Skip to main content
Log in

PCOS and Depression: Common Links and Potential Targets

  • Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

PCOS or polycystic ovary syndrome is a common endocrine disorder that occurs during the reproductive age in females. It manifests in the form of a wide range of symptoms including (but not limited to) hirsutism, amenorrhea, oligomenorrhea, obesity, acne vulgaris, infertility, alopecia, and insulin resistance. The incidence of depression in PCOS population is increasing as compared to the general population. Increased depression in PCOS significantly alters the quality of life (QOL) of affected females. Also, self-esteem is found to be low in both depression and PCOS. The loss in self-esteem in such patients can be largely attributed to the associated factors including (but not limited to) obesity, acne, androgenic alopecia, and hirsutism. The reason behind the occurrence of depression in PCOS remains elusive to date. Literature suggests that there is an overlap of clinical symptoms between depression and PCOS. As the symptoms overlap, there is a possibility of common associations between depression, PCOS, and PCOS-associated abnormalities including insulin resistance (IR), obesity, CVD, and androgen excess. Studies demonstrate that depression is an inflammatory disorder marked with increased levels of inflammatory markers. On the other hand, PCOS is also regarded as a pro-inflammatory state that is characterized by increased levels of pro-inflammatory markers. Thus, there is a possibility of an inflammatory relationship existing between depression and PCOS. It is also possible that the inflammatory markers in PCOS can cross the blood–brain barrier (BBB) leading to the development of depression. Through the present review, we have attempted to shed light on common associations/shared links between depression and PCOS with respect to the levels of cortisol, androgen, vitamin D, neurotransmitters, monoaminoxidase (MAO), and insulin-like growth factor-1 (IGF-1). Tracking down common associations between depression and PCOS will help find potential drug therapies and improve the QOL of females with depression in PCOS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

PCOS:

Polycystic ovary syndrome

T2DM:

Type 2 diabetes mellitus

QOL:

Quality of life

CVD:

Cardiovascular disease

NIH:

National Institutes of Health Criteria

ROT:

Rotterdam criteria

AES:

Androgen Excess Society

CYP17A1:

17α-Hydroxylase or 17,20 lyase

CYP11A1:

Cholesterol side-chain cleaving enzyme

HSD3B2:

3-Beta-hydroxysteroid dehydrogenase type II

LH:

Luteinizing hormone

HPG:

Hypothalamic-pituitary–gonadal axis

GnRH:

Gonadotropin-releasing hormone

FSH:

Follicle-stimulating hormone

IR:

Insulin resistance

11β-HSD1:

11β-Hydroxysteroid dehydrogenase type 1

ACTH:

Adrenocorticotropic hormone

GDF-9:

Growth differentiation factor 9

BMP-15:

Bone morphogenetic protein 15

MAOI:

Monoamine oxidase inhibitor

SSRI:

Serotonin reuptake inhibitors

MDD:

Major depressive disorder

NE:

Norepinephrine

DA:

Dopamine

NAc:

Nucleus accumbens

HPA axis:

Hypothalamic-pituitary-adrenal axis

BDNF:

Brain-derived neurotrophic factor

TrkB:

Tyrosine kinase B receptor

CNS:

Central nervous system

DHEAS:

Dehydroepiandrosterone

GAD:

Generalized anxiety disorder

MAO-A:

Monoaminoxidase A

MAO-B:

Monoaminoxidase B

GABA:

Gamma-aminobutyric acid

5HIAA:

5-Hydroxyindoleacetic acid

HVA:

Homovanillic acid

25OHD:

25-Hydroxy vitamin D

1,25OHD:

1,25-Dihydroxy vitamin D

IGF-1:

Insulin-like growth factor-1

IGFBP:

IGF binding proteins

CRP:

C-reactive protein

IL:

Interleukin

TNF-α:

Tumor necrosis factor alpha

GLUT-4:

Glucose transporter-4

IRS-1:

Insulin receptor substrate-1

IFN-γ:

Interferon-γ

BBB:

Blood-brain barrier

References

  1. Zangeneh FZ, Jafarabadi M, Naghizadeh MM, et al. Psychological distress in women with polycystic ovary syndrome from imam khomeini hospital, tehran. J Reprod Infertil. 2012;13:111–5.

    PubMed  PubMed Central  Google Scholar 

  2. Chaudhari AP, Mazumdar K, Mehta PD. Anxiety, depression, and quality of life in women with polycystic ovarian syndrome. Indian J Psychol Med. 2018;40:239–46. https://doi.org/10.4103/IJPSYM.IJPSYM_561_17.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Benson S, Hahn S, Tan S, et al. Maladaptive coping with illness in women with polycystic ovary syndrome. J Obstet Gynecol Neonatal Nurs. 2010;39:37–45. https://doi.org/10.1111/j.1552-6909.2009.01086.x.

    Article  PubMed  Google Scholar 

  4. Cooney LG, Lee I, Sammel MD, Dokras A. High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2017;32:1075–91. https://doi.org/10.1093/humrep/dex044.

    Article  PubMed  Google Scholar 

  5. Dokras A, Clifton S, Futterweit W, Wild R. Increased prevalence of anxiety symptoms in women with polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril. 2012;97:225-230.e2. https://doi.org/10.1016/j.fertnstert.2011.10.022.

    Article  PubMed  Google Scholar 

  6. Himelein MJ, Thatcher SS. Polycystic ovary syndrome and mental health: a review. Obstet Gynecol Surv. 2006;61:723–32. https://doi.org/10.1097/01.ogx.0000243772.33357.84.

    Article  PubMed  Google Scholar 

  7. Janssen O, Hahn S, Tan S, et al. Mood and sexual function in polycystic ovary syndrome. Semin Reprod Med. 2008;26:045–52. https://doi.org/10.1055/s-2007-992924.

    Article  Google Scholar 

  8. Jones GL, Hall JM, Balen AH, Ledger WL. Health-related quality of life measurement in women with polycystic ovary syndrome: a systematic review. Hum Reprod Update. 2007;14:15–25. https://doi.org/10.1093/humupd/dmm030.

    Article  PubMed  Google Scholar 

  9. Eggers S, Kirchengast S. The polycystic ovary syndrome–a medical condition but also an important psychosocial problem. Coll Antropol. 2001;25:673–85.

    CAS  PubMed  Google Scholar 

  10. Sadeeqa S, Mustafa T, Latif S. Polycystic ovarian syndrome–related depression in adolescent girls: a review. J Pharm Bioall Sci. 2018;10:55. https://doi.org/10.4103/JPBS.JPBS_1_18.

