Endocrine and Cytogenetic Studies in a Patient with Turner's Phenotype and a Ring Chromosome ROBERT M. BOYAR,1 R. H. K. WU, P. Y. LIAO, AND J. W. FINKELSTEIN Departments of Oncology and Pathology, Montefiore Hospital and Medical Center, Bronx, New York 10467 LH response to LH-RH is similar to what is found in men with germinal cell aplasia (Sertoli-cell only). The synchronous initiation of normal LH and abnormally augmented FSH secretory episodes in this patient suggests the absence or decrease of some factor normally produced by the ovarian follicle which modulates the release of FSH in response to LH-RH. {J Clin Endocrinol Metab 44: 340, 1977)
ABSTRACT. A 27-year-old woman with secondary amenorrhea and some of the somatic stigmata of Turner's syndrome was found to have a ring chromosome. Laparoscopy and ovarian biopsy showed hypoplastic ovaries and an absence of primordial follicles. Endocrine evaluation showed a normal 24-h mean LH level (12.5 mlU/ml), an elevated FSH level (28 mlU/ml) and a normal plasma estradiol level (64 pg/ml). The augmented FSH and normal
T
URNER'S syndrome associated with an X ring chromosome (Xr) has been reported infrequently (1). In general, these patients have exhibited less severe phenotypic aberrations than patients with XO gonadal dysgenesis. Although careful cytogenetic studies have been performed in patients with ring chromosomes, there have been no reports that attempted to correlate the clinical, endocrinologic, cytogenetic and histopathologicfindingsin patients with this unusual type of Turner's syndrome. We recently studied a patient with the somatic stigmata of Turner's syndrome who was found to have Xo/XXr mosaicism. The study of this patient's 24-h LH and FSH secretory patterns, LH and FSH response to LH-RH and ovarian histology forms the basis of this report. Materials and Methods Case history A 27-year-old married woman presented to the Montefiore Hospital Gynecology Clinic with secondary amenorrhea of three years' duration. Menarche occurred at age 15 with regular cyclic menses over the ensuing six years, after which Received June 4, 1976. Supported by USPHS grant RR-53 and CA 07304. 1 Dr. Boyar's present address is the Department of Internal Medicine, University of Texas Health Science Center, Dallas, Texas 75235.
secondary amenorrhea developed. She had been married for seven years and was unable to conceive during the first four years of her marriage when she was still menstruating regularly. The patient had short stature (134.6 cm), round face, bilateral ptosis and cubitus valgus (Fig. 1). There were no other features of Turner's syndrome. There was normal breast development and normal amounts of axillary and pubic hair. Pelvic examination showed a pinhole cervical os and a small uterus. The remainder of the physical examination was normal. Methods The patient was admitted to the Clinical Research Center, Montefiore Hospital and Medical Center for a 20-min interval blood sampling study (2) for measurement of LH, FSH and estradiol. The patient was also given 100 fxg of LH-RH (Ayerst) and plasma LH and FSH were measured. Plasma LH (3), FSH (4) and estradiol (5) were measured by radioimmunoassay. The 24-h mean LH and FSH levels were calculated by averaging the results of the individual 72 specimens obtained during the course of the 24-h sampling study. The 24-h mean estradiol level was obtained by assaying a pool of the 72 individual specimens.
Results
Laparoscopy and ovarian biopsy At laparoscopy, hypoplastic ovaries and uterus were found. The ovarian histology
340
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RING X CHROMOSOME IN TURNER'S SYNDROME
341
FIG. 1. Appearance of the patient at the time of initial presentation. Note the ptosis and cubitus valgus.
showed complete absence of primordial fol- mlU/ml and 28 mlU/ml, respectively. There licles in specimens examined from both was excellent correlation between the initiaovaries (Fig. 2). The stromal tissue appeared tion of LH and FSH secretory episodes throughout the 24-h period. The response normal. to LH-RH is shown in Table 1. The plasma Endocrine studies LH rose from a basal value of 7.1 mlU/ml The 24-h episodic pattern of LH and FSH (mean of two basal values) to a maximum of is shown in Fig. 3. LH and FSH secretory 45.5 mlU/ml at 30 min. The plasma FSH episodes occurred with equal frequency rose from a basal level (mean of two values) throughout the day and night. The 24-h of 20.7 mlU/ml to a peak of 52.8 mlU/ml at mean LH and FSH concentrations were 12.5 60 min. The 24-h mean estradiol level was
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JCE & M • 1977 Vol 44 • No 2
BOYAR ET AL.
