0021-972X/9l/7206-1195$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 72, No. 6 Printed in U.S.A.
The Nocturnal Serum Thyrotropin Surge is Abolished in Patients with Adrenocorticotropin (ACTH)-Dependent or ACTH-Independent Cushing's Syndrome L. BARTALENA, E. MARTINO, L. PETRINI, F. VELLUZZI, A. LOVISELLI, L. GRASSO, C. MAMMOLI, AND A. PINCHERA Istituto di Endocrinologia, University of Pisa (L.B., L.G., CM., A.P.), and Cattedra di Endocrinologia, University of Cagliari (EM., L.P., F. V., A.L.), Cagliari, Italy
ABSTRACT. TSH secretion was evaluated in 10 patients with ACTH-dependent (pituitary microadenoma, n = 5) or ACTHindependent [adrenal adenoma (n = 4) or carcinoma (n = 1)] Cushing's syndrome, and in 12 normal controls matched for age and sex. Serum TSH concentration was assayed at night, from 2200-0200 h, and in the morning, both basally and 30 min after iv injection of 200 ng synthetic TRH. Patients with hypercortisolism showed significantly reduced serum total T4 and T3 and free T 3 concentrations and increased serum reverse T 3 levels. Their mean baseline serum TSH concentration in the morning, albeit slightly lower, did not significantly differ from those of controls. The mean peak TSH value after TRH was significantly reduced, and a blunted TSH response to TRH was found in 4 out of 10 patients. At variance with normal controls, who showed nighttime TSH values 63-228% higher than morning values, 9
I
t is well established that TSH secretion shows circadian variations, and that the highest serum concentrations of the hormone are found in the late evening or early morning (1-8). The nocturnal serum TSH rise may be abolished in central hypothyroidism (6, 9, 10), thyrotoxicosis (7, 9), during L-T4 suppressive therapy (9, 11), in severe nonthyroidal illness (12, 13) or during fasting (14). Nocturnal serum TSH surge is also lacking in most patients with untreated major depression (15, 16) or undergoing major nonthyroidal surgery (17). The latter two conditions share an increase in serum cortisol concentrations which occurs chronically in depressives and acutely in surgical patients. Thus, although other neuroendocrine factors may contribute to the above changes (18), the high endogenous cortisol levels are likely to play an important role in the pathogenesis of the abnorReceived September 17,1990. Address correspondence and requests for reprints to: Professor Enio Martino, Cattedra di Endocrinologia, University of Cagliari, Via S. Giorgio, 12, 09124 Cagliari, Italy. This study was supported in part by funds from the Ministero della Pubblica Istruzione (60%), Rome, Italy.
out of 10 patients had nighttime levels not different from or even lower than those in the morning; the remaining patient had nighttime TSH values marginally (33%) higher than in the morning. An inverse relationship (r = 0.80, P < 0.001) was found between serum cortisol and TSH values both at night and in the morning. No differences were found either in the pattern of TSH secretion or in the TSH response to TRH between patients with ACTH-dependent and those with ACTH-independent Cushing's syndrome.These results show a substantial impairment of TSH secretion, and in particular the loss of the nocturnal surge of the hormone, in patients with Cushing's syndrome. Although the origin of the nocturnal TSH rise is probably multifactorial, cortisol, at least when secreted in excess, appears to play an important role in its regulation. (J Clin Endocrinol Metab 72: 1195-1199, 1991)
malities of TSH secretion found in depressed and surgical patients. This is in keeping with the notion that not only pharmacological, but even physiological doses of glucocorticoids may reduce TSH secretion both in man (19) and in animals (20). An indirect support to this concept comes from the observation that the correction of glucocorticoid deficiency in patients with Addison's disease is associated with a decrease in serum TSH concentrations (21). Patients with Cushing's syndrome have reduced serum T4 and T 3 concentrations (22, 23), associated with reduced baseline TSH concentrations and an impaired TSH response to TRH (24-26). Scanty data are available on the behavior of the nocturnal TSH rise in these patients, although Van Cauter et al. (27), using a conventional and relatively insensitive TSH RIA, reported no differences between night and morning serum TSH levels in two patients with hypercortisolism. Aim of the present study was to evaluate the TSH secretion, using a sensitive TSH immunoradiometric assay, with particular regard to the nocturnal surge of the hormone, in patients with ACTH-dependent or ACTH-independent Cushing's syndrome. 1195
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 January 2016. at 16:11 For personal use only. No other uses without permission. . All rights reserved.