    Article  Google Scholar 

  11. Månsson M, Holte J, Landin-Wilhelmsen K, et al. Women with polycystic ovary syndrome are often depressed or anxious—a case control study. Psychoneuroendocrinology. 2008;33:1132–8. https://doi.org/10.1016/j.psyneuen.2008.06.003.

    Article  PubMed  Google Scholar 

  12. Fauser BCJM, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97:28-38.e25. https://doi.org/10.1016/j.fertnstert.2011.09.024.

    Article  PubMed  Google Scholar 

  13. Malik S, Jain K, Talwar P, et al. Management of polycystic ovary syndrome in India. Fertil Sci Res. 2014;1:23.

    Google Scholar 

  14. Firmino Murgel AC, Santos Simões R, Maciel GAR, et al. Sexual dysfunction in women with polycystic ovary syndrome: systematic review and meta-analysis. J Sex Med. 2019;16:542–50. https://doi.org/10.1016/j.jsxm.2019.01.313.

    Article  PubMed  Google Scholar 

  15. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007;370:685–97. https://doi.org/10.1016/S0140-6736(07)61345-2.

    Article  CAS  PubMed  Google Scholar 

  16. Legro RS, Driscoll D, Strauss JF, et al. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci. 1998;95:14956–60. https://doi.org/10.1073/pnas.95.25.14956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nelson VL, Legro RS, Strauss JF, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol. 1999;13:946–57. https://doi.org/10.1210/mend.13.6.0311.

    Article  CAS  PubMed  Google Scholar 

  18. Chaudhari N, Dawalbhakta M, Nampoothiri L. GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile. Reprod Biol Endocrinol. 2018;16:37. https://doi.org/10.1186/s12958-018-0354-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Witchel SF, Oberfield SE, Peña AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc. 2019;3:1545–73. https://doi.org/10.1210/js.2019-00078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ehrmann DA. Polycystic Ovary Syndrome. N Engl J Med. 2005;352:1223–36. https://doi.org/10.1056/NEJMra041536.

    Article  CAS  PubMed  Google Scholar 

  21. Tsilchorozidou T, Overton C, Conway GS. The pathophysiology of polycystic ovary syndrome. Clin Endocrinol. 2004;60:1–17. https://doi.org/10.1046/j.1365-2265.2003.01842.x.

    Article  CAS  Google Scholar 

  22. Jonard S. The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest. Hum Reprod Update. 2004;10:107–17. https://doi.org/10.1093/humupd/dmh010.

    Article  PubMed  Google Scholar 

  23. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale’s Pharmacology E-Book: with STUDENT CONSULT Online Access. 2014.

  24. Malhi GS, Mann JJ. Depression. Lancet. 2018;392:2299–312. https://doi.org/10.1016/S0140-6736(18)31948-2.

    Article  PubMed  Google Scholar 

  25. Murthy RS. National Mental Health Survey of India 2015–2016. Indian J Psychiatry. 2017;59:21–6. https://doi.org/10.4103/psychiatry.IndianJPsychiatry_102_17.

    Article  PubMed  PubMed Central  Google Scholar 

  26. World Health Organization. Depression and other common mental disorders: global health estimates. World Health Organization; 2017.

  27. Sadeeqa S, Mustafa T, Latif S. Polycystic ovarian syndrome-related depression in adolescent girls: a review. J Pharm Bioallied Sci. 2018;10:55–9. https://doi.org/10.4103/JPBS.JPBS_1_18.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ibáñez L, Oberfield SE, Witchel S, et al. An international consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm Res Paediatr. 2017;88:371–95. https://doi.org/10.1159/000479371.

    Article  CAS  PubMed  Google Scholar 

  29. Diamanti-Kandarakis E. Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev Mol Med. 2008;10: e3. https://doi.org/10.1017/S1462399408000598.

    Article  PubMed  Google Scholar 

  30. Diamanti-Kandarakis E. PCOS in adolescents. Best Pract Res Clin Obstet Gynaecol. 2010;24:173–83. https://doi.org/10.1016/j.bpobgyn.2009.09.005.

    Article  PubMed  Google Scholar 

  31. Wood JR, Ho CKM, Nelson-Degrave VL, et al. The molecular signature of polycystic ovary syndrome (PCOS) theca cells defined by gene expression profiling. J Reprod Immunol. 2004;63:51–60. https://doi.org/10.1016/j.jri.2004.01.010.

    Article  CAS  PubMed  Google Scholar 

  32. Fekadu N, Shibeshi W, Engidawork E. Major depressive disorder: pathophysiology and clinical management. J Depress Anxiety. 2017;06. https://doi.org/10.4172/2167-1044.1000255.

  33. Saveanu RV, Nemeroff CB. Etiology of depression: genetic and environmental factors. Psychiatr Clin N Am. 2012;35:51–71. https://doi.org/10.1016/j.psc.2011.12.001.

    Article  Google Scholar 

  34. McCauley J, Kern DE, Kolodner K, et al. Clinical characteristics of women with a history of childhood abuse: unhealed wounds. JAMA. 1997;277:1362–8.

    Article  CAS  PubMed  Google Scholar 

  35. Mullen PE, Martin JL, Anderson JC, et al. The long-term impact of the physical, emotional, and sexual abuse of children: a community study. Child Abuse Negl. 1996;20:7–21. https://doi.org/10.1016/0145-2134(95)00112-3.

    Article  CAS  PubMed  Google Scholar 

  36. Young EA, Abelson JL, Curtis GC, Nesse RM. Childhood adversity and vulnerability to mood and anxiety disorders. Depress Anxiety. 1997;5:66–72.

    Article  CAS  PubMed  Google Scholar 

  37. Zlotnick C, Ryan CE, Miller IW, Keitner GI. Childhood abuse and recovery from major depression. Child Abuse Negl. 1995;19:1513–6. https://doi.org/10.1016/0145-2134(95)00098-6.

    Article  CAS  PubMed  Google Scholar 

  38. Heim C, Newport DJ, Mletzko T, et al. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology. 2008;33:693–710. https://doi.org/10.1016/j.psyneuen.2008.03.008.

    Article  CAS  PubMed  Google Scholar 

  39. Kaplan MJ, Klinetob NA. Childhood emotional trauma and chronic posttraumatic stress disorder in adult outpatients with treatment-resistant depression. J Nerv Ment Dis. 2000;188:596–601. https://doi.org/10.1097/00005053-200009000-00006.

