Hypersecretion of LH and FSH by a Pituitary Adenoma PETER J. SNYDER AND FRANCIS H. STERLING Endocrine Section, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pa. 19174 ABSTRACT. A 51 year-old man who had a pituitary adenoma that appeared to be hypersecreting LH and FSH is described. Not only were serum LH and FSH concentrations above the normal ranges, but the serum concentrations of testosterone, free testosterone, and dihydrotestosterone were also above normal. Serum LH and FSH concentrations in-
creased in response to synthetic thyrotropin-releasing hormone as well as to synthetic gonadotropin-releasing hormone. The elevated hormone concentrations decreased following an initial partial hypophysectomy and decreased further following repeat hypophysectomy. (J Clin Endocrinol Metab 42: 544, 1976)
P
and right retro-orbital headaches for about one year prior to admission. Fatigue, vague muscle weakness, and loss of libido and potency had been present for about a year, and there had been a gradual weight loss of 25 kg over the preceding 5 years. No changes in hair, skin, or pigmentation were noted. Past medical history included documented peptic ulcer disease, treated medically, and syphilis, treated 30 years previously with arsenicals. Examination disclosed a man who spoke and responded slowly and who appeared older than his stated age. Height was 1.83 m; weight, 69.0 kg; blood pressure, 118/85 lying and 85/40 standing. A murmur of aortic regurgitation was noted. There were no other abnormalities except the visual field impairment and slightly delayed relaxation of the Achilles reflexes. Axillary hair was scant, but pubic hair and beard were normal. The prostate was moderately and symmetrically enlarged. The penis was of adult male size. The testes were 7.0 x 3.5 cm in size bilaterally and normal in consistency. The hematocrit, leukocyte count, urinalysis, and serum concentrations of creatinine, glucose, and electrolytes were all normal. The VDRL was negative, but the FTA was strongly positive. Materials and Methods Skull X-ray, bilateral carotid angiograms, and pneumoencephalogram were consistent with a Case Report pituitary adenoma with suprasellar extension. First admission. A 51 year-old man was admitted Following evaluation of pituitary function (Data to the Philadelphia VA Hospital on November given in Table 1 and in Figs. 1-3), a right frontal 15, 1973, for evaluation of bi-temporal hemianop- craniotomy was performed on December 10, sia, detected by an ophthalmologist. The patient 1973, and an intrasellar tumor was partially exhad noted loss of visual acuity in the right eye cised. Hematoxylin-eosin-stained sections of the tumor were diagnosed histologically as showing a "chromophobe adenoma." Post-operative reReceived June 24, 1975. Supported in part by USPHS grants RR-40, AM covery were uneventful. Subsequently, 4600 r of radiotherapy was delivered to the pituitary fossa. 05649, and HD 08555. ITUITARY adenomas often hypersecrete hormones. Hypersecretion of growth hormone and ACTH by pituitary adenomas has long been recognized, and hypersecretion of prolactin (1-3) and, less commonly, of TSH (4-6) have been documented in the last few years. Two patients have recently been described who had pituitary adenomas that hypersecreted FSH (7,8), but no patient has yet been reported who had a pituitary adenoma that secreted both LH and FSH. Since both LH and FSH appear to be secreted by the same pituitary cell (9), one would expect that hypersecretion of one hormone might well be accompanied by hypersecretion of the other. This report describes a man who had a pituitary adenoma that appeared to be hypersecreting LH and FSH. Not only were the serum concentrations of LH and FSH supranormal, but the concentrations of testosterone, free testosterone, and dihydrotestosterone were also supranormal.
544
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545
LH-FSH-SECRETING PITUITARY ADENOMA TABLE 1. Tests of pituitary function in a patient with an LH-FSH-secreting pituitary adenoma Patient Serum thyroxine, Mg/100 ml Serum triiodothyronine, ng/100 ml Serum TSH, basal, /xU/ml Maximum A TSH*, /xU/ml Time of Maximum A TSH, min Serum prolactin, basal, ng/ml Maximum A prolactin,* ng/ml Maximum serum growth hormone,! ng/ml Maximum plasma deoxycortisol, \ ^g/100 ml
PARTIAL HYPOPHYSECTOMY
60
Normal range
5.1
5 . 0 - 11.0 (10)
82 4.6 5.9
70 - 150 (10) < 2 - 8 . 0 (10) >2 (2)
90
7.0 (12)
1.4
>10 (12)
The above tests were all performed in November, 1973, prior to the initial partial hypophysectomy. * Maximum increment above the basal level in response to the acute iv administration of 400 fig of synthetic thyrotropin-releasing hormone. t In response to a propranolol-glucagon stimulus. $ In response to metyrapone.
