Insulin-like growth factor 1 and growth hormone binding protein in depression: a preliminary communication

\ PERGAMON

Journal of Psychiatric Research 22 "0888# 010Ð016

Insulin!like growth factor 0 and growth hormone binding protein in depression] a preliminary communication Bettina Franza\ Daniel J[ Buysseb\ Christine R[ Cherryb\ Nicola S[ Grayb\ Victoria J[ Grochocinskib\ Ellen Frankb\ David J[ Kupferb\ b

a Department of Psychiatry and Behavioral Sciences\ Stanford University\ 390 Quarry Road\ Stanford\ CA\ USA Department of Psychiatry\ University of Pittsburgh Medical Center\ Western Psychiatric Institute and Clinic\ 2700 O|Hara Street\ Pittsburgh\ PA 04102\ USA

Received 16 May 0887^ received in revised form 1 September 0887^ accepted 02 November 0887

Abstract This study was undertaken in order to advance our understanding of the distal growth hormone axis in depression[ Insulin!like growth factor 0 "IGF!0# and growth hormone binding protein "GHBP# were measured in a group of 08 depressed women and a group of 05 healthy women[ Using a generalized linear model\ IGF!0 levels were negatively correlated with age "p9[9990#\ in~uenced by menstrual phase "p9[905#\ and signi_cantly increased in the depressed group "p9[91#[ Using the same type of analysis\ GHBP was signi_cantly related to menstrual phase "p9[9990# and body mass index "p9[9990#\ but was not signi_cantly di}erent in patients and controls[ IGF!0 and GHBP were positively correlated among healthy subjects "r9[35\ p9[97#\ but not among depressed patients "r−9[05\ p9[40#\ although these correlation coe.cients were not statistically signi_cantly di}erent from each other[ These _ndings con_rm the importance of several physiological factors in the regulation of IGF!0 and GHBP\ and suggest that depression further in~uences this regulation[ Þ 0888 Elsevier Science Ltd[ All rights reserved[ Key words] Growth hormone^ Insulin!like growth factor 0 "IGF!0#^ Growth hormone binding^ Protein "GHBP#^ Depression

0[ Introduction Major depressive disorder "MDD# is characterized by a number of neuroendocrine alterations[ With few excep! tions "Contreras et al[\ 0885#\ MDD is associated with reduced spontaneous sleep!related growth hormone "GH# secretion in adults "Mendlewicz et al[\ 0874^ Steiger et al[\ 0878^ Jarrett et al[\ 0889^ Rubin et al[\ 0889^ Voderholzer et al[\ 0882^ Sakkas et al[\ 0887#[ Some stud! ies have also reported a relative hypersecretion of GH during wakefulness in MDD "Mendlewicz et al[\ 0874^ Jarrett et al[\ 0883#[ Total 13!h secretion of GH has been reported to be either increased "Mendlewicz et al[\ 0874# or decreased "Voderholzer et al[\ 0882^ Fiasche et al[\ 0884#[ Depressed patients also have blunted GH responses to GHRH "Contreras et al[\ 0885# and clon! idine "Siever et al[\ 0881#[ Reduced GH secretion and blunted GH responsiveness to clonidine both persist into recovery from depression\ and these patterns may be

 Corresponding author[ Tel[] ¦0!301!513!1242^ fax] ¦0!301!513! 7904^ e!mail] kupferdjÝmsx[upmc[edu[

associated with clinical course[ Jarrett et al[ "0883# found that the reduction in spontaneous sleep!related GH secretion persists in patients who maintained recovery from depression for three years[ Recently we showed that patients who sustained a remission from depression had relatively higher presleep GH secretion than patients who relapsed "Franz et al[\ 0884#[ Although GH secretion patterns have been thoroughly investigated in MDD\ much less attention has been paid to the GH axis distal to secretion[ Such studies can help to clarify the physiological impact of abnormal GH secretion\ and may also shed light on the functioning of feedback control mechanisms in the GH axis[ GH exerts its biological actions by binding to a growth hormone receptor "GHR#\ which comprises an extra! cellular domain\ a single membrane!spanning region and an intracellular domain[ The biological activity of GH is determined both by its serum concentration and the availability of its cellular receptor[ Thus\ in order to understand the biological signi_cance of reduced GH secretion\ it is necessary to measure GHR as well as GH levels[ Unfortunately\ measurement of GHR is not feasible in human studies[ However\ GHR expression