    Article  CAS  PubMed  Google Scholar 

  40. Lara ME, Klein DN, Kasch KL. Psychosocial predictors of the short-term course and outcome of major depression: a longitudinal study of a nonclinical sample with recent-onset episodes. J Abnorm Psychol. 2000;109:644–50. https://doi.org/10.1037/0021-843X.109.4.644.

    Article  CAS  PubMed  Google Scholar 

  41. Hasler G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World Psychiatry. 2010;9:155–61. https://doi.org/10.1002/j.2051-5545.2010.tb00298.x.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cowen P. Serotonin and depression: pathophysiological mechanism or marketing myth? Trends Pharmacol Sci. 2008;29:433–6. https://doi.org/10.1016/j.tips.2008.05.004.

    Article  CAS  PubMed  Google Scholar 

  43. Saldanha D, Kumar N, Ryali V, et al. Serum serotonin abnormality in depression. Med J Armed Forces India. 2009;65:108–12. https://doi.org/10.1016/S0377-1237(09)80120-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kanchanatawan B, Sirivichayakul S, Thika S, et al. Physio-somatic symptoms in schizophrenia: association with depression, anxiety, neurocognitive deficits and the tryptophan catabolite pathway. Metab Brain Dis. 2017;32:1003–16. https://doi.org/10.1007/s11011-017-9982-7.

    Article  CAS  PubMed  Google Scholar 

  45. Gałecki P, Talarowska M. Inflammatory theory of depression. Psychiatr Pol. 2018;52:437–447. https://doi.org/10.12740/PP/76863.

  46. Anderson G. Editorial (Thematic Issue: The kynurenine and melatonergic pathways in psychiatric and CNS disorders). CPD. 2016;22:947–8. https://doi.org/10.2174/1381612822999160104143932.

    Article  CAS  Google Scholar 

  47. Raghavendra V, Kulkarni SK. Melatonin reversal of DOI-induced hypophagia in rats; possible mechanism by suppressing 5-HT2A receptor-mediated activation of HPA axis. Brain Res. 2000;860:112–8. https://doi.org/10.1016/S0006-8993(00)02031-X.

    Article  CAS  PubMed  Google Scholar 

  48. Terzieva DD, Orbetzova MM, Mitkov MD, Mateva NG. Serum melatonin in women with polycystic ovary syndrome. Folia Med. 2013;55:10–5. https://doi.org/10.2478/folmed-2013-0012.

    Article  CAS  Google Scholar 

  49. De Berardis D, Orsolini L, Serroni N, et al. The role of melatonin in mood disorders. CPT. 2015;65. https://doi.org/10.2147/CPT.S41761.

  50. Groves JO. Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry. 2007;12:1079–88. https://doi.org/10.1038/sj.mp.4002075.

    Article  CAS  PubMed  Google Scholar 

  51. Ranabir S, Reetu K. Stress and hormones. Indian J Endocrinol Metab. 2011;15:18–22. https://doi.org/10.4103/2230-8210.77573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. de Souza DN, de Almeida Corrêa LM, Assunção LR, et al. Relation between depression and hormonal dysregulation. OJD. 2017;06:69–78. https://doi.org/10.4236/ojd.2017.63005.

    Article  Google Scholar 

  53. Basu BR, Chowdhury O, Saha SK. Possible link between stress-related factors and altered body composition in women with polycystic ovarian syndrome. J Hum Reprod Sci. 2018;11:10–8. https://doi.org/10.4103/jhrs.JHRS_78_17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hollinrake E, Abreu A, Maifeld M, et al. Increased risk of depressive disorders in women with polycystic ovary syndrome. Fertil Steril. 2007;87:1369–76. https://doi.org/10.1016/j.fertnstert.2006.11.039.

    Article  PubMed  Google Scholar 

  55. Rasgon NL, Carter MS, Elman S, et al. Common treatment of polycystic ovarian syndrome and major depressive disorder: case report and review. Curr Drug Targets Immune Endocr Metabol Disord. 2002;2:97–102.

    Article  CAS  PubMed  Google Scholar 

  56. Nathan RS, Sachar EJ, Asnis GM, et al. Relative insulin insensitivity and cortisol secretion in depressed patients. Psychiatry Res. 1981;4:291–300. https://doi.org/10.1016/0165-1781(81)90031-7.

    Article  CAS  PubMed  Google Scholar 

  57. Tashiro A, Hongo M, Ota R, et al. Hyper-insulin response in a patient with depression: changes in insulin resistance during recovery from depression. Diabetes Care. 1997;20:1924–5. https://doi.org/10.2337/diacare.20.12.1924.

    Article  CAS  PubMed  Google Scholar 

  58. Winokur A, Maislin G, Phillips JL, Amsterdam JD. Insulin resistance after oral glucose tolerance testing in patients with major depression. Am J Psychiatry. 1988;145:325–30. https://doi.org/10.1176/ajp.145.3.325.

    Article  CAS  PubMed  Google Scholar 

  59. Okamura F, Tashiro A, Utumi A, et al. Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metabolism. 2000;49:1255–60. https://doi.org/10.1053/meta.2000.9515.

    Article  CAS  PubMed  Google Scholar 

  60. Sam S. Obesity and polycystic ovary syndrome. Obes Manag. 2007;3:69–73. https://doi.org/10.1089/obe.2007.0019.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Dixon JB, Dixon ME, O’Brien PE. Depression in association with severe obesity: changes with weight loss. Arch Intern Med. 2003;163:2058. https://doi.org/10.1001/archinte.163.17.2058.

    Article  PubMed  Google Scholar 

  62. Lee SH, Paz-Filho G, Mastronardi C, et al. Is increased antidepressant exposure a contributory factor to the obesity pandemic? Transl Psychiatry. 2016;6:e759–e759. https://doi.org/10.1038/tp.2016.25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ranabir S, Reetu K. Stress and hormones. Indian J Endocr Metab. 2011;15:18. https://doi.org/10.4103/2230-8210.77573.

    Article  CAS  Google Scholar 

  64. Björntorp P. Do stress reactions cause abdominal obesity and comorbidities? Obes Rev. 2001;2:73–86. https://doi.org/10.1046/j.1467-789x.2001.00027.x.

    Article  PubMed  Google Scholar 

  65. Adali E, Yildizhan R, Kurdoglu M, et al. The relationship between clinico-biochemical characteristics and psychiatric distress in young women with polycystic ovary syndrome. J Int Med Res. 2008;36:1188–96. https://doi.org/10.1177/147323000803600604.

    Article  CAS  PubMed  Google Scholar 

  66. Elsenbruch S, Benson S, Hahn S, et al. Determinants of emotional distress in women with polycystic ovary syndrome. Hum Reprod. 2006;21:1092–9. https://doi.org/10.1093/humrep/dei409.

