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Hormonal Contraception and Depression: Updated Evidence and Implications in Clinical Practice

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Abstract

Hormonal contraceptives are used worldwide by more than 100 million women. Some studies have been published about the possible appearance of depressive symptoms when using hormonal contraceptives, but this link is still a matter of debate. The purpose of this review is to provide an update of the literature on this issue, and to investigate the possible explanations of this problem based on animal and human studies. The main pathway responsible for menstrual cycle-related mood changes is the γ-aminobutyric acid pathway, which is sensitive to changes in the levels of progesterone and of its metabolites, the neurosteroids. In particular, allopregnanolone is a potentiating neurosteroid with anxiolytic and anti-convulsant effects whose levels change during a normal menstrual cycle together with progesterone levels. Progestins have different effects on allopregnanolone, mainly owing to their diverse androgenicity. Moreover, they might affect brain structure and function, even though the meaning of these changes has yet to be clarified. It is important to define the groups of women in which negative mood disorders are more likely to occur. Adolescence is a critical period and this age-specific vulnerability is complex and likely bidirectional. Moreover, women with a history of mood affective disorders or premenstrual dysphoric syndrome are at a higher risk when taking contraceptives. In this review, we aim to provide clinicians with advice on how to approach these difficult situations.

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References

  1. Stomati M, Genazzani AD, Petraglia F, Genazzani AR. Contraception as prevention and therapy: sex steroids and the brain. Eur J Contracept Reprod Health Care. 1998;3:21–8.

    CAS  PubMed  Google Scholar 

  2. Genazzani AR, Monteleone P, Gambacciani M. Hormonal influence on the central nervous system. Maturitas. 2002;43:11–7.

    Google Scholar 

  3. Wittchen H-U, Essau CA, von Zerssen D, et al. Lifetime and six-month prevalence of mental disorders in the Munich follow-up study. Eur Arch Psychiatry Clin Neurosci. 1992;241:247–58.

    CAS  PubMed  Google Scholar 

  4. Kaunitz AM. Menstruation: choosing whether … and when. Contraception. 2000;62:277–84.

    CAS  PubMed  Google Scholar 

  5. Pinkerton JV, Guico-Pabia CJ, Taylor HS. Menstrual cycle-related exacerbation of disease. Am J Obstet Gynecol. 2010;202:221–31.

    PubMed  PubMed Central  Google Scholar 

  6. Bahamondes L, Valeria Bahamondes M, Shulman LP. Non-contraceptive benefits of hormonal and intrauterine reversible contraceptive methods. Hum Reprod Update. 2015;21:640–51.

    CAS  PubMed  Google Scholar 

  7. Rapkin AJ, Biggio G, Concas A. Oral contraceptives and neuroactive steroids. Pharmacol Biochem Behav. 2006;84:628–34.

    CAS  PubMed  Google Scholar 

  8. Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Association of hormonal contraception with depression. JAMA Psychiatry. 2016;73:1154–62.

    PubMed  Google Scholar 

  9. Skovlund CW, Mørch LS, Kessing LV, et al. Association of hormonal contraception with suicide attempts and suicides. Am J Psychiatry. 2018;175:336–42.

    PubMed  Google Scholar 

  10. Poromaa IngS, Segebladh B. Adverse mood symptoms with oral contraceptives. Acta Obstet Gynecol Scand. 2012;91:420–7.

    CAS  PubMed  Google Scholar 

  11. Rapkin AJ, Morgan M, Sogliano C, et al. Decreased neuroactive steroids induced by combined oral contraceptive pills are not associated with mood changes. Fertil Steril. 2006;85:1371–8.

    PubMed  Google Scholar 

  12. McKetta S, Keyes KM. Oral contraceptive use and depression among adolescents. Ann Epidemiol. 2019;29:46–51.

    PubMed  Google Scholar 

  13. Schaffir J, Worly BL, Gur TL. Combined hormonal contraception and its effects on mood: a critical review. Eur J Contracept Reprod Health Care. 2016;21:347–55.

    CAS  PubMed  Google Scholar 

  14. Böttcher B, Radenbach K, Wildt L, Hinney B. Hormonal contraception and depression: a survey of the present state of knowledge. Arch Gynecol Obstet. 2012;286:231–6.

    PubMed  Google Scholar 

  15. Bitzer J. Hormonal contraception and depression: another pill scandal? Eur J Contracept Reprod Health Care. 2017;22:1–2.

