002l-972X/91/7202-0256$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 72, No. 2 Printed in U.S.A.
Pituitary Size in Depression* K. RANGA RAMA KRISHNAN, P. MURALI DORAISWAMY, SCOTT N. LURIE, GARY S. FIGIEL, MUSTAFA M. HUSAIN, OREST B. BOYKO, EVERETT H. ELLINWOOD, JR., AND CHARLES B. NEMEROFF Departments of Psychiatry (K.R.R.K., P.M.D., S.N.L., G.S.F., M.M.H., E.H.E., C.B.N.), Radiology (O.B.B.), and Pharmacology (E.H.E., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710
(P = 0.007) than the controls. This difference was particularly prominent in elderly depressed patients compared to elderly controls. These results provide the first demonstration of structural alterations in the pituitary gland in major depression. (J Clin Endocrinol Metab 72: 256-259,1991)
ABSTRACT. Magnetic resonance images centered at the pituitary stalk were used to measure pituitary gland size in 19 patients with major depression compared with that in ageand sex-matched controls. Depressed patients had significantly greater pituitary cross-sectional area (P = 0.0009) and volume
A
N ESTIMATED 10% of the population will have an affective disorder, primarily depression, sometime in their life. The most common biological abnormalities seen in these patients are neuroendocrine in nature and involve the pituitary gland. Hypothalamopituitary-adrenal axis hyperactivity is the most frequent of these abnormalities (1, 2) and may play a role in the pathophysiology of depression. This is characterized by sustained hypercortisolemia and nonsuppression of serum cortisol after the administration of dexamethasone (1, 2). A number of studies have suggested that there is a central overdrive by CRF of the pituitary corticotroph in patients with depression (3, 4). Von Bardeleben et at. (5) and Lisansky et al. (6) have shown that the corticotropin (ACTH) response to CRF after metyrapone administration is increased in depressed patients compared to that in controls. These studies indicate that either the corticotroph is sensitized to CRF (possibly by increased secretion of vasopressin) or that there is hypertrophy of the corticotroph. Animal studies have shown that chronic administration of CRF can lead to a marked increase in the number and volume of corticotroph cells (and, therefore, pituitary volume) (7, 8). This led us to hypothesize that patients with depression may have pituitary enlargement due to hypersecretion of trophic releasing factors. In this study we measured pituitary gland size on Received May 25,1990. Address requests for reprints to: Dr. K. Ranga Rama Krishnan, Department of Psychiatry, Duke University Medical Center, Box 3215, Durham, North Carolina 27710. * This work was supported in part by NIMH Grants MH-44716, MH-42088, MH-40159, and MH-17632.
magnetic resonance images (MRI) centered at the pituitary stalk in a group of 19 patients with depression in comparison with 19 age- and sex-matched controls.
Materials and Methods Subjects Between March and December 1989, 20 consecutive patients who satisfied Diagnostic and Statistical Manual of Mental Disorders criteria for major depression and met selection criteria, and 39 normal volunteers participated in a standardized brain MRI protocol. The selection criteria included screening for medications known to elovate hypothalamo-pituitary-adrenal axis activity in patients with affective disorders as well as significant endocrine, hepa;ic, or renal disease; medications such as reserpine, phenytoin. or carbamazepine; morbid obesity; organic brain syndrome; encephalitis; and pregnancy (1). Of these 20 patients, 1 was excluded due to a history of pituitary surgery for an adenoma, and the remaining 19 [14 females, 8 postmenopausal; mean age ± SD, 54.7 ± 19 yr; age range, 2380 yr (21-30 yr, n = 2; 31-40 yr, n = 4; 41-50 yr, n = 3; 51-60 yr, n = 4; 71-80 yr, n = 6)] were included for this study. Diagnosis of major depression was based on all available information, including clinical psychiatric interview and medical records. Eighteen subjects were scanned as in-patients at Duke University Medical Center and 1 subject, a recent in-patient at another institution, was scanned as an out-patient at Duke University Medical Center. Of the 19 patients, 16 had unipolar and 3 had bipolar depression, and 14 patients were diagnosed as having recurrent major depression. The control group consisted of normal community volunteers (aged 24-79 yr) who had been recruited to serve as controls for ongoing brain MRI and cognitive studies. They were screened by one of us (G.S.F.) by comprehensive neurological, psychiatric, and physical examination and were determined to be free of psychiatric (DSM-
256
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2015. at 12:20 For personal use only. No other uses without permission. . All rights reserved.
