most constant somatic anomaly is short stature. In short patients, growth retardation starts in intrauterine life, as evidenced by low birth weight, usually less than five pounds, in spite of term delivery. A position on the growth chart below the third percentile along with a normal rate of growth is maintained in the individual with untreated gonadal dysgenesis throughout childhood and early adolescence. Growth spurt does not occur and growth velocity declines before finally stopping. Skeletal age is usually equal to chronologie age but begins to fall progressively behind the chronologie age at the expected time of puberty. Bone demineralization is common even in early life. Sexual infantilism, primary amenorrhea, and menopausal ranges of serum FSH evidence primary ovarian failure. Absence of the growth spurt, delay in skeletal maturation, sexual infantilism, and early osteoporosis are secondary to lack of gonadal steroid production. Estrogen replacement therapy will initiate breast development, growth spurt, and prevent early bone loss, but the final height is still subnormal. Although gonadal failure is a consistent sequela of sex chromosome privation, it is not necessarily an all-or-none phenomenon. Follicular depletion may be incomplete and a few residual follicles under the effect of elevated gonadotropins may produce periodic bursts of estrogenic activity and even fertility. While short stature represents the principal phenotypic feature of this group of gonadal dysgenesis with sex chromosome privation, other associated somatic anomalies of the Turner phenotype including webbed neck, high arched palate, wide shield chest, cubitus valgus, short fourth metacarpal, multiple nevi, and lymphedema at birth and during infancy constitute the minor somatic anomalies and do not consistently accompany the diminished stature. Other more serious somatic anomalies comprise cardiovascular renal malformations, essentially coarctation of the aorta and horseshoe kidney. Figure 1 illustrates absence of the left kidney and partial obstruction of the right kidney seen in one of our patients with 45,X/46,X,i(Xq) gonadal dysgenesis. Renal malformations compromising renal function in patients with gonadal dysgenesis are rare. Two intact active X chromosomes are necessary for normal somatic development and follicular formation. Genotype-phenotype correlations seem to suggest that gonadal determinants are located near the centromere on both the long and short arms of the X chromosome and on the short arm of the Y chromosome. Statural determinants are probably on the short arm of the X and Y chromosomes. Among 82 patients seen in our institution with gonadal dysgenesis, 52 (63 per cent) presented with sex chromosome anomalies (Fig. 2). 22 The most common genotype in this CIGD group is X chromosome mosaicism (27/52 or 51 per cent). The classical 45,X complement constitutes only 32 per cent (18/52) of the chromosomally incompetent group. The most common chromosome mosaicism, in our experience, is

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Figure 1. Congenital absence of the left kidney and partial obstruction of the right kidney on an intravenous pyelogram in patient F. J. with 45,X/46,X,i(Xq).

ABNORMAL

27

18

52

MOSAICS

X

SHORT • 51"-61" MENSES • 11.5%

I

I

I®IM;J NORMAL

~LQ.QJ

27

30

XX

NORMAL• 63"-76" MENSES= 40%

10

20

30

40

50

TOTAL PATIENTS Figure 2. Cytogenetic constitution of 82 patients with gonadal dysgenesis. The circled 6 represents six 45,X/46,XY mosaics with bilateral rudimeptary streak gonads who are nonmasculinized. The other three, 45,X/46,XY individuals are masculinized, two with clitoromegaly and one with frank sexual ambiguity. (From McDonough, P. G., Byrd, J. R., Tho, P. T. eta!.: Fertil. Steril., 28:638, 1977, with permission.)

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45,X/46,XY. The cytogenetic and phenotypic features of this 45,X/46,XY subgroup deserve special discussion. The frequent association of structural rearrangements of the Y and mosaicism seems to suggest that 45,X/46,XY can arise following a single disruptive event that occurs in a zygote with a normal 46,XY complement. This event leads to the formation of a structurally abnormal Y which fails to behave normally during mitosis, causing secondary intrachromosomal rearrangements. Anaphase lag of the defective Y gives rise to a cell line with 45,X. One patient exhibits a 45,X/46,XF karyotype and another 45,X/46,XYnr* complement in our series of nine 45,X/46,XY patients. The minute fragment in the 45,X/46,XF genotype was assumed to be Y derived because the patient not only presented as a female with Turner phenotype but also harbored a right gonadoblastoma. A nonfluorescent Y chromosome has been reported with increased frequency in the 45,X/46,XY form of gonadal dysgenesis. Although the ynr is relatively short, it is obviously longer than the nonfluorescent part of the father's Y chromosome. The normal sized or nearly normal sized nonfluorescent Y more likely results from an alteration in the DNA base sequence rather than from a deletion of the fluorescent position. 19 Intrachromosomal rearrangement of defective Y might not be the only mechanism since a normal Y chromosome is frequently found in association with 45,X/46,XY mosaicism. The increased incidence of identical twinning in sibships involving 45,X/46,XY form seems to suggest a postsegmentation divisional error following an attempt for 46,XY identical twinning. There appears to be no consistent correlation between the relative representation , of 45,X and 46,XY cell lines to modify toward streak or testicular formation. While short stature was uniformly seen and cardiovascular renal anomalies were frequent, the phenotypical variability from typical Turner features to degrees of sexual ambiguity and tumor occurrence represent the two additional characteristics. These patients are individualized into three subgroups based on the degree of masculinization. 9 Figure 3 illustrates the phenotypic spectrum of 45,X/46,XY gonadal dysgenesis. In our study, six of the 45,X/46,XY patients presented at the expected age of puberty for evaluation of delayed sexual development (see Fig. 2). They were unmasculinized and had bilateral streak gonads, normal fallopian tubes, and a uterus. Three 45,X/46,XY patients were seen at birth and in early childhood because of varying degrees of masculinization. In two patients the masculinization was mild, evidenced only by clitoromegaly, and both were raised as females. In both, an intra-abdominal testis, a contralateral rudimentary streak, bilateral fallopian tubes, and a normal uterus were present. The third masculinized patient was seen at birth with frank sexual ambiguity. The sex of assignment was male and it was reversed to female at two weeks of age. The infant had a scrotal testis with accompanying vas deferens and a contralateral intraabdominal rudimentary streak, and a normal appearing uterus and vagina. In this particular case, the Y chromosome was not fluorescent and was also abnormal on banding techniques. This supports the fact that absence of fluorescence does not exclude the genetically active portion of the Y chromosome. The paternal Y was normal in this case. Gonadoblastoma occurred in one unmasculinized patient and in one patient with clitoromegaly. *nf = nonfluore·scent.

