FSH and LH Secreting Pituitary Adenoma R. DEMURA,* O. KUBO,** H. DEMURA,* AND K. SHIZUME* * Department of Internal Medicine, Tokyo Women's Medical College, Tokyo, Japan, and ** Department of Neurosurgenj, Neurosurgical Institute, Tokyo Women's Medical College, Tokyo, Japan ABSTRACT. A case of FSH and LH secreting pituitary adenoma which was not preceded by hypogonadism is reported. The patient, a 50-year-old man, was admitted to the hospital because of left temporal hemianopsia. No clinical evidence of hypogonadism was demonstrated. Endocrine studies revealed markedly elevated plasma FSH of 295 mlU/ml and slightly elevated LH of 35 mlU/ml (2nd IRP-HMG). Plasma FSH and LH did not respond to the administration of LRF, conjugated equine estrogens and testosterone.
G
ONADOTROPIN secreting pituitary adenomas are very rare. There have been several reports of gonadotropin secreting pituitary adenoma, usually associated with hypogonadism (1-4), but these were based on clinical observations and lack adequate endocrine studies. The only convincing reports of FSH secreting pituitary adenoma are those by Woolf and Shenk (5) and Friend et at. (6) and that of FSH and LH secreting adenoma by Snyder and Sterling (7). We will present a case of an FSH and LH secreting pituitary adenoma which was not associated with hypogonadism. Case Report
A 50-year-old man was admitted to the hospital because of left temporal hemianopsia. Eight years earlier, sellar enlargement had been found by chance and he received pituitary irradiation with a tumor dose of 2,000 rads. He had been well until a year before admission when visual acuity decreased. Three months before admission left superior temporal hemianopsia appeared. He had been married for 28 years and had 3 children 25, 21 and 14 years old. He had not lost libido or potency. On physical examination he was a well nourished, normally developed man 165 cm tall Received April 1, 1976. Supported by a research grant for "Specific Diseases" of the Japanese Ministry of Health and Welfare, and by a research grant from the Japanese Ministry of Education (No. 837019).
Plasma testosterone was 691 ng/dl and rose normally after pregnant mare's serum gonadotropin. Sperm count was 46 x 106/ml. Transfrontal hypophysectomy was followed by a marked decrease of both FSH (to 19 mlU/ml) and LH (to 22 mlU/ml). Histologic examination of the tumor revealed 90% chromophobe cells and 10% slightly eosinophilic cells. Two sizes of secretory granules were demonstrated. Tumor cells in tissue culture secreted both FSH and LH. (J Clin Endocrinol Metab 45: 653, 1977)
weighing 65 kg. Pubic and axillary hair were well preserved. Testes and phallus were normal in size and consistency. Urinalysis, complete blood counts and routine blood chemical determinations were normal. Plasma FSH was markedly elevated (295 mlU/ml) and LH was slightly elevated (35 mlU/ml). Sperm count was 46 x 106/ml. Testicular biopsy showed active spermatogenesis and slightly hypertrophied Leydig cells and was considered normal for his age. Other endocrine findings are included in the results section. Skull x-ray showed an enlarged sella. Computerized axial tomography and pneumoencephalography showed a pituitary tumor with marked suprasellar extension. This was removed by craniotomy on the 20th hospital day. On histologic examination, the tumor consisted of 90% chromophobe cells with 10% acidophilic cells. There were two sizes of secretory granules with diameters of 100-200 m/x and 300-500 n\(i electronmicroscopically. Two weeks after operation, plasma FSH and LH decreased to 19 and 22 mlU/ml, respectively. Materials and Methods LH and FSH in plasma and in tissue culture media were measured by radioimmunoassay (RIA) using kits of Daiichi RI Laboratory with a reference standard of the 2nd IRP-HMG expressed in mlU/ml. GH, ACTH and TSH were also measured using commercial RIA kits available in Japan. Prolactin was measured by RIA using Friesen #2 kit, kindly provided by the National Institute of Arthritis, Metabolism and Digestive Diseases, Bethesda, Md. Plasma tes-
653
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654
DEMURA ET AL.