The patient was given L-thyroxine, 0.1 mg, and hydrocortisone, 30 mg, daily. Penicillin was given for syphilis. Following discharge the patient felt well except for daily headaches. Within one month after beginning thyroxine and hydrocortisone his libido and potency returned, and he began to have sexual intercourse 3 to 4 times weekly. No testosterone was administered. On July 25, 1974, hormonal re-evaluation of gonadal function was performed. Second admission. On August 7, 1974, 9 months following surgery and 8 months following completion of pituitary irradiation, the patient was readmitted because of deteriorating vision. Tangent screen examination showed considerable dimunition of the visual fields compared with those noted after completion of radiation therapy. Visual acuity was also worse. Repeated contrast radiography showed changes consistent with either prior surgery, radiation, or tumor recurrence. Repeated partial excision of the adenoma was performed on September 4, 1974. Following the operation he developed permanent diabetes insipidus, but had no change in his visual fields. Basal hormone levels were determined again on September 28, 1974.
=
REPEAT HYPOPHYSECTOMY
12/10/73
9/4/74
40
§ 1 K E UJ
20
5=
30
§ 2
20
w
10
~
—n-—
0 1600
1 0
h .E§ E
60 40
-rii
20 0 240
1 160 ~
80
11/2711/28
1973
7/25
9/28
1974
FIG. 1. The serum FSH, LH, testosterone, free testosterone, and dihydrotestosterone concentrations in a 51-year-old man with a pituitary adenoma before and after each of 2 partial hypophysectomies. Each bar represents the hormone concentration in a separate serum sample on the date indicated. The areas between the dashed lines indicate the ranges of normal for each hormone concentration.
Methods Synthetic gonadotropin-releasing hormone (GnRH) (Abbott Laboratories, North Chicago, 111.) was administered as a 250 fig iv bolus, and
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546
SNYDER AND STERLING
JCE & M • 1976 Vol 42 • No 3
140 pre-operative (11/27/73) post-operative (7/25/74) =-=— normal range
FIG. 2. Serum LH and FSH concentrations before and after the acute iv administration of 250 fj.g of synthetic gonadotropinreleasing hormone to a 51-yearold man with an LH and FSHsecreting pituitary adenoma before and after partial hypophysectomy and radiation therapy. The dashed lines indicate the ranges of LH and FSH responses of normal 40-59year-old men (22).
60 TIME(min)
f£o~
blood was sampled at -30, - 1 5 , 0, 10, 20, 30, 45, 60, 90, 120, 150, and 180 minutes in relation to the dose. Synthetic thyrotropin-releasing hormone (TRH) was administered as previously described (10). The metyrapone test (11) and propranolol-glucagon test (12) were also performed as previously described. Serum FSH and LH were measured by doubleantibody immunoassays using reagents supplied by the NIAMDD. Preparation LER 907 was used as the standard in both assays. Results are expressed in terms of the 2nd IRP-HMG, on the basis of one /xg LER 907 equals 38 mU FSH and 219 mU LH (13). Assay sensitivities and mean intra- and inter-assay coefficients of variation were 2 mlU/ml, 7.7% and 14.5% for FSH, and 2 mlU/ml, 6.6%, and 14.9% for LH. Serum testosterone was measured by immunoassay (14), using an antiserum generously provided by Dr. Richard Horton. This assay had a sensitivity of 12.5 ng/100 ml, and mean intra-
and interassay coefficients of variation of 14.5 and 17.1%. The free testosterone fraction was determined by equilibrium dialysis of 1:5 diluted serum (15,16). The per cent of dialyzable testosterone was corrected for the dilution by multiplying by 0.367, a figure obtained experimentally as the ratio of the percentage of dialyzable testosterone in an undiluted serum pool (3.2%) to that in the same pool diluted 1:5 (9.4%), corrected for the 10.8% volume change when undiluted serum was used (17). The per cent dialyzable testosterone was then multiplied times the total testosterone concentration to get the free testosterone concentration. The intraand inter-assay coefficients of variation for this assay were 9.3 and 10.2%. Serum dihydrotestosterone was measured at Endocrine Sciences Laboratories, Tarzana, Cal. Serum TSH (18), triiodothyronine (T3) (19), and prolactin (20), were measured by immunoassays. Serum thyroxine (T4) (21) and plasma
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 11:39 For personal use only. No other uses without permission. . All rights reserved.