JCE&M«1991 Vol 72 • No 6
BARTALENA ET AL.
1196 Materials and Methods Subjects
Ten patients (five men and five women, age range 40-59 yr, mean 49 yr) with hypercorticolism were enrolled in this study: five patients had ACTH-dependent Cushing's disease due to pituitary microadenoma, five patients had ACTH-independent Cushing's syndrome, due to adrenal adenoma in four cases and to functioning adrenal carcinoma in one case. These patients had no known thyroid disorder, nor goiter and thyroid-directed autoantibodies. No patient was taking drugs known to interfere with thyroid function tests. A group of 12 healthy subjects with no thyroid dysfunction, matched for age and sex served as controls. All patients and subjects gave their informed consent to this study. Study design Blood was drawn in all subjects at hourly intervals between 2200 h and 0200 h, and between 0700 h and 0900 h. This protocol of blood sampling provides, as pointed out by Caron et al. (6), a reasonable assessment of the nocturnal serum TSH surge. The highest morning and nighttime TSH values were taken for comparison. The nocturnal TSH surge was calculated by dividing the difference between nighttime and morning TSH values by the morning TSH value, and then multiplying the result by 100. After the morning baseline sampling, a TRH stimulation test (200 ng iv) was performed, and blood was drawn after 30 min for TSH measurement.
Statistical analysis Data were expressed as mean ± SE. Results were analyzed by two-tailed Student's t test for paired and unpaired data, and by linear regression analysis, as appropriate. The level of significance was taken as P < 0.05.
Results Figure 1 illustrates the individual results of serum total and free thyroid hormone measurements in patients with hypercortisolism and in normal controls. Patients with Cushing's syndrome showed a significant reduction of mean serum TT 4 (94.3 ± 4.7 vs. 122.8 ± 6.8 nmol/L, P < 0.01), TT 3 (1.2 ± 0.05 vs. 2.7 ± 0.11 nmol/L, P < 0.001), and FT 3 (3.9 ± 0.2 vs. 6.3 ± 0.4 pmol/L, P < 0.005). Mean serum FT 4 values (10.4 ± 0.6 vs. 12.3 ± 0.8 pmol/L) did not significantly differ in the two groups. However, one patient has subnormal and two had lownormal serum FT 4 levels (Fig. 1). Mean serum rT3 values were significantly increased in patients with hypercortisolism, whereas serum TBG values did not significantly differ in patients and in controls. No differences in all these parameters were observed between patients with ACTH-dependent and those with ACTH-independent Cushing's syndrome. Figure 2 shows that mean morning serum TSH con2 0 0 -,
- 2
Assays Serum TSH was measured in duplicate using a sensitive immunoradiometric assay (Sucrosep TSH IRMA, Boots Celltech, United Kingdom) having a limit of detection of 0.07 mU/ L (28): the intraassay coefficient of variation was less than 10% at 0.07-0.2 mU/L, 4% at 0.25-200 mU/L. The TSH response to TRH was defined as blunted when the TSH peak was less than or equal to 2.9 mU/L, the value 3 SD below the peak TSH value observed in normal subjects. Serum total T4 (TT4) and T 3 (TT3) were assayed by ARIA IIRIA methods (Becton Dickinson Laboratory Systems, Milan, Italy); serum free T4 (FT4) and T 3 (FT3) were determined by the Lisophase kits (Sclavo S.p.A., Siena, Italy); serum rT3 and cortisol were measured by RIA (Radim S.p.A., Rome, Italy). Serum T4-binding globulin (TBG) was determined by a twosite immunoradiometric assay (Corning Medical Kontron S.p.A., Milan, Italy). All measurements were carried out in a single run to avoid interassay variations. Normal values in our laboratory were as follows: TT4, 51.6144.5 nmol/L; TT3,1.5-3.2 nmol/L; FT4,8.4-21.3 pmol/L; FT3, 3.9-8.5 pmol/L; rT3, 0.14-0.54 nmol/L; TSH, 0.4-4.6 mU/L; TBG, 10.2-30.6 mg/L; cortisol at 0800 h, 175-632 nmol/L; at 2400 h, 27-233 nmol/L.