    Article  PubMed  Google Scholar 

  67. Rasgon NL, Rao RC, Hwang S, et al. Depression in women with polycystic ovary syndrome: clinical and biochemical correlates. J Affect Disord. 2003;74:299–304. https://doi.org/10.1016/s0165-0327(02)00117-9.

    Article  PubMed  Google Scholar 

  68. Acién P, Quereda F, Matallı́n P, et al. Insulin, androgens, and obesity in women with and without polycystic ovary syndrome: a heterogeneous group of disorders. Fertil Steril. 1999;72:32–40. https://doi.org/10.1016/S0015-0282(99)00184-3.

    Article  PubMed  Google Scholar 

  69. Annagür BB, Tazegül A, Uguz F, et al. Biological correlates of major depression and generalized anxiety disorder in women with polycystic ovary syndrome. J Psychosom Res. 2013;74:244–7. https://doi.org/10.1016/j.jpsychores.2013.01.002.

    Article  PubMed  Google Scholar 

  70. Weber B, Lewicka S, Deuschle M, et al. Testosterone, androstenedione and dihydrotestosterone concentrations are elevated in female patients with major depression. Psychoneuroendocrinology. 2000;25:765–71. https://doi.org/10.1016/S0306-4530(00)00023-8.

    Article  CAS  PubMed  Google Scholar 

  71. Weiner CL. Androgens and mood dysfunction in women: comparison of women with polycystic ovarian syndrome to healthy controls. Psychosom Med. 2004;66:356–62. https://doi.org/10.1097/01.psy.0000127871.46309.fe.

    Article  CAS  PubMed  Google Scholar 

  72. Meyer JH, Ginovart N, Boovariwala A, et al. Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry. 2006;63:1209–16. https://doi.org/10.1001/archpsyc.63.11.1209.

    Article  CAS  PubMed  Google Scholar 

  73. Moriguchi S, Wilson AA, Miler L, et al. Monoamine oxidase B total distribution volume in the prefrontal cortex of major depressive disorder: an [ 11 C]SL25.1188 positron emission tomography study. JAMA Psychiatry. 2019;76:634. https://doi.org/10.1001/jamapsychiatry.2019.0044.

  74. Shi X, Zhang L, Fu S, Li N. Co-involvement of psychological and neurological abnormalities in infertility with polycystic ovarian syndrome. Arch Gynecol Obstet. 2011;284:773–8. https://doi.org/10.1007/s00404-011-1947-1.

    Article  PubMed  Google Scholar 

  75. Thomson RL, Spedding S, Buckley JD. Vitamin D in the aetiology and management of polycystic ovary syndrome. Clin Endocrinol. 2012;77:343–50. https://doi.org/10.1111/j.1365-2265.2012.04434.x.

    Article  CAS  Google Scholar 

  76. Moran LJ, Teede HJ, Vincent AJ. Vitamin D is independently associated with depression in overweight women with and without PCOS. Gynecol Endocrinol. 2015;31:179–82. https://doi.org/10.3109/09513590.2014.975682.

    Article  CAS  PubMed  Google Scholar 

  77. Krul-Poel YHM, Koenders PP, Steegers-Theunissen RP, et al. Vitamin D and metabolic disturbances in polycystic ovary syndrome (PCOS): a cross-sectional study. PLoS ONE. 2018;13: e0204748. https://doi.org/10.1371/journal.pone.0204748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Li HWR, Brereton RE, Anderson RA, et al. Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome. Metabolism. 2011;60:1475–81. https://doi.org/10.1016/j.metabol.2011.03.002.

    Article  CAS  PubMed  Google Scholar 

  79. Hahn S, Haselhorst U, Tan S, et al. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2006;114:577–83. https://doi.org/10.1055/s-2006-948308.

    Article  CAS  PubMed  Google Scholar 

  80. Pal L, Shu J, Zeitlian G, Hickmon C. Vitamin D insufficiency in reproductive years may be contributory to ovulatory infertility and PCOS. Fertil Steril. 2008;90:S14. https://doi.org/10.1016/j.fertnstert.2008.07.382.

    Article  Google Scholar 

  81. Wehr E, Pilz S, Schweighofer N, et al. Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol. 2009;161:575–82. https://doi.org/10.1530/EJE-09-0432.

    Article  CAS  PubMed  Google Scholar 

  82. Yildizhan R, Kurdoglu M, Adali E, et al. Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet. 2009;280:559–63. https://doi.org/10.1007/s00404-009-0958-7.

    Article  PubMed  Google Scholar 

  83. Shi H, Wang B, Xu X. Antidepressant effect of vitamin D: a literature review. Neuropsychiatry. 2018;07. https://doi.org/10.4172/Neuropsychiatry.1000219.

  84. Antai-Otong D. Vitamin D: an anti-inflammatory treatment option for depression? Issues Ment Health Nurs. 2014;35:227–34. https://doi.org/10.3109/01612840.2013.875086.

    Article  PubMed  Google Scholar 

  85. Blundell TL, Humbel RE. Hormone families: pancreatic hormones and homologous growth factors. Nature. 1980;287:781–7. https://doi.org/10.1038/287781a0.

    Article  CAS  PubMed  Google Scholar 

  86. Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem. 1978;253:2769–76.

    Article  CAS  PubMed  Google Scholar 

  87. Laron Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. MP Mol Pathol. 2001;54:311–6. https://doi.org/10.1136/mp.54.5.311.

    Article  CAS  PubMed  Google Scholar 

  88. D’Ercole AJ, Applewhite GT, Underwood LE. Evidence that somatomedin is synthesized by multiple tissues in the fetus. Dev Biol. 1980;75:315–28. https://doi.org/10.1016/0012-1606(80)90166-9.

    Article  PubMed  Google Scholar 

  89. Baserga R. The IGF-I receptor in cancer research. Exp Cell Res. 1999;253:1–6. https://doi.org/10.1006/excr.1999.4667.

    Article  CAS  PubMed  Google Scholar 

  90. Nilsson A, Isgaard J, Lindahl A, et al. Regulation by growth hormone of number of chondrocytes containing IGF-I in rat growth plate. Science. 1986;233:571–4. https://doi.org/10.1126/science.3523759.

    Article  CAS  PubMed  Google Scholar 

  91. Kelley KM, Oh Y, Gargosky SE, et al. Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. Int J Biochem Cell Biol. 1996;28:619–37. https://doi.org/10.1016/1357-2725(96)00005-2.