    PubMed  Google Scholar 

  16. Wimberly YH, Cotton S, Wanchick AM, et al. Attitudes and experiences with levonorgestrel 100 μg/ethinyl estradiol 20 μg among women during a 3-month trial. Contraception. 2002;65:403–6.

    CAS  PubMed  Google Scholar 

  17. Robakis T, Williams KE, Nutkiewicz L, Rasgon NL. Hormonal contraceptives and mood: review of the literature and implications for future research. Curr Psychiatry Rep. 2019;21:57.

    PubMed  Google Scholar 

  18. de Wit AE, Booij SH, Giltay EJ, et al. Association of use of oral contraceptives with depressive symptoms among adolescents and young women. JAMA Psychiatry. 2020;77:52–9.

    PubMed  Google Scholar 

  19. Zettermark S, Perez Vicente R, Merlo J. Hormonal contraception increases the risk of psychotropic drug use in adolescent girls but not in adults: a pharmacoepidemiological study on 800 000 Swedish women. PLoS ONE. 2018;13:e0194773.

    PubMed  PubMed Central  Google Scholar 

  20. Lewis CA, Kimmig ACS, Zsido RG, et al. Effects of hormonal contraceptives on mood: a focus on emotion recognition and reactivity, reward processing, and stress response. Curr Psychiatry Rep. 2019;21:115.

    PubMed  PubMed Central  Google Scholar 

  21. Juraska JM, Sisk CL, DonCarlos LL. Sexual differentiation of the adolescent rodent brain: hormonal influences and developmental mechanisms. Horm Behav. 2013;64:203–10.

    CAS  PubMed  Google Scholar 

  22. Shaw P, Kabani NJ, Lerch JP, et al. Neurodevelopmental trajectories of the human cerebral cortex. J Neurosci. 2008;28:3586–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Rehbein E, Hornung J, Sundström Poromaa I, Derntl B. Shaping of the female human brain by sex hormones: a review. Neuroendocrinology. 2020. https://doi.org/10.1159/000507083.

    Article  PubMed  Google Scholar 

  24. Guapo VG, Graeff FG, Zani ACT, et al. Effects of sex hormonal levels and phases of the menstrual cycle in the processing of emotional faces. Psychoneuroendocrinology. 2009;34:1087–94.

    CAS  PubMed  Google Scholar 

  25. Derntl B, Windischberger C, Robinson S, et al. Facial emotion recognition and amygdala activation are associated with menstrual cycle phase. Psychoneuroendocrinology. 2008;33:1031–40.

    PubMed  PubMed Central  Google Scholar 

  26. Derntl B, Kryspin-Exner I, Fernbach E, et al. Emotion recognition accuracy in healthy young females is associated with cycle phase. Horm Behav. 2008;53:90–5.

    PubMed  Google Scholar 

  27. Reed SC, Levin FR, Evans SM. Changes in mood, cognitive performance and appetite in the late luteal and follicular phases of the menstrual cycle in women with and without PMDD (premenstrual dysphoric disorder). Horm Behav. 2008;54:185–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sundström-Poromaa I, Gingnell M. Menstrual cycle influence on cognitive function and emotion processing: from a reproductive perspective. Front Neurosci. 2014;8:380.

    PubMed  PubMed Central  Google Scholar 

  29. Harris GW. Electrical stimulation of the hypothalamus and the mechanism of neural control of the adenohypophysis. J Physiol. 1948;107:418–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Gruber CJ, Tschugguel W, Schneeberger C, Huber JC. Production and actions of estrogens. N Engl J Med. 2002;346:340–52.

    CAS  PubMed  Google Scholar 

  31. Cunningham RL, Lumia AR, McGinnis MY. Androgen receptors, sex behavior, and aggression. Neuroendocrinology. 2012;96:131–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Toffoletto S, Lanzenberger R, Gingnell M, et al. Emotional and cognitive functional imaging of estrogen and progesterone effects in the female human brain: a systematic review. Psychoneuroendocrinology. 2014;50:28–52.

    CAS  PubMed  Google Scholar 

  33. Comasco E, Sundström-Poromaa I. Neuroimaging the menstrual cycle and premenstrual dysphoric disorder. Curr Psychiatry Rep. 2015;17:77.

    PubMed  Google Scholar 

  34. van Wingen GA, Ossewaarde L, Bäckström T, et al. Gonadal hormone regulation of the emotion circuitry in humans. Neuroscience. 2011;191:38–45.