JCE & M • 1977 Vol 45 • No 4
tion curves of culture media were compared with standard curves of LH and FSH. Piitient Normal ranges An LRF test was performed by iv administraProvocative Basal Peak Hormone tests Basal Peak tion of 100 /xg of LRF to the fasting patient. Estrogen suppression was performed by iv adminisGH ng/ml ITT 0.8 0-6 10- 50 0.8 tration of 10 mg of conjugated equine estrogens. TSH fiVlm\ 8- 40 TRH 0-6 1.3 13.0 Testosterone suppression was done by the im injection of depot testosterone 100 mg per day for PRL ng/ml TRH 2.8 9.0 2-20 8 - 80 3 days. Pregnant mare's serum (PMS) was injected ACTH pg/ml Rapid metyim 2,000 IU per day for 2 days. An insulin toler20-75 55-550 53.6 571 rapone ance test (ITT) was performed by iv administration of 0.1 U/kg of body weight of regular insulin. A rapid metyrapone test was performed by adtosterone was measured by RIA using antisera ministering a single oral dose of 1.5 g of metyraraised in our laboratory. pone. A TRH test was performed by the iv adminTissue culture was performed using freshly ob- istration of 500 /xg of TRH. Blood samples were tained tumor tissues. Tissues were cut into small drawn at the intervals shown in Table 1 and Figs. pieces of 2-3 mm3 and filtered through a platinic 1-3. mesh of 0.17 mm. Mechanically dispersed tisNormal basal values and responses of various sues were put into Petri dishes contained 3 ml of hormones to suppression and stimulation tests Eagle's MEM media with 20% fetal calf serum shown in the result were those obtained from at and processed to monolayer tissue culture under least 5 normal subjects with comparable age 95% air with 5% CO2 at 37 C. Cell counts were and sex to the patient. adjusted to 1 x 105/ml at the beginning of the culture. The medium was changed every 3-4 days and concentrations of LH and FSH were measResults ured. To examine the effect of the culture media on the immunoreactivity of the hormones, diluGH reserve was diminished but the responses of other pituitary hormones to various provocative tests were normal (Table 1). FSH Basal levels of plasma FSH and LH were always elevated and ranged between 176295 mlU/ml and 35-67 mlU/ml, respectively, compared with normal levels of 27 ± 7.3 mlU/ml for FSH and 17 ± 4.2 mlU/ml for LH. Both FSH and LH failed to rise normally after LRF compared with normal responses of more than 2 times basal levels for both LH and FSH (Fig. 1). Administration of conjugated equine estrogens was associated with a minimal decrease in plasma FSH concentration and no substantial change in plasma LH concentration (Fig. 2). In normal subjects prompt suppression of both LH and FSH occurred with minimal values 30 ± 18 and 72 ± 11% of the initial levels, respectively, for LH and FSH at 12 h after injection. Testosterone administration did not suppress FSH but suppressed LH gradually 15 30 45 60 90 120 to 50% of the initial level by 6 days (Fig. 3) minutes compared with normal gradual suppression FIG. 1. Responses of plasma LH and FSH to LRF. Open of both LH and FSH to 38 ± 12 and 12 ± 6% circles indicate LH and closed circles FSH. TABLE 1. Pituitary reserve tests
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FSH AND LH SECRETING PITUITARY ADENOMA LH
FSH
nrtfU
Premarin 10 mg i. v.
300.
655
In tissue culture the tumor cells secreted both LH and FSH. The concentrations of LH and FSH in the tissue culture media when plotted as a function of time on semilogarithmic paper decreased almost as a straight line (Figs. 4 and 5). Very small amounts of LH and FSH were produced by tumor tissues from 7 other patients with pituitary adenomas shown as controls. No other pituitary hormones than LH and FSH were found in tissue culture media of this particular patient on the 3rd day of culture. Dilution curves of tissue culture media were parallel to standard curves of both FSH and LH (Fig. 6). Discussion
24
36
60
hours
FJC. 2. Responses of plasma LH and FSH to testosterone. Open circles indicate LH and closed circles FSH. Shaded area show normal ranges.
of the initial levels, respectively, by 12 days. Basal plasma testosterone levels ranged between 580 and 691 ng/dl and increased normally to 868 ng/dl 24 h after administration of PMS compared with normal basal levels and peak values of 520 ± 62 and 800 ± 88 ng/dl, respectively.