342
TABLE 1. LH and FSH response to LH-RH (100 /xg iv) LH mlU/ml
Time 0915 0930 LH-RH 0931 0945 1000 1015 1030 1100 1130 1200 1230
FSH mlU/ml
6.8 7.4
22.4 19.0
34.0 45.5 40.0 34.0 30.0 20.3 16.3 15.9
39.8 46.0 52.6 52.8 48.8 43.6 39.4 46.2
Cytogenetic studies
FIG. 2. Microscopic appearance of the ovary showing ovarian stroma and absent primordial follicles.
68 pg/ml. The patient's 24-h mean T4, T3, TSH, hGH, prolactin and cortisol values were all normal. No antithyroglobulin or anti-microsomal thyroid antibodies were detected.
mlU/ml 40-
FSH
The study of 100 lymphocyte metaphases (Giemsa stain) showed 62% of cells had 46 XXr (Fig. 4), 34% 45X (Fig. 5), 1% 47 XXrXr (Fig. 6), 2% polyploidy (1 with 2 rings and 1 with no rings) and 1% 45 XXr (random loss—"D" group with very large ring). Some of the rings appear to represent only one X chromosome (Fig. 4), while some represent two or more X chromosomes (Fig. 7). Discussion Ring chromosomes are formed after a chromosome breaks and reunites on both
o-o-o
353025-
FIG. 3. Twenty-four hour LH and FSH secretory pattern. Note the coincident initiation of LH and FSH secretory episodes.
2015105-
I I I I ( I I I I I I I | I I I I I I r I I 1 I I 0800
1200
1600
2000 CLOCK TIME
2400
0400
0800
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RING X CHROMOSOME IN TURNER'S SYNDROME sides of the centromere. The ring actually represents deleted chromosomal material distal to the sites of reunion. Ring chromosomes are unstable and therefore give rise to smaller and larger rings as was the case in our patient. This would explain the complex mosaicism observed. The etiology of ring chromosomes is unclear but it does appear that ionizing radiation in vitro and in vivo can produce the aberration. Autosomal ring chromosomes have been reported to involve the No. 18 (6), 16-18 (7), 13-15 (8) and 6-12 groups (9). The first patient with a ring X chromosome was reported by Lindsten et at. (10). The patient was a 22-year-old girl with short stature, normal secondary sexual characteristics and secondary amenorrhea. Ovarian biopsy showed a few primordial and Graafian follicles. Three of four postpubertal patients with a ring X chromosome,
343
** *>
it u Art A*
Kit
**
*•
FIG. 5. Karyotype of cell with 46 XO.
it l i i i it u it
»n «» *« »» H
FIG. 4. Karyotype of cell with 46 XXr.
in whom no XX cell line was detected, had well developed secondary sexual characteristics and regular menses (11). The finding of hypoplastic ovaries devoid of primordial follicles provides an explanation for the patient's infertility. The finding of normal LH and estradiol levels suggests that the ovarian stroma was capable of producing sufficient estradiol or estradiol precursors to result in the maintenance of normal secondary sexual characteristics, normal LH levels and a normal LH response to LHRH. The elevated FSH levels and abnormally increased FSH response to LH-RH suggests that some factor produced by the ovarian follicle in addition to estradiol is an important modulator of FSH release. It is of additional interest that the LH and FSH secretory episodes were frequently initiated synchronously, suggesting decreased activity of the putative FSH suppressor ("inhibin")
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 18:27 For personal use only. No other uses without permission. . All rights reserved.