24 -,
•o •o »O •
•o o
a
w
0 0 0
OO
aaa
• • •o OO
FT4
FT3
FIG. 1. Individual serum TT 4 and TT 3 (top panel) and FT4 and FT3 (bottom panel) concentrations in patients with hypercortisolism due to ACTH-dependent (•) or ACTH-independent Cushing's syndrome (0) and in normal controls (•). The dashed columns represent the normal ranges.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 January 2016. at 16:11 For personal use only. No other uses without permission. . All rights reserved.
NOCTURNAL TSH SURGE IN PATIENTS WITH HYPERCORTISOLISM
1197
out of 10 Cushing patients had nighttime values lower than morning values (up to -70%), 3 had superimposable nighttime and morning levels, and only 1 had a blunted nocturnal TSH surge (+33%). No differences were found either in the pattern of TSH secretion or in the TSH response to TRH between patients with ACTH-dependent and those with ACTH-independent Cushing's syndrome. A significant inverse relationship (r = 0.80, P < 0.001) was found between serum cortisol and TSH values both at night and in the morning in patients with hypercortisolism (data not shown).
15 -i
Discussion Night TSH
Morning TSH
Peak TSH
FIG. 2. Mean (+SE) TSH values at night, in the morning and after TRH administration in patients with Cushing's syndrome and in normal controls.
300 n
I 20 °
• • •• •••• •
100 -
o-
• ••• ••• ••
-100 Cushing Controls FIG. 3. Nocturnal serum TSH surge (relative increase of night TSH over morning TSH) in patients with Cushing's syndrome and in controls.
centrations, although slightly reduced in patients with Cushing's syndrome (0.9 ±0.1 vs. 1.3 ± 0.2 mU/L), were not statistically different from those of controls, whereas mean night serum TSH levels were significantly lower in patients with hypercortisolism (0.7 ± 0.1 vs. 3.3 ± 0.6 mU/L, P < 0.01). At variance with the control group, nighttime and morning TSH values did not differ in patients with hypercortisolism (Fig. 2). Mean peak TSH values after TRH were also significantly lower in patients with Cushing's syndrome (4.6 ± 0.7 vs. 12.5 ± 1.8 mU/ L, P < 0.01, Fig. 2): a blunted TSH response to TRH (serum TSH peak
Vol. 72, No. 6 Printed in U.S.A.
The Nocturnal Serum Thyrotropin Surge is Abolished in Patients with Adrenocorticotropin (ACTH)-Dependent or ACTH-Independent Cushing's Syndrome L. BARTALENA, E. MARTINO, L. PETRINI, F. VELLUZZI, A. LOVISELLI, L. GRASSO, C. MAMMOLI, AND A. PINCHERA Istituto di Endocrinologia, University of Pisa (L.B., L.G., CM., A.P.), and Cattedra di Endocrinologia, University of Cagliari (EM., L.P., F. V., A.L.), Cagliari, Italy
ABSTRACT. TSH secretion was evaluated in 10 patients with ACTH-dependent (pituitary microadenoma, n = 5) or ACTHindependent [adrenal adenoma (n = 4) or carcinoma (n = 1)] Cushing's syndrome, and in 12 normal controls matched for age and sex. Serum TSH concentration was assayed at night, from 2200-0200 h, and in the morning, both basally and 30 min after iv injection of 200 ng synthetic TRH. Patients with hypercortisolism showed significantly reduced serum total T4 and T3 and free T 3 concentrations and increased serum reverse T 3 levels. Their mean baseline serum TSH concentration in the morning, albeit slightly lower, did not significantly differ from those of controls. The mean peak TSH value after TRH was significantly reduced, and a blunted TSH response to TRH was found in 4 out of 10 patients. At variance with normal controls, who showed nighttime TSH values 63-228% higher than morning values, 9
I
t is well established that TSH secretion shows circadian variations, and that the highest serum concentrations of the hormone are found in the late evening or early morning (1-8). The nocturnal serum TSH rise may be abolished in central hypothyroidism (6, 9, 10), thyrotoxicosis (7, 9), during L-T4 suppressive therapy (9, 11), in severe nonthyroidal illness (12, 13) or during fasting (14). Nocturnal serum TSH surge is also lacking in most patients with untreated major depression (15, 16) or undergoing major nonthyroidal surgery (17). The latter two conditions share an increase in serum cortisol concentrations which occurs chronically in depressives and acutely in surgical patients. Thus, although other neuroendocrine factors may contribute to the above changes (18), the high endogenous cortisol levels are likely to play an important role in the pathogenesis of the abnorReceived September 17,1990. Address correspondence and requests for reprints to: Professor Enio Martino, Cattedra di Endocrinologia, University of Cagliari, Via S. Giorgio, 12, 09124 Cagliari, Italy. This study was supported in part by funds from the Ministero della Pubblica Istruzione (60%), Rome, Italy.
