Hormonal Contraceptives and Mood: Review of the Literature and Implications for Future Research

Abstract

Purpose of Review

We examine recent studies that investigate the effects of hormonal contraception on mood in different populations of women, including women in the general population and women with diagnosed psychiatric and gynecologic disorders. We address the mechanisms of several types of hormonal contraceptives and assess how these may affect mood and gynecologic disorders.

Recent Findings

The effects of hormonal contraceptives seem to be most relevant in selected subsets of women, as they may promote improved mental health in particular psychiatric disorders such as PMDD.

Summary

Currently, there is no consistent evidence for negative effects of most hormonal contraceptives in the general population. Even though some studies reveal that certain individuals appear susceptible to negative mood effects from some forms of hormonal contraceptives, more research is needed to better identify these susceptible individuals.

This is a preview of subscription content, access via your institution.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Christin-Maitre S. History of oral contraceptive drugs and their use worldwide. Best Pract Res Clin Endocrinol Metab. 2013;27:3–12.

    CAS  Article  Google Scholar 

  2. 2.

    United Nations. World contraceptive use 2007 http://www.un.org/esa/population/publications/contraceptive2007/contraceptive2007.htm

  3. 3.

    United Nations. World family planning 2017. http://www.un.org/en/development/desa/population/publications/pdf/family/WFP2017_Highlights.pdf

  4. 4.

    Robakis T & Rasgon NL. Hormonal influences on behavior. Reference Module in Biomedical Sciences. 2014

  5. 5.

    Messinis IE. Ovarian feedback, mechanism of action and possible clinical implications. Hum Reprod Update. 2006;12:557–71.

    CAS  Article  Google Scholar 

  6. 6.

    Choi J, Smitz J. Luteinizing hormone and human chorionic gonadotropin: distinguishing unique physiologic roles. Gynecol Endocrinol. 2013;30:174–81.

    Article  Google Scholar 

  7. 7.

    Hall KS, Trussell J. Types of combined oral contraceptives used by US women. Contraception. 2012;86:659–65.

    Article  Google Scholar 

  8. 8.

    Stanczyk FZ. Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev Endocr Metab Disord. 2002;3:211–24.

    CAS  Article  Google Scholar 

  9. 9.

    Nappi RE, Kaunitz AM, Bitzer J. Extended regimen combined oral contraception: a review of evolving concepts and acceptance by women and clinicians. Eur J Contracept Reprod Health Care. 2016;21:106–15.

    CAS  Article  Google Scholar 

  10. 10.

    Trenor CC, Chung RJ, Michelson AD, Neufeld EJ, Gordon CM, Laufer MR, et al. Hormonal contraception and thrombotic risk: a multidisciplinary approach. Pediatrics. 2011;127:347–57.

    Article  Google Scholar 

  11. 11.

    Diaz S, Peralta O, Juez G, Herreros C, Casado ME, Salvatierra ME, et al. Fertility regulation in nursing women: III. Short-term influence of a low-dose combined oral contraceptive upon lactation and infant growth. Contraception. 1983;27:1–11.

    CAS  Article  Google Scholar 

  12. 12.

    Wildemeersch D. New intrauterine technologies for contraception and treatment in nulliparous/adolescent and parous women. Facts Views Vis Obgyn. 2009;1:223–32.

  13. 13.

    Toffol E, Heikinheimo O, Koponen P, Luoto R, Partonen T. Hormonal contraception and mental health: results of a population-based study. Hum Reprod. 2011;26:3085–93.

    CAS  Article  Google Scholar 

  14. 14.

    Toffol E, Heikinheimo O, Koponen P, Luoto R, Partonen T. Further evidence for lack of negative associations between hormonal contraception and mental health. Contraception. 2012;86:470–80.

    CAS  Article  Google Scholar 

  15. 15.

    Keyes KM, Cheslack-Postava K, Westhoff C, Heim CM, Haloossim M, Walsh K, et al. Association of hormonal contraceptive use with reduced levels of depressive symptoms: a national study of sexually active women in the United States. Am J Epidemiol. 2013;178:1378–88.

    Article  Google Scholar 

  16. 16.

    Duke JM, Sibbritt DW, Young AF. Is there an association between the use of oral contraception and depressive symptoms in young Australian women? Contraception. 2007;75:27–31.

    CAS  Article  Google Scholar 

  17. 17.