    Article  CAS  PubMed  Google Scholar 

  92. Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP)superfamily*. Endocr Rev. 1999;20:761–87. https://doi.org/10.1210/edrv.20.6.0382.

    Article  CAS  PubMed  Google Scholar 

  93. Baxter RC. Insulin-like growth factor binding proteins in the human circulation: a review. Horm Res. 1994;42:140–4. https://doi.org/10.1159/000184186.

    Article  CAS  PubMed  Google Scholar 

  94. Lee PDK, Giudice LC, Conover CA, Powell DR. Insulin-like growth factor binding protein-1: recent findings and new directions. Exp Biol Med. 1997;216:319–57. https://doi.org/10.3181/00379727-216-44182.

    Article  CAS  Google Scholar 

  95. Laron Z, Suikkari A-M, Klinger B, et al. Growth hormone and insulin-like growth factor regulate insulin-like growth factor-binding protein-1 in Laron type dwarfism, growth hormone deficiency and constitutional short stature. Acta Endocrinol. 1992;127:351–8. https://doi.org/10.1530/acta.0.1270351.

    Article  CAS  Google Scholar 

  96. Bredt DS, Furey ML, Chen G, et al. Translating depression biomarkers for improved targeted therapies. Neurosci Biobehav Rev. 2015;59:1–15. https://doi.org/10.1016/j.neubiorev.2015.09.013.

    Article  CAS  PubMed  Google Scholar 

  97. Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008;33:88–109. https://doi.org/10.1038/sj.npp.1301574.

    Article  CAS  PubMed  Google Scholar 

  98. Duman RS. Role of neurotrophic factors in the etiology and treatment of mood disorders. NMM. 2004;5:011–26. https://doi.org/10.1385/NMM:5:1:011.

    Article  CAS  Google Scholar 

  99. Szczęsny E, Ślusarczyk J, Głombik K, et al. Possible contribution of IGF-1 to depressive disorder. Pharmacol Rep. 2013;65:1622–31. https://doi.org/10.1016/S1734-1140(13)71523-8.

    Article  PubMed  Google Scholar 

  100. Russo VC, Gluckman PD, Feldman EL, Werther GA. The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev. 2005;26:916–43. https://doi.org/10.1210/er.2004-0024.

    Article  CAS  PubMed  Google Scholar 

  101. Lobo RA, Carmina E. The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med. 2000;132:989. https://doi.org/10.7326/0003-4819-132-12-200006200-00010.

    Article  CAS  PubMed  Google Scholar 

  102. Elting MW, Korsen TJM, Bezemer PD, Schoemaker J. Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Hum Reprod. 2001;16:556–60. https://doi.org/10.1093/humrep/16.3.556.

    Article  CAS  PubMed  Google Scholar 

  103. Escobar-Morreale HF, Roldán B, Barrio R, et al. High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus1. J Clin Endocrinol Metab. 2000;85:4182–7. https://doi.org/10.1210/jcem.85.11.6931.

    Article  CAS  PubMed  Google Scholar 

  104. Kelly CJG, Speirs A, Gould GW, et al. Altered vascular function in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87:742–6. https://doi.org/10.1210/jcem.87.2.8199.

    Article  CAS  PubMed  Google Scholar 

  105. Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril. 2000;73:150–6. https://doi.org/10.1016/S0015-0282(99)00468-9.

    Article  CAS  PubMed  Google Scholar 

  106. Dessapt-Baradez C, Reza M, Sivakumar G, et al. Circulating vascular progenitor cells and central arterial stiffness in polycystic ovary syndrome. PLoS ONE. 2011;6: e20317. https://doi.org/10.1371/journal.pone.0020317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Desai NA, Patel SS. Increased insulin-like growth factor-1 in relation to cardiovascular function in polycystic ovary syndrome: friend or foe? Gynecol Endocrinol. 2015;31:801–7. https://doi.org/10.3109/09513590.2015.1075497.

    Article  CAS  PubMed  Google Scholar 

  108. Homburg R, Pariente C, Lunenfeld B, Jacobs HS. The role of insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) in the pathogenesis of polycystic ovary syndrome. Hum Reprod. 1992;7:1379–83. https://doi.org/10.1093/oxfordjournals.humrep.a137577.

    Article  CAS  PubMed  Google Scholar 

  109. Conway GS, Jacobs HS, Holly JMP, Wass JAH. Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulinlike growth factor small binding protein 1 in the polycystic ovary syndrome. Clin Endocrinol. 2009;33:593–603. https://doi.org/10.1111/j.1365-2265.1990.tb03897.x.

    Article  Google Scholar 

  110. Iwashita M, Mimuro T, Watanabe M, et al. Plasma levels of insulin-like growth factor-I and its binding protein in polycystic ovary syndrome. Horm Res. 1990;33:21–6. https://doi.org/10.1159/000181561.

    Article  CAS  PubMed  Google Scholar 

  111. van Dessel HJHMT, Lee PDK, Faessen G, et al. Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome 1. J Clin Endocrinol Metab. 1999;84:3030–5. https://doi.org/10.1210/jcem.84.9.5941.

    Article  Google Scholar 

  112. Carmina E, Wong L, Chang L, et al. Endocrine abnormalities in ovulatory women with polycystic ovaries on ultrasound. Hum Reprod. 1997;12:905–9. https://doi.org/10.1093/humrep/12.5.905.

    Article  CAS  PubMed  Google Scholar 

  113. Wang H, Chard T. IGFs and IGF-binding proteins in the regulation of human ovarian and endometrial function. J Endocrinol. 1999;161:1–13. https://doi.org/10.1677/joe.0.1610001.

    Article  CAS  PubMed  Google Scholar 

  114. Barbieri RL. Hyperandrogenism, insulin resistance and acanthosis nigricans. 10 years of progress. J Reprod Med. 1994;39:327–36.

    CAS  PubMed  Google Scholar 

  115. Bergh C, Carlsson B, Olsson J-H, et al. Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin**Supported by grant no. 5987 from the Swedish Medical Research Council, Swedish Medical Society, The Medical Society of Göteborg, Kabi-Pharmacia Ltd., Nordisk Insulin Foundation, Hjalmar Svenssons Research Foundation, Swedish Society for Medical Research, and the University of Göteborg, Göteborg, Sweden. Fertil Steril. 1993;59:323–31. https://doi.org/10.1016/S0015-0282(16)55675-1.

    Article  CAS  PubMed  Google Scholar 

  116. Nagamani M, Stuart CA. Specific binding sites for insulin-like growth factor I in the ovarian stroma of women with polycystic ovarian disease and stromal hyperthecosis. Am J Obstet Gynecol. 1990;163:1992–7. https://doi.org/10.1016/0002-9378(90)90786-7.