9911!2845:, ! see front matter Þ 0888 Elsevier Science Ltd[ All rights reserved[ PII] S 9 9 1 1 ! 2 8 4 5 " 8 7 # 9 9 9 5 5 ! 0

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can be estimated by measuring serum concentrations of growth hormone binding protein "GHBP# "Daughaday et al[\ 0876#[ GHBP is a high a.nity\ low capacity binding protein in human serum "Baumann et al[\ 0875\ 0877^ Herrington et al[\ 0875#[ It appears to be identical to the extracellular domain of the GHR and is thought to arise through proteolytic cleavage of the cellular receptor upon GH binding "Barnard et al[\ 0878#[ Although GHR and GHBP expression are sensitive to GH levels in animals and man "Gluckman et al[\ 0889^ Hochberg et al[\ 0880#\ GHBP levels remain fairly constant throughout a 13! h period and do not display the diurnal variation in concentration that is exhibited by GH "Snow et al[\ 0889#[ According to the {somatomedin C hypothesis| "Salmon and Daughaday\ 0846^ Rechler et al[\ 0876#\ somato! medin C\ also called insulin!like growth factor 0 "IGF!0# is secreted by the liver in response to GH binding with its membrane!bound receptor on the surface of hepatocytes[ GH de_ciency leads to lower IGF!0 concentrations\ while GH excess leads to elevated IGF!0 "Furlanetto\ 0889#[ IGF!0\ in turn\ serves as part of a negative feedback loop regulating GH release from the pituitary "Berelowitz et al[\ 0870#[ Indeed\ the magnitude of the GH response to GHRH is directly related to the amount of spontaneous GH secretion and negatively correlated with circulating levels of IGF!0 "Van Cauter et al[\ 0881#[ Because IGF! 0 has a half!life of 19 h or more\ IGF!0 concentrations remain fairly stable throughout the day\ although there is a modest 29) decrease in serum IGF!0 concentration that coincides with the peak of GH secretion after sleep onset "MacGillivray\ 0870#[ Thus a single serum sample drawn during the daytime can be used to determine IGF! 0 levels[ This\ in turn\ has been used as a convenient measure of the biological activity of GH "Clemmons and Van Wyk\ 0873#[ Previous studies have shown IGF!0 to be elevated in depressed patients "Lesch et al[\ 0877a\ 0877b^ Rupprecht et al[\ 0878^ Deuschle et al[\ 0886#[ The present study was undertaken in order to examine the distal growth hormone axis in depression[ Serum GHBP and IGF!0 concentrations were compared in rep! resentative subsets of control subjects and patients with unipolar depression who were enrolled in ongoing studies at the University of Pittsburgh[

1[ Methods 1[0[ Patients The 08 depressed patients included in this study were recruited from two protocols conducted at the University of Pittsburgh] "0# Maintenance Psychotherapy in Recur! rent Depression "06 subjects# and "1# SleepÐMood Relationships and Partial Sleep Deprivation "two subjects#[ Maintenance Psychotherapy in Unipolar Depression is a protocol designed to test the e}ectiveness

of psychotherapy as a maintenance treatment for recur! rent depression[ This study includes only women because of the particular importance of nondrug treatments during the child!bearing years[ The advantage of recruit! ing patients from this study is that it eliminated anti! depressant medications as a confounding variable[ Consequently\ only women were recruited as controls[ Both protocols required subjects to meet criteria for major depressive syndrome as de_ned in the Research Diagnostic Criteria "RDC# "Spitzer et al[\ 0867#[ None of the subjects from either protocol were on any psy! chotropic medications at the time of study[ Patients were evaluated with the Schedule for A}ective Disorders and Schizophrenia "SADS# "Endicott and Spitzer\ 0867# or the Structured Clinical Interview for DSM!III!R "SCID# "Spitzer et al[\ 0877#[ Eighteen of the 08 patients had recurrent depression[ A minimum score of 04 on the Hamilton Rating Scale for Depression "HRSD# "Hamilton\ 0859# and a minimum score of 6 on the Ras! kin Severity of Depression Scale "Raskin et al[\ 0858# were also required[ Clinical characteristics of the patients are shown in Table 0[ Patients were excluded from the study if they met for! mal criteria for any other axis I diagnoses except panic disorder or generalized anxiety disorder\ or if they met criteria for substance abuse or antisocial or borderline personality disorder[ However\ patients with some bor! derline or antisocial traits were included[ Patients were excluded if the index episode could be attributed to medi! cally prescribed drugs or medical illness[ The patient group included 08 women with mean age of 23[6 "S[D[ 7[7#[ 1[1[ Healthy subjects This study also included 05 healthy women between the ages of 19 and 59 years recruited from the Pittsburgh Study of Normal Sleep "mean age 25[0\ S[D[ 5[5#[ Scre! ening for psychopathological conditions\ alcohol abuse\ drug abuse or the use of psychotropic medication was accomplished using the SADS[ Subjects who successfully completed this screening process then underwent a com!