547
LH-FSH-SECRETING PITUITARY ADENOMA deoxycortisol (10) were measured by competitive protein-binding assays. Serum growth hormone was measured at Bio Science Laboratories, Van Nuys, Gal.
I 10 100
V
1 50
Results Prior to the first partial hypophysectomy the serum concentrations of FSH, LH, testosterone, free testosterone, and dihydrotestosterone were all elevated, as shown in Fig. 1. The dashed lines show the normal ranges, which were determined in a group of 14 normal, 40-59-year-old men (22), except in the case of serum dihydrotestosterone, where the normal range is that determined at Endocrine Sciences Laboratories. Three basal samples of blood were taken at 15 min intervals on November 27, and again on November 28, 1973. In these samples the serum FSH concentrations ranged from 30.3 to 53.0 mlU/ml (normal range, 5 to 15 mlU/ml); the LH ranged from 23.6 to 26.0 mlU/ml (normal range, 5 to 15 mlU/ml); testosterone, 1380 to 1485 ng/100 ml (normal, 400 to 1200 ng/100 ml); serum free testosterone, 60.8 to 64.0 ng/100 ml (normal, 8 to 24 ng/100 ml); and serum dihydrotestosterone, 204 and 224 ng/100 ml (normal, 30 to 85 ng/100 ml). This patient's serum exhibited parallelism with the LHFSH standard, preparation LER 907, in both the LH and FSH assays. On July 25, 1974, 7 months following the initial partial hypophysectomy, these parameters were reevaluated, and all were found to be lower. The serum FSH concentration was 15.2 to 27.8 mlU/ml; serum LH, 12.2 to 14.1 mlU/ml; serum testosterone, 545 to 609 ng/100 ml; serum free testosterone, 11.5 and 14.1 ng/100 ml; and dihydrotestosterone, 36 and 40 ng/100 ml. On September 28, 1974, 24 days after repeat hypophysectomy, the levels of all of the hormones were still lower: FSH, 9.3 mlU/ml; LH, 8.9 mlU/ml; testosterone, 42 ng/100 ml; and dihydrotestosterone, 16 ng/100 ml. Serum LH and FSH concentrations increased following the acute iv administration of a single dose of 250 fig of GnRH,
i—i
E 40
5
30
20 S V) 10
100
90 80
| 70 • — • 31 y.o.
creased in response to synthetic thyrotropin-releasing hormone as well as to synthetic gonadotropin-releasing hormone. The elevated hormone concentrations decreased following an initial partial hypophysectomy and decreased further following repeat hypophysectomy. (J Clin Endocrinol Metab 42: 544, 1976)
P
and right retro-orbital headaches for about one year prior to admission. Fatigue, vague muscle weakness, and loss of libido and potency had been present for about a year, and there had been a gradual weight loss of 25 kg over the preceding 5 years. No changes in hair, skin, or pigmentation were noted. Past medical history included documented peptic ulcer disease, treated medically, and syphilis, treated 30 years previously with arsenicals. Examination disclosed a man who spoke and responded slowly and who appeared older than his stated age. Height was 1.83 m; weight, 69.0 kg; blood pressure, 118/85 lying and 85/40 standing. A murmur of aortic regurgitation was noted. There were no other abnormalities except the visual field impairment and slightly delayed relaxation of the Achilles reflexes. Axillary hair was scant, but pubic hair and beard were normal. The prostate was moderately and symmetrically enlarged. The penis was of adult male size. The testes were 7.0 x 3.5 cm in size bilaterally and normal in consistency. The hematocrit, leukocyte count, urinalysis, and serum concentrations of creatinine, glucose, and electrolytes were all normal. The VDRL was negative, but the FTA was strongly positive. Materials and Methods Skull X-ray, bilateral carotid angiograms, and pneumoencephalogram were consistent with a Case Report pituitary adenoma with suprasellar extension. First admission. A 51 year-old man was admitted Following evaluation of pituitary function (Data to the Philadelphia VA Hospital on November given in Table 1 and in Figs. 1-3), a right frontal 15, 1973, for evaluation of bi-temporal hemianop- craniotomy was performed on December 10, sia, detected by an ophthalmologist. The patient 1973, and an intrasellar tumor was partially exhad noted loss of visual acuity in the right eye cised. Hematoxylin-eosin-stained sections of the tumor were diagnosed histologically as showing a "chromophobe adenoma." Post-operative reReceived June 24, 1975. Supported in part by USPHS grants RR-40, AM covery were uneventful. Subsequently, 4600 r of radiotherapy was delivered to the pituitary fossa. 05649, and HD 08555. ITUITARY adenomas often hypersecrete hormones. Hypersecretion of growth hormone and ACTH by pituitary adenomas has long been recognized, and hypersecretion of prolactin (1-3) and, less commonly, of TSH (4-6) have been documented in the last few years. Two patients have recently been described who had pituitary adenomas that hypersecreted FSH (7,8), but no patient has yet been reported who had a pituitary adenoma that secreted both LH and FSH. Since both LH and FSH appear to be secreted by the same pituitary cell (9), one would expect that hypersecretion of one hormone might well be accompanied by hypersecretion of the other. This report describes a man who had a pituitary adenoma that appeared to be hypersecreting LH and FSH. Not only were the serum concentrations of LH and FSH supranormal, but the concentrations of testosterone, free testosterone, and dihydrotestosterone were also supranormal.