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Figure 3. Three representatives of the phenotype spectrum of 45,X/46,XY gonadal dysgenesis. Left, E. W., 14 year old girl with bilateral rudimentary streak gonads. Right, S. T., 5 year old girl with marked clitoromegaly and empty labioscrotal pouches. The left rudimentary streak and right testis were both intra-abdominal. Illustration continued on opposite page.

The principal single cell line chromosomal anomalies in patients with CIGD are 45,X and 46,X,i(Xq). The classical 45,X complement should alert some precaution since an XY cell line might be missed if generous cell counts are not carried out and supplemented with H-Y antigen studies to detect a 46,XY cell line. The genotype with long arm X iso'-hromosome 46,X,i(Xq) should require periodic evaluation of the thyroid since thyroid autoimmune disorders are frequently associated with this X chromosomal anomaly. One case of Hashimoto thyroiditis and one case of thyroid carcinoma out of six patients with long arm X isochromosome were present in our series. A practical point concerning this genotype is that it is not infrequent to mistake a long arm isochromosome X with a normal X chromosome if a banding cytogenetic technique is not used. Combined short stature and ovarian failure should call for suspicion of miskaryotyping if the report is normal 46,XX. All our adolescents with CIGD are short with a height of less than 63 inches. Cardiovascular renal anomalies were identified in 12 of the 52 patients (23 per cent) with CIGD. Among our 52 patients with CIOF, 11.5 per cent experienced a short menstrual life. Figure 4 illustrates a 15 year old patient with 45,X who presented with short stature and irregular bleeding in whom secondary sex characteristics developed spontaneously. Exploratory laparoto-

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Figure 3 (Continued). Newborn infant with frank sexual ambiguity and clitoromegaly. The right testis was labial in location and the left streak located intra-abdominally. (Left, From McDonough, P. G., and Byrd, J.. R.: Endocrine causes of menstrual disorders. In Givens, J.. R. (ed.): Endocrine Causes of Menstrual Disorders. Chicago, Year Book Medical Publishers, 1978, with permission. Right, From McDonough, P. G., and Simmons, R. G.: Obstet. Gynecol., 37:368, 1971, with permission.)

my was performed because a tumor mass was visualized on the right streak gonad. It was found to be a functional theca lutein cyst on histological examination. 23 We had one patient with 45,X/47,XXX who presented for evaluation of secondary amenorrhea at the age of 26 after 12 years of menstrual life and the birth of a six year old normal female child. There have been increasing reports of fertility in patients with CIGD who were under low dose estrogen replacement therapy. The most likely explanation is that estrogen enhances the response of follicles to FSH and causes an increased receptor content for FSH and LH. 27

Chromosomally Competent Gonadal Dysgenesis (CCGD) Unlike patients with CIGD, the individuals with intact sex chromosomes and rudimentary streak gonads present with normal female phenotype, normal stature, and with heights greater than 63 inches. They have either 46,XX or 46,XY sex chromosome constitutions and represent 30 out of the 82 patients (36 per cent) with primary ovarian failure. The intact chromosomes account for normal stature. Ovarian failure with deficient estrogen production

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Figure 4. L. M., 15 year old girl with 45,X gonadal dysgenesis, short stature, normal secondary sex characteristics," irregular bleeding, and cystic enlargement (large arrow) of the right streak (functional theca lutein cysts). Small dark arrows depict streaks. (From McDonough, P. G., and Tho, P. T.: Am. J. Obstet. Gynecol., 119:565, 1974, with permission.)