Table 0 Demographic and clinical characteristics of depressed subjects "N08# mean2S[D[ "median# Age Age at onset of _rst episode "years# Duration of index episode "weeks# Number of prior episodes Endogenous subtype Hamilton Rating Scale for Depression 06!item score Raskin Depression Rating score Global Assessment Scale score

23[627[7 "23# 10[826[5 "10# 13[5206[1 "19# 3[022[9 "3# 6 de_nite\ 3 probable\ 7 no 07[722[8 "06# 7[620[2 "7# 43[625[9 "44#

B[ Franz et al[ : Journal of Psychiatric Research 22 "0888# 010Ð016

prehensive physical examination and appropriate lab! oratory studies to exclude possible concurrent medical illness[ Subjects with a family history of a}ective illness or alcoholism in _rst!degree relatives were excluded by direct interviews with _rst!degree relatives[ 1[2[ Additional criteria All subjects were excluded if they had signi_cant medi! cal illness\ including cardiovascular disease\ renal or liver disorders\ epilepsy\ uncontrolled hypertension and uncontrolled endocrine disease\ such as thyroid dys! function and diabetes[ Patients with hypertension con! trolled by medications not known to have psychotropic e}ects were not excluded[ Subjects were also excluded if they were pregnant or had a history of growth disorders "e[g[ dwar_sm or acromegaly#[ Also\ menopausal women with estrogen replacement therapy were excluded[ Each of these conditions can a}ect IGF!0 and GHBP levels "Dawson!Hughes et al[\ 0875^ Weissberger et al[\ 0880#[ Two of the depressed subjects and none of the control subjects were on antihypertensive medications[ No sub! jects were on thyroid medication or were being treated for diabetes 1[3[ Study desi`n After obtaining written informed consent\ one 04!ml tube of blood was drawn in the morning[ Depressed subjects were studied within four weeks of presentation in the index episode of depression[ HRSD and Raskin scores were determined at the time of presentation and at weekly intervals[ All depressed patients had a mini! mum of 04 on HRSD and 6 on Raskin at the time of blood draw[ Control subjects were studied at the time they participated in the sleep study as part of the Pitts! burgh Study of Normal Sleep protocol[ The blood was centrifuged at 1999×g for 09 min at 3>C\ and the serum was separated and stored at −69>C until the samples were sent to the Nichols Institute laboratory in Irvine\ CA[ One sample was sent for each subject[ For the IGF! 0 assays\ Nichols Institute reports a lower limit of detec! tion of 9[09 ng:ml with an interassay limiting coe.cient of variation "CV# of 04) and intra assay CV of 2[2Ð 7[2)[ For the GHBP assays\ they report a lower limit of detection of 05 pmol:L with an interassay CV of 19) and intra assay CV of 5[2Ð7[8)[ Samples from depressed and control subjects were analyzed in the same run[ To standardize results as much as possible\ we requested that the subjects fast overnight prior to the blood draw[ Several physiological factors which can in~uence IGF! 0 and GHBP were also assessed[ Menstrual phase was assessed by information given by subjects and veri_ed by measurement of plasma estradiol and progesterone concentrations[ Speci_cally\ history and hormone levels were used to categorize subjects into follicular\ midcycle

