Cytogenetics of fifty patients with primary amenorrhea

Cytogenetics of fifty patients with primary amenorrhea GLORIA Madison,

E.

SARTO,

M.D.,

PH.D.

Wisconsin

This investigation represents a cytogenetic study of 50 women with primary amenorrhea and 50 women of known fertility. The latter served primarily as technical controls /or buccal smear and chromosome analyses. Nineteen of 50 patients with primary amenorrhea were found to have a chromosome abnormality. These included: nine with a 45,X constitution; two 45,X/46,Xx/47,XxX; one 45,X/46,X,i(Xq); one 46,X,i(Xq); and one 46,XXq-. There were two patients with a translocation between two C group chromosomes; one was 46,XX,t(lOq+; 12q-) and the other had a 46,XY constitution. The incidence of 46,X,t(Xq-; 12q+). Three “women” the various causes of primary amenorrhea, cytogenetic and others, is discussed.

PRIMARY

AMENORRHEA

Cytogenetic studies were done on 50 women, ascertained on the basis of primary amenorrhea, and on 50 control women of proved fertility. To avoid bias, the analyses of the chromosomes and X-chromatin were done on coded slides. This had not been done in any of the previous primary amenorrhea studies nor have the earlier studies included controls. The chromosomally more interesting patients found in the present study have been dealt with in greater detail in separate papers. 43s5” Other aspects of the study are to be published at a later date.

is acondi-

tion which may occur in many different disorders. Its etiology is heterogeneous and, thus, it may be a clue to more or less serious abnormalities of structure and function of the gonads and/or genitalia and, at times, of other parts of the body. For the purposes of this presentation, primary amenorrhea is defined as the condition in which a woman 18 years or older has never menstruated. The aim of the present investigation was to determine the frequency of chromosomal and/or genetic causes of primary amenorrhea; an attempt was made to elucidate the etiology of the disorder in those patients whose chromosomes appeared normal.

Materials

From the Department of Gynecology and Obstetrics, University of Wisconsin Medical School. This study was supported by Grant HD 3084 from the National Institutes of Health and the Racine Health Fund, Inc. Central Association Award Paper, presented at the Forty-first Annual Meeting of the Central Association Obstetricians and Gynecologists, Scottsdale, Arizona, October 18-20, 1973.

and

methods

The material consisted of 50 women with primary amenorrhea: 32 referred to the University of Wisconsin Departments of Medicine and/or Gynecology and Obstetrics for evaluation of this complaint and 18 who had the major portion of their examinations done by their private, local physicians, who referred them primarily for cytogenetic evaluation. The control group consisted of 50 women who were postpartum patients on the maternity ward at the University of Wisconsin Hospitals. No attempt was made to select the controls apart from avoiding patients who were not feeling well, i.e., those who had had recent surgery or had a post-

of

Reprint requests: Dr. Gloria E. Sarto, Department of Gynecology and Obstetrics, University of Wisconsin Medical Center, 1300 University Ave., Madison, Wisconsin 53706. 14

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119 1

partum infection. These women served as controls for X-chromatin determinations and chromosome analyses. Complete medical and family histories were obtained and a physical examination was done by the author on 47 patients. In three instances, the information had to be obtained from another physician’s records. Data were obtained relating to the sexual development and reproductive capabilities of the parents and siblings. In addition to anomalies of the genital tract, other somatic malformations were observed and noted. The author performed a pelvic examination on all the 47 personally examined patients. In 16 patients, the internal genitalia were examined for purposes of diagnosis and, in some, tissues (primarily gonadal) were biopsied for histologic studies. Urinary pituitary gonadotropin and/or 17ketosteroid excretion were measured in 28 patients. Since these tests were carried out in different laboratories, various techniques not be described. were used ; these will Selected radiologic examinations (i.e., bone age, intravenous pyelography, skull films, etc.) were done on certain patients. Chromosome studies on lymphocytes and X-chromatin analysis on buccal smears were performed on all subjects. Slides of five patients and five controls were stained simultaneously in an effort to avoid differential staining. Buccal smear slides of both groups were likewise processed together. The slides from each group were coded according to a method used by Patau and his collaborators in the Madison Blind Study.47 When analysis was completed and a definite cytogenetic conclusion had been reached on each subject in the group of 10, the code was broken. The lymphocytes were cultured by means of a modification of the technique described by Moorhead and associates.35 A minimum of 11 technically good metaphase plates of each patient were analyzed. If a chromosome abnormality was found in one of the 11 cells, additional plates were analyzed according to a method devised by Patau and described by Summitt.” Identification of individual