PITUITARY SIZE IN DEPRESSION III checklist) and significant neurological (stroke, transient ischemic attacks, seizure, tumor, dementia) disorders. None of the controls had a clinical indication for brain MRI, and they were scanned exclusively for research purposes. All controls gave prior written informed consent, and this protocol was approved by the Institutional Review Board at Duke University Medical Center. For this study, 19 of these normal subjects were matched by sex and age with the depressed patients. Matching of controls to patients was carried out in a blind manner to all pituitary measurements. Because of the logistics of volunteer recruitment, age matching was not identical, but was usually within 5 yr. When there was more than 1 control of the same age and sex, matching was performed randomly. The mean age (±SD) for the 19 matched controls was 54.3 ± 19.5 yr, and there were 14 female (8 postmenopausal and 6 premenopausal) and 5 male subjects. MRI methods All brain MRI studies were performed on a General Electric 1.5 Tesla Signa System (Milwaukee, WI). The patients' heads were positioned with their canthomeatal lines perpendicular to their Z-axes (longitudinal axis of the patient). For all patients and controls the locations of the midsagittal and parasagittal images were graphically prescribed using an axial localizer series by one of two experienced physicians (P.M.D. or G.S.F.). The sagittal images were 3- to 5-mm thick slices acquired with a TR 500/TE 20/128-256 matrix, 1-4 NEX, 18-22 FOV acquisition. Coronal images were graphically prescribed from the midsagittal slice and obtained perpendicular to the bicommisural line. The coronal images were 5 mm thick contiguous and acquired with a TR 500/TE 20,128-192 matrix 20 FOV and 12 NEX acquisition. Four controls and one patient did not complete the protocol beyond the sagittal images, and coronal images were not available in these subjects for measuring pituitary width or estimating pituitary volume. Data on pituitary area, height, and length for these five subjects were included in the analyses.
of data analysis, this subject's pituitary dimensions were assigned values equal to the smallest among the rest of the sample. All measurements were obtained independently by two experienced physicians (P.M.D. and S.N.L.), blinded to the clinical diagnosis, on an off-line console with the GE CLIPS software program. Identical methods have been previously used by the rater(s) for studies of pituitary gland size in normal aging (12) as well as in eating disorders (13). Interrater reliability (evaluated with Pearson's correlation coefficient) between the 2 raters is excellent: pituitary area, r = 0.96; height, r = 0.96; length, r = 0.83; width, r = 0.86; pituitary-optic chiasma distance, r = 0.96 (P = 0.0001 for all of the above). Statistical analyses Data were analyzed using PC-SAS (SAS Institute, Cary, NC). The two-tailed t test procedure was used to evaluate significant differences between groups, and Pearson's correlation coefficient (two tailed) was used to evaluate correlations between variables. P < 0.05 was considered significant.