delays epiphyseal closure leading to increased final height. These patients escape the diagnosis of ovarian failure at younger ages. They usually present at chronologie age of puberty for evaluation of sexual infantilism and amenorrhea. Forty per cent of the chromosomally competent females with ovarian failure in our series have a brief menstrual history. None of these patients has reported a history of pregnancy. Determination of FSH levels is the clue to diagnosing ovarian failure in this group. Most of these individuals have streak gonads. Rarely they present well preserved small ovaries with complete follicular exhaustion. Uncommon patients with Savage syndrome have normal sized ovaries and numerous intact primordial follicles in spite of elevated gonadotropins. 16 Diagnostic laparoscopy and ovarian biopsy are necessary for gonadal visualization and histologic distinction between follicular depletion and follicular dormancy types of ovarian failure. The etiologies of chromosomally competent ovarian failure are diverse and mostly ill defined. XY Forms of CCGD. This form is infrequent but constitutes an important group since its diagnosis requires gonadal extirpation for the patient and a search for other affected female siblings in the family. Testicular regression occurring before the production of miillerian inhibiting factor (MIF) is the most likely pathologic mechanism. Therefore unlike patients with the syndrome of feminizing testes, all have a uterus and a vagina. These patients have normal female external genitalia, miillerian systems, bilateral streak gonads, and elevated gonadotropin concentrations, and H-Y antigen studies may be positive 5 or negative.U Although sexual infantilism and primary amenorrhea are the usual features, occasional patients with XY gonadal dysgenesis have fairly well developed breast tissue. Neoplasia of the streak gonad, usually a

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gonadoblastoma or rarely a dysgerminoma, frequently occurs in patients with 46,XY gonadal dysgenesis.t. 30 All patients diagnosed as having 46,XY gonadal dysgenesis should have the ridges removed. Gonadoblastoma was present at laparotomy in two of the three patients with XY gonadal dysgenesis in our series. Figure 5 illustrates a 19 year old girl with normal stature, sexual infantilism, 46,XY gonadal dysgenesis, and bilateral gonadoblastorr ~- The right tumor was larger and more extensively calcified than the left one and was visualized on an anteroposterior film of the pelvis. All three patients were sexually infantile and amenorrheic. No renal cardiovascular anomalies were present in our series of three patients with XY gonadal dysgenesis. Familial aggregation has been documented by reports of affected siblings, concordant monozygotic twins, and affected individuals in a sibship with transmission through unaffected females. Vertical transmission and absence of consanguinity suggest the possible role of an X-linked gene. 6 With the advent of H-Y antigen, two forms of XY gonadal dysgenesis can be identified. In the 46,XY gonadal dysgenesis with negative H-Y antigen typing, failure of testicular development is due to a mutational suppression of the testis determining gene, located on theY short arm by a regulatory gene on the X chromosome. In the 46,XY gonadal dysgenesis individual with positive H-Y antigen, testicular developmental failure is due to deficiency of specific gonadal receptors for H-Y antigen. 31 Early teratogenic effect interfering with germ cell migration or further testicular development prior to production of MIF could

Figure 5. D. J., a 19 year old girl with 46,XY gonadal dysgenesis, normal stature, sexual infantilism, and bilateral gonadoblastoma. The right gonadoblastoma was larger than the left and was more extensively calcified. The floccular calcification is visualized in the region of the right gonadal tumor.

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Table 1.

G.

McDONOUGH

Etiologies of 46,XX Forms of Chromosomally Competent Ovarian Failure (CCOF) Autosomal recessive (familial) Environmental factors Virus Radiation therapy Cytotoxic drugs Autosomal abnormalities Autoimmune disease Infectious process- infiltrative disease Myotonia dystrophica Ataxia telangiectasia 17-Alpha-hydroxylase deficiency Resistant ovary syndrome

be the etiology of nonfamilial, H-Y antigen positive 46,XY gonadal dysgenesis, but this has not been proven. XX Forms of CCGD. Most of these patients have streak gonads as the only abnormal finding and the prevailing consensus as to etiology is autosomal recessive inheritance. The genetic theory is probably an oversimplification of the problem and etiologic factors in this group are likely diverse (Table 1). Most of these individuals are phenotypic females with streak gonads resulting in eunuchoid habitus, lack of secondary sexual development, and primary amenorrhea. Their gonadal streaks are identical to those seen in CIGD. As in the patients with X chromosome privations, they have a wide spectrum of residual follicular population, and a significant percentage of patients with 46,XX gonadal dysgenesis have estrogenic function with some degree of breast development and a menstrual history varying from one menses to several years of monthly periods, but mostly oligohypomenorrhea. Among our series of27 patients with 46,XX chromosomally competent ovarian failure, 12 have normal female secondary sex characteristics and experience an abbreviated menstrual history. None of them presented a normal long-term menstruallife. 22 Gonadal visualization was performed on 24 of the 27 patients with chromosomally competent ovarian failure and the gonadal morphology was consistently rudimentary streaks. The only exceptions were two patients in whom normal ovarian contour was preserved but the ovaries were reduced in size (approximately 2 em x 1 em) and bilateral ovarian biopsy in both instances revealed only fibrous stroma with absence of follicular apparatus. The etiologic factors possibly responsible for early primary failure in the 46,XX individuals are as follows. Single Ge~e Etiology -Autosomal Recessive. The frequent occurrence of 46,XX pure gonadal dysgenesis in siblings has been documented. 26 In some sibships, neuroauditory defects have been seen in affected sisters, suggesting a single autosomal gene that may be closely linked to an ovary controlling gene. Argument for an autosomal recessive gene is further suggested by genetic linkage of gonadal dysgenesis in two siblings with SS and SA genotypes for sickle hemoglobin in our series (Fig. 6). 24 Besides this set of sisters, another family has two female siblings affected with rudimentary streak gonads among our 27 patients with 46,XX constitution and primary