012

or luteal phases[ Subjects were designated as being in the follicular phase if progesterone concentrations were below 79 pg:ml\ with estrogen concentrations 19Ð049 pg:ml\ luteal phase if progesterone concentrations were above 299 pg:ml\ with estrogen concentrations 29Ð349 pg:ml and mid!cycle for progesterone values 79Ð299 pg:ml\ with estrogen concentrations 049Ð649 pg:ml\ as recommended by Nichols Institute[ Estradiol and pro! gesterone measurements were carried out by Nichols Institute using the same serum samples described above[ For estradiol\ they report a lower limit of detection of less than 1 pg:ml with an interassay CV of 02[8)[ For progesterone\ the lower limit of detection is 09 ng:dL with an interassay CV of 06[3)[ Information given by the patient was used to con_rm assignment and was con! sistent with the assignment in all cases where it was avail! able[ Four depressed and three healthy subjects could not recall the date of their LMP[ Oral contraceptive users were considered in a separate category\ regardless of the timing of their cycle[ The two subjects who said they were in menopause both had progesterone levels less than 04 pg:ml and estrogen levels less than 09 pg:ml\ and were also considered a separate category[ Obesity also a}ects IGF!0 and GHBP secretion "Jo rgensen et al[\ 0884#[ Subjects were measured and weighed at the time of blood draw\ and body mass index "BMI^ kg:m1# was calculated[ Subjects were also ques! tioned about the time\ type and duration of most recent exercise\ another factor that acutely a}ects GH secretion "Roth et al[\ 0852#[ Subjects were dichotomized according to whether or not they had exercised within the 13 h before the blood draw[ The number of calories per week expended on exercise was calculated for each subject as described previously "Pa}enbarger et al[\ 0882^ Ain! sworth et al[\ 0882#[ We also compared subgroups of subjects that exercised regularly to those that did not[ 1[4[ Data analysis and statistics Data analysis proceeded in three steps[ First\ di}er! ences between patient and control samples were assessed for clinical measures "e[g[ age\ BMI\ exercise#[ Where appropriate\ two!sample t!tests were performed[ For variables with skewed variance\ log! or square root!trans! formations were used[ If variances could not be nor! malized with transformation\ the nonparametric MannÐ Whitney U test was used[ Categorical variables were ana! lyzed with Fisher|s exact test[ Patient and control data are shown in Table 1[ Second\ the in~uence of clinical measures on IGF!0 and GHBP was assessed using Pearson productÐmoment correlations for continuous measures "e[g[ body mass index# and t!tests between groups for dichotomous mea! sures "e[g[ regular exercise vs[ no regular exercise#[ These analyses were conducted on the entire sample of patients and controls[

013

B[ Franz et al[ : Journal of Psychiatric Research 22 "0888# 010Ð016 Table 1 Clinical measures in depressed "N08# and control "N05# subjects

Variable

Depressed mean2S[D[ or N

Healthy mean2S[D[ or N

Test statistic

p!value

Mean IGF!0 "ng:ml# Mean GHBP "pmol:L# Age Body mass index Exercise "cal:wk# Plasma estradiol "pg:ml# Plasma progesterone "pg:dl#

1782097 123282 2428 1524 017421999 091266 3922326

117247 1812059 2526 1324 02832855 80289 0502135

2[19a 9[15a 9[49b −0[07b 0[26a −9[66b\c 2[20a

9[96 9[50 9[51 9[14 9[13 9[34 9[96

Menstrual Phase Follicular Midcycle Leuteal OCP"I# Menopause

4 1 09 0 0

2 4 1 4 0

−

9[94d

01 6

3 01

−

9[93d

7 3

09 3

−

0[99d

Regular exercise No Yes Last exercise ¾13 h ×13 h a

MannÐWhitney U test[ Two!sample t!test[ c Square!root transformed[ d Fisher|s exact test[ b

Third\ we assessed di}erences in IGF!0 and GHBP between patients and controls using information from the _rst two sets of analyses[ Speci_cally\ we performed generalized linear models for IGF!0 and GHBP sep! arately using group "patient vs[ control# as a main e}ect[ The models included as covariates all clinical measures which were signi_cantly di}erent between depressed and control samples " from step one#\ and all clinical measures which were signi_cantly associated with IGF!0 or GHBP values " from step two#[ Any nonsigni_cant group or covariate e}ects were dropped from the _nal model[ We used a conservative a level of 9[94 to determine statistical signi_cance[ Finally\ correlations between IGF!0 and GHBP were assessed with Pearson productÐmoment correlations[ These were conducted separately for patients and control subjects[ 2[ Results In step one of the analysis\ depressed and control groups di}ered signi_cantly in terms of the proportion getting regular exercise "higher in control subjects# and in terms of the proportion in di}erent menstrual phases Table 1[ In step two\ IGF!0 levels were negatively cor! related with age "r−9[50\ p9[9990#[ GHBP levels were positively correlated with BMI "r9[46\ p9[9992#