Results Depressed patients had significantly larger pituitary gland area (t = -3.62; df = 36; P = 0.0009; Figs. 1 and 2), volume (t = 2.85; df = 31; P = 0.007; Fig. 3), and length (t = 2.05; df = 36; P = 0.04) compared to ageand sex-matched controls (Table 1). Pituitary height and width also tended to be larger in depressed patients. Age was strongly negatively correlated with pituitary area (r = -0.64; P = 0.002), height (r = -0.49; P = 0.03), and volume (r = —0.57; P = 0.02) in controls. Age was correlated with pituitary height (r = -0.46; P = 0.04), but not with pituitary area (r = 0.14; P = 0.56) or volume (r = -0.30; P = 0.22) in depressed patients. Consistent with these correlations, elderly (>50 yr; n = 11) depressed patients had significantly larger pituitary gland areas
Pituitary measurements A board-certified neuroradiologist (O.B.B.) evaluated all of the scans and determined the manner in which measurements were made. None of the subjects had MRI evidence of pituitary adenoma or cyst. Two controls (and none of the 19 patients) had scans suggestive of a partially empty sella. The midsagittal T l image centered at the pituitary stalk was used to measure the central height, maximum length, and cross-sectional area of the pituitary gland (9, 10). The coronal T l image through the pituitary stalk was used to measure the maximum gland width. Pituitary gland volume was estimated using the formula area X width in the 15 controls and 18 depressed patients for whom width measurements were available. Although the pituitary volume estimated by this formula may slightly overestimate the actual volume, this method may be adequate for purposes of group comparisons. Subjects with a partially empty sella were not excluded from the analyses, since this condition has been reported to be a very common incidental finding in normal subjects (11). One control with a partially empty sella had a pituitary that was too small to measure. For the purpose
257
Pituitary Gland Areas i \J
(p=0.0009) A A
60
A A
50
•
CVJ
E 40 30
• • • •• _ •_
A
Xk
AA A *
•A A
20
•:
m 10 Controls (n = 19)
Depressed (n = 19)
FIG. 1. Pituitary gland area in depressed patients and matched controls.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2015. at 12:20 For personal use only. No other uses without permission. . All rights reserved.
KRISHNAN ET AL.
258
TABLE 1. Pituitary gland measurements in depressed patients and matched controls
Age vs. Pituitary Gland Area* 70 A
-§5OH A
A ...
A
r=0.14 (p=0.6)
A A
A
A
2 30 r=-0.64 (p=0.002)
20 - - •» depressed (n=19) — • control (n=19)
10 20
30
40
50
Depressed
A
60 -
to a> < 40 -
JCE&M-1991 Vol 72 • No 2
70
60
80
Demographic data Sample size (n) Age (mean ± SD) Male/female ratio Postmenopausal/premenopausal ratio Pituitary data (mean ± SD) Area (mm2) Vol (mm3) Length (mm) Ht (mm) Width (mm)
Controls
19 54.74 ± 19 5/14 6/8
19 54.26 ± 19 5/14 6/8
43 ± 10577.5 ± 1676 10.8 ± 1.2" 5.4 ± 1.1 13.1 ± 2.7
32 ± 9 408.4 ± 172 9.9 ± 1.5 4.9 ± 1.5 12.0 ± 3.0
' P = 0.0009, by two-tailed t test. 6 P = 0.007, by two-tailed t test. c
P = 0.04, by two-tailed t test.
Age (years) *cross-sectional midsagittal area
FIG. 2. Pituitary area vs. age in depressed patients and matched controls. 1000
Pituitary Gland volumes* (p-0.007)
A
eoo
A
800 700
JT600 E £500
r
I ••
400
^§-
300
i •
200 mn
Controls (n * 15)
A
_A4. A
Depressed (n -18)
' Estimated from area & width FIG. 3. Pituitary gland volumes in depressed patients and controls.
(t = -5.15; P = 0.0001), volume (t = -3.2; P = 0.005), and length {t = -3.1; df = 19; P = 0.005) than elderly (>50 yr) controls. Mean (±SD) pituitary volumes and areas were 538 ± 144 mm3 and 45 ± 9 mm2 for elderly depressed patients and 330 ±114 mm3 and 26 ± 6 mm2 for elderly controls, respectively. We reanalyzed the data after excluding the control subject whose pituitary was too small to measure. The results were essentially unchanged, and differences between patients and controls remained highly significant for pituitary area (t = -3.4; P < 0.0018) and pituitary volume {t = -2.6; P < 0.016).
