Skip to main content
×
Home
    • Aa
    • Aa

Regulation of mRNA expression encoding chaperone and co-chaperone proteins of the glucocorticoid receptor in peripheral blood: association with depressive symptoms during pregnancy

  • E. R. Katz (a1), Z. N. Stowe (a1) (a2), D. J. Newport (a1), M. E. Kelley (a3), T. W. Pace (a1), J. F. Cubells (a1) (a4) and E. B. Binder (a1) (a5)...
Abstract
Background

Major depressive disorder during pregnancy associates with potentially detrimental consequences for mother and child. The current study examined peripheral blood gene expression as a potential biomarker for prenatal depressive symptoms.

Method

Maternal RNA from whole blood, plasma and the Beck Depression Inventory were collected longitudinally from preconception through the third trimester of pregnancy in 106 women with a lifetime history of mood or anxiety disorders. The expression of 16 genes in whole blood involved in glucorticoid receptor (GR) signaling was assessed using real-time polymerase chain reaction. In parallel, plasma concentrations of progesterone, estradiol and cortisol were measured. Finally, we assessed ex vivo GR sensitivity in peripheral blood cells from a subset of 29 women.

Results

mRNA expression of a number of GR-complex regulating genes was up-regulated over pregnancy. Women with depressive symptoms showed significantly smaller increases in mRNA expression of four of these genes – FKBP5, BAG1, NCOA1 and PPID. Ex vivo stimulation assays showed that GR sensitivity diminished with progression of pregnancy and increasing maternal depressive symptoms. Plasma concentrations of gonadal steroids and cortisol did not differ over pregnancy between women with and without clinically relevant depressive symptoms.

Conclusions

The presence of prenatal depressive symptoms appears to be associated with altered regulation of GR sensitivity. Peripheral expression of GR co-chaperone genes may serve as a biomarker for risk of developing depressive symptoms during pregnancy. The presence of such biomarkers, if confirmed, could be utilized in treatment planning for women with a psychiatric history.