    PubMed  Google Scholar 

  35. van Wingen GA, van Broekhoven F, Verkes RJ, et al. Progesterone selectively increases amygdala reactivity in women. Mol Psychiatry. 2008;13:325–33.

    PubMed  Google Scholar 

  36. van Wingen G, Mattern C, Verkes RJ, et al. Testosterone reduces amygdala–orbitofrontal cortex coupling. Psychoneuroendocrinology. 2010;35:105–13.

    PubMed  Google Scholar 

  37. Sergerie K, Chochol C, Armony JL. The role of the amygdala in emotional processing: a quantitative meta-analysis of functional neuroimaging studies. Neurosci Biobehav Rev. 2008;32:811–30.

    PubMed  Google Scholar 

  38. Goldstein JM. Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging. J Neurosci. 2005;25:9309–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Belelli D, Lambert JJ. Neurosteroids: endogenous regulators of the GABAA receptor. Nat Rev Neurosci. 2005;6:565–75.

    CAS  PubMed  Google Scholar 

  40. McEwen BS. Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol Sci. 1991;12:141–7.

    CAS  PubMed  Google Scholar 

  41. Compagnone NA, Mellon SH. Neurosteroids: biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol. 2000;21:1–56.

    CAS  PubMed  Google Scholar 

  42. Del Río JP, Alliende MI, Molina N, et al. Steroid hormones and their action in women’s brains: the importance of hormonal balance. Front Public Health. 2018;6:141.

    PubMed  PubMed Central  Google Scholar 

  43. Kalueff AV, Nutt DJ. Role of GABA in anxiety and depression. Depress Anxiety. 2007;24:495–517.

    CAS  PubMed  Google Scholar 

  44. Tsutsui K. Biosynthesis, mode of action and functional significance of neurosteroids in the developing Purkinje cell. J Steroid Biochem Mol Biol. 2006;102:187–94.

    CAS  PubMed  Google Scholar 

  45. Lambert JJ, Belelli D, Peden DR, et al. Neurosteroid modulation of GABAA receptors. Prog Neurobiol. 2003;71:67–80.

    CAS  PubMed  Google Scholar 

  46. Shungin D, Winkler T, Croteau-Chonka DC, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Seljeset S, Laverty D, Smart TG. Inhibitory neurosteroids and the GABAA receptor. Adv Pharmacol. 2015;72:165–87.

    CAS  PubMed  Google Scholar 

  48. di Scalea LT, Pearlstein T. Premenstrual dysphoric disorder. Med Clin N Am. 2019;103:613–28.

    Google Scholar 

  49. Gibbs TT, Russek SJ, Farb DH. Sulfated steroids as endogenous neuromodulators. Pharmacol Biochem Behav. 2006;84:555–67.

    CAS  PubMed  Google Scholar 

  50. Wang M. Neurosteroids and GABA-A receptor function. Front Endocrinol (Lausanne). 2011;2:1–23.

    Google Scholar 

  51. Porcu P, Serra M, Concas A. The brain as a target of hormonal contraceptives: evidence from animal studies. Front Neuroendocrinol. 2019;55:100799.

    CAS  PubMed  Google Scholar 

  52. Bäckström T, Bixo M, Johansson M, et al. Allopregnanolone and mood disorders. Prog Neurobiol. 2014;113:88–94.

    PubMed  Google Scholar 

  53. Uzunova V, Sheline Y, Davis JM, et al. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA. 1998;95:3239–44.

    CAS  PubMed  Google Scholar 

  54. Schüle C, Nothdurfter C, Rupprecht R. The role of allopregnanolone in depression and anxiety. Prog Neurobiol. 2014;113:79–87.

    PubMed  Google Scholar 

  55. Vandever MA, Kuehl TJ, Sulak PJ, et al. Evaluation of pituitary–ovarian axis suppression with three oral contraceptive regimens. Contraception. 2008;77:162–70.

    CAS  PubMed  Google Scholar 

  56. Estrada-Camarena E, López-Rubalcava C, Vega-Rivera N, et al. Antidepressant effects of estrogens: a basic approximation. Behav Pharmacol. 2010;21:451–64.

    CAS  PubMed  Google Scholar 

  57. Santoro N, Torrens J, Crawford S, et al. Correlates of circulating androgens in mid-life women: the study of women’s health Across the Nation. J Clin Endocrinol Metab. 2005;90:4836–45.