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I Figure 6. Pedigree of siblings with CCGD and sickle cell gene. (From McDonough, P. G., and Byrd, J. R.: Primary ovarian failure. In Givens, J. R., eel.: Endocrine Causes of Menstrual Disorders. Chicago, Year Book Medical Publishers, 1978, pp. 201-221, with permission.)

n 18

0 18

Hb A[AA) Ill Sickle Cell Trait ~) Sickle Cell Anemia [ss] GD=Gonadal Dysgenesis Hemoglobin genotypes shown in brackets.

ovarian failure. Familial aggregation, association with autosomal defects in the affected siblings, and parental consanguinity seem to support the hypothesis of female-limited autosomal recessive inheritance. But this etiology does not seem to account for the sporadic cases of 46,XX gonadal dysgenesis. Environmental Etiology. Extrinsic factors can prevent germ cell migration, disturb early mitotic activity in the genital ridge, disrupt meiotic pairing of chromosomes, or disrupt the follicular apparatus of the fully developed ovary. Viruses, radiation, and cytotoxic drugs have been incriminated. Virus. We have in our series of patients with CCGD a monozygotic twin discordant for ovarian failure with her otherwise identical twin sister. Both twins had rubella at the age of two with much higher fever in the affected twin than in her normal twin sister. 25 The monozygotic twin situation and the clinical history of viral illness suggest that environmental insult is the most likely etiology for rapid follicular atresia and consequently development of rudimentary streak gonads. Radiation. Doses of irradiation to the ovaries above 500 rads were associated with endocrine ovarian failure. Such doses occurred in the inverted Y exposure in which 3500 rads were delivered to the para-aortic, iliac, and inguinal nodes in the treatment of Hodgkin's disease. Review of several series of patients receiving radiation therapy indicates that prolonged abdominal radiation inhibits follicular growth and destroys the small nonproliferating follicles. Cytotoxic drugs. Prolonged treatment over one to two years with alkylating agents such as cyclophosphamide destroys the small follicles through a direct effect on the granulosa cells. 14 There appears to be no disease-related ovarian susceptibility but rather a progressive loss of ovarian function related to duration of treatment. This is not always the outcome. One series of 25 adolescent girls treated with cyclophosphamide for nephrosis in childhood showed that all the girls had normal ovarian function. The risk of testicular sclerosis was gr~ater in boys and was virtually negligible in girls. Ovarian failure associated with autosomal anomalies. Recent observations of the ovaries of fetuses and infants with trisomies 13 and 18 and group D chromosome aberrations have indicated varying degrees of histologic gonadal maldevelopment. 17 • 28 The autosomal aberrations might cause diffi-

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culty in meiotic pairing as in X chromosome aneuploidy resulting in premature follicular growth and accelerated follicular atresia. Immunologic etiology. Immunologic studies in patients with ovarian failure have defined a small group of patients with high circulating antiovarian antibody titers. However, while autoantibodies to cytoplasmic components of the ovary have been found in patients with premature ovarian failure and other immune disorders, the ovarian antigens and the autoimmune mechanism responsible for the destruction of the ovarian tissue remain to be elucidated. Infectious process- infiltrative diseases. Tuberculosis, sarcoidosis, actinomycosis, and schistosomiasis rarely destroy the entire ovarian parenchyma by the granulomatous process. Infiltrative diseases such as betathalassemia and mucopolysaccharidosis rarely cause extensive infiltration of the ovary resulting in ovarian failure. It is uncertain whether follicular growth was inhibited by the disease itself or by cytotoxic drugs since most children are under treatment. The fact that the ovaries of leukemic children who had been under treatment for a week were normal and that prolonged exposure to the combined corticosteroids and alkylating agents inhibited follicular growth and destroyed small oocytes seemed to indicate that the disturbance in follicular development is an effect of the cytotoxic drugs and not an effect of the disease itself. Myotonia dystrophica in association with ovarian failure. The occurrence of myotonia dystrophica and premature ovarian failure 13 in chromosomally intact individuals suggests that the gene controlling ovarian development may be closely linked to the gene producing myotonia dystrophica. The gene causing myotonia dystrophica is an autosomal dominant gene, transmitted from affected individuals to 50 per cent of their offspring. A satisfactory study of the incidence of gonadal failure within a myotonia dystrophica pedigree is however not available. Ataxia telangiectasia in association with ovarian failure. This syndrome of oculocutaneous telangiectasia and cerebellar ataxia has been suggested to be due to a demyelinating process and to have an autoimmune basis. At autopsy the affected individuals may be found to have ovarian dysgenesis and even dysgerminoma. 17-Hydroxylase deficiency. Impaired 17-alpha-hydroxylation of progesterone and pregnenolone causes estrogen and androgen deficiency and excessive production of mineralocorticoid precursors of aldosterone. These patients present with symptoms of sexual immaturity, primary amenorrhea, and hypertension accompanied by high serum gonadotropins and undetectable serum androgens and estrogensY Resistant ovary syndrome (Savage syndrome). It has been postulated as resulting from deficient FSH hormone receptor on the follicular cell membrane. Ovarian biopsies from these women show only primordial follicles with no progression to follicular maturation. These patients usually present with primary amenorrhea, hypoestrogenism, hypergonadotropism but normal secondary sex characteristics and may respond to induction of ovulation with excessive doses of exogenous gonadotropins. A successful pregnancy was recently reported in a patient with resistant ovary syndrome subsequent to estrogen replacement therapy. 29