Copyright
Corresponding author
*Address for correspondence: E. B. Binder, MD PhD, Max-Planck Institute of Psychiatry, Kraepelinstr. 2–10, 80804 Munich, Germany. (Email: binder@mpipsykl.mpg.de)
References
Hide All
Akesson A, Bjellerup P, Berglund M, Bremme K, Vahter M (1998). Serum transferrin receptor: a specific marker of iron deficiency in pregnancy. American Journal of Clinical Nutrition 68, 12411246.
Allolio B, Hoffmann J, Linton EA, Winkelmann W, Kusche M, Schulte HM (1990). Diurnal salivary cortisol patterns during pregnancy and after delivery: relationship to plasma corticotrophin-releasing-hormone. Clinical Endocrinology 33, 279289.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961). An inventory for measuring depression. Archives of General Psychiatry 4, 561571.
Bimston D, Song J, Winchester D, Takayama S, Reed JC, Morimoto RI (1998). BAG-1, a negative regulator of Hsp70 chaperone activity, uncouples nucleotide hydrolysis from substrate release. EMBO Journal 17, 68716878.
Bloch M, Daly RC, Rubinow DR (2003). Endocrine factors in the etiology of postpartum depression. Comprehensive Psychiatry 44, 234246.
Brennan PA, Pargas R, Walker EF, Green P, Jeffrey Newport D, Stowe Z (2008). Maternal depression and infant cortisol: influences of timing, comorbidity and treatment. Journal of Child Psychology and Psychiatry 49, 10991107.
Brett K, Barfield W (2008). Prevalence of self-reported postpartum depressive symptoms. In Morbidity and Mortality Weekly Report, 11 April. Center for Disease Control: Atlanta, GA.
Brummelte S, Galea LA (2009). Depression during pregnancy and postpartum: contribution of stress and ovarian hormones. Progress in Neuro-Psychopharmacology and Biological Psychiatry 34, 766776.
Bunevicius R, Kusminskas L, Mickuviene N, Bunevicius A, Pedersen CA, Pop VJ (2009). Depressive disorder and thyroid axis functioning during pregnancy. World Journal of Biological Psychiatry 10, 324329.
Burke KC, Burke Jr. JD, Rae DS, Regier DA (1991). Comparing age at onset of major depression and other psychiatric disorders by birth cohorts in five US community populations. Archives of General Psychiatry 48, 789795.
Carr BR, Parker CR Jr., Madden JD, MacDonald PC, Porter JC (1981). Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. American Journal of Obstetrics and Gynecology 139, 416422.
Cheadle C, Vawter MP, Freed WJ, Becker KG (2003). Analysis of microarray data using Z score transformation. Journal of Molecular Diagnostics 5, 7381.
Choi JW, Im MW, Pai SH (2000). Serum transferrin receptor concentrations during normal pregnancy. Clinical Chemistry 46, 725727.
Clark PM (1998). Programming of the hypothalamo-pituitary-adrenal axis and the fetal origins of adult disease hypothesis. European Journal of Pediatrics 157 (Suppl. 1), S7–S10.
Cox JL, Murray D, Chapman G (1993). A controlled study of the onset, duration and prevalence of postnatal depression. British Journal of Psychiatry 163, 2731.
Davies TH, Ning YM, Sanchez ER (2002). A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. Journal of Biological Chemistry 277, 45974600.
DeRijk RH, Petrides J, Deuster P, Gold PW, Sternberg EM (1996). Changes in corticosteroid sensitivity of peripheral blood lymphocytes after strenuous exercise in humans. Journal of Clinical Endocrinology and Metabolism 81, 228235.
Duncan MR, Duncan GR (1979). An in vivo study of the action of antiglucocorticoids on thymus weight ratio, antibody titre and the adrenal-pituitary-hypothalamus axis. Journal of Steroid Biochemistry 10, 245259.
Evans J, Heron J, Francomb H, Oke S, Golding J (2001). Cohort study of depressed mood during pregnancy and after childbirth. British Medical Journal 323, 257260.
Evans LM, Myers MM, Monk C (2008). Pregnant women's cortisol is elevated with anxiety and depression – but only when comorbid. Archives of Women's Mental Health 11, 239248.
Field T, Diego MA, Hernandez-Reif M, Figueiredo B, Ascencio A, Schanberg S, Kuhn C (2008). Prenatal dysthymia versus major depression effects on maternal cortisol and fetal growth. Depression and Anxiety 25, E11E16.
First M, Spitzer R, Gibbon M, Williams J (1995). Structured Clinical Interview for DSM-IV Axis I Disorders – Patient Edition (SCID-I/P, Version 2.0). NY State Psychiatric Institute, Biometrics Research Dept: New York.
Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T (2005). Perinatal depression: a systematic review of prevalence and incidence. Obstetrics and Gynecology 106, 10711083.
Goland RS, Jozak S, Warren WB, Conwell IM, Stark RI, Tropper PJ (1993). Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses. Journal of Clinical Endocrinology and Metabolism 77, 11741179.
Gotlib IH, Whiffen VE, Wallace PM, Mount JH (1991). Prospective investigation of postpartum depression: factors involved in onset and recovery. Journal of Abnormal Psychology 100, 122132.
Grad I, Picard D (2007). The glucocorticoid responses are shaped by molecular chaperones. Molecular and Cellular Endocrinology 275, 2–12.
Greenwood J, Parker G (1984). The dexamethasone suppression test in the puerperium. Australian and New Zealand Journal of Psychiatry 18, 282284.
Holsboer F (2000). The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477501.