    Hassoun LA, Chahal DS, Sivamani RK, Larsen LN. The use of hormonal agents in the treatment of acne. Semin Cutan Med Surg. 2016;35:68–73.

    Article  Google Scholar 

  18. 18.

    Wong CL, Farquhar C, Roberts H, Proctor M. Oral contraceptive pill for primary dysmenorrhoea. Cochrane Database Syst Rev. 2009:7, CD002120. https://doi.org/10.1002/14651858.CD002120.pub3.

  19. 19.

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

    Article  Google Scholar 

  20. 20.

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

    Article  Google Scholar 

  21. 21.

    Zettermark S, Vicente RP, 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.

    Article  Google Scholar 

  22. 22.

    Garbers S, Correa N, Tobier N, Blust S, Chiasson MA. Association between symptoms of depression and contraceptive method choices among low-income women at urban reproductive health centers. Matern Child Health J. 2010;14(1):102.

    Article  Google Scholar 

  23. 23.

    Moore M, Kwitowski M, Javier S. Examining the influence of mental health on dual contraceptive method use among college women in the United States. Sex Reprod Healthc. 2017;12:24–9.

    Article  Google Scholar 

  24. 24.

    Callegari LS, Zhao X, Nelson KM, Lehavot K, Bradley KA, Borrero S. Associations of mental illness and substance use disorders with prescription contraception use among women veterans. Contraception. 2014;90(1):97–103.

    Article  Google Scholar 

  25. 25.

    Steinberg JR, Adler NE, Thompson KM, Westhoff C, Harper CC. Current and past depressive symptoms and contraceptive effectiveness level method selected among women seeking reproductive health services. Soc Sci Med. 2018;214:20–5.

    Article  Google Scholar 

  26. 26.

    •• Lundin C, Danielsson KG, Bixo M, Moby L, Bengtsdotter H, Jawad I, et al. Combined oral contraceptive use is associated with both improvement and worsening of mood in the different phases of the treatment cycle—A double-blind, placebo-controlled randomized trial. Psychoneuroendocrinology. 2017;76:135–43 This large randomized, double-blind, placebo-controlled trial showed small positive mood benefit in the premenstrual phase and a smaller negative effect on mood in the intermenstrual phase, the latter effect driven by a subpopulation of susceptible women.

    CAS  Article  Google Scholar 

  27. 27.

    O’Connell K, Davis AR, Kerns J. Oral contraceptives: side effects and depression in adolescent girls. Contraception. 2007;75:299–304.

    Article  Google Scholar 

  28. 28.

    Graham CA, Ramos R, Bancroft J, Maglaya C, Farley TM. The effects of steroidal contraceptives on the well-being and sexuality of women: a double-blind, placebo-controlled, two-centre study of combined and progestogen-only methods. Contraception. 1995;52:363–9.

    CAS  Article  Google Scholar 

  29. 29.

    Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clinical epidemiology. 2013;6:1–13. https://doi.org/10.2147/CLEP.S37559.

  30. 30.

    Bishop S, Basch S, Futterweit W. Polycystic ovary syndrome, depression, and affective disorders. Endocr Pract. 2009;15:475–82.

    Article  Google Scholar 

  31. 31.

    Costello MF, Shrestha B, Eden J, Johnson NP, Sjoblom P. Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. Hum Reprod. 2007;22:1200–9.

    CAS  Article  Google Scholar 

  32. 32.

    Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4565–92.

    CAS  Article  Google Scholar 

  33. 33.

    Rasgon NL, Rao RC, Hwang S, Altshuler LL, Elman S, Zuckerbrow-Miller J, et al. Depression in women with polycystic ovary syndrome: clinical and biochemical correlates. J Affect Disord. 2003;74:299–304.

    Article  Google Scholar 

  34. 34.

    Cinar N, Harmanci A, Demir B, Yildiz BO. Effect of an oral contraceptive on emotional distress, anxiety and depression of women with polycystic ovary syndrome: a prospective study. Hum Reprod. 2012;27:1840–5.

    CAS  Article  Google Scholar 

  35. 35.

    Rubinow DR, Schmidt PJ. Gonadal steroid regulation of mood: the lessons of premenstrual syndrome. Front Neuroendocrinol. 2006;27:210–6.

    CAS  Article  Google Scholar 

  36. 36.

    Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998;338:209–16.

    CAS  Article  Google Scholar 

  37. 37.