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APPROACH TO DIAGNOSIS Essential Aids Cytogenetic Studies Including H-Y Antigen. Cytogenetic studies establish the diagnosis in individuals with Turner phenotype at any age as well as in newborn infants with diverse degrees of sexual ambiguity. A minimal number of 50 cells should be counted because of the prevalence of mosaicism in this group of patients with chromosomally incompetent gonadal dysgenesis. Recent banding techniques provide for the diagnosis of precise structural anomalies of the X and Y chromosomes. Quinacrine staining of the chromosomes and their analysis by fluorescence microscopy show a distinctive pattern of fluorescent or Q bands for each chromosome. Characteristically the human Y chromosome exhibits a very intense fluorescence of the distal two thirds of the long arm. The intensely fluorescent portion is heterochromatic and genetically inactive. Lack of fluorescence therefore does not signify absence of the genetically active Y component. The nonfluorescent Y has been reported in 46,XY gonadal dysgenesis 8 and repeatedly in 45,X/46,XY 3 • 1" mosaicism as ~ell as in Y-X and Y-autosomal translocations. C banding is obtained by denaturation of the chromosomes with NaOH followed by Giemsa staining. This technique stains the heterochromatin near the centromere in all autosomes and the X chromosome and the distal two thirds of the Y chromosome. These C bands vary considerably in size without phenotypic expression of the variability. The G-banding technique consists of treating the chromosomes by proteolytic enzymes such as trypsin and then staining them with Giemsa stain. They take up the stain in a pattern of dark and light bands (G-bands) very similar to Q bands. Giemsa banding has been widely used because of its simplicity, low cost, and effectiveness. Bromodeoxyuridine treatment followed by acridine orange staining and fluorescence microscopy examination evidences the differential despiralization between an euchromatic early replicating X and a heterochromatic late replicating X chromosome. This technique is helpful in the identification of the abnormal X chromosome by its mode of inactivation especially in dicentric X, X-X translocation and X-autosomal translocation. It is also used to demonstrate that a structurally altered chromosome is not X derived in the absence of its late replication. None of these recent cytogenetic techniques is efficient in identifying the minute chromosomes which probably consist oflittle more than the centrometric regions of either X or Y chromosome. Usually small rings or centric fragments fail to fluoresce or to demonstrate late completion of DNA synthesis. H-Y antigen studies in the near future will help to disclose theY-derived minute fragments and therefore limit prophylactic gonadectomy to only patients with H-Y positive gonadal dysgenesis. H-Y antigen is detected by cytotoxicity of the H-Y antiserum from male-sensitized inbred female mice on mouse epididymal sperm. Presence of H-Y antigen in different tissues may be demonstrated by their capacity to absorb H-Y antibodies, thereby limiting the reactivity of H-Y antiserum with mouse sperm. H-Y antiserum is divided into

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four parts: one part is unabsorbed, one part is absorbed with blood leukocytes from normal XX females, one part is absorbed with blood leukocytes from normal XY males, and one part is absorbed with blood leukocytes from the patient. H-Y antigen typing is ascertained by comparing the absorptive capacity of cells from the patient with the absorptive capacity of the same number of cells from normal male and female controls in individual assays. Cytogenetic studies are therefore essential for the diagnosis of gonadal dysgenesis by precise identification of the sex chromosome privation. They should be supplemented with H-Y antigen assays in genotypes with minute fragments or 45,X monosomy complement to detect a genetically active Y component which codes for testicular structures and therefore makes the dysgenetic gonads at risk for tumor formation. Figure 7 illustrates the second cell line of a 45,X/46,XF genotype of a 21 year old woman who presented a left rudimentary streak and a right tumor mass which was histologically diagnosed as a gonadoblastoma. Serum Gonadotropin Determination by RIA. Elevated gonadotropins, especially FSH, constitute the most sensitive diagnostic test of primary ovarian failurt. A level of FSH above 50 miU per ml signifies markedly decreased or absent follicles. This test is indicated in all adolescents with primary or secondary amenorrhea. It should also be included in the recycling failure (anovulation) work-up in infertility patients, since anovulation and refractoriness to ovulation induction therapy not unusually are preliminary signs of eventual permanent ovarian failure. This diagnosis should be established as soon as possible so that these young women can cease their futile search for fertility. Since the diagnosis of ovarian failure is a serious one for the patient and since the gonadotropins fluctuate considerably, it should be

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Figure 7. Karyotype of a 21 year old (H. J.) woman with 4f>,.X/46,XF constitution and right gonadoblastoma. (From McDonough, P. G., Greenblatt, R. B., and Hastings, E. V.: Obstet. Gynecol., 29:54, 1967, with permission.)