Cytogenetics

and

primary

amenorrhea

15

chromosomes was based on the criteria described by Patau.“” Buccal smears were obtained from all 100 subjects. Plump nuclei with finely granular chromatin and a smooth nuclear membrane were examined. Only those nuclei in which the heterochromatic mass was in contact with the nuclear membrane were scored as “X-chromatin positive.” Nuclei with a heterochromatic mass in the center, or with multiple chromatin clumps, were excluded from the count. A minimum of 100 suitable nuclei was scored, and, in cases in which the percentage of positive cells was low, 200 nuclei. Unusual observations pertaining to the size of the X-chromatin were carefully recorded. On selected women, skin fibroblast cultures were made for chromosome studies and Barr body analyses.15 In some cases, autoradiographic studies were performed on lymphocyte and fibroblast cultures; in a number of cases, the identity of the chromosome was determined by means of fluorescence microscopy. Results Of the 50 patients with primary amenorrhea, 19 were found to have either abnormal chromosomes or sex chromosomes of the opposite sex. These included nine patients with a 45,X” constitution, two 45,X/46,Xx/47, XXX, one 45,X/46,X,i(Xq), one 46,X,i (Xq), and 46,XXq-. Two patients had a translocation between two C group chromosomes: in one t ( lOq+;12q-) and in the other t (Xq-;12q+). Three “women” had a 46,XY constitution. Of these, one had feminizing testis syndrome (FTS) , one Swyer syndrome (XY pure gonadal [testicular] dysgenesis) , and the third pseudovaginal perineoscrotal hypospadias syndrome (PPSH) . Of the remaining 31 with an apparently normal female karyotype, 11 had a developmental abnormality of the Miillerian ducts. One patient, with the chromosome constitution 46,XX,t ( lOq+; 12q-) , had vaginal and uterine agenesis. Twenty patients had a 46,Xx karyotype and normal vagina and *Nomenclature Paris Conference

is consistent (1971) .=

with

that

recommended

at the

16

May 1, 1974 Am. J. Obstet. Gynecol.

Sarto

Table

I. Cytogenetic

studies of patients

with

Number

primary

of cases with

amenorrhea

chromosome

constitution

Aneuploids

Structural

anomalies

Nonmosaics

Author Present Bjeros Philip and associates40 Jagiello and associates26 Rigo and associates41 Kadotani and associates?s Kallio?”

Totals “Test

Total cases

Mosaics

Unbalanced

45,X/46,Xx 45,X/46,Xx, 47,xxx 45,X/46,XY

45,X/46,X,i (Xq) 46,X,i(Xq) 46,XXq46,XXp45,X/46, xxp-

Balanced 46,XXJ (IOq+; 12q-) 46,X,t (Xq-; 12q+) 46,X,t (Xq-; 21q+)

Total: acbhnpoo7mmolf~ somes* and 46,XY

46,Xx

46,XY

50 a5

31 69

3 3

9 9

2 2

3 2

2 0

19 16

38 19

101

60

18

12

9

2

0

41

41

18

3

0

8

4

3

0

15

83

17

10

2

3

2

0

0

7

41

16

1 6

2 9

5 2

2 2

0 1

10 20

38 20

!s

1e

26 100 39f

of homogeneity:

- 80 269 ~21; = 40.4;

33 P =

45,X

Ei

3

No.