    Article  CAS  PubMed  Google Scholar 

  117. Poretsky L, Chandrasekher YA, Bai C, et al. Insulin receptor mediates inhibitory effect of insulin, but not of insulin-like growth factor (IGF)-I, on IGF binding protein 1 (IGFBP-1) production in human granulosa cells. J Clin Endocrinol Metab. 1996;81:493–6. https://doi.org/10.1210/jcem.81.2.8636256.

    Article  CAS  PubMed  Google Scholar 

  118. Deuschle M, Blum WF, Strasburger CJ, et al. Insulin-like growth factor-I (IGF-I) plasma concentrations are increased in depressed patients. Psychoneuroendocrinology. 1997;22:493–503. https://doi.org/10.1016/S0306-4530(97)00046-2.

    Article  CAS  PubMed  Google Scholar 

  119. Kopczak A, Stalla GK, Uhr M, et al. IGF-I in major depression and antidepressant treatment response. Eur Neuropsychopharmacol. 2015;25:864–72. https://doi.org/10.1016/j.euroneuro.2014.12.013.

    Article  CAS  PubMed  Google Scholar 

  120. Sievers C, Auer MK, Klotsche J, et al. IGF-I levels and depressive disorders: results from the Study of Health in Pomerania (SHIP). Eur Neuropsychopharmacol. 2014;24:890–6. https://doi.org/10.1016/j.euroneuro.2014.01.008.

    Article  CAS  PubMed  Google Scholar 

  121. Jedel E, Gustafson D, Waern M, et al. Sex steroids, insulin sensitivity and sympathetic nerve activity in relation to affective symptoms in women with polycystic ovary syndrome. Psychoneuroendocrinology. 2011;36:1470–9. https://doi.org/10.1016/j.psyneuen.2011.04.001.

    Article  CAS  PubMed  Google Scholar 

  122. Franz B, Buysse DJ, Cherry CR, et al. Insulin-like growth factor 1 and growth hormone binding protein in depression: a preliminary communication. J Psychiatr Res. 1999;33:121–7. https://doi.org/10.1016/S0022-3956(98)00066-1.

    Article  CAS  PubMed  Google Scholar 

  123. Bot M, Milaneschi Y, Penninx BWJH, Drent ML. Plasma insulin-like growth factor I levels are higher in depressive and anxiety disorders, but lower in antidepressant medication users. Psychoneuroendocrinology. 2016;68:148–55. https://doi.org/10.1016/j.psyneuen.2016.02.028.

    Article  CAS  PubMed  Google Scholar 

  124. Ferketich AK, Schwartzbaum JA, Frid DJ, Moeschberger ML. Depression as an antecedent to heart disease among women and men in the NHANES I study. Arch Intern Med. 2000;160:1261. https://doi.org/10.1001/archinte.160.9.1261.

    Article  CAS  PubMed  Google Scholar 

  125. Katon WJ, Lin EHB, Russo J, et al. Cardiac risk factors in patients with diabetes mellitus and major depression. J Gen Intern Med. 2004;19:1192–9. https://doi.org/10.1111/j.1525-1497.2004.30405.x.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2010;16:347–63. https://doi.org/10.1093/humupd/dmq001.

    Article  CAS  PubMed  Google Scholar 

  127. Boquist S, Ruotolo G, Skoglund-Andersson C, et al. Correlation of serum IGF-I and IGFBP-1 and -3 to cardiovascular risk indicators and early carotid atherosclerosis in healthy middle-aged men. Clin Endocrinol. 2008;68:51–8. https://doi.org/10.1111/j.1365-2265.2007.02998.x.

    Article  CAS  Google Scholar 

  128. Jörn Schneider H, Klotsche J, Saller B, et al. Associations of age-dependent IGF-I SDS with cardiovascular diseases and risk conditions: cross-sectional study in 6773 primary care patients. Eur J Endocrinol. 2008;158:153–61. https://doi.org/10.1530/EJE-07-0600.

    Article  CAS  Google Scholar 

  129. Al-Obaidi MK, Hon JKF, Stubbs PJ, et al. Plasma insulin-like growth factor-1 elevated in mild-to-moderate but not severe heart failure. Am Heart J. 2001;142:11A-15A. https://doi.org/10.1067/mhj.2001.118116.

    Article  Google Scholar 

  130. Andreassen M, Raymond I, Kistorp C, et al. IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population. Eur J Endocrinol. 2009;160:25–31. https://doi.org/10.1530/EJE-08-0452.

    Article  CAS  PubMed  Google Scholar 

  131. Fischer F, Schulte H, Mohan S, et al. Associations of insulin-like growth factors, insulin-like growth factor binding proteins and acid-labile subunit with coronary heart disease. Clin Endocrinol. 2004;61:595–602. https://doi.org/10.1111/j.1365-2265.2004.02136.x.

    Article  CAS  Google Scholar 

  132. van Bunderen CC, van Nieuwpoort IC, van Schoor NM, et al. The association of serum insulin-like growth factor-I with mortality, cardiovascular disease, and cancer in the elderly: a population-based study. J Clin Endocrinol Metab. 2010;95:4616–24. https://doi.org/10.1210/jc.2010-0940.

    Article  CAS  PubMed  Google Scholar 

  133. Spallarossa P, Brunelli C, Minuto F, et al. Insulin-like growth factor-1 and angiographically documented coronary artery disease. Am J Cardiol. 1996;77:200–2. https://doi.org/10.1016/S0002-9149(96)90600-1.

    Article  CAS  PubMed  Google Scholar 

  134. Juul A, Scheike T, Davidsen M, et al. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002;106:939–44. https://doi.org/10.1161/01.CIR.0000027563.44593.CC.

    Article  CAS  PubMed  Google Scholar 

  135. Laughlin GA, Barrett-Connor E, Criqui MH, Kritz-Silverstein D. The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo Study. J Clin Endocrinol Metab. 2004;89:114–20. https://doi.org/10.1210/jc.2003-030967.

    Article  CAS  PubMed  Google Scholar 

  136. Cicoira M, Kalra PR, Anker SD. Growth hormone resistance in chronic heart failure and its therapeutic implications. J Cardiac Fail. 2003;9:219–26. https://doi.org/10.1054/jcaf.2003.23.

    Article  CAS  Google Scholar 

  137. Jankowska EA, Biel B, Majda J, et al. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006;114:1829–37. https://doi.org/10.1161/CIRCULATIONAHA.106.649426.