Discussion The finding that depressed patients had larger pituitaries than controls may indicate not only functional but also structural alterations in the neuroendocrine axis in
depression. These findings probably reflect differences in anterior rather than the posterior pituitary size for the following reasons: 1) the posterior pituitary comprises less than 20% of the total pituitary volume and has to increase several times in size to account for the increase seen in the depressed patients; and 2) the posterior pituitary is of neural origin, and there are no known conditions (other than nonendocrine tumors) associated with posterior pituitary enlargement. There are some limitations in interpreting the findings of this study. We studied- a heterogenous group of depressed patients, which included both first episode and recurrent depressions and three patients with bipolar disorder. Future studies of a larger number of subjects will allow for these and other clinical variables to be controlled, although the expense of the MRI is a limitation. This study also does not address the causal nature of the link between depression and pituitary size; all of the patients had major depression at the time they were studied, and none had a baseline MRI for comparison. Therefore, we cannot say whether the pituitary glands of the patients enlarged as a result of their depression or were larger than controls before the onset of illness. Further controlled studies as well as follow-up MRI scans are needed to determine; whether pituitary size is increased in conditions other than depression, if pituitary size increases with depression and if it changes after treatment or with recurrence, and whether pituitary size reflects the neuroendocrine mileau in depression.
Acknowledgments The authors wish to thank Mr. Robert A. Burn and the MRI Staff for expert technical assistance.
References 1. Carroll BJ, Feinberg M, Greden JF et al. A specific laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry. 1981;38:
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2015. at 12:20 For personal use only. No other uses without permission. . All rights reserved.
PITUITARY SIZE IN DEPRESSION 15-22. 2. Krishnan KRR, Nemeroff CB, Carroll BJ. Hypercortisolemia and mental illness. In: Rose CF, ed. The control of the hypothalamopituitary-adrenocortical axis. Madison: International Universities Press; 1989;29:419-35. 3. Nemeroff CB, Widerlov E, Bissette G, et al. Elevated concentrations of CSF corticotropin releasing factor-like immunoreactivity in depressed patients. Science. 1984;226:1342-4. 4. Gold PW, Chrousos G, Kellner C, et al. Psychiatric implication of basic and clinical studies with corticotropin releasing factor. Am J Psychiatry. 1984;141:619-27. 5. Van Bardeleben U, Stalla GK, Muller OA, Holsboer F. Blunting of ACTH response to human CRF in depressed patients is avoided by metyrapone treatment. Biol Psychiatry. 1988;24:782-5. 6. Lisansky J, Peake GT, Strassman J, et al. Augmented pituitary corticotropin response to threshold dosage of human CRF in depressives pretreated with metyrapone. Arch Gen Psychiatry. 1989;46:641-3. 7. Westlund KN, Aguilera G, Childs GV. Quantification of morphological changes in pituitary corticotropes produced by in vivo corticotropin-releasing factor stimulation and adrenalectomy. En-
259
docrinology. 1985;116:439-45. 8. Gertz BJ, Contreras LN, McComb DJ, Kovacs K, Tyrrall JB, Dallman MF. Chronic administration of CRF increases pituitary corticotroph numbers. Endocrinology. 1987;120:381-8. 9. Hayakawa K, Konishi Y, Matsuda T, et al. Development and aging of brain midline structures: assessment with brain MR imaging. Radiology. 1989;172:171-7. 10. Lemort M, Haesendonck P, Louryan S, Rodesch C, Baleriaux D. MRI of the sellar region and suprasellar cisterns: normal morphology on sagittal sections. In: Gouaze A, Salamon G, eds. Brain anatomy and magnetic resonance imaging. New York: SpringerVerlag, 1988;158-63. 11. Chakeres DW, Curtin A, Ford G. Magnetic resonance imaging of the pituitary and parasellar abnormalities. Radiol Clin North Am. 1989;27:265-81. 12. Doraiswamy PM, Krishnan KRR, Figiel GS, et al. A brain magnetic resonance imaging study of pituitary gland morphology in anorexia nervosa and bulimia. Biol Psychiatry. 1990;28:110-5. 13. Lurie SN, Doraiswamy PM, Figiel GS, et al. In vivo assessment of pituitary gland volume with MRI: effect of age. J Clin Endocrinol Metab. 1990;71:505-8.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2015. at 12:20 For personal use only. No other uses without permission. . All rights reserved.