128

/

%

32

3.8 x 10-l.

uterus. In three cases the etiology for the amenorrhea was presumed to be ovarian, as determined by elevated gonadotropin excretion and/or streak gonads. In eight cases, the amenorrhea was thought to be due to hypothalamic-hypophysial-ovarian axis dysfunction as determined by low pituitary gonadotropin excretion and/or underdeveloped ovaries. In eight cases, the amenorrhea was thought to be due to other causes including adrenocortical hyperfunction, polycystic ovaries, and anorexia nervosa. One case had no endocrine studies or evaluation of gonadal structure, thus a clinical diagnosis was not made. One major chromosome abnormality was found in the control group. One woman had a translocation, 46,XX,t (9q-; 1Oq+) . Another control had a G-like chromosome instead of a C in some cells. However, in a repeated lymphocyte culture, such cells were absent. Two other women had minor variants; in one, the long arm of one 16 was longer than its homologue; the other had an unusually prominent fuzzy region in one No. 9 chromosome.

Comment This discussion will deal primarily with the frequency of the various causes of primary amenorrhea-cytogenetic and others -and, to a limited extent, with the clinical picture of the various syndromes. It will be based on the data from the present investigation and from similar studies of primary amenorrhea which make pooling of the observations practical (Table I) . Patients with primary amenorrhea can be divided into two main groups: those which have an abnormal chromosome constitution or sex chromosomes in disagreement with the phenotype and those who have a normal 46,Xx chromosome constitution. Both groups consist of several subgroups which will be dealt with separately. Patients with abnormal chromosome constitution and/or sex chromosomes in disagreement with phenotype. The frequency of sex chromosome abnormalities in a selected population varies with the method of ascertainment. Earlier studies, designed primarily to uncover various types of X chromosome abnormalities, included patients

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119 1

Cytogenetics

Table II. Nongenital abnormalities complement

and

primary

amenorrhea

17

anomalies in patients with structural chromosome to those found in patients with 45,X chromosome

compared

Presumed

chromosome

abnormality

45,x*

Anomalies

Shortness of stature (5 150 cm.) Webbed neck Low posterior hairline Inner epicanthic folds Highly arched palate Micrognathia Ear anomaly Pigmented nevi Cubitus valgus Nail anomaly Lymphedema dorsum, hands and feet Short (fourth) metacarpal Shield chest Breast development Elevated gonadotropins

15/18 7/18

2/2 o/2

2/2 o/2

+o 0

14/18

l/2

2/2

B

2/9

l/l

l/l

0

5/9 5/9 8/9

l/l l/l l/l 2/2 2/2 l/2

O/l l/l O/l 2/2 2/2 2/2

0 0

l/l

l/l

0

0

0

0

5/19 1 l/18

2/2 2/2

l/2 l/2

B +

B 0

0 0

0

O/18

o/2

o/2

0

+

0

0

13/13

l/l

l/l

0

14/18 12/18 9/18 5/9

*Includes

nine

thcludes

one case from

cases from

0 0

0

t 0 0

B +

+

Kallio.*9 Kallio.”

$Kallio.2s It,

Present;

-,

not

done

or not

recorded;

0, absent;

B, borderline.

with a particular syndrome. For instance, de la Chapellel” studied 24 patients wi.th “gonadal dysgenesis.” The ascertainment was based on the criteria of shortness of stature, underdeveloped or apparently absent uterus, high urinary gonadotropins, and low production of estrogens. Only in two out of the 24 patients was the chromosome constitution 46,Xx. Lindsten32 studied 57 patients with Turner’s syndrome as diagnosed on the basis of short stature, manifestations of ovarian dysgenesis, and certain somatic malformations. Thirty-five of the 57 patients had a 45,X constitution, 11 had a presumptive X long arm isochromosome, seven showed 45, X/46,Xx mosaicism, and only one was 46,Xx. Three were mosaics with a structural abnormality of the X chromosome in one