out of 10 patients had nighttime levels not different from or even lower than those in the morning; the remaining patient had nighttime TSH values marginally (33%) higher than in the morning. An inverse relationship (r = 0.80, P < 0.001) was found between serum cortisol and TSH values both at night and in the morning. No differences were found either in the pattern of TSH secretion or in the TSH response to TRH between patients with ACTH-dependent and those with ACTH-independent Cushing's syndrome.These results show a substantial impairment of TSH secretion, and in particular the loss of the nocturnal surge of the hormone, in patients with Cushing's syndrome. Although the origin of the nocturnal TSH rise is probably multifactorial, cortisol, at least when secreted in excess, appears to play an important role in its regulation. (J Clin Endocrinol Metab 72: 1195-1199, 1991)
malities of TSH secretion found in depressed and surgical patients. This is in keeping with the notion that not only pharmacological, but even physiological doses of glucocorticoids may reduce TSH secretion both in man (19) and in animals (20). An indirect support to this concept comes from the observation that the correction of glucocorticoid deficiency in patients with Addison's disease is associated with a decrease in serum TSH concentrations (21). Patients with Cushing's syndrome have reduced serum T4 and T 3 concentrations (22, 23), associated with reduced baseline TSH concentrations and an impaired TSH response to TRH (24-26). Scanty data are available on the behavior of the nocturnal TSH rise in these patients, although Van Cauter et al. (27), using a conventional and relatively insensitive TSH RIA, reported no differences between night and morning serum TSH levels in two patients with hypercortisolism. Aim of the present study was to evaluate the TSH secretion, using a sensitive TSH immunoradiometric assay, with particular regard to the nocturnal surge of the hormone, in patients with ACTH-dependent or ACTH-independent Cushing's syndrome. 1195
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 January 2016. at 16:11 For personal use only. No other uses without permission. . All rights reserved.
JCE&M«1991 Vol 72 • No 6
BARTALENA ET AL.
1196 Materials and Methods Subjects
Ten patients (five men and five women, age range 40-59 yr, mean 49 yr) with hypercorticolism were enrolled in this study: five patients had ACTH-dependent Cushing's disease due to pituitary microadenoma, five patients had ACTH-independent Cushing's syndrome, due to adrenal adenoma in four cases and to functioning adrenal carcinoma in one case. These patients had no known thyroid disorder, nor goiter and thyroid-directed autoantibodies. No patient was taking drugs known to interfere with thyroid function tests. A group of 12 healthy subjects with no thyroid dysfunction, matched for age and sex served as controls. All patients and subjects gave their informed consent to this study. Study design Blood was drawn in all subjects at hourly intervals between 2200 h and 0200 h, and between 0700 h and 0900 h. This protocol of blood sampling provides, as pointed out by Caron et al. (6), a reasonable assessment of the nocturnal serum TSH surge. The highest morning and nighttime TSH values were taken for comparison. The nocturnal TSH surge was calculated by dividing the difference between nighttime and morning TSH values by the morning TSH value, and then multiplying the result by 100. After the morning baseline sampling, a TRH stimulation test (200 ng iv) was performed, and blood was drawn after 30 min for TSH measurement.
Statistical analysis Data were expressed as mean ± SE. Results were analyzed by two-tailed Student's t test for paired and unpaired data, and by linear regression analysis, as appropriate. The level of significance was taken as P < 0.05.