344
JCE & M • 1977 Vol 44 • No 2
BOYAR ET AL.
at the pituitary level. It is of additional interest that patients with Stein-Leventhal syndrome who have excessive numbers of follicular cysts have low FSH levels despite normal or elevated LH levels (12). These findings taken together suggest that a factor of follicular origin may be an important regulator of FSH release acting at the pituitary level. The finding of normal basal LH and elevated FSH as well as a normal LH and increased FSH response to the acute iv administration of LH-RH is similar to what has been reported in germinal cell aplasia (13). However, recent studies have shown that the constant infusion of LH-RH in terminal cell aplasia results in exaggerated LH responses, despite normal responses to the acute iv injection (14). The increased FSH response to LH-RH in our patient is similar in magnitude to that reported by Yen et al. (15) in hypogonadal
't-
A.V
/-
u
n
fl
na il ii i: si flt
I * #
At
K
4ft
«0
FIG. 7. Karyotype of cell with 46 XXr (large).
subjects. The absence of germinal cell elements in Sertoli-cell only syndrome and the absence of primordial follicles in our patient, as well as the normal basal LH and sex steroid values in both disorders, suggest a functional similarity between them. It adds further to the body of evidence that FSH must be regulated by some factor ("inhibin") associated with the germinal cell elements of the testis and ovary. Acknowledgments
H I
)) » I I U }{ » K (I
M M tit
j*
Mira Fein, Ed Rosario, and Nate Katz provided technical assistance. The LH and FSH radioimmunoassay reagents were provided by the NIAMDD. The secretarial assistance of Marilyn Hurler is also appreciated. The authors express their appreciation to Dr. Jack Oppenheimer for referring this patient for evaluation.
»«
(00
FIG. 6. Karyotype of cell with 46 XXr Xr.
References 1. Grumbach, M. M., and J. J. Van Wyk, In Williams, R. H. (ed), Textbook of Endocrinology, W. B. Saunders Co., Philadelphia, 1974, p. 462.
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RING X CHROMOSOME IN TURNER'S SYNDROME 2. Hellvnan, L., F. Nakada, J. Curti, E. D. Weitzman, J. Kream, H. Roffwarg, S. Ellman, D. Fukushima, and T. Gallagher, Cortisol is secreted episodically by normal man,/ Clin Endocrinol Metab 30: 411, 1970. 3. Boyar, R., J. Finkelstein, R. David, H. Roffwarg, S. Kapen, E. Weitzman, and L. Hellman, Synchronization of augmented luteinizing hormone secretion with sleep during puberty, N EnglJ Med 287: 582, 1972. 4. Midgley, A. R., Radioimmunoassay for human follicle-stimulating hormone, J Clin Endocrinol Metab 27: 295, 1967. 5. Aso, T., R. Guerrero, Z. Cekan, and E. Diczfalusy, A rapid 5 hour radioimmunoassay of plasma progesterone and estradiol in human plasma, Clin Endocrinol 4: 173, 1975. 6. Kemp, N. H., M. K. Lucas, and J. R. Ellis, An autosomal ring chromosome in a human female with congenital malformations, Heredity 18: 123, 1963. 7. Genest, P., R. Leclerc, and C. Auger, Ring chromosome and partial translocation in the same cell, Lancet 2: 1426, 1963. 8. Wang, H. C., J. Melnyk, L. T. McDonald, I. A. Uchida, D. H. Carr, and B. Goldberg, Ring chromosomes in human beings, Nature 195: 733, 1962. 9. Smith-White, S. W., J. Peacock, B. Turner, and G.
10.
11.
12.
13.
14.
15.
345
M. Den-Dulk, A ring chromosome in man, Nature 197: 102, 1963. Lindsten, J., and K. G. Tillinger, Self perpetuating ring chromosome in a patient with gonadal dysgenesis. Lancet 1: 593, 1962. Morishima, A., and M. M. Grumbach, The interrelationship and phenotype in the syndrome of gonadal dysgenesis and its variants, Ann NY Acad Sci 155: 695, 1968. Rebar, R., H. L. Judd, S. S. C. Yen, J. Rakoff, G. Vandenberg, and F. Naftolin, Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome, J Clin Invest 57: 1320, 1976. Mecklenberg, R. S., and R. J. Sherins, Gonadotropin response to luteinizing hormone releasing hormone in men with germinal aplasia, / Clin Endocrinol Metab 38: 1005, 1975. Dekretzer, D. M., H. G. Burger, and R. Dumpys, Serum LH and FSH in four hour infusions of luteinizing hormone releasing hormone in normal men, Sertoli-cell only syndrome, and Klinefelter's syndrome, / Clin Endocrinol Metab 41: 876, 1975. Siler, T. M., and S. S. C. Yen, Augmented gonadotropin response to synthetic LRF in hypogonadal state, J Clin Endocrinol Metab 37: 491, 1973.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 18:27 For personal use only. No other uses without permission. . All rights reserved.