cell line. The main disadvantage of such studies is that only patients demonstrating a severe form of the disease are included ; mildly affected or dubious cases are eliminated. This selection explains not only the high frequency of chromosome abnormalities in these two studies as compared to the present investigation but also the high percentage of patients with a 45,X chromosome constitution. In several other studies the patients were ascertained on the basis of primary amenorrhea. In some, only selected patients were analyzed cytogenetically.5, 24, ‘“, 45 These are not included in Table I, which summarizes the reports on primary amenorrhea in which cytogenetic studies were done on all cases.6, 9‘3, 28, 99, 4% 41 In the present

study,

19 out of 50 pheno-

18

Sarto

typic women with primary amenorrhea were found to have an apparent chromosome abnormality. The frequency of 38 per cent does not differ significantly from the average of 3 1 per cent (for the 347 cases, excluding the author’s study) in those studies in which patients were selected for primary amenorrhea and in which cytogenetic studies were done on all of them.“, 26. 28. “9. 40, .I1 Though results of the studies listed in Table I are not homogeneous, it still seems appropriate to assume that a woman with primary amenorrhea has approximately a one-third probability of having an abnormal chromosome constitution or one disagreeing with the phenotype. A. Patients with 45,X chromosome constitution, 45,X/46,Xx chromosome mosaicism, or X chromosome deletion. All patients in the present study with only one X chromosome or structural X chromosome abnormality showed a failure of secondary sexual development, except for a few women who had very minimal breast development and/ or growth of axillary and pubic hair. All had normal though infantile female external genitalia and Miillerian duct differentiation. Of the combined series, 52 of 397 individuals with primary amenorrhea had a 45,X chromosome constitution. The frequency of certain somatic anomalies in such patients, taken from the present investigation and that of Kallio,‘” is presented in Table II. Only three of the 18 patients with a 45,X constitution were taller than 150 cm. Mental retardation has often been described as associated with the 45,X constitution but, when ascertained because of primary amenorrhea and not because of shortness of stature and certain somatic malfunctions, as done previously,l”, 33 this does not seem to be a common finding. X-chromosome mosaicism is not an infrequent finding in patients ascertained because of primary amenorrhea. Of the total of 397 patients with primary amenorrhea, 26 were mosaics (Table I) The phenotype associated with such mosaicism ranges from typical Turner’s syndrome to normal female capable of reproduction. The two patients

May 1, 1974 Am. J. Obstet. Gynecol.

with mosaicism in the present investigation had no extragenital anomalies except for cubitus valgus in one of them. The most common structural X-chromosome abnormality is the long arm isochromosome, either in a 46,X,i(Xq) constitution or combined with an X0 cell line. Two of 50 patients in the present investigation had such an abnormality. There were 11 in the total number of 397 cases (Table I) . Phenotypically, the individuals who lack the X short arm are indistinguishable from those in whom the entire X is missing (Table II). The patient in the present investigation with 46,XXqis the only one of this kind ascertained through a primary amenorrhea survey. The phenotype of nonmosaic 46,XXqpatients has ranged from Turner-like”l to otherwise normal women with lack of secondary sexual characteristics.“, I”, ” Several explanations may be given to explain the wide range in phenotype: different ascertainment, hidden mosaicism with an X0 cell line, and/or the deletion allowing the expression of various recessive genes on the normal X. B. Balanced X-autosomal translocation cases. The combined series of primary amenorrhea patients (Table I) contains two presumably balanced X-autosomal translocations; both lack secondary sexual development, but have practically no other anomalies. The present patient had t(Xq-; 12q+) and that of KallioZg t(Xq-;21+). A number of other balanced X-autosomal cases have had primary amenorrhea.” However, in four families,‘. ‘2 I’. 48 the women with X translocations were normally developed and three were fertile. To explain the amenorrhea in some balanced translocation carriers Sarto and associates’” have put forward two alternative hypotheses. First, since in all the cells the same-the normal-X chromosome is inactivated, a recessive X-linked gene in a functionally hemizygous state could cause the amenorrhea. The second possibility is that the break in the X chromosome must occur inside a certain region of Xq to result in streak gonads and lack of secondary sexual development. If the recessive gene postulated