The clinical manifestations of this particular case were that of a non-functioning pituitary adenoma; however, the abnormally elevated concentrations of FSH and LH in plasma for his age and sex, associated with partial impairment of other pituitary functions led us to suspect that he had a gonadotropin secreting pituitary adenoma. The lack of responsiveness of LH and FSH to LRF suggested that the secretion of gonadotropin in this patient was not dependent on hypothalamic control or the pituitary productions were already maximal even if the tissue were responsive. Suppression LH
FIG. 3. Responses of plasma LH and FSH to conjugated equine estrogens. Open circles indicate LH and closed circles FSH. Shaded area show normal ranges.
0 6
48
72 hours
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JCE & M • 1977 Vol 45 • No 4
DEMURA ETAL.
656
FSH
"55* O O •
O present case (top) O chromophobe adenoma • acromegaly
10
I 0
10
20
days
FIG. 4. Changes in the concentration of FSH in the culture media.
tests showed that the secretion of LH but not FSH was partially suppressed by testosterone; however, both FSH and LH did not respond to administrations of estrogens. These observations may suggest that gonadotropin secretion in this particular case was not under normal feedback regulation. In most of the previously reported patients with gonadotropin secreting pituitary tumors (1-4), it has been assumed that end organ failure led to the development of pituitary tumors through a decrease in negative feedback inhibition. In some of these patients, replacement therapy with either estrogens or androgens was effective in decreasing urinary gonadotropins. In contrast, gonadotropin secretion in our patient seemed to be relatively autonomous. None of the clinical findings or results of endocrine studies or testicular biopsy indicated hypogonadism. The absence of hypogonadism and the autonomous secretion of gonadotropins suggest that the pituitary tumor was primary and not secondary to end organ failure.
It could be expected that the patient might have an increased spermatogenesis or an overproduction of testosterone due to increased FSH and LH; however, no such evidence was found. The possibility can not be excluded that hypersecreted FSH and/or LH were not completely biologically active hormones even though they were immunologically indistinguishable from ESH and LH. Finally, the demonstration of excessive secretions of FSH and LH by the tumor tissue in vitro clearly documented that this patient had an FSH and LH secreting pituitary adenoma. The absence of other pituitary hormones except for LH and FSH in tissue culture media demonstrated that there was no contamination of normal pituitary tissue. Recently, Woolf and Shenk (5) reported a case of FSH secreting pituitary adenoma, in which FSH production was also confirmed by tissue culture. In conclusion, we have reported a patient with an FSH and LH secreting pituitary adenoma. Since hypogonadism was not ob10 LH mill
O O
O present case (top) O chromophobe adenoma acromegaly
20
30
10
10
10 days
FlG. 5. Changes in the concentration of LH in the culture media.
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FSH AND LH SECRETING PITUITARY ADENOMA
FSH
657
L H
FIG. 6. Dilution curves of culture media compared with standard curves of FSH and LH.
I 10
served in our patient, the pathogenesis of the pituitary tumor seemed to be primary rather than secondary to end organ failure. Acknowledgments We wish to thank Dr. C. A. Nugent, Univ. of Arizona, for reviewing the manuscript and Dr. N. Sasano, Tohoku Univ. Japan, for interpreting the testicular biopsy.
References 1. Leiba, S., B. Landau, and A. Bar, Target gland insufficiency and pituitary tumors, Ada Endocrinol (Kbh) 60: 112, 1960. 2. Kelly, L. W., Ovarian dwarfism with pituitary tumor, J Clin Endocrinol Metab 23: 50, 1963.
10 too
50 " I 10
10 100
50
mlU
3. Gordon, S. J., and A. M. Mosco, Multiple endocrine organ refractoriness to trophic hormone stimulation. A patient with an enlarged sella turcica and increased FSH secretion, Ann Intern Med 63: 313, 1965. 4. Bower, B. F., Pituitary enlargement secondary to untreated hypogonadism, Ann Intern Med 69: 107, 1968. 5. Woolf, P. D., and E. A. Schenk, An FSH-producing pituitary tumor in a patient with hypogonadism, J Clin Endocrinol Metab 38: 561, 1974. 6. Friend, J. N., D. M. Judge, and R. J. Santen, Functioning, suppressible FSH secreting pituitary adenoma associated with normal spermatogenesis, Program of the 57th annual meeting of the Endocrine Society, 1975, p. 166. 7. Snyder, P. J., and Sterling, F. H., Hypersecretion of LH and FSH by a pituitary adenoma, J Clin Endocrinol Metab 42: 544, 1976.