and were signi_cantly di}erent according to menstrual phase "F3[64\ df3\ 29\ p9[993#[ Depressed patients had a trend toward higher median values of IGF!0 than control subjects "Mann Whitney U2[19\ p9[96# Table 1\ but these values do not take into account other variables which may in~uence IGF!0\ and which may di}er between groups[ Group "depressed vs[ control#\ regular exercise\ menstrual phase and age were entered into the generalized linear model for IGF! 0[ Regular exercise was removed from the _nal model for nonsigni_cance[ IGF!0 values were signi_cantly related to age "F18[21^ df 0\ 17\ p9[9990#\ menstrual phase "F2[56\ df 3\ 17\ p9[905# and group "F5[02\ df 0\ 17^ p9[91#[ The overall model with these three values predicted 53) of the variance in IGF!0 values "R19[53\ F7[26\ df 5\ 17\ p9[9990#[ Uncorrected mean values of GHBP were not di}erent in the two groups "t9[15\ p9[50#[ Group\ regular exer! cise\ menstrual phase and BMI were entered into the generalized linear model for GHBP[ Regular exercise and group were removed from the _nal model for non! signi_cance[ GHBP levels were signi_cantly related to menstrual phase "F09[93\ df 3\ 18\ p9[9990# and body mass index "F23[94\ df 0\ 18\ p9[9990#[ The overall model predicted 61) of the variance in GHBP "R19[61\ F03[68\ df 4\ 18\ p9[9990#[ In order to determine whether IGF!0 and GHBP levels

B[ Franz et al[ : Journal of Psychiatric Research 22 "0888# 010Ð016

were related to each other\ we performed Pearson productÐmoment correlations for depressed and control groups separately[ Among depressed patients\ IGF!0 and GHBP were not signi_cantly correlated "r−9[05\ p9[40#\ but in healthy subjects\ there was a positive correlation which approached statistical signi_cance "r9[35\ p9[97#[ These correlations were not sig! ni_cantly di}erent from one another "Z0[65\ p9[97#[

3[ Discussion We found signi_cantly higher IGF!0 concentrations in the depressed group compared to healthy control subjects when controlled for age and menstrual phase[ The _nding of increased IGF!0 in depression agrees with prior reports "Lesch et al[\ 0877a\ 0877b^ Rupprecht et al[\ 0878#[ Lesch et al[ "0877a# did not detect an e}ect of menstrual phase or age on IGF!0[ It is possible that di}erent study popu! lations account for this di}erence[ Fourteen out of 12 of the depressed women and an unknown proportion of control women in their study were postmenopausal\ whereas only one of 08 depressed women in the current study was postmenopausal[ Lesch et al[ also included men in their study\ as well as six patients with bipolar depression[ Both types of patients were excluded from the present study[ Most recently\ Deuschle et al[ "0886# also reported increase in IGF!0 in depressed patients compared to con! trols[ Their study included 02 male patients and 00 female patients with 11 male controls and 00 female controls[ The issue of menstrual phase in the female subjects was not mentioned[ They did _nd age to have a signi_cant e}ect on IGF!0\ as did we[ They measured GH from a pooled sample of blood drawn from patients between 07]99 and 13]99 and found that this did not correlate with IGF!0 levels[ In a previous study we have shown that a subset of depressed patients has a relative increase in presleep onset GH secretion while maintaining the decreased secretions of GH in the _rst 099 min after sleep onset "Franz et al[\ 0884#[ This makes the _nding of no relationship between IGF!0 and GH somewhat di.cult to interpret[ IGF!0 in serum largely results from hepatic production in response to GH binding to its membrane!bound recep! tor "D|Ercole et al[\ 0873#[ Studies in nondepressed humans have found close correlation between GH levels and IGF!0 levels "Furlanetto\ 0889#[ There is some controversy in the literature regarding GH secretion during depression[ Mendlewicz et al[ "0874# found noc! turnal hyposecretion of GH with daytime hypersecretion resulting in elevated 13!h GH levels[ If there is daytime hypersecretion\ this could stimulate the increase in IGF! 0 seen in this and other studies[ The other investigators who have documented increased IGF!0 in depression have favored this hypothesis[