Vol. 72, No. 2 Printed in U.S.A.
Pituitary Size in Depression* K. RANGA RAMA KRISHNAN, P. MURALI DORAISWAMY, SCOTT N. LURIE, GARY S. FIGIEL, MUSTAFA M. HUSAIN, OREST B. BOYKO, EVERETT H. ELLINWOOD, JR., AND CHARLES B. NEMEROFF Departments of Psychiatry (K.R.R.K., P.M.D., S.N.L., G.S.F., M.M.H., E.H.E., C.B.N.), Radiology (O.B.B.), and Pharmacology (E.H.E., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710
(P = 0.007) than the controls. This difference was particularly prominent in elderly depressed patients compared to elderly controls. These results provide the first demonstration of structural alterations in the pituitary gland in major depression. (J Clin Endocrinol Metab 72: 256-259,1991)
ABSTRACT. Magnetic resonance images centered at the pituitary stalk were used to measure pituitary gland size in 19 patients with major depression compared with that in ageand sex-matched controls. Depressed patients had significantly greater pituitary cross-sectional area (P = 0.0009) and volume
A
N ESTIMATED 10% of the population will have an affective disorder, primarily depression, sometime in their life. The most common biological abnormalities seen in these patients are neuroendocrine in nature and involve the pituitary gland. Hypothalamopituitary-adrenal axis hyperactivity is the most frequent of these abnormalities (1, 2) and may play a role in the pathophysiology of depression. This is characterized by sustained hypercortisolemia and nonsuppression of serum cortisol after the administration of dexamethasone (1, 2). A number of studies have suggested that there is a central overdrive by CRF of the pituitary corticotroph in patients with depression (3, 4). Von Bardeleben et at. (5) and Lisansky et al. (6) have shown that the corticotropin (ACTH) response to CRF after metyrapone administration is increased in depressed patients compared to that in controls. These studies indicate that either the corticotroph is sensitized to CRF (possibly by increased secretion of vasopressin) or that there is hypertrophy of the corticotroph. Animal studies have shown that chronic administration of CRF can lead to a marked increase in the number and volume of corticotroph cells (and, therefore, pituitary volume) (7, 8). This led us to hypothesize that patients with depression may have pituitary enlargement due to hypersecretion of trophic releasing factors. In this study we measured pituitary gland size on Received May 25,1990. Address requests for reprints to: Dr. K. Ranga Rama Krishnan, Department of Psychiatry, Duke University Medical Center, Box 3215, Durham, North Carolina 27710. * This work was supported in part by NIMH Grants MH-44716, MH-42088, MH-40159, and MH-17632.
magnetic resonance images (MRI) centered at the pituitary stalk in a group of 19 patients with depression in comparison with 19 age- and sex-matched controls.
Materials and Methods Subjects Between March and December 1989, 20 consecutive patients who satisfied Diagnostic and Statistical Manual of Mental Disorders criteria for major depression and met selection criteria, and 39 normal volunteers participated in a standardized brain MRI protocol. The selection criteria included screening for medications known to elovate hypothalamo-pituitary-adrenal axis activity in patients with affective disorders as well as significant endocrine, hepa;ic, or renal disease; medications such as reserpine, phenytoin. or carbamazepine; morbid obesity; organic brain syndrome; encephalitis; and pregnancy (1). Of these 20 patients, 1 was excluded due to a history of pituitary surgery for an adenoma, and the remaining 19 [14 females, 8 postmenopausal; mean age ± SD, 54.7 ± 19 yr; age range, 2380 yr (21-30 yr, n = 2; 31-40 yr, n = 4; 41-50 yr, n = 3; 51-60 yr, n = 4; 71-80 yr, n = 6)] were included for this study. Diagnosis of major depression was based on all available information, including clinical psychiatric interview and medical records. Eighteen subjects were scanned as in-patients at Duke University Medical Center and 1 subject, a recent in-patient at another institution, was scanned as an out-patient at Duke University Medical Center. Of the 19 patients, 16 had unipolar and 3 had bipolar depression, and 14 patients were diagnosed as having recurrent major depression. The control group consisted of normal community volunteers (aged 24-79 yr) who had been recruited to serve as controls for ongoing brain MRI and cognitive studies. They were screened by one of us (G.S.F.) by comprehensive neurological, psychiatric, and physical examination and were determined to be free of psychiatric (DSM-
256
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2015. at 12:20 For personal use only. No other uses without permission. . All rights reserved.