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above exists, it could also, when homozygous, cause ovarian dysgenesis in some patients with 46,Xx chromosome constitutions which, phenotypically, are not dissimilar from the two X autosomal translocation cases discussed above. As mentioned above, approximately one third of women presenting with primary amenorrhea may have abnormal chromosomes. Those patients who in addition have extragenital anomalies, such as shortness of stature, webbed neck, low posterior hairline, shield chest, highly arched palate, micrognathia, cubitus valgus, or hyperconvex nails, may have a 45,X chromosome constitution or a structural X abnormality in which the short arm of the second X chromosome, partially or totally, is absent. Mosaicism involving the X chromosome may be associated with a phenotype which ranges all the way from Turner’s syndrome to normal female capable of reproduction. Women with balanced X autosomal translocations have few if any extragenital anomalies; three have been capable of reproduction.l, ‘9 48 C. 46,XY chromosome constitution with female phenotype. The combined data (Table I) show that in eight per cent (33 of 397) of the cases, primary amenorrhea in phenotypic females is found together with a 46,XY chromosome constitution. In 23 of the total of the 33 cases with 46,XY chromosome constitution, the diagnosis was that of feminizing testis syndrome (FTS) ; in nine, the diagnosis was presumed to be XY pure gonadal (testicular) dysgenesis; in one case the diagnosis was pseudovaginal perineoscrotal hypospadias syndrome (PPSH) . Feminizing testis syndrome is the most common and best known of the various “XY female” syndromes (see review by Sarto”“) . Previously it has been reviewed extensively, for instance, by Hauser,ls Lenz,31 Zurli and associates,55 and Inhorn and Opitz.23 Generally, the FTS patients appear to be normal females, usually with excellent breast development, whereas axillary and pubic hair is often lacking. External genitalia are those of a normal female; the vagina ends blindly at various depths. Testes are accompanied

Cytogenetics

and primary

amenorrhea

19

by extremely hypoplastic Wolffian duct remnants without vas deferentia; Miillerian duct derivatives are not detectable. At times the testes may descend into an inguinal hernia. It should be noted that these gonads possess neoplastic potential of unknown magnitude. Many families with several affected members have been reported. In rodents, a corresponding gene has been found to be Xlinked.3” In man, linkage studies have been inconclusive. Thus, two possible modes of inheritance remain open : X-linked recessive or an autosomal dominant mutant with expression limited to the male sex. The second most common of the XY female syndromes is the XY pure gonadal (testicular) dysgenesis or Swyer’s? syndrome. This disorder is characterized by severe early testicular dysgenesis which results in streak gonads, devoid of germ cells, but sometimes containing undifferentiated hilar mesonephric cells and tissues capable of undergoing neoplasia (see review by Sarto”‘) . Hilar cells may, at times, respond to gonadotropins with some androgen production and subsequent clitoral enlargement. These patients, except for the gonads, have external and internal genitalia normal for a female and no unusual extragenital anomalies; they are of normal intelligence. They are usually of normal height with more or less eunuchoidal body proportions. Most are sporadic cases, but the syndrome has been reported in sisters73 *I and in several sibships of a single fami1y.l” Though XY pure gonadal (testicular) dysgenesis appears to be inherited in a manner similar to FTS, either as an X-linked recessive or as an autosomal dominant limited in expression to the male sex, genetic data presently available do not exclude the possibility of an autosomal recessive gene limited in expression to the male sex. Thus, unless there is a positive family history, or in the case of the feminizing testis syndrome a diagnosis made because of a testis found at the time of inguinal herniorrhaphy in a phenotypic female, it is not unusual for such disorders to go undiagnosed until they present because of primary amenorrhea. In the feminizing testis syndrome, an

20

May 1, 1974 Am. J. Obstet. Gynecol.