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made only after at least two serum gonadotropin determinations done at the time of the first evaluation to rule out laboratory error, and a third gonadotropin assay should be repeated six months later to see whether the pituitary gonadotropins are persistently elevated. In a prepubertal or adolescent child who is potentially subject to have ovarian failure because of X chromosome privation or because of a history of abdominal radiation or chemotherapy, a normal or low level of gonadotropins does not rule out the possibility of ovarian failure, even in the presence of some sexual development. Periodic gonadotropin determinations will allow the physician to establish the diagnosis by the time of further hypothalamic pituitary maturation. Administration of GnRH or Clomid by inducing exaggerated responses after age of 11 would clarify the ambiguous serum values.

Supplementary Evaluation Evaluation of Cardiovascular and Renal Anomalies. An intravenous pyelogram and a careful evaluation of the cardiovascular system are crucial steps as soon as the diagnosis of chromosomally incompetent ovarian failure is established, since a coarctation of the aorta or a renal anomaly may pose a serious threat to the life expectancy of these patients. Thyroid Evaluation, Including Antithyroid Antibodies, Should Be Performed On All Patients with Ovarian Failure. Autoimmune thyroiditis not only is frequently seen in association with a long arm isochromosome X, but also with a 46,XX ovarian failure of immunologic etiology. Gonadal Visualization. The easy availability of serum gonadotropin radioimmunoassay has rendered endoscopic visualization and ovarian biopsy unnecessary. Laparoscopic inspection and histologic examination may fail to distinguish ovarian failure from an unstimulated ovary and the presence of a few scattered primordial follicles is usual in ovarian failure. Furthermore, gonadal visualization has no place in patients known to have a Y chromosome. Laparotomy and gonadal extirpation should be performed at any age as soon as the diagnosis is made because of a 25 per cent incidence of neoplasia associated with gonadal dysgenesis and the presence of a Y component in the genotype. The real controversy for diagnostic laparoscopy and ovarian biopsy in ovarian failure revolves around a few distinctive patients with high levels of gonadotropins who exhibit numerous primordial follicles, suggestive of an FSH receptor defect and an ovary resistant to gonadotropins.

Determination of Bone Age Status and Anteroposterior Radiograph of the Pelvis. The fourth important supplementary study for all patients in whom gonadal dysgenesis is suspected includes obtaining a film of the hand for determination of bone age and an anteroposterior film of the pelvis. Bone age in these children progresses satisfactorily until expected endocrine menarche at which time it stops, usually about the chronologie age of 11 to 12 years. Bone age arrest dates the onset of gonadal failure. An anteroposterior film of the pelvis is taken for visualization of the maturation of the iliac epiphysis and for identification of calcification in the areas of the rudimentary streaks. Ossification of the iliac epiphysis is under the influence of gonadal steroids. In patients with gonadal dysgenesis and absence of ovarian function, the epiphysis does not undergo ossification. Partial ossification is seen in the forms of gonadal dysgenesis with limited estrogenic ridge activity.

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The anteroposterior film of the pelvis may reveal calcification within the area of the rudimentary streaks, suggesting the presence of a gonadoblastoma. The gonadoblastoma characteristically undergoes degenerative calcification that outlines the contour of the tumor (see Fig. 5). Calcification of this neoplasm is frequently visualized roentgenographically long before it is palpable on pelvic examination.

COUNSELING, THERAPY, AND FOLLOW-UP Counseling Counseling the adolescent and her mother requires a considerable amount of tact on the part of the physician. It is important to give the adolescent some idea of her final height and her future secondary sex characteristics as results of successful treatment. It is psychologically reassuring for the patient to meet another patient with gonadal dysgenesis and to see that other individuals are able to adapt to the compromised stature. Sterility should be explained to her so that she can plan her future. In the young woman seeking fertility, laparoscopic or laparotomy ovarian biopsy would aid the physician in identification of the rare patient with resistant ovary syndrome who may benefit from a high dose of exogenous gonadotropins for ovulation induction. She should also be informed of the rare possibility of becoming pregnant following replacement therapy. An excellent inexpensive publication entitled Good Things Come in Small Packages is available. 26 a

Therapy Medical. Most patients with rudimentary streak gonads have severe estrogen deficiency and need estrogen replacement therapy. Figure 8 illustrates a 51 year old woman with 46,X,i(Xq) complement with premature aging. She had never initiated menses or received hormonal therapy. Initiation of substitution therapy in low doses at chronologie age 11 simulates the normal physiologic rise in estrogen occurring at this time. Anabolic steroids including testosterone have been used with equivocal success. Normal level of serum FSH when associated with clinical onset of puberty signifies spontaneous estrogenic ridge activity, and therapy should be postponed until ovarian failure is evidenced by a castrate level of serum FSH. Initial therapy consists of a sequential regimen, utilizing 20 J.tg of ethinyl estradiol for 21 days a month and Provera or Norlutate, 10 mg a day for the last seven days of the monthly course of estrogen until breast development is complete. Since that point in time she will follow a combined regimen of 1 mg of norethindrone and 20 J.tg of ethinyl estradiol (Loestrin l/20) to insure good neutralization of the endometrium and physiologic withdrawal bleeding, and the systemic vascular side-effects are minimal. Endometrial biopsy will be considered in cases of inappropriate bleeding to exclude the possibility of endometrial hyperplasia or adenocarcinoma. Consistently the endometrial histology in the patients so treated in our unit exhibits a marked progestin effect and no evidence of endometrial hyperplasia has been shown. At least 12 cases of adenocarcinoma of the endometrium have been reported in patients