PITUITARY SIZE IN DEPRESSION III checklist) and significant neurological (stroke, transient ischemic attacks, seizure, tumor, dementia) disorders. None of the controls had a clinical indication for brain MRI, and they were scanned exclusively for research purposes. All controls gave prior written informed consent, and this protocol was approved by the Institutional Review Board at Duke University Medical Center. For this study, 19 of these normal subjects were matched by sex and age with the depressed patients. Matching of controls to patients was carried out in a blind manner to all pituitary measurements. Because of the logistics of volunteer recruitment, age matching was not identical, but was usually within 5 yr. When there was more than 1 control of the same age and sex, matching was performed randomly. The mean age (±SD) for the 19 matched controls was 54.3 ± 19.5 yr, and there were 14 female (8 postmenopausal and 6 premenopausal) and 5 male subjects. MRI methods All brain MRI studies were performed on a General Electric 1.5 Tesla Signa System (Milwaukee, WI). The patients' heads were positioned with their canthomeatal lines perpendicular to their Z-axes (longitudinal axis of the patient). For all patients and controls the locations of the midsagittal and parasagittal images were graphically prescribed using an axial localizer series by one of two experienced physicians (P.M.D. or G.S.F.). The sagittal images were 3- to 5-mm thick slices acquired with a TR 500/TE 20/128-256 matrix, 1-4 NEX, 18-22 FOV acquisition. Coronal images were graphically prescribed from the midsagittal slice and obtained perpendicular to the bicommisural line. The coronal images were 5 mm thick contiguous and acquired with a TR 500/TE 20,128-192 matrix 20 FOV and 12 NEX acquisition. Four controls and one patient did not complete the protocol beyond the sagittal images, and coronal images were not available in these subjects for measuring pituitary width or estimating pituitary volume. Data on pituitary area, height, and length for these five subjects were included in the analyses.
of data analysis, this subject's pituitary dimensions were assigned values equal to the smallest among the rest of the sample. All measurements were obtained independently by two experienced physicians (P.M.D. and S.N.L.), blinded to the clinical diagnosis, on an off-line console with the GE CLIPS software program. Identical methods have been previously used by the rater(s) for studies of pituitary gland size in normal aging (12) as well as in eating disorders (13). Interrater reliability (evaluated with Pearson's correlation coefficient) between the 2 raters is excellent: pituitary area, r = 0.96; height, r = 0.96; length, r = 0.83; width, r = 0.86; pituitary-optic chiasma distance, r = 0.96 (P = 0.0001 for all of the above). Statistical analyses Data were analyzed using PC-SAS (SAS Institute, Cary, NC). The two-tailed t test procedure was used to evaluate significant differences between groups, and Pearson's correlation coefficient (two tailed) was used to evaluate correlations between variables. P < 0.05 was considered significant.