Sarto

Table

III.

Patients

with

primary

amenorrhea

and 46,Xx

I 46,Xx and abnormal Miillerian duct development

I Author Present Bjerro” Philip and associates40 Jagiello and associates26 Rigo and associates3* Kallioz” Totals

Total No. 1 studied

/ ; I

No. with 46,Xx

Normal

chromosome Miillerian

Elevated gonadotropins and/or streak gonads

Total

constitution

duct development chromosomes Low gonadotropins and/or underdeveloped ovaries

and 46,Xx

Normal gonadotropin levels and others

Unknown

50 85

31 69

11

20

25

44

3 7

8 12

8 18

1 7

101

60

11

49

15

12

22

0

18

3

0

3

0

3

0

0

17 100 371

10 80 253 (68%)

2 25 7% (20%)

8 55 179 (48%)

2 19 4s

3 8 4s

3 28 75

0

X-chromatin-negative buccal smear and/or a 46iXY chromosome constitution and the lack of body hair differentiates it from the 46,Xx patients with uterine agenesis or from patients with Mtillerian duct malformations. Phenotypically the 46,XY pure gonadal dysgenesis syndrome cannot be distinguished from the 46,Xx pure gonadal dysgenesis syndrome. There are other very rare 46,XY syndromes which display primary amenorrhea. An example is the case with pseudovaginal perineoscrotal hypospadias (PPSH) found in the present investigation. Phenotypically, such patients have few if any extragenital anomalies, but usually have intersex external genitalia and masculinize at puberty (see review by Opitz and associates”“). Another such syndrome is that which has been called true agonadism by Overzier”’ and, most recently, XY gonadal agenesis.’ This syndrome is characterized by female phenotype, l&k of secondary sexual characteristics, female external genitalia, and absent vagina, uterus, and gonads. It should be noted that the cause of primary amenorrhea in the various syndromes with XY sex chromosomes is not the chromosome constitution as such, but gene mutations, which influence sexua1 development to the extent wherein a non-

s

I

mosaic 46,XY chromosome constitution may be associated with a female phenotype.

II. Patients with a normal 46,Xx chromosome constitution. A. Patients with 46,Xx chromosome constitution with a deuelopmental abnormality of the Miillerian ducts. A developmental abnormality of the vagina and/or uterus is one of the most common causes of primary amenorrhea in an otherwise normally developed woman. In the present study, approximately 11 of the 50 patients suffered from such a condition. In the primary amenorrhea studies in which the causes of primary amenorrhea in chromosomally normal women could be determined,0v “L “!), IO, 41 74 out of 253 had abnormalities of the uterus and/or abnormalities of Miillerian duct differentiation (Table III). The MayerKokitansky-Kuster syndrome, as it is known in Europedn literature, has been reviewed previously."3 8, 179 20 Generally the vagina is aplastic but there may be varying degrees of uterine development. The uterine horns may extend laterally and end as small dilatations. Rudimentary Fallopian tubes may be present. If a rudimentary horn contains functioning endometrium, abdominal pain may be the major complaint and hematometra may be found. The ovaries are

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normal and the secondary sexual characteristics develop normally. Abnormalities of the urinary tract have been described frequently in association with vaginal/uterine atresia,fi’ PO>w 51 as well as abnormalities of the extremities, aortic arch, sacral vertebrae, and anorectal region. In the author’s series of patients, 10 out of 13 patients had urinary tract investigations. Five of these 10 were found to have a malformation of this organ complex. A normal 46,Xx karyotype has been reported in vaginal syndrome agenesis caSeS 2. 3, 10, 17 In the author’s series two patients with uterine/vaginal aplasia had chromosome abnormalities, one a 46,XX,t ( lOq+; 12q-) and the other a 45,X/46,Xx/ 47,XxX chromosome constitution; in Kallio’sZB study one had a 45,X/46,xX. There is probably no etiologic relationship between the chromosome aberrations and the anatomical defect since, as a rule, no chromosome abnormalities have been found in such cases. The lack of patients with imperforate hymen in the present series is most likely the result of selection of patients. Such patients would probably present to the physician at an earlier age with the complaint of intermittent abdominal pain, which would result in the surgical correction of the imperforate hymen.