ABSTRACT. A 27-year-old woman with secondary amenorrhea and some of the somatic stigmata of Turner's syndrome was found to have a ring chromosome. Laparoscopy and ovarian biopsy showed hypoplastic ovaries and an absence of primordial follicles. Endocrine evaluation showed a normal 24-h mean LH level (12.5 mlU/ml), an elevated FSH level (28 mlU/ml) and a normal plasma estradiol level (64 pg/ml). The augmented FSH and normal
T
URNER'S syndrome associated with an X ring chromosome (Xr) has been reported infrequently (1). In general, these patients have exhibited less severe phenotypic aberrations than patients with XO gonadal dysgenesis. Although careful cytogenetic studies have been performed in patients with ring chromosomes, there have been no reports that attempted to correlate the clinical, endocrinologic, cytogenetic and histopathologicfindingsin patients with this unusual type of Turner's syndrome. We recently studied a patient with the somatic stigmata of Turner's syndrome who was found to have Xo/XXr mosaicism. The study of this patient's 24-h LH and FSH secretory patterns, LH and FSH response to LH-RH and ovarian histology forms the basis of this report. Materials and Methods Case history A 27-year-old married woman presented to the Montefiore Hospital Gynecology Clinic with secondary amenorrhea of three years' duration. Menarche occurred at age 15 with regular cyclic menses over the ensuing six years, after which Received June 4, 1976. Supported by USPHS grant RR-53 and CA 07304. 1 Dr. Boyar's present address is the Department of Internal Medicine, University of Texas Health Science Center, Dallas, Texas 75235.
secondary amenorrhea developed. She had been married for seven years and was unable to conceive during the first four years of her marriage when she was still menstruating regularly. The patient had short stature (134.6 cm), round face, bilateral ptosis and cubitus valgus (Fig. 1). There were no other features of Turner's syndrome. There was normal breast development and normal amounts of axillary and pubic hair. Pelvic examination showed a pinhole cervical os and a small uterus. The remainder of the physical examination was normal. Methods The patient was admitted to the Clinical Research Center, Montefiore Hospital and Medical Center for a 20-min interval blood sampling study (2) for measurement of LH, FSH and estradiol. The patient was also given 100 fxg of LH-RH (Ayerst) and plasma LH and FSH were measured. Plasma LH (3), FSH (4) and estradiol (5) were measured by radioimmunoassay. The 24-h mean LH and FSH levels were calculated by averaging the results of the individual 72 specimens obtained during the course of the 24-h sampling study. The 24-h mean estradiol level was obtained by assaying a pool of the 72 individual specimens.
Results
Laparoscopy and ovarian biopsy At laparoscopy, hypoplastic ovaries and uterus were found. The ovarian histology
340
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RING X CHROMOSOME IN TURNER'S SYNDROME
341
FIG. 1. Appearance of the patient at the time of initial presentation. Note the ptosis and cubitus valgus.
showed complete absence of primordial fol- mlU/ml and 28 mlU/ml, respectively. There licles in specimens examined from both was excellent correlation between the initiaovaries (Fig. 2). The stromal tissue appeared tion of LH and FSH secretory episodes throughout the 24-h period. The response normal. to LH-RH is shown in Table 1. The plasma Endocrine studies LH rose from a basal value of 7.1 mlU/ml The 24-h episodic pattern of LH and FSH (mean of two basal values) to a maximum of is shown in Fig. 3. LH and FSH secretory 45.5 mlU/ml at 30 min. The plasma FSH episodes occurred with equal frequency rose from a basal level (mean of two values) throughout the day and night. The 24-h of 20.7 mlU/ml to a peak of 52.8 mlU/ml at mean LH and FSH concentrations were 12.5 60 min. The 24-h mean estradiol level was
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 18:27 For personal use only. No other uses without permission. . All rights reserved.
JCE & M • 1977 Vol 44 • No 2
BOYAR ET AL.