544
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 11:39 For personal use only. No other uses without permission. . All rights reserved.
545
LH-FSH-SECRETING PITUITARY ADENOMA TABLE 1. Tests of pituitary function in a patient with an LH-FSH-secreting pituitary adenoma Patient Serum thyroxine, Mg/100 ml Serum triiodothyronine, ng/100 ml Serum TSH, basal, /xU/ml Maximum A TSH*, /xU/ml Time of Maximum A TSH, min Serum prolactin, basal, ng/ml Maximum A prolactin,* ng/ml Maximum serum growth hormone,! ng/ml Maximum plasma deoxycortisol, \ ^g/100 ml
PARTIAL HYPOPHYSECTOMY
60
Normal range
5.1
5 . 0 - 11.0 (10)
82 4.6 5.9
70 - 150 (10) < 2 - 8 . 0 (10) >2 (2)
90
7.0 (12)
1.4
>10 (12)
The above tests were all performed in November, 1973, prior to the initial partial hypophysectomy. * Maximum increment above the basal level in response to the acute iv administration of 400 fig of synthetic thyrotropin-releasing hormone. t In response to a propranolol-glucagon stimulus. $ In response to metyrapone.
The patient was given L-thyroxine, 0.1 mg, and hydrocortisone, 30 mg, daily. Penicillin was given for syphilis. Following discharge the patient felt well except for daily headaches. Within one month after beginning thyroxine and hydrocortisone his libido and potency returned, and he began to have sexual intercourse 3 to 4 times weekly. No testosterone was administered. On July 25, 1974, hormonal re-evaluation of gonadal function was performed. Second admission. On August 7, 1974, 9 months following surgery and 8 months following completion of pituitary irradiation, the patient was readmitted because of deteriorating vision. Tangent screen examination showed considerable dimunition of the visual fields compared with those noted after completion of radiation therapy. Visual acuity was also worse. Repeated contrast radiography showed changes consistent with either prior surgery, radiation, or tumor recurrence. Repeated partial excision of the adenoma was performed on September 4, 1974. Following the operation he developed permanent diabetes insipidus, but had no change in his visual fields. Basal hormone levels were determined again on September 28, 1974.
=
REPEAT HYPOPHYSECTOMY
12/10/73
9/4/74
40
§ 1 K E UJ
20
5=
30
§ 2
20
w
10
~
—n-—
0 1600
1 0
h .E§ E
60 40
-rii
20 0 240
1 160 ~
80
11/2711/28
1973
7/25
9/28
1974
FIG. 1. The serum FSH, LH, testosterone, free testosterone, and dihydrotestosterone concentrations in a 51-year-old man with a pituitary adenoma before and after each of 2 partial hypophysectomies. Each bar represents the hormone concentration in a separate serum sample on the date indicated. The areas between the dashed lines indicate the ranges of normal for each hormone concentration.
Methods Synthetic gonadotropin-releasing hormone (GnRH) (Abbott Laboratories, North Chicago, 111.) was administered as a 250 fig iv bolus, and
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 11:39 For personal use only. No other uses without permission. . All rights reserved.
546
SNYDER AND STERLING
JCE & M • 1976 Vol 42 • No 3
140 pre-operative (11/27/73) post-operative (7/25/74) =-=— normal range
FIG. 2. Serum LH and FSH concentrations before and after the acute iv administration of 250 fj.g of synthetic gonadotropinreleasing hormone to a 51-yearold man with an LH and FSHsecreting pituitary adenoma before and after partial hypophysectomy and radiation therapy. The dashed lines indicate the ranges of LH and FSH responses of normal 40-59year-old men (22).