    CAS  PubMed  Google Scholar 

  58. Sitruk-Ware R, Nath A. The use of newer progestins for contraception. Contraception. 2010;82:410–7.

    CAS  PubMed  Google Scholar 

  59. Giatti S, Melcangi RC, Pesaresi M. The other side of progestins: effects in the brain. J Mol Endocrinol. 2016;57:R109–26.

    CAS  PubMed  Google Scholar 

  60. Stanczyk FZ. All progestins are not created equal. Steroids. 2003;68:879–90.

    CAS  PubMed  Google Scholar 

  61. Porcu P, Mostallino MC, Sogliano C, et al. Long-term administration with levonorgestrel decreases allopregnanolone levels and alters GABAA receptor subunit expression and anxiety-like behavior. Pharmacol Biochem Behav. 2012;102:366–72.

    CAS  PubMed  Google Scholar 

  62. Follesa P, Porcu P, Sogliano C, et al. Changes in GABAA receptor γ2 subunit gene expression induced by long-term administration of oral contraceptives in rats. Neuropharmacology. 2002;42:325–36.

    CAS  PubMed  Google Scholar 

  63. Santoru F, Berretti R, Locci A, et al. Decreased allopregnanolone induced by hormonal contraceptives is associated with a reduction in social behavior and sexual motivation in female rats. Psychopharmacology. 2014;231:3351–64.

    CAS  PubMed  Google Scholar 

  64. Paoletti AM, Lello S, Fratta S, et al. Psychological effect of the oral contraceptive formulation containing 3 mg of drospirenone plus 30 μg of ethinyl estradiol. Fertil Steril. 2004;81:645–51.

    CAS  PubMed  Google Scholar 

  65. Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons. Am J Obstet Gynecol. 1998;179:577–82.

    CAS  PubMed  Google Scholar 

  66. Pluchino N, Lenzi E, Merlini S, et al. Selective effect of chlormadinone acetate on brain allopregnanolone and opioids content. Contraception. 2009;80:53–62.

    CAS  PubMed  Google Scholar 

  67. Genazzani AR, Pluchino N, Begliuomini S, et al. Drospirenone increases central and peripheral beta-endorphin in ovariectomized female rats. Menopause. 2007;14:63–73.

    PubMed  Google Scholar 

  68. Lenzi E, Pluchino N, Begliuomini S, et al. Effects of nomegestrol acetate administration on central and peripheral beta-endorphin and allopregnanolone in ovx rats. J Steroid Biochem Mol Biol. 2008;110:67–75.

    CAS  PubMed  Google Scholar 

  69. Kelly S, Davies E, Fearns S, et al. Effects of oral contraceptives containing ethinylestradiol with either drospirenone or levonorgestrel on various parameters associated with well-being in healthy women. Clin Drug Investig. 2010;30:325–36.

    CAS  PubMed  Google Scholar 

  70. Machado RB, Pompei LM, Badalotti M, et al. Effects of an extended flexible regimen of an oral contraceptive pill containing 20 μg ethinylestradiol and 3 mg drospirenone on menstrual-related symptoms: a randomised controlled trial. Eur J Contracept Reprod Health Care. 2017;22:11–6.

    CAS  PubMed  Google Scholar 

  71. Lopez LM, Kaptein AA, Helmerhorst FM. Oral contraceptives containing drospirenone for premenstrual syndrome. Cochrane Database Syst Rev. 2012;15(2):CD006586.

    Google Scholar 

  72. Witjes H, Creinin MD, Sundström-Poromaa I, et al. Comparative analysis of the effects of nomegestrol acetate/17 β-estradiol and drospirenone/ethinylestradiol on premenstrual and menstrual symptoms and dysmenorrhea. Eur J Contracept Reprod Health Care. 2015;20:296–307.

    CAS  PubMed  Google Scholar 

  73. Huber JC, Heskamp MLS, Schramm GAK. Effect of an oral contraceptive with chlormadinone acetate on depressive mood: analysis of data from four observational studies. Clin Drug Investig. 2008;28:783–91.

    CAS  PubMed  Google Scholar 

  74. Ditch S, Roberts TA, Hansen S. The influence of health care utilization on the association between hormonal contraception initiation and subsequent depression diagnosis and antidepressant use. Contraception. 2020;101:237–43.