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G
ONADOTROPIN secreting pituitary adenomas are very rare. There have been several reports of gonadotropin secreting pituitary adenoma, usually associated with hypogonadism (1-4), but these were based on clinical observations and lack adequate endocrine studies. The only convincing reports of FSH secreting pituitary adenoma are those by Woolf and Shenk (5) and Friend et at. (6) and that of FSH and LH secreting adenoma by Snyder and Sterling (7). We will present a case of an FSH and LH secreting pituitary adenoma which was not associated with hypogonadism. Case Report
A 50-year-old man was admitted to the hospital because of left temporal hemianopsia. Eight years earlier, sellar enlargement had been found by chance and he received pituitary irradiation with a tumor dose of 2,000 rads. He had been well until a year before admission when visual acuity decreased. Three months before admission left superior temporal hemianopsia appeared. He had been married for 28 years and had 3 children 25, 21 and 14 years old. He had not lost libido or potency. On physical examination he was a well nourished, normally developed man 165 cm tall Received April 1, 1976. Supported by a research grant for "Specific Diseases" of the Japanese Ministry of Health and Welfare, and by a research grant from the Japanese Ministry of Education (No. 837019).
Plasma testosterone was 691 ng/dl and rose normally after pregnant mare's serum gonadotropin. Sperm count was 46 x 106/ml. Transfrontal hypophysectomy was followed by a marked decrease of both FSH (to 19 mlU/ml) and LH (to 22 mlU/ml). Histologic examination of the tumor revealed 90% chromophobe cells and 10% slightly eosinophilic cells. Two sizes of secretory granules were demonstrated. Tumor cells in tissue culture secreted both FSH and LH. (J Clin Endocrinol Metab 45: 653, 1977)
weighing 65 kg. Pubic and axillary hair were well preserved. Testes and phallus were normal in size and consistency. Urinalysis, complete blood counts and routine blood chemical determinations were normal. Plasma FSH was markedly elevated (295 mlU/ml) and LH was slightly elevated (35 mlU/ml). Sperm count was 46 x 106/ml. Testicular biopsy showed active spermatogenesis and slightly hypertrophied Leydig cells and was considered normal for his age. Other endocrine findings are included in the results section. Skull x-ray showed an enlarged sella. Computerized axial tomography and pneumoencephalography showed a pituitary tumor with marked suprasellar extension. This was removed by craniotomy on the 20th hospital day. On histologic examination, the tumor consisted of 90% chromophobe cells with 10% acidophilic cells. There were two sizes of secretory granules with diameters of 100-200 m/x and 300-500 n\(i electronmicroscopically. Two weeks after operation, plasma FSH and LH decreased to 19 and 22 mlU/ml, respectively. Materials and Methods LH and FSH in plasma and in tissue culture media were measured by radioimmunoassay (RIA) using kits of Daiichi RI Laboratory with a reference standard of the 2nd IRP-HMG expressed in mlU/ml. GH, ACTH and TSH were also measured using commercial RIA kits available in Japan. Prolactin was measured by RIA using Friesen #2 kit, kindly provided by the National Institute of Arthritis, Metabolism and Digestive Diseases, Bethesda, Md. Plasma tes-
653
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654
DEMURA ET AL.