B. Patients with 46,Xx chromosome constitution and normal Miillerian ducts. Many of the patients with primary amenorrhea have a 46,Xx chromosome constitution and normally developed Miillerian ducts. In the present investigation, 20 of 50 women represented this group, of the combined cases, 179 of 371 (48 per cent) (Table III). Some authors have divided these patients into subgroups based upon the gross and/or microscopic examination of the ovaries,G others on the basis of gonadotropin excretion.29 Thus it is difficult to combine the cases from different sources. For purposes of this discussion, however, they will be placed into the following subgroups: ( 1) cases with presumed ovarian etiology, including those cases with elevated gonadotropins and/or streak

Cytogenetics

and primary

amenorrhea

21

gonads; (2) cases with presumed hypothalamic-hypophysial ovarian axis dysfunction, including those with low gonadotropins and those with small undeveloped ovaries; and (3) others, including those with normal gonadotropins, with polycystic ovaries, and with other endocrinologic disorders such as adrenocortical hyperplasia. Out of 371 cases, 46 had a 46,Xx chromosome constitution and elevated gonadotropins and/or streak gonads. Included in this group (i.e., streak gonads and elevated gonadotropins) are the patients with XX pure gonadal (ovarian) dysgenesis.ls, ‘* They are characterized by normal or eunuchoidal growth, normal intelligence, no extragenital anomalies, lack of secondary sexual characteristics, normal external genitalia, a uterus, The Fallopian tubes, and streak gonads. streak gonads are usually found when laparoscopy and/or laparotomy are done. Two of the 50 patients in the author’s series had this diagnosis; one had a similarly affected sister. Though most reported cases are sporadic, in some instances more than one member of the family has been affected ; for a review of this syndrome see Simpson and associates.4F Another syndrome which may be included in this group has been described by Jones and de MoraesRuehsen.27 These patients show hypergonadotropism but the ovaries are not fibrous streaks; instead, they contain many primordial follicles, a few of which show progression to the antral stage, but none that develop further.“‘, w so9 62 Slight estrogen effect may be evident. Jones and de MoraesRuehsen” assume that these patients have either an abnormal FSH which is not biologically active or a follicular apparatus which is resistant to gonadotropin stimulation. In the combined series, there were 46 out of 371 patients in whom the etiology of the amenorrhea was assumed to be caused by a hypothalamic-pituitary-ovarian axis dysfunction. Apparent isolated deficiency of pituitary gonadotropins is recognized as a clinical entity and would fall into this subgroup. This disorder is characterized by

22

May 1, 1974 Am. J. Obstet. Gynecol.

Sarto

varying degrees of hypogonadism; in some patients secondary sexual development is completely lacking whereas other patients have had several menstrual periods and seek advice because of infertility. Those ascertained because of primary amenorrhea often have no or minimal breast development; they are of normal height but frequently have eunuchoidal body proportions. Urine levels of pituitary gonadotropins are low: 17-ketosteroid levels may be low. The ovaries are small or of normal size but with small follicles.“, “’ This disorder is often referred to as hypogonadotropic eunuchoidism or hypogonadotropic amenorrhea.

The group with normal gonadotropins contains patients with varying etiologies for the primary amenorrhea, including adrenocortical hyperplasia, poylcystic ovaries, and anorexia nervosa. In addition, a condition with normally developed secondary sexual characteristics, normal gonadotropins, normal the ovaries, and no known cause for amenorrhea has been described.“. “‘9 ” Zourlas and ComnioP discussed 10 such patients and reported on the histology of the gonads. All had “unstimulated” follicles.

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20 21. 22. 23.

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