    Article  CAS  PubMed  Google Scholar 

  138. Vasan RS, Sullivan LM, D’Agostino RB, et al. Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Ann Intern Med. 2003;139:642. https://doi.org/10.7326/0003-4819-139-8-200310210-00007.

    Article  CAS  PubMed  Google Scholar 

  139. Felger JC. Role of inflammation in depression and treatment implications. In: Macaluso M, Preskorn SH, editors. Antidepressants. Cham: Springer International Publishing; 2018. p. 255–86.

    Chapter  Google Scholar 

  140. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosomat Med. 2009;71:171–86. https://doi.org/10.1097/PSY.0b013e3181907c1b.

    Article  CAS  Google Scholar 

  141. Miller AH, Haroon E, Felger JC. Therapeutic implications of brain–immune interactions: treatment in translation. Neuropsychopharmacology. 2017;42:334–59. https://doi.org/10.1038/npp.2016.167.

    Article  CAS  PubMed  Google Scholar 

  142. Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. Fertil Steril. 2011;95:1048-1058.e2. https://doi.org/10.1016/j.fertnstert.2010.11.036.

    Article  CAS  PubMed  Google Scholar 

  143. Escobar-Morreale HF, Calvo RM, Villuendas G, et al. Association of polymorphisms in the interleukin 6 receptor complex with obesity and hyperandrogenism. Obes Res. 2003;11:987–96. https://doi.org/10.1038/oby.2003.136.

    Article  CAS  PubMed  Google Scholar 

  144. Peral B, San Millán JL, Castello R, et al. The methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. J Clin Endocrinol Metab. 2002;87:3977–83. https://doi.org/10.1210/jcem.87.8.8715.

    Article  CAS  PubMed  Google Scholar 

  145. Villuendas G, San Millán JL, Sancho J, Escobar-Morreale HF. The −597 G→A and −174 G→C polymorphisms in the promoter of the IL-6 gene are associated with hyperandrogenism. J Clin Endocrinol Metab. 2002;87:1134–41. https://doi.org/10.1210/jcem.87.3.8309.

    Article  CAS  PubMed  Google Scholar 

  146. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women 1. J Clin Endocrinol Metab. 1999;84:165–9. https://doi.org/10.1210/jcem.84.1.5393.

    Article  CAS  PubMed  Google Scholar 

  147. Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev. 2003;24:302–12. https://doi.org/10.1210/er.2003-0004.

    Article  PubMed  Google Scholar 

  148. Vgontzas AN, Bixler EO, Chrousos GP. Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. J Intern Med. 2003;254:32–44. https://doi.org/10.1046/j.1365-2796.2003.01177.x.

    Article  CAS  PubMed  Google Scholar 

  149. Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest. 1994;94:1543–9. https://doi.org/10.1172/JCI117495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Chen L, Chen R, Wang H, Liang F. Mechanisms linking inflammation to insulin resistance. Int J Endocrinol. 2015;2015:1–9. https://doi.org/10.1155/2015/508409.

    Article  Google Scholar 

  151. Halawa B, Salomon P, Jołda-Mydłowska B, Zyśko D. Levels of tumor necrosis factor (TNF-alpha) and interleukin 6 (IL-6) in serum of patients with acute myocardial infarction. Pol Arch Med Wewn. 1999;101:197–203.

    CAS  PubMed  Google Scholar 

  152. Gao L, Gu Y, Yin X. High Serum tumor necrosis factor-alpha levels in women with polycystic ovary syndrome: a meta-analysis. PLoS ONE. 2016;11: e0164021. https://doi.org/10.1371/journal.pone.0164021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Araya AV, Aguirre A, Romero C, et al. Evaluation of tumor necrosis factor alpha production in ex vivo short term cultured whole blood from women with polycystic ovary syndrome. Eur Cytokine Netw. 2002;13:419–24.

    CAS  PubMed  Google Scholar 

  154. Choi YS, Yang HI, Cho S, et al. Serum asymmetric dimethylarginine, apelin, and tumor necrosis factor-α levels in non-obese women with polycystic ovary syndrome. Steroids. 2012;77:1352–8. https://doi.org/10.1016/j.steroids.2012.08.005.

    Article  CAS  PubMed  Google Scholar 

  155. Sayin NC, Gücer F, Balkanli-Kaplan P, et al. Elevated serum TNF-alpha levels in normal-weight women with polycystic ovaries or the polycystic ovary syndrome. J Reprod Med. 2003;48:165–70.

    CAS  PubMed  Google Scholar 

  156. Tarkun I, Cetinarslan B, Türemen E, et al. Association between circulating tumor necrosis factor-alpha, interleukin-6, and insulin resistance in normal-weight women with polycystic ovary syndrome. Metab Syndr Relat Disord. 2006;4:122–8. https://doi.org/10.1089/met.2006.4.122.

    Article  CAS  PubMed  Google Scholar 

  157. Thathapudi S, Kodati V, Erukkambattu J, et al. Tumor necrosis factor-alpha and polycystic ovarian syndrome: a clinical, biochemical, and molecular genetic study. Genet Test Mol Biomarkers. 2014;18:605–9. https://doi.org/10.1089/gtmb.2014.0151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Victor VM, Rocha M, Bañuls C, et al. Induction of oxidative stress and human leukocyte/endothelial cell interactions in polycystic ovary syndrome patients with insulin resistance. J Clin Endocrinol Metab. 2011;96:3115–22. https://doi.org/10.1210/jc.2011-0651.

    Article  CAS  PubMed  Google Scholar 

  159. Xiong Y, Liang X, Yang X, et al. Low-grade chronic inflammation in the peripheral blood and ovaries of women with polycystic ovarian syndrome. Eur J Obstet Gynecol Reprod Biol. 2011;159:148–50. https://doi.org/10.1016/j.ejogrb.2011.07.012.

    Article  CAS  PubMed  Google Scholar 

  160. Jakubowska J, Bohdanowicz-Pawlak A, Milewicz A, et al. Plasma cytokines in obese women with polycystic ovary syndrome, before and after metformin treatment. Gynecol Endocrinol. 2008;24:378–84. https://doi.org/10.1080/09513590802128968.

    Article  CAS  PubMed  Google Scholar 

  161. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409–15. https://doi.org/10.1172/JCI117936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes. 1994;43:1271–8. https://doi.org/10.2337/diab.43.11.1271.

    Article  CAS  PubMed  Google Scholar 

  163. Roytblat L, Rachinsky M, Fisher A, et al. Raised interleukin-6 levels in obese patients. Obes Res. 2000;8:673–5. https://doi.org/10.1038/oby.2000.86.