JCE & M • 1977 Vol 45 • No 4
tion curves of culture media were compared with standard curves of LH and FSH. Piitient Normal ranges An LRF test was performed by iv administraProvocative Basal Peak Hormone tests Basal Peak tion of 100 /xg of LRF to the fasting patient. Estrogen suppression was performed by iv adminisGH ng/ml ITT 0.8 0-6 10- 50 0.8 tration of 10 mg of conjugated equine estrogens. TSH fiVlm\ 8- 40 TRH 0-6 1.3 13.0 Testosterone suppression was done by the im injection of depot testosterone 100 mg per day for PRL ng/ml TRH 2.8 9.0 2-20 8 - 80 3 days. Pregnant mare's serum (PMS) was injected ACTH pg/ml Rapid metyim 2,000 IU per day for 2 days. An insulin toler20-75 55-550 53.6 571 rapone ance test (ITT) was performed by iv administration of 0.1 U/kg of body weight of regular insulin. A rapid metyrapone test was performed by adtosterone was measured by RIA using antisera ministering a single oral dose of 1.5 g of metyraraised in our laboratory. pone. A TRH test was performed by the iv adminTissue culture was performed using freshly ob- istration of 500 /xg of TRH. Blood samples were tained tumor tissues. Tissues were cut into small drawn at the intervals shown in Table 1 and Figs. pieces of 2-3 mm3 and filtered through a platinic 1-3. mesh of 0.17 mm. Mechanically dispersed tisNormal basal values and responses of various sues were put into Petri dishes contained 3 ml of hormones to suppression and stimulation tests Eagle's MEM media with 20% fetal calf serum shown in the result were those obtained from at and processed to monolayer tissue culture under least 5 normal subjects with comparable age 95% air with 5% CO2 at 37 C. Cell counts were and sex to the patient. adjusted to 1 x 105/ml at the beginning of the culture. The medium was changed every 3-4 days and concentrations of LH and FSH were measResults ured. To examine the effect of the culture media on the immunoreactivity of the hormones, diluGH reserve was diminished but the responses of other pituitary hormones to various provocative tests were normal (Table 1). FSH Basal levels of plasma FSH and LH were always elevated and ranged between 176295 mlU/ml and 35-67 mlU/ml, respectively, compared with normal levels of 27 ± 7.3 mlU/ml for FSH and 17 ± 4.2 mlU/ml for LH. Both FSH and LH failed to rise normally after LRF compared with normal responses of more than 2 times basal levels for both LH and FSH (Fig. 1). Administration of conjugated equine estrogens was associated with a minimal decrease in plasma FSH concentration and no substantial change in plasma LH concentration (Fig. 2). In normal subjects prompt suppression of both LH and FSH occurred with minimal values 30 ± 18 and 72 ± 11% of the initial levels, respectively, for LH and FSH at 12 h after injection. Testosterone administration did not suppress FSH but suppressed LH gradually 15 30 45 60 90 120 to 50% of the initial level by 6 days (Fig. 3) minutes compared with normal gradual suppression FIG. 1. Responses of plasma LH and FSH to LRF. Open of both LH and FSH to 38 ± 12 and 12 ± 6% circles indicate LH and closed circles FSH. TABLE 1. Pituitary reserve tests
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FSH AND LH SECRETING PITUITARY ADENOMA LH
FSH
nrtfU
Premarin 10 mg i. v.
300.
655
In tissue culture the tumor cells secreted both LH and FSH. The concentrations of LH and FSH in the tissue culture media when plotted as a function of time on semilogarithmic paper decreased almost as a straight line (Figs. 4 and 5). Very small amounts of LH and FSH were produced by tumor tissues from 7 other patients with pituitary adenomas shown as controls. No other pituitary hormones than LH and FSH were found in tissue culture media of this particular patient on the 3rd day of culture. Dilution curves of tissue culture media were parallel to standard curves of both FSH and LH (Fig. 6). Discussion
24
36
60
hours
FJC. 2. Responses of plasma LH and FSH to testosterone. Open circles indicate LH and closed circles FSH. Shaded area show normal ranges.
of the initial levels, respectively, by 12 days. Basal plasma testosterone levels ranged between 580 and 691 ng/dl and increased normally to 868 ng/dl 24 h after administration of PMS compared with normal basal levels and peak values of 520 ± 62 and 800 ± 88 ng/dl, respectively.
The clinical manifestations of this particular case were that of a non-functioning pituitary adenoma; however, the abnormally elevated concentrations of FSH and LH in plasma for his age and sex, associated with partial impairment of other pituitary functions led us to suspect that he had a gonadotropin secreting pituitary adenoma. The lack of responsiveness of LH and FSH to LRF suggested that the secretion of gonadotropin in this patient was not dependent on hypothalamic control or the pituitary productions were already maximal even if the tissue were responsive. Suppression LH
FIG. 3. Responses of plasma LH and FSH to conjugated equine estrogens. Open circles indicate LH and closed circles FSH. Shaded area show normal ranges.