Results Figure 1 illustrates the individual results of serum total and free thyroid hormone measurements in patients with hypercortisolism and in normal controls. Patients with Cushing's syndrome showed a significant reduction of mean serum TT 4 (94.3 ± 4.7 vs. 122.8 ± 6.8 nmol/L, P < 0.01), TT 3 (1.2 ± 0.05 vs. 2.7 ± 0.11 nmol/L, P < 0.001), and FT 3 (3.9 ± 0.2 vs. 6.3 ± 0.4 pmol/L, P < 0.005). Mean serum FT 4 values (10.4 ± 0.6 vs. 12.3 ± 0.8 pmol/L) did not significantly differ in the two groups. However, one patient has subnormal and two had lownormal serum FT 4 levels (Fig. 1). Mean serum rT3 values were significantly increased in patients with hypercortisolism, whereas serum TBG values did not significantly differ in patients and in controls. No differences in all these parameters were observed between patients with ACTH-dependent and those with ACTH-independent Cushing's syndrome. Figure 2 shows that mean morning serum TSH con2 0 0 -,
- 2
Assays Serum TSH was measured in duplicate using a sensitive immunoradiometric assay (Sucrosep TSH IRMA, Boots Celltech, United Kingdom) having a limit of detection of 0.07 mU/ L (28): the intraassay coefficient of variation was less than 10% at 0.07-0.2 mU/L, 4% at 0.25-200 mU/L. The TSH response to TRH was defined as blunted when the TSH peak was less than or equal to 2.9 mU/L, the value 3 SD below the peak TSH value observed in normal subjects. Serum total T4 (TT4) and T 3 (TT3) were assayed by ARIA IIRIA methods (Becton Dickinson Laboratory Systems, Milan, Italy); serum free T4 (FT4) and T 3 (FT3) were determined by the Lisophase kits (Sclavo S.p.A., Siena, Italy); serum rT3 and cortisol were measured by RIA (Radim S.p.A., Rome, Italy). Serum T4-binding globulin (TBG) was determined by a twosite immunoradiometric assay (Corning Medical Kontron S.p.A., Milan, Italy). All measurements were carried out in a single run to avoid interassay variations. Normal values in our laboratory were as follows: TT4, 51.6144.5 nmol/L; TT3,1.5-3.2 nmol/L; FT4,8.4-21.3 pmol/L; FT3, 3.9-8.5 pmol/L; rT3, 0.14-0.54 nmol/L; TSH, 0.4-4.6 mU/L; TBG, 10.2-30.6 mg/L; cortisol at 0800 h, 175-632 nmol/L; at 2400 h, 27-233 nmol/L.
24 -,
•o •o »O •
•o o
a
w
0 0 0
OO
aaa
• • •o OO
FT4
FT3
FIG. 1. Individual serum TT 4 and TT 3 (top panel) and FT4 and FT3 (bottom panel) concentrations in patients with hypercortisolism due to ACTH-dependent (•) or ACTH-independent Cushing's syndrome (0) and in normal controls (•). The dashed columns represent the normal ranges.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 January 2016. at 16:11 For personal use only. No other uses without permission. . All rights reserved.
NOCTURNAL TSH SURGE IN PATIENTS WITH HYPERCORTISOLISM
1197
out of 10 Cushing patients had nighttime values lower than morning values (up to -70%), 3 had superimposable nighttime and morning levels, and only 1 had a blunted nocturnal TSH surge (+33%). No differences were found either in the pattern of TSH secretion or in the TSH response to TRH between patients with ACTH-dependent and those with ACTH-independent Cushing's syndrome. A significant inverse relationship (r = 0.80, P < 0.001) was found between serum cortisol and TSH values both at night and in the morning in patients with hypercortisolism (data not shown).
15 -i
Discussion Night TSH
Morning TSH
Peak TSH
FIG. 2. Mean (+SE) TSH values at night, in the morning and after TRH administration in patients with Cushing's syndrome and in normal controls.
300 n
I 20 °
• • •• •••• •
100 -
o-
• ••• ••• ••
-100 Cushing Controls FIG. 3. Nocturnal serum TSH surge (relative increase of night TSH over morning TSH) in patients with Cushing's syndrome and in controls.
centrations, although slightly reduced in patients with Cushing's syndrome (0.9 ±0.1 vs. 1.3 ± 0.2 mU/L), were not statistically different from those of controls, whereas mean night serum TSH levels were significantly lower in patients with hypercortisolism (0.7 ± 0.1 vs. 3.3 ± 0.6 mU/L, P < 0.01). At variance with the control group, nighttime and morning TSH values did not differ in patients with hypercortisolism (Fig. 2). Mean peak TSH values after TRH were also significantly lower in patients with Cushing's syndrome (4.6 ± 0.7 vs. 12.5 ± 1.8 mU/ L, P < 0.01, Fig. 2): a blunted TSH response to TRH (serum TSH peak