    CAS  PubMed  Google Scholar 

  75. Pletzer B, Kronbichler M, Aichhorn M, et al. Menstrual cycle and hormonal contraceptive use modulate human brain structure. Brain Res. 2010;1348:55–62.

    CAS  PubMed  Google Scholar 

  76. Craig MC, Fletcher PC, Daly EM, et al. A study of visuospatial working memory pre- and post-gonadotropin hormone releasing hormone agonists (GnRHa) in young women. Horm Behav. 2008;54:47–59.

    CAS  PubMed  Google Scholar 

  77. De Bondt T, Van Hecke W, Veraart J, et al. Does the use of hormonal contraceptives cause microstructural changes in cerebral white matter? Preliminary results of a DTI and tractography study. Eur Radiol. 2013;23:57–64.

    PubMed  Google Scholar 

  78. Petersen N, Kilpatrick LA, Goharzad A, Cahill L. Oral contraceptive pill use and menstrual cycle phase are associated with altered resting state functional connectivity. Neuroimage. 2014;90:24–32.

    CAS  PubMed  Google Scholar 

  79. Graham BM, Milad MR. Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women. Biol Psychiatry. 2013;73:371–8.

    CAS  PubMed  Google Scholar 

  80. Hwang MJ, Zsido RG, Song H, et al. Contribution of estradiol levels and hormonal contraceptives to sex differences within the fear network during fear conditioning and extinction. BMC Psychiatry. 2015;15:295.

    PubMed  PubMed Central  Google Scholar 

  81. Vigil P, del Río JP, Carrera B, et al. Influence of sex steroid hormones on the adolescent brain and behavior: an update. Linacre Q. 2016;83:308–29.

    PubMed  PubMed Central  Google Scholar 

  82. Merikangas KR, He J, Burstein M, et al. Lifetime prevalence of mental disorders in US adolescents: results from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010;49:980–9.

    PubMed  PubMed Central  Google Scholar 

  83. Hamstra DA, de Kloet ER, van Hemert AM, et al. Mineralocorticoid receptor haplotype, oral contraceptives and emotional information processing. Neuroscience. 2015;286:412–22.

    CAS  PubMed  Google Scholar 

  84. Bengtsdotter H, Lundin C, Gemzell Danielsson K, et al. Ongoing or previous mental disorders predispose to adverse mood reporting during combined oral contraceptive use. Eur J Contracept Reprod Health Care. 2018;23:45–51.

    CAS  PubMed  Google Scholar 

  85. Rapkin AJ, Korotkaya Y, Taylor KC. Contraception counseling for women with premenstrual dysphoric disorder (PMDD): current perspectives. Open Access J Contracept. 2019;10:27–39.

    PubMed  PubMed Central  Google Scholar 

  86. Ismaili E, Walsh S, O’Brien PMS, et al. Fourth consensus of the International Society for Premenstrual Disorders (ISPMD): auditable standards for diagnosis and management of premenstrual disorder. Arch Womens Ment Health. 2016;19:953–8.

    PubMed  Google Scholar 

  87. Sangthawan M, Taneepanichskul S. A comparative study of monophasic oral contraceptives containing either drospirenone 3 mg or levonorgestrel 150 μg on premenstrual symptoms. Contraception. 2005;71:1–7.

    CAS  PubMed  Google Scholar 

  88. Pagano HP, Zapata LB, Berry-Bibee EN, Nanda K, Curtis KM. Safety of hormonal contraception and intrauterine devices among women with depressive and bipolar disorders: a systematic review. Contraception. 2016;94(6):641–9. https://doi.org/10.1016/j.contraception.2016.06.012.

    Article  CAS  PubMed  Google Scholar 

  89. Koukopoulos AE, Angeletti G, Sani G, et al. Perinatal mixed affective state: wherefore art thou? Psychiatr Clin N Am. 2020;43:113–26.

    Google Scholar 

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  1. Department of Obstetrics and Gynecology, Pisa University Hospital of S. Chiara, Azienda Ospedaliera Universitaria, Via Roma 65, 56126, Pisa, Italy

    Franca Fruzzetti & Tiziana Fidecicchi

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Fruzzetti, F., Fidecicchi, T. Hormonal Contraception and Depression: Updated Evidence and Implications in Clinical Practice. Clin Drug Investig 40, 1097–1106 (2020). https://doi.org/10.1007/s40261-020-00966-8

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