Holsboer F, Barden N (1996). Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocrine Reviews 17, 187205.
Hubler TR, Denny WB, Valentine DL, Cheung-Flynn J, Smith DF, Scammell JG (2003). The FK506-binding immunophilin FKBP51 is transcriptionally regulated by progestin and attenuates progestin responsiveness. Endocrinology 144, 23802387.
Hubler TR, Scammell JG (2004). Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids. Cell Stress Chaperones 9, 243252.
Iga J, Ueno S, Yamauchi K, Numata S, Kinouchi S, Tayoshi-Shibuya S, Song H, Ohmori T (2007). Altered HDAC5 and CREB mRNA expressions in the peripheral leukocytes of major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 31, 628632.
Jaaskelainen T, Makkonen H, Palvimo JJ (2011). Steroid up-regulation of FKBP51 and its role in hormone signaling. Current Opinion in Pharmacology 11, 326331.
Ji S, Long Q, Newport DJ, Na H, Knight B, Zach EB, Morris NJ, Kutner M, Stowe ZN (2010). Validity of depression rating scales during pregnancy and the postpartum period: impact of trimester and parity. Journal of Psychiatric Research 45, 213219.
Kammerer M, Taylor A, Glover V (2006). The HPA axis and perinatal depression: a hypothesis. Archives of Women's Mental Health 9, 187196.
Karalis K, Goodwin G, Majzoub JA (1996). Cortisol blockade of progesterone: a possible molecular mechanism involved in the initiation of human labor. Nature Medicine 2, 556560.
Karlen Y, McNair A, Perseguers S, Mazza C, Mermod N (2007). Statistical significance of quantitative PCR. BMC Bioinformatics 8, 131.
Keller-Wood M, Silbiger J, Wood CE (1988). Progesterone attenuates the inhibition of adrenocorticotropin responses by cortisol in nonpregnant ewes. Endocrinology 123, 647651.
Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS (1994). Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Archives of General Psychiatry 51, 8–19.
Kimmins S, MacRae TH (2000). Maturation of steroid receptors: an example of functional cooperation among molecular chaperones and their associated proteins. Cell Stress Chaperones 5, 7686.
King NM, Chambers J, O'Donnell K, Jayaweera SR, Williamson C, Glover VA (2010). Anxiety, depression and saliva cortisol in women with a medical disorder during pregnancy. Archives of Women's Mental Health 13, 339345.
Kullmann M, Schneikert J, Moll J, Heck S, Zeiner M, Gehring U, Cato AC (1998). RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis. Journal of Biological Chemistry 273, 1462014625.
Kumar P, Mark PJ, Ward BK, Minchin RF, Ratajczak T (2001). Estradiol-regulated expression of the immunophilins cyclophilin 40 and FKBP52 in MCF-7 breast cancer cells. Biochemical and Biophysical Research Communications 284, 219225.
Kurihara I, Shibata H, Suzuki T, Ando T, Kobayashi S, Hayashi M, Saito I, Saruta T (2000). Transcriptional regulation of steroid receptor coactivator-1 (SRC-1) in glucocorticoid action. Endocrine Research 26, 10331038.
Lowy MT, Reder AT, Antel JP, Meltzer HY (1984). Glucocorticoid resistance in depression: the dexamethasone suppression test and lymphocyte sensitivity to dexamethasone. American Journal of Psychiatry 141, 13651370.
Lowy MT, Reder AT, Gormley GJ, Meltzer HY (1988). Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: relationship to the dexamethasone suppression test. Biological Psychiatry 24, 619630.
McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R (1995). A placental clock controlling the length of human pregnancy. Nature Medicine 1, 460463.
Marcus S, Lopez JF, McDonough S, Mackenzie MJ, Flynn H, Neal Jr. CR, Gahagan S, Volling B, Kaciroti N, Vazquez DM (2010). Depressive symptoms during pregnancy: impact on neuroendocrine and neonatal outcomes. Infant Behavior and Development 34, 2634.
Mathers CD, Loncar D (2006). Projections of global mortality and burden of disease from 2002 to 2030. PLoS Medicine 3, e442.
Meaney MJ, Szyf M, Seckl JR (2007). Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health. Trends in Molecular Medicine 13, 269277.
Meijer OC, Kalkhoven E, van der Laan S, Steenbergen PJ, Houtman SH, Dijkmans TF, Pearce D, de Kloet ER (2005). Steroid receptor coactivator-1 splice variants differentially affect corticosteroid receptor signaling. Endocrinology 146, 14381448.
Meltzer-Brody S, Stuebe A, Dole N, Savitz D, Rubinow D, Thorp J (2010). Elevated corticotropin releasing hormone (CRH) during pregnancy and risk of postpartum depression (PPD). Journal of Clinical Endocrinology and Metabolism 96, E40E47.
Miller GE, Rohleder N, Stetler C, Kirschbaum C (2005). Clinical depression and regulation of the inflammatory response during acute stress. Psychosomatic Medicine 67, 679687.
Morishima Y, Kanelakis KC, Silverstein AM, Dittmar KD, Estrada L, Pratt WB (2000). The Hsp organizer protein hop enhances the rate of but is not essential for glucocorticoid receptor folding by the multiprotein Hsp90-based chaperone system. Journal of Biological Chemistry 275, 68946900.
O'Hara MW, Neunaber DJ, Zekoski EM (1984). Prospective study of postpartum depression: prevalence, course, and predictive factors. Journal of Abnormal Psychology 93, 158171.