    Article  CAS  PubMed  Google Scholar 

  164. Straczkowski M, Dzienis-Straczkowska S, Stêpieñ A, et al. Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-alpha system. J Clin Endocrinol Metab. 2002;87:4602–6. https://doi.org/10.1210/jc.2002-020135.

    Article  CAS  PubMed  Google Scholar 

  165. Visser M, Bouter LM, McQuillan GM, et al. Elevated C-reactive protein levels in overweight and obese adults. JAMA. 1999;282:2131–5. https://doi.org/10.1001/jama.282.22.2131.

    Article  CAS  PubMed  Google Scholar 

  166. Mobeen H, Afzal N, Kashif M. Polycystic ovary syndrome may be an autoimmune disorder. Scientifica (Cairo). 2016;2016:4071735. https://doi.org/10.1155/2016/4071735.

    Article  CAS  Google Scholar 

  167. Rasquin Leon LI, Mayrin JV, Polycystic ovarian disease (Stein-Leventhal syndrome). In: StatPearls. StatPearls Publishing: Treasure Island; 2020.

  168. Romitti M, Fabris VC, Ziegelmann PK, et al. Association between PCOS and autoimmune thyroid disease: a systematic review and meta-analysis. Endocr Connect. 2018;7:1158–67. https://doi.org/10.1530/EC-18-0309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Shelton RC, Miller AH. Inflammation in depression: is adiposity a cause? Dialogues Clin Neurosci. 2011;13:41–53.

    Article  PubMed  Google Scholar 

  170. Xiong Y, Liang X, Yang X, et al. Low-grade chronic inflammation in the peripheral blood and ovaries of women with polycystic ovarian syndrome. Eur J Obstet Gynecol Reprod Biol. 2011;159:148–50. https://doi.org/10.1016/j.ejogrb.2011.07.012.

    Article  CAS  PubMed  Google Scholar 

  171. Mobeen H, Afzal N, Kashif M. Polycystic ovary syndrome may be an autoimmune disorder. Scientifica. 2016;2016:1–7. https://doi.org/10.1155/2016/4071735.

    Article  CAS  Google Scholar 

  172. Haapakoski R, Ebmeier KP, Alenius H, Kivimäki M. Innate and adaptive immunity in the development of depression: an update on current knowledge and technological advances. Prog Neuropsychopharmacol Biol Psychiatry. 2016;66:63–72. https://doi.org/10.1016/j.pnpbp.2015.11.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Quan N, Banks WA. Brain-immune communication pathways. Brain Behav Immun. 2007;21:727–35. https://doi.org/10.1016/j.bbi.2007.05.005.

    Article  CAS  PubMed  Google Scholar 

  174. Blakely RD, Berson HE. Molecular biology of serotonin receptors and transporters. Clin Neuropharmacol. 1992;15:351A-352A. https://doi.org/10.1097/00002826-199201001-00182.

    Article  PubMed  Google Scholar 

  175. Zhu C-B, Carneiro AM, Dostmann WR, et al. p38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process. J Biol Chem. 2005;280:15649–58. https://doi.org/10.1074/jbc.M410858200.

    Article  CAS  PubMed  Google Scholar 

  176. Zhu C-B, Lindler KM, Owens AW, et al. Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology. 2010;35:2510–20. https://doi.org/10.1038/npp.2010.116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Hardy OT, Czech MP, Corvera S. What causes the insulin resistance underlying obesity? Curr Opin Endocrinol Diabetes Obes. 2012;19:81–7. https://doi.org/10.1097/MED.0b013e3283514e13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Miller GE, Freedland KE, Carney RM, et al. Pathways linking depression, adiposity, and inflammatory markers in healthy young adults. Brain Behav Immun. 2003;17:276–85. https://doi.org/10.1016/S0889-1591(03)00057-6.

    Article  CAS  PubMed  Google Scholar 

  179. Moran LJ, Pasquali R, Teede HJ, et al. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril. 2009;92:1966–82. https://doi.org/10.1016/j.fertnstert.2008.09.018.

    Article  PubMed  Google Scholar 

  180. Akbaraly TN, Kivimaki M, Brunner EJ, et al. Association between metabolic syndrome and depressive symptoms in middle-aged adults: results from the Whitehall II study. Diabetes Care. 2009;32:499–504. https://doi.org/10.2337/dc08-1358.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Gil K, Radziłłowicz P, Zdrojewski T, et al. Relationship between the prevalence of depressive symptoms and metabolic syndrome. Results of the SOPKARD Project. Kardiol Pol. 2006;64:464–9.

    PubMed  Google Scholar 

  182. Heiskanen TH, Niskanen LK, Hintikka JJ, et al. Metabolic syndrome and depression: a cross-sectional analysis. J Clin Psychiatry. 2006;67:1422–7. https://doi.org/10.4088/JCP.v67n0913.

    Article  PubMed  Google Scholar 

  183. Kinder LS, Carnethon MR, Palaniappan LP, et al. Depression and the metabolic syndrome in young adults: findings from the Third National Health and Nutrition Examination Survey. Psychosom Med. 2004;66:316–22. https://doi.org/10.1097/01.psy.0000124755.91880.f4.

    Article  PubMed  Google Scholar 

  184. Raikkonen K, Matthews KA, Kuller LH. Depressive symptoms and stressful life events predict metabolic syndrome among middle-aged women: a comparison of World Health Organization, Adult Treatment Panel III, and International Diabetes Foundation definitions. Diabetes Care. 2007;30:872–7. https://doi.org/10.2337/dc06-1857.

    Article  PubMed  Google Scholar 

  185. Räikkönen K, Matthews KA, Kuller LH. The relationship between psychological risk attributes and the metabolic syndrome in healthy women: antecedent or consequence? Metab Clin Exp. 2002;51:1573–7. https://doi.org/10.1053/meta.2002.36301.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the Institute of Pharmacy, Nirma University, for their support in successful completion of this work.

Author information

Authors and Affiliations

Authors

Contributions

Jagruti V. Kolhe, Abu Sufiyan Chhipa: Conceptualization, writing—original draft; Shital Butani: manuscript drafting; Vishal Chavda: manuscript drafting; Snehal S. Patel: supervision.

Corresponding author

Correspondence to Snehal S. Patel.

Ethics declarations

Conflict of interest

None to declare.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

All authors have read the manuscript and approved for publication.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kolhe, J.V., Chhipa, A.S., Butani, S. et al. PCOS and Depression: Common Links and Potential Targets. Reprod. Sci. 29, 3106–3123 (2022). https://doi.org/10.1007/s43032-021-00765-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-021-00765-2

Keywords

Navigation