Results Depressed patients had significantly larger pituitary gland area (t = -3.62; df = 36; P = 0.0009; Figs. 1 and 2), volume (t = 2.85; df = 31; P = 0.007; Fig. 3), and length (t = 2.05; df = 36; P = 0.04) compared to ageand sex-matched controls (Table 1). Pituitary height and width also tended to be larger in depressed patients. Age was strongly negatively correlated with pituitary area (r = -0.64; P = 0.002), height (r = -0.49; P = 0.03), and volume (r = —0.57; P = 0.02) in controls. Age was correlated with pituitary height (r = -0.46; P = 0.04), but not with pituitary area (r = 0.14; P = 0.56) or volume (r = -0.30; P = 0.22) in depressed patients. Consistent with these correlations, elderly (>50 yr; n = 11) depressed patients had significantly larger pituitary gland areas
Pituitary measurements A board-certified neuroradiologist (O.B.B.) evaluated all of the scans and determined the manner in which measurements were made. None of the subjects had MRI evidence of pituitary adenoma or cyst. Two controls (and none of the 19 patients) had scans suggestive of a partially empty sella. The midsagittal T l image centered at the pituitary stalk was used to measure the central height, maximum length, and cross-sectional area of the pituitary gland (9, 10). The coronal T l image through the pituitary stalk was used to measure the maximum gland width. Pituitary gland volume was estimated using the formula area X width in the 15 controls and 18 depressed patients for whom width measurements were available. Although the pituitary volume estimated by this formula may slightly overestimate the actual volume, this method may be adequate for purposes of group comparisons. Subjects with a partially empty sella were not excluded from the analyses, since this condition has been reported to be a very common incidental finding in normal subjects (11). One control with a partially empty sella had a pituitary that was too small to measure. For the purpose
257
Pituitary Gland Areas i \J
(p=0.0009) A A
60
A A
50
•
CVJ
E 40 30
• • • •• _ •_
A
Xk
AA A *
•A A
20
•:
m 10 Controls (n = 19)
Depressed (n = 19)
FIG. 1. Pituitary gland area in depressed patients and matched controls.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2015. at 12:20 For personal use only. No other uses without permission. . All rights reserved.
KRISHNAN ET AL.
258
TABLE 1. Pituitary gland measurements in depressed patients and matched controls
Age vs. Pituitary Gland Area* 70 A
-§5OH A
A ...
A
r=0.14 (p=0.6)
A A
A
A
2 30 r=-0.64 (p=0.002)
20 - - •» depressed (n=19) — • control (n=19)
10 20
30
40
50
Depressed
A
60 -
to a> < 40 -
JCE&M-1991 Vol 72 • No 2
70
60
80
Demographic data Sample size (n) Age (mean ± SD) Male/female ratio Postmenopausal/premenopausal ratio Pituitary data (mean ± SD) Area (mm2) Vol (mm3) Length (mm) Ht (mm) Width (mm)
Controls
19 54.74 ± 19 5/14 6/8
19 54.26 ± 19 5/14 6/8
43 ± 10577.5 ± 1676 10.8 ± 1.2" 5.4 ± 1.1 13.1 ± 2.7
32 ± 9 408.4 ± 172 9.9 ± 1.5 4.9 ± 1.5 12.0 ± 3.0
' P = 0.0009, by two-tailed t test. 6 P = 0.007, by two-tailed t test. c
P = 0.04, by two-tailed t test.
Age (years) *cross-sectional midsagittal area
FIG. 2. Pituitary area vs. age in depressed patients and matched controls. 1000
Pituitary Gland volumes* (p-0.007)
A
eoo
A
800 700
JT600 E £500
r
I ••
400
^§-
300
i •
200 mn
Controls (n * 15)
A
_A4. A
Depressed (n -18)
' Estimated from area & width FIG. 3. Pituitary gland volumes in depressed patients and controls.
(t = -5.15; P = 0.0001), volume (t = -3.2; P = 0.005), and length {t = -3.1; df = 19; P = 0.005) than elderly (>50 yr) controls. Mean (±SD) pituitary volumes and areas were 538 ± 144 mm3 and 45 ± 9 mm2 for elderly depressed patients and 330 ±114 mm3 and 26 ± 6 mm2 for elderly controls, respectively. We reanalyzed the data after excluding the control subject whose pituitary was too small to measure. The results were essentially unchanged, and differences between patients and controls remained highly significant for pituitary area (t = -3.4; P < 0.0018) and pituitary volume {t = -2.6; P < 0.016).