0 6
48
72 hours
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JCE & M • 1977 Vol 45 • No 4
DEMURA ETAL.
656
FSH
"55* O O •
O present case (top) O chromophobe adenoma • acromegaly
10
I 0
10
20
days
FIG. 4. Changes in the concentration of FSH in the culture media.
tests showed that the secretion of LH but not FSH was partially suppressed by testosterone; however, both FSH and LH did not respond to administrations of estrogens. These observations may suggest that gonadotropin secretion in this particular case was not under normal feedback regulation. In most of the previously reported patients with gonadotropin secreting pituitary tumors (1-4), it has been assumed that end organ failure led to the development of pituitary tumors through a decrease in negative feedback inhibition. In some of these patients, replacement therapy with either estrogens or androgens was effective in decreasing urinary gonadotropins. In contrast, gonadotropin secretion in our patient seemed to be relatively autonomous. None of the clinical findings or results of endocrine studies or testicular biopsy indicated hypogonadism. The absence of hypogonadism and the autonomous secretion of gonadotropins suggest that the pituitary tumor was primary and not secondary to end organ failure.
It could be expected that the patient might have an increased spermatogenesis or an overproduction of testosterone due to increased FSH and LH; however, no such evidence was found. The possibility can not be excluded that hypersecreted FSH and/or LH were not completely biologically active hormones even though they were immunologically indistinguishable from ESH and LH. Finally, the demonstration of excessive secretions of FSH and LH by the tumor tissue in vitro clearly documented that this patient had an FSH and LH secreting pituitary adenoma. The absence of other pituitary hormones except for LH and FSH in tissue culture media demonstrated that there was no contamination of normal pituitary tissue. Recently, Woolf and Shenk (5) reported a case of FSH secreting pituitary adenoma, in which FSH production was also confirmed by tissue culture. In conclusion, we have reported a patient with an FSH and LH secreting pituitary adenoma. Since hypogonadism was not ob10 LH mill
O O
O present case (top) O chromophobe adenoma acromegaly
20
30
10
10
10 days
FlG. 5. Changes in the concentration of LH in the culture media.
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FSH AND LH SECRETING PITUITARY ADENOMA
FSH
657
L H
FIG. 6. Dilution curves of culture media compared with standard curves of FSH and LH.
I 10
served in our patient, the pathogenesis of the pituitary tumor seemed to be primary rather than secondary to end organ failure. Acknowledgments We wish to thank Dr. C. A. Nugent, Univ. of Arizona, for reviewing the manuscript and Dr. N. Sasano, Tohoku Univ. Japan, for interpreting the testicular biopsy.
References 1. Leiba, S., B. Landau, and A. Bar, Target gland insufficiency and pituitary tumors, Ada Endocrinol (Kbh) 60: 112, 1960. 2. Kelly, L. W., Ovarian dwarfism with pituitary tumor, J Clin Endocrinol Metab 23: 50, 1963.
10 too
50 " I 10
10 100
50
mlU
3. Gordon, S. J., and A. M. Mosco, Multiple endocrine organ refractoriness to trophic hormone stimulation. A patient with an enlarged sella turcica and increased FSH secretion, Ann Intern Med 63: 313, 1965. 4. Bower, B. F., Pituitary enlargement secondary to untreated hypogonadism, Ann Intern Med 69: 107, 1968. 5. Woolf, P. D., and E. A. Schenk, An FSH-producing pituitary tumor in a patient with hypogonadism, J Clin Endocrinol Metab 38: 561, 1974. 6. Friend, J. N., D. M. Judge, and R. J. Santen, Functioning, suppressible FSH secreting pituitary adenoma associated with normal spermatogenesis, Program of the 57th annual meeting of the Endocrine Society, 1975, p. 166. 7. Snyder, P. J., and Sterling, F. H., Hypersecretion of LH and FSH by a pituitary adenoma, J Clin Endocrinol Metab 42: 544, 1976.
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