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Figure 8. E. R., a 51 year old woman with 46,X,i(Xq) which was untreated, exhibits premature aging.

with gonadal dysgenesis who were on long term hormonal replacement therapy. Most of these patients were on estrogen alone and some were on estrogen followed by ethisterone or dimethisterone. 18 Blood pressure, blood sugar and serum triglycerides are periodically assessed before and during replacement therapy. Surgical. In patients with a Y chromosome, prophylactic extirpation of the gonads is mandatory at any age as soon as the diagnosis is established because of the highly malignant potential of these dysgenetic gonads. If neoplastic formations are found during laparotomy concomitant hysterectomy is a controversial subject. Some patients with gonadal dysgenesis, in spite of normal urinary steroid values, may exhibit adrenal hypofunction under stressful situations, possibly because of adrenal deficiency in 17-hydroxylation. This is an infrequent accompaniment of gonadal dysgenesis but important to recognize, especially if signs of adrenal insufficiency develop following surgical stress.

Follow-up Height Surveillance. The height of children and adolescents with gonadal dysgenesis should be carefully measured at periodic intervals, recording graphs of both linear growth and velocity growth as related to both chronologie age and bone age. The final adult height is roughly related to the degree of sex chromosome privation and the genetic imprint of mid-parental height, that is, tall parents have taller gonadal dysgenetic offspring. Anabolic

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agents have not been successful in increasing ultimate height in these girls but temporarily accelerate growth velocity and may be of value in girls of very short stature with a two to three year lag in bone age. The increased rate of growth helps to buffer the ever-widening gap that is perceived by the patient and her peers. Tumor Surveillance. Pelvic examination alone will not usually detect gonadoblastoma since most of these tumors are in the 4 to 5 em category. Roentgen calcification is an early finding and is almost diagnostic of dysgenetic ridge tumor. A single anteroposterior film of the pelvis each year is adequate for diagnosis and poses minimal radiation hazard.

CONCLUSION Comprehending gonadal failure in phenotypic females with privation of sex chromosome material has improved over the past decade. Continued inquiry into X inactivation in somatic and germ cells and recent identification and quantitation of H-Y antigen have provided further insight into genetic factors affecting ovarian and testicular development. Gonadal dysgenesis in chromosomally intact 46,XX individuals is still a source of mystery and requires further investigation of the genetic control of ovarian development. The concept of gonadal receptor to H-Y antigen has provided for a better understanding of the H-Y antigen function in the 46,XY gonadal dysgenesis. Future availability of H-Y antigen determination will serve for easy detection of the Y component unrecognizable by current cytogenetic techniques in the 45,X gonadal dysgenesis subjects. In all etiologic groups, gonadal failure is the consistent lesion and recent longitudinal radioimmunoassay measurements of gonadotropin levels have shown the biphasic pattern of gonadotropin secretion before attaining the typical castrate level seen in agonadal children at the anticipated time of puberty. Biphasic pattern of gonadotropins is characterized by high levels of gonadotropins from birth to five years of age, followed by lower levels from ages five to nine and gradual increase to higher adult levels after age nine in normal females or to castrate agonadal levels in patients with gonadal dysgenesis. Long-term hormonal replacement therapy in this particular group of young females with gonadal dysgenesis deserves a critical prospective and retrospective assessment as to its role in the development of adenocarcinoma of the endometrium. An appropriate dose and schedule regimen for estrogen and progestin is of utmost importance in the prevention of this complication.

REFERENCES 1. Amarose, A. P., Kyriasis, A. A., Dorus, E., eta!.: Clinical, pathologic and genetic findings in a case of 46,XY pure gonadal dysgenesis (Swyer's syndrome) I - Dysgerminoma and gonadoblastoma. Am. J. Obstet. Gynecol., 127:824, 1977. 2. Conte, F. A., Grumbach, M. M., Kaplan, S. L., et a!.: Correlation of luteinizing hormone releasing factor induced LH and FSH release from infancy to 19 years with changing pattern of gonadotropin secretion in agonadal patients. Relation to the restraint of puberty. J. Clin. Endocrinol. Metab., 50:163, 1980. 3. Curtis, W. R. S., White, B. J., Lucky, A. W., eta!.: Gonadal dysgenesis with mosaicism and a nonfluorescent Y chromosome. Report of two cases with correlation of clinical, pathologic and cytogenetic findings. Am. J. Obstet. Gynecol., 136:639, 1980.