O'Hara MW, Rehm LP, Campbell SB (1983). Postpartum depression. A role for social network and life stress variables. Journal of Nervous and Mental Disease 171, 336341.
O'Hara MW, Schlechte JA, Lewis DA, Varner MW (1991). Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. Journal of Abnormal Psychology 100, 6373.
O'Hara MW, Zekoski EM, Philipps LH, Wright EJ (1990). Controlled prospective study of postpartum mood disorders: comparison of childbearing and nonchildbearing women. Journal of Abnormal Psychology 99, 3–15.
O'Keane V, Lightman S, Marsh M, Pawlby S, Papadopoulos AS, Taylor A, Moore R, Patrick K (2010). Increased pituitary-adrenal activation and shortened gestation in a sample of depressed pregnant women: a pilot study. Journal of Affective Disorders 130, 300305.
Odunuga OO, Longshaw VM, Blatch GL (2004). Hop: more than an Hsp70/Hsp90 adaptor protein. Bioessays 26, 10581068.
Oretti RG, Hunter C, Lazarus JH, Parkes AB, Harris B (1997). Antenatal depression and thyroid antibodies. Biological Psychiatry 41, 11431146.
Paakinaho V, Makkonen H, Jaaskelainen T, Palvimo JJ (2010). Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions. Molecular Endocrinology 24, 511525.
Pariante CM (2004). Glucocorticoid receptor function in vitro in patients with major depression. Stress 7, 209219.
Pariante CM, Miller AH (2001). Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biological Psychiatry 49, 391404.
Patel FA, Challis JR (2002). Cortisol/progesterone antagonism in regulation of 15-hydroxysteroid dehydrogenase activity and mRNA levels in human chorion and placental trophoblast cells at term. Journal of Clinical Endocrinology and Metabolism 87, 700708.
Paykel ES, Emms EM, Fletcher J, Rassaby ES (1980). Life events and social support in puerperal depression. British Journal of Psychiatry 136, 339346.
Ramakers C, Ruijter JM, Deprez RH, Moorman AF (2003). Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neuroscience Letters 339, 6266.
Ratajczak T, Ward BK, Minchin RF (2003). Immunophilin chaperones in steroid receptor signalling. Current Topics in Medicinal Chemistry 3, 13481357.
Robinson BG, Emanuel RL, Frim DM, Majzoub JA (1988). Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proceedings of the National Academy of Sciences 85, 52445248.
Rothenberger SE, Resch F, Doszpod N, Moehler E (2011). Prenatal stress and infant affective reactivity at five months of age. Early Human Development 87, 129136.
Rousseau GG, Baxter JD, Tomkins GM (1972). Glucocorticoid receptors: relations between steroid binding and biological effects. Journal of Molecular Biology 67, 99–115.
Schneikert J, Hubner S, Langer G, Petri T, Jaattela M, Reed J, Cato AC (2000). Hsp70-RAP46 interaction in downregulation of DNA binding by glucocorticoid receptor. EMBO Journal 19, 65086516.
Segman RH, Goltser-Dubner T, Weiner I, Canetti L, Galili-Weisstub E, Milwidsky A, Pablov V, Friedman N, Hochner-Celnikier D (2010). Blood mononuclear cell gene expression signature of postpartum depression. Molecular Psychiatry 15, 93–100.
Smith R, Nicholson RC (2007). Corticotrophin releasing hormone and the timing of birth. Frontiers in Bioscience 12, 912918.
Smith R, Owens PC, Brinsmead MW, Singh B, Hall C (1987). The nonsuppressibility of plasma cortisol persists after pregnancy. Hormone and Metabolic Research 19, 4142.
Talge NM, Neal C, Glover V (2007). Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? Journal of Child Psychology and Psychiatry 48, 245261.
Tang PZ, Gannon MJ, Andrew A, Miller D (1995). Evidence for oestrogenic regulation of heat shock protein expression in human endometrium and steroid-responsive cell lines. European Journal of Endocrinology 133, 598605.
U M, Shen L, Oshida T, Miyauchi J, Yamada M, Miyashita T (2004). Identification of novel direct transcriptional targets of glucocorticoid receptor. Leukemia 18, 18501856.
Üstün TB, Ayuso-Mateos J-L, Chatterji S, Mathers C, Murray CJL (2004). Global burden of depressive disorders in the year 2000. British Journal of Psychiatry 184, 386392.
van den Bergh BR, van Calster B, Smits T, van Huffel S, Lagae L (2008). Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: a prospective study on the fetal origins of depressed mood. Neuropsychopharmacology 33, 536545.
Vermeer H, Hendriks-Stegeman BI, van Suylekom D, Rijkers GT, van Buul-Offers SC, Jansen M (2004). An in vitro bioassay to determine individual sensitivity to glucocorticoids: induction of FKBP51 mRNA in peripheral blood mononuclear cells. Molecular and Cellular Endocrinology 218, 4955.
Wisner KL, Stowe ZN (1997). Psychobiology of postpartum mood disorders. Seminars in Reproductive Endocrinology 15, 7789.
Yonkers KA, Vigod S, Ross LE (2011). Diagnosis, pathophysiology, and management of mood disorders in pregnant and postpartum women. Obstetrics and Gynecology 118, 708709.
Zonana J, Gorman JM (2005). The neurobiology of postpartum depression. CNS Spectrums 10, 792799, 805.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords:

Metrics

Full text views

Total number of HTML views: 2
Total number of PDF views: 45 *
Loading metrics...

Abstract views

Total abstract views: 237 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 21st October 2017. This data will be updated every 24 hours.