342
TABLE 1. LH and FSH response to LH-RH (100 /xg iv) LH mlU/ml
Time 0915 0930 LH-RH 0931 0945 1000 1015 1030 1100 1130 1200 1230
FSH mlU/ml
6.8 7.4
22.4 19.0
34.0 45.5 40.0 34.0 30.0 20.3 16.3 15.9
39.8 46.0 52.6 52.8 48.8 43.6 39.4 46.2
Cytogenetic studies
FIG. 2. Microscopic appearance of the ovary showing ovarian stroma and absent primordial follicles.
68 pg/ml. The patient's 24-h mean T4, T3, TSH, hGH, prolactin and cortisol values were all normal. No antithyroglobulin or anti-microsomal thyroid antibodies were detected.
mlU/ml 40-
FSH
The study of 100 lymphocyte metaphases (Giemsa stain) showed 62% of cells had 46 XXr (Fig. 4), 34% 45X (Fig. 5), 1% 47 XXrXr (Fig. 6), 2% polyploidy (1 with 2 rings and 1 with no rings) and 1% 45 XXr (random loss—"D" group with very large ring). Some of the rings appear to represent only one X chromosome (Fig. 4), while some represent two or more X chromosomes (Fig. 7). Discussion Ring chromosomes are formed after a chromosome breaks and reunites on both
o-o-o
353025-
FIG. 3. Twenty-four hour LH and FSH secretory pattern. Note the coincident initiation of LH and FSH secretory episodes.
2015105-
I I I I ( I I I I I I I | I I I I I I r I I 1 I I 0800
1200
1600
2000 CLOCK TIME
2400
0400
0800
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 18:27 For personal use only. No other uses without permission. . All rights reserved.
RING X CHROMOSOME IN TURNER'S SYNDROME sides of the centromere. The ring actually represents deleted chromosomal material distal to the sites of reunion. Ring chromosomes are unstable and therefore give rise to smaller and larger rings as was the case in our patient. This would explain the complex mosaicism observed. The etiology of ring chromosomes is unclear but it does appear that ionizing radiation in vitro and in vivo can produce the aberration. Autosomal ring chromosomes have been reported to involve the No. 18 (6), 16-18 (7), 13-15 (8) and 6-12 groups (9). The first patient with a ring X chromosome was reported by Lindsten et at. (10). The patient was a 22-year-old girl with short stature, normal secondary sexual characteristics and secondary amenorrhea. Ovarian biopsy showed a few primordial and Graafian follicles. Three of four postpubertal patients with a ring X chromosome,
343
** *>
it u Art A*
Kit
**
*•
FIG. 5. Karyotype of cell with 46 XO.
it l i i i it u it
»n «» *« »» H
FIG. 4. Karyotype of cell with 46 XXr.
in whom no XX cell line was detected, had well developed secondary sexual characteristics and regular menses (11). The finding of hypoplastic ovaries devoid of primordial follicles provides an explanation for the patient's infertility. The finding of normal LH and estradiol levels suggests that the ovarian stroma was capable of producing sufficient estradiol or estradiol precursors to result in the maintenance of normal secondary sexual characteristics, normal LH levels and a normal LH response to LHRH. The elevated FSH levels and abnormally increased FSH response to LH-RH suggests that some factor produced by the ovarian follicle in addition to estradiol is an important modulator of FSH release. It is of additional interest that the LH and FSH secretory episodes were frequently initiated synchronously, suggesting decreased activity of the putative FSH suppressor ("inhibin")
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 18:27 For personal use only. No other uses without permission. . All rights reserved.
344
JCE & M • 1977 Vol 44 • No 2
BOYAR ET AL.
at the pituitary level. It is of additional interest that patients with Stein-Leventhal syndrome who have excessive numbers of follicular cysts have low FSH levels despite normal or elevated LH levels (12). These findings taken together suggest that a factor of follicular origin may be an important regulator of FSH release acting at the pituitary level. The finding of normal basal LH and elevated FSH as well as a normal LH and increased FSH response to the acute iv administration of LH-RH is similar to what has been reported in germinal cell aplasia (13). However, recent studies have shown that the constant infusion of LH-RH in terminal cell aplasia results in exaggerated LH responses, despite normal responses to the acute iv injection (14). The increased FSH response to LH-RH in our patient is similar in magnitude to that reported by Yen et al. (15) in hypogonadal
't-
A.V
/-
u
n
fl
na il ii i: si flt
I * #
At
K
4ft
«0
FIG. 7. Karyotype of cell with 46 XXr (large).