014

In contrast\ Voderholzer et al[ "0882# and Fiasche et al[ "0884# found reduced 13!h GH secretion[ If 13!h GH secretion is reduced in depression\ as suggested by these studies\ it is not clear what is causing the elevated IGF! 0[ Perhaps a brief surge of GH at sometime during the 13 h causes enough IGF!0 to be produced that it then negatively feeds back to decrease GH secretion[ Alter! natively\ IGF!0 produced at nonhepatic sites might be contributing to the pool of circulating IGF!0[ Nonhepatic IGF!0 production is largely GH!independent and is directly in~uenced by a wide variety of hormones includ! ing ACTH\ TSH\ estradiol\ and PTH "D|Ercole et al[\ 0873^ Furlanetto\ 0889#[ Although IGF!0 produced at nonhepatic sites is thought to have primarily autocrine or paracrine functions\ it is possible that such IGF!0 contributes to serum levels[ Other endocrine states are known to be di}erent in health and depression and may contribute to elevated IGF!0[ For instance\ cortisol secretion is altered in depression[ Deuschle et al[ "0886# found IGF!0 levels to be signi_cantly associated with mean 13!h cortisol levels\ which were signi_cantly elevated in depressed patients[ Thyroid hormone could also potentially a}ect IGF!0\ however\ all of our subjects were euthyroid and none were on replacement therapy[ Also\ although we assessed BMI for each subject\ we did not address weight loss prior to entering the study or dietary habits[ Both of these factors could potentially account for a di}erence in IGF! 0 in depression and health[ Finally\ previous studies characterizing the relationship between GH and IGF!0 were carried out with nondepressed subjects[ It is possible that this relationship is altered in depressed subjects\ and that IGF!0 may not simply re~ect GH secretion in these patients[ GHBP was not statistically di}erent in depressed and healthy subjects[ This _nding agrees with those of Deuschle et al[ We also found a signi_cant e}ect of BMI and menstrual phase on GHBP[ Menstrual phase was not addressed in the Deuschle study[ Wide variation in GHBP levels in normal subjects has been described "Baumann et al[\ 0878#[ The literature on the relationship of GH to GHBP is contradictory[ On the one hand\ fairly normal GHBP levels have been found in clinical situations of extreme GH excess or de_ciency such as acromegaly and panhypopituitarism "Baumann et al[\ 0878^ Davila et al[\ 0883#[ On the other hand\ Marsha et al[ "0880# found that serum GHBP levels negatively correlated with mean 13!h serum GH concentrations[ Two studies "Postel!Vinay et al[\ 0880^ Hochberg et al[\ 0880# found that GHBP and GH were directly correlated[ Jo rgensen et al[ "0884# found no correlation between GH and GHBP levels[ There is some evidence that GHBP levels are more closely related to the pulsatility of GH secretion than to GH concentrations "Hochberg et al[\ 0882#[ Healthy subjects in this study showed a trend toward

015

B[ Franz et al[ : Journal of Psychiatric Research 22 "0888# 010Ð016

a positive correlation between IGF!0 and GHBP[ Postel! Vinay et al[ "0880# also reported a positive correlation between IGF!0 and GHBP activity in healthy subjects[ In our depressed subjects there was no signi_cant cor! relation between IGF!0 and GHBP[ This may re~ect altered regulation of the GH axis distal to GH secretion in depression[ However\ the correlation coe.cients in depressed and control subjects were not signi_cantly di}erent\ which likely re~ects low power in our analyses[ One limitation of the present study is the absence of GH data\ making it impossible to directly correlate IGF! 0 or GHBP secretion with GH secretion[ To assess fully the reason for the elevated IGF!0 in depression\ 13!h studies of GH secretion as well as IGF!0 would be needed[ Furthermore\ in order to characterize the di}erence in regulation of the distal GH axis\ GHBP levels should also be studied[ Another limitation of the present study is the small sample size\ which limited our power to detect signi_cant group di}erences and correlations[ A _nal limitation was the inability to completely match the depressed and control subjects for reproductive hormone status[ Given the signi_cant correlations between estro! gen and progesterone and both IGF!0 and GHBP\ future studies will need to strictly control endocrine status[ We suggest that further studies be done to fully charac! terize the potential di}erences between depressed and healthy subjects in the GH axis distal to the secretion of GH[ Elevated IGF!0 levels\ despite reduced GH secretion or possibly causing reduced GH secretion\ would suggest that regulation of the distal growth hormone axis may be disrupted in depression and that IGF!0 and GH may have very di}erent relationships in depressed and healthy subjects[

Acknowledgements Supported by National Institute of Mental Health grants MH!29804\ MH!13541\ MH!38004 and MH! 37780\ and by a grant from the Theodore and Vada Stanley Foundation[ We are grateful to Dr[ Judy Cameron for helpful discussions of this work[

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