    •• Schmidt PJ, Martinez PE, Nieman LK, Koziol DE, Thompson KD, Schenkel L, et al. Premenstrual dysphoric disorder symptoms following ovarian suppression: triggered by change in ovarian steroid levels but not continuous stable levels. Am J Psychiatr. 2017;174:980–9 This single-blind study of ovarian suppression followed by exogenous hormone treatment in women with PMDD demonstrated that it is the abrupt transition, rather than steady-state hormone concentration, that is associated with mood disruption.

    Article  Google Scholar 

  38. 38.

    •• Dubey N, Hoffman JF, Schuebel K, Yuan Q, Martinez PE, Nieman LK, Rubinow DR, et al. The ESC/E (Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Molecular Psychiatry 2017:22:1172. This RNA-seq study of cultured cells from women with PMDD showed that PMDD sufferers underexpress an estrogen-regulated gene silencing complex and that the effects of gonadal steroids on expression of these genes differ between PMDD sufferers and controls.

  39. 39.

    Freeman EW, Halbreich U, Grubb GS, Rapkin AJ, Skouby SO, Smith L, et al. An overview of four studies of a continuous oral contraceptive (levonorgestrel 90 mcg/ethinyl estradiol 20 mcg) on premenstrual dysphoric disorder and premenstrual syndrome. Contraception. 2012;85:437–45.

    CAS  Article  Google Scholar 

  40. 40.

    • Eisenlohr-Moul TA, Girdler SS, Johnson JL, Schmidt PJ, Rubinow DR. Treatment of premenstrual dysphoria with continuous versus intermittent dosing of oral contraceptives: results of a three-arm randomized controlled trial. Depress Anxiety. 2017;34:908–17 This randomized controlled trial showed positive benefits in all treatment arms, underscoring the powerful placebo effect in PMDD.

    CAS  Article  Google Scholar 

  41. 41.

    Yonkers KA, Brown C, Pearlstein TB, Foegh M, Sampson-Landers C, Rapkin A. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol. 2005;106:492–501.

    CAS  Article  Google Scholar 

  42. 42.

    Marr J, Niknian M, Shulman LP, Lynen R. Premenstrual dysphoric disorder symptom cluster improvement by cycle with the combined oral contraceptive ethinylestradiol 20 mcg plus drospirenone 3 mg administered in a 24/4 regimen. Contraception. 2011;84:81–6.

    CAS  Article  Google Scholar 

  43. 43.

    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;94:641–9.

    CAS  Article  Google Scholar 

  44. 44.

    Cirillo PC, Passos RBF, do Nascimento Bevilaqua MC, López JRRA, Nardi AE. Bipolar disorder and Premenstrual Syndrome or Premenstrual Dysphoric Disorder comorbidity: a systematic review. Rev Bras Psiquiatr. 2012;34:467–79.

    Article  Google Scholar 

  45. 45.

    Teatero ML, Mazmanian D, Sharma V. Effects of the menstrual cycle on bipolar disorder. Bipolar Disord. 2014;16:22–36.

    Article  Google Scholar 

  46. 46.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). Arlington: American Psychiatric Publishing; 2013.

    Book  Google Scholar 

  47. 47.

    Balzafiore D, Robakis T, Borish S, Budhan V, Rasgon N. The treatment of bipolar disorder in women. In: Carvalho AF, Vieta E, editors. The treatment of bipolar disorder: integrative clinical strategies and future directions: Oxford University Press; 2017.

  48. 48.

    Jensvold MF, Reed K, Jarrett DB, Hamilton JA. Menstrual cycle-related depressive symptoms treated with variable antidepressant dosage. J Women's Health. 1992;1:109–15.

    Article  Google Scholar 

  49. 49.

    • Yonkers KA, Kornstein SG, Gueorguieva R, Merry B, Van Steenburgh K, Altemus M. Symptom-onset dosing of sertraline for the treatment of premenstrual dysphoric disorder: a randomized clinical trial. JAMA Psychiatry. 2015;72:1037–44 This large multicenter RCT supported the rapid efficacy of symptom-onset dosing of antidepressants for PMDD, with no evidence of withdrawal effects on cessation.

    Article  Google Scholar 

  50. 50.

    Dias RS, Lafer B, Russo C, Del Debbio A, Nierenberg AA, Sachs GS, et al. Longitudinal follow-up of bipolar disorder in women with premenstrual exacerbation: Findings from STEP-BD. Am J