Discussion The finding that depressed patients had larger pituitaries than controls may indicate not only functional but also structural alterations in the neuroendocrine axis in
depression. These findings probably reflect differences in anterior rather than the posterior pituitary size for the following reasons: 1) the posterior pituitary comprises less than 20% of the total pituitary volume and has to increase several times in size to account for the increase seen in the depressed patients; and 2) the posterior pituitary is of neural origin, and there are no known conditions (other than nonendocrine tumors) associated with posterior pituitary enlargement. There are some limitations in interpreting the findings of this study. We studied- a heterogenous group of depressed patients, which included both first episode and recurrent depressions and three patients with bipolar disorder. Future studies of a larger number of subjects will allow for these and other clinical variables to be controlled, although the expense of the MRI is a limitation. This study also does not address the causal nature of the link between depression and pituitary size; all of the patients had major depression at the time they were studied, and none had a baseline MRI for comparison. Therefore, we cannot say whether the pituitary glands of the patients enlarged as a result of their depression or were larger than controls before the onset of illness. Further controlled studies as well as follow-up MRI scans are needed to determine; whether pituitary size is increased in conditions other than depression, if pituitary size increases with depression and if it changes after treatment or with recurrence, and whether pituitary size reflects the neuroendocrine mileau in depression.
Acknowledgments The authors wish to thank Mr. Robert A. Burn and the MRI Staff for expert technical assistance.
References 1. Carroll BJ, Feinberg M, Greden JF et al. A specific laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry. 1981;38:
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2015. at 12:20 For personal use only. No other uses without permission. . All rights reserved.
PITUITARY SIZE IN DEPRESSION 15-22. 2. Krishnan KRR, Nemeroff CB, Carroll BJ. Hypercortisolemia and mental illness. In: Rose CF, ed. The control of the hypothalamopituitary-adrenocortical axis. Madison: International Universities Press; 1989;29:419-35. 3. Nemeroff CB, Widerlov E, Bissette G, et al. Elevated concentrations of CSF corticotropin releasing factor-like immunoreactivity in depressed patients. Science. 1984;226:1342-4. 4. Gold PW, Chrousos G, Kellner C, et al. Psychiatric implication of basic and clinical studies with corticotropin releasing factor. Am J Psychiatry. 1984;141:619-27. 5. Van Bardeleben U, Stalla GK, Muller OA, Holsboer F. Blunting of ACTH response to human CRF in depressed patients is avoided by metyrapone treatment. Biol Psychiatry. 1988;24:782-5. 6. Lisansky J, Peake GT, Strassman J, et al. Augmented pituitary corticotropin response to threshold dosage of human CRF in depressives pretreated with metyrapone. Arch Gen Psychiatry. 1989;46:641-3. 7. Westlund KN, Aguilera G, Childs GV. Quantification of morphological changes in pituitary corticotropes produced by in vivo corticotropin-releasing factor stimulation and adrenalectomy. En-
259
docrinology. 1985;116:439-45. 8. Gertz BJ, Contreras LN, McComb DJ, Kovacs K, Tyrrall JB, Dallman MF. Chronic administration of CRF increases pituitary corticotroph numbers. Endocrinology. 1987;120:381-8. 9. Hayakawa K, Konishi Y, Matsuda T, et al. Development and aging of brain midline structures: assessment with brain MR imaging. Radiology. 1989;172:171-7. 10. Lemort M, Haesendonck P, Louryan S, Rodesch C, Baleriaux D. MRI of the sellar region and suprasellar cisterns: normal morphology on sagittal sections. In: Gouaze A, Salamon G, eds. Brain anatomy and magnetic resonance imaging. New York: SpringerVerlag, 1988;158-63. 11. Chakeres DW, Curtin A, Ford G. Magnetic resonance imaging of the pituitary and parasellar abnormalities. Radiol Clin North Am. 1989;27:265-81. 12. Doraiswamy PM, Krishnan KRR, Figiel GS, et al. A brain magnetic resonance imaging study of pituitary gland morphology in anorexia nervosa and bulimia. Biol Psychiatry. 1990;28:110-5. 13. Lurie SN, Doraiswamy PM, Figiel GS, et al. In vivo assessment of pituitary gland volume with MRI: effect of age. J Clin Endocrinol Metab. 1990;71:505-8.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 04 June 2015. at 12:20 For personal use only. No other uses without permission. . All rights reserved.