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4. Cussen, L. J., and MacMahon, R. A.: Germ cells and ova in dysgenetic gonads of a 46,XY female dizygotic twin. Am. J. Dis. Child., 133:373, 1979. 5. Dorus, E., Amarose, A. P., Koo, G., eta!.: Clinical, pathologic and genetic findings in a case of 46,XY pure gonadal dysgenesis (Swyer's syndrome) I I - Presence of H-Y antigen. Am. J. Obstet. Gynecol., 127:829, 1977. 6. Espiner, E. A., Veal, A. M. 0., Sands, V. E., eta!.: Familial syndrome of streak gonads and normal male karyotype in five phenotypic females. N. Engl. J. Med., 283:6, 1970. 7. Ford, C. E., Jones, K. W., and Polani, P. E.: A sex chromosome anomaly in a case of gonadal dysgenesis (Turner's syndrome). Lancet, 1:711, 1959. 8. Gaal, M., Laszlo, J., and Bosze, P.: 46,XY pure gonadal dysgenesis with nonfiuorescent Y chromosome. Clin. Genet., 14:83, 1978. 9. Gantt, P. A., Byrd, J. R., and McDonough, P. G.: A clinical and cytogenetic study of 15 patients with 45,X/46,XY gonadal dysgenesis. Fertil. Steril., 34:216, 1980. 10. Cartier, S. M., Liskay, R. M., and Cant, N.: Two functional X chromosomes in human fetal oocytes. Exp. Cell Res., 82:464, 1973. 11. Ghosh, S. N., Shah, P. N., and Gharpure, H. M.: Absence of H-Y antigen in XY females with dysgenetic gonads. Nature, 276:180, 1978. 12. Goldsmith, 0., Solomon, D. H., and Horton, R.: Hypogonadism and mineralocorticoid excess. The 17 hydroxylase deficiency syndrome. N. Engl. J. Med., 277:673, 1967. 13. Harper, P. S., and Dyken, P. R.: Early onset dystrophica myotonia. Lancet, 2:53, 1972. 14. Himelstein-Braw, R., and Faber, M.: Influence of irradiation and chemotherapy on the ovaries of children with abdominal tumors. Br. J. Cancer, 36:269, 1977. 15. Jirasek, J. E.: Principles of reproductive embryology. IV. Development of the ovary. In Simpson, J. L. (ed.): Disorders of Sexual Differentiation. New York, Academic Press, 1976, pp. 75-92. 16. Jones, G. S., and DeMoraes-Ruehsen, M.: A new syndrome of amenorrhea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. Am. J. Obstet. Gynecol., 104:597, 1969. 17. Kennedy, J. R., Freeman, M. G., and Bemirschke, K.: Ovarian dysgenesis and chromosome abnormalities. Obstet. Gynecol., 50:13, 1977. 18. Krishnamurthy, S., Adcock, L., and Okagaki, T.: Endometrial carcinoma following estrogen progestogen therapy in Turner's syndrome. A case report and review of the literature. Gynecol. Oncol., 5:291, 1977. 19. Madan, K., Gooren', L., and Schoemaker, J.: Three cases of sex chromosome mosaicism with a nonfiuorescent Y. Hum. Genet., 46:295, 1979. 20. Migeon, B. R., and Kennedy, J. B.: Evidence for the inactivation of an X chromosome early in the development of the human female. Am. J. Hum. Genet., 27:233, 1975. 21. McDonough, P. G.: Gonadal dysgenesis and its variants. PEDIATR. CLIN. NORTH AM., 19:631, 1972. 22. McDonough, P. G., Byrd, J. R., Tho, P. T., eta!.: Phenotypic and cytogenetic findings in 82 patients with ovarian failure. Changing trends. Fertil. Steril., 28:638, 1977. 23. McDonough, P. G., and Tho, P. T.: Gonadal dysgenesis with atypical bleeding, functional cyst in rudimentary streak gonads. Am. J. Obstet. Gynecol., 119:565, 1974. 24. McDonough, P. G., and Byrd, J. R.: Gonadal dysgenesis and sickle cell anemia: Autosomal recessive inheritance. Int. J. Gynaecol. Obstet., 8:193, 1970. 25. McDonough, P. G., Tho, P. T., and Byrd, J. R.: Twins discordant for 46,XX gonadal dysgenesis. Fertil. Steril., 28:251, 1977. 26. Nazareth, H. R. S., Farah, L. M. S., Cunah, A. J. B., eta!.: Pure gonadal dysgenesis (type XX). Report on a family with four affected sibs. Hum. Genet., 37:117, 1977. 26a. Plumridge, D.: Good Things Come in Small Packages: The Whys and Rows of Turner's Syndrome. University of Oregon Health Sciences Center, Crippled Children's Division, 1976. 27. Richards, J. S., Ireland, J. J., Rao, M. C., et a!.: Ovarian follicular development in the rat: Hormone receptor regulation by estradiol, follicle stimulating hormone and luteinizing hormone. Endocrinology, 99:1562, 1976. 28. Russell, P., and Altshuler, G.: The ovarian dysgenesis of trisomy 18. Pathology, 7:149, 1975. 29. Shangold, M. M., Turksoy, R. N., Bashford, R. A., eta!.: Pregnancy following the "insensitive ovary syndrome." Fertil. Steril., 28:1179, 1977. 30. Schellhas, H. F., Trujillo, J. M., Rutledge, F. N., eta!.: Germ cell tumors associated with XY gonadal dysgenesis. Am. J. Obstet. Gynecol., 109:1197, 1971. 31. Wachtel, S. S.: The genetics of intersexuality: Clinical and theoretic perspectives. Obstet. Gynecol., 54:671, 1979. Department of Obstetrics and Gynecology Reproductive Endocrine Division Medical College of Georgia 1120 Fifteenth Street Augusta, Georgia 30901