60 TIME(min)
f£o~
blood was sampled at -30, - 1 5 , 0, 10, 20, 30, 45, 60, 90, 120, 150, and 180 minutes in relation to the dose. Synthetic thyrotropin-releasing hormone (TRH) was administered as previously described (10). The metyrapone test (11) and propranolol-glucagon test (12) were also performed as previously described. Serum FSH and LH were measured by doubleantibody immunoassays using reagents supplied by the NIAMDD. Preparation LER 907 was used as the standard in both assays. Results are expressed in terms of the 2nd IRP-HMG, on the basis of one /xg LER 907 equals 38 mU FSH and 219 mU LH (13). Assay sensitivities and mean intra- and inter-assay coefficients of variation were 2 mlU/ml, 7.7% and 14.5% for FSH, and 2 mlU/ml, 6.6%, and 14.9% for LH. Serum testosterone was measured by immunoassay (14), using an antiserum generously provided by Dr. Richard Horton. This assay had a sensitivity of 12.5 ng/100 ml, and mean intra-
and interassay coefficients of variation of 14.5 and 17.1%. The free testosterone fraction was determined by equilibrium dialysis of 1:5 diluted serum (15,16). The per cent of dialyzable testosterone was corrected for the dilution by multiplying by 0.367, a figure obtained experimentally as the ratio of the percentage of dialyzable testosterone in an undiluted serum pool (3.2%) to that in the same pool diluted 1:5 (9.4%), corrected for the 10.8% volume change when undiluted serum was used (17). The per cent dialyzable testosterone was then multiplied times the total testosterone concentration to get the free testosterone concentration. The intraand inter-assay coefficients of variation for this assay were 9.3 and 10.2%. Serum dihydrotestosterone was measured at Endocrine Sciences Laboratories, Tarzana, Cal. Serum TSH (18), triiodothyronine (T3) (19), and prolactin (20), were measured by immunoassays. Serum thyroxine (T4) (21) and plasma
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 11:39 For personal use only. No other uses without permission. . All rights reserved.
547
LH-FSH-SECRETING PITUITARY ADENOMA deoxycortisol (10) were measured by competitive protein-binding assays. Serum growth hormone was measured at Bio Science Laboratories, Van Nuys, Gal.
I 10 100
V
1 50
Results Prior to the first partial hypophysectomy the serum concentrations of FSH, LH, testosterone, free testosterone, and dihydrotestosterone were all elevated, as shown in Fig. 1. The dashed lines show the normal ranges, which were determined in a group of 14 normal, 40-59-year-old men (22), except in the case of serum dihydrotestosterone, where the normal range is that determined at Endocrine Sciences Laboratories. Three basal samples of blood were taken at 15 min intervals on November 27, and again on November 28, 1973. In these samples the serum FSH concentrations ranged from 30.3 to 53.0 mlU/ml (normal range, 5 to 15 mlU/ml); the LH ranged from 23.6 to 26.0 mlU/ml (normal range, 5 to 15 mlU/ml); testosterone, 1380 to 1485 ng/100 ml (normal, 400 to 1200 ng/100 ml); serum free testosterone, 60.8 to 64.0 ng/100 ml (normal, 8 to 24 ng/100 ml); and serum dihydrotestosterone, 204 and 224 ng/100 ml (normal, 30 to 85 ng/100 ml). This patient's serum exhibited parallelism with the LHFSH standard, preparation LER 907, in both the LH and FSH assays. On July 25, 1974, 7 months following the initial partial hypophysectomy, these parameters were reevaluated, and all were found to be lower. The serum FSH concentration was 15.2 to 27.8 mlU/ml; serum LH, 12.2 to 14.1 mlU/ml; serum testosterone, 545 to 609 ng/100 ml; serum free testosterone, 11.5 and 14.1 ng/100 ml; and dihydrotestosterone, 36 and 40 ng/100 ml. On September 28, 1974, 24 days after repeat hypophysectomy, the levels of all of the hormones were still lower: FSH, 9.3 mlU/ml; LH, 8.9 mlU/ml; testosterone, 42 ng/100 ml; and dihydrotestosterone, 16 ng/100 ml. Serum LH and FSH concentrations increased following the acute iv administration of a single dose of 250 fig of GnRH,
i—i
E 40
5
30
20 S V) 10
100
90 80
| 70 • — • 31 y.o.