subjects. The absence of germinal cell elements in Sertoli-cell only syndrome and the absence of primordial follicles in our patient, as well as the normal basal LH and sex steroid values in both disorders, suggest a functional similarity between them. It adds further to the body of evidence that FSH must be regulated by some factor ("inhibin") associated with the germinal cell elements of the testis and ovary. Acknowledgments
H I
)) » I I U }{ » K (I
M M tit
j*
Mira Fein, Ed Rosario, and Nate Katz provided technical assistance. The LH and FSH radioimmunoassay reagents were provided by the NIAMDD. The secretarial assistance of Marilyn Hurler is also appreciated. The authors express their appreciation to Dr. Jack Oppenheimer for referring this patient for evaluation.
»«
(00
FIG. 6. Karyotype of cell with 46 XXr Xr.
References 1. Grumbach, M. M., and J. J. Van Wyk, In Williams, R. H. (ed), Textbook of Endocrinology, W. B. Saunders Co., Philadelphia, 1974, p. 462.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 18:27 For personal use only. No other uses without permission. . All rights reserved.
RING X CHROMOSOME IN TURNER'S SYNDROME 2. Hellvnan, L., F. Nakada, J. Curti, E. D. Weitzman, J. Kream, H. Roffwarg, S. Ellman, D. Fukushima, and T. Gallagher, Cortisol is secreted episodically by normal man,/ Clin Endocrinol Metab 30: 411, 1970. 3. Boyar, R., J. Finkelstein, R. David, H. Roffwarg, S. Kapen, E. Weitzman, and L. Hellman, Synchronization of augmented luteinizing hormone secretion with sleep during puberty, N EnglJ Med 287: 582, 1972. 4. Midgley, A. R., Radioimmunoassay for human follicle-stimulating hormone, J Clin Endocrinol Metab 27: 295, 1967. 5. Aso, T., R. Guerrero, Z. Cekan, and E. Diczfalusy, A rapid 5 hour radioimmunoassay of plasma progesterone and estradiol in human plasma, Clin Endocrinol 4: 173, 1975. 6. Kemp, N. H., M. K. Lucas, and J. R. Ellis, An autosomal ring chromosome in a human female with congenital malformations, Heredity 18: 123, 1963. 7. Genest, P., R. Leclerc, and C. Auger, Ring chromosome and partial translocation in the same cell, Lancet 2: 1426, 1963. 8. Wang, H. C., J. Melnyk, L. T. McDonald, I. A. Uchida, D. H. Carr, and B. Goldberg, Ring chromosomes in human beings, Nature 195: 733, 1962. 9. Smith-White, S. W., J. Peacock, B. Turner, and G.
10.
11.
12.
13.
14.
15.
345
M. Den-Dulk, A ring chromosome in man, Nature 197: 102, 1963. Lindsten, J., and K. G. Tillinger, Self perpetuating ring chromosome in a patient with gonadal dysgenesis. Lancet 1: 593, 1962. Morishima, A., and M. M. Grumbach, The interrelationship and phenotype in the syndrome of gonadal dysgenesis and its variants, Ann NY Acad Sci 155: 695, 1968. Rebar, R., H. L. Judd, S. S. C. Yen, J. Rakoff, G. Vandenberg, and F. Naftolin, Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome, J Clin Invest 57: 1320, 1976. Mecklenberg, R. S., and R. J. Sherins, Gonadotropin response to luteinizing hormone releasing hormone in men with germinal aplasia, / Clin Endocrinol Metab 38: 1005, 1975. Dekretzer, D. M., H. G. Burger, and R. Dumpys, Serum LH and FSH in four hour infusions of luteinizing hormone releasing hormone in normal men, Sertoli-cell only syndrome, and Klinefelter's syndrome, / Clin Endocrinol Metab 41: 876, 1975. Siler, T. M., and S. S. C. Yen, Augmented gonadotropin response to synthetic LRF in hypogonadal state, J Clin Endocrinol Metab 37: 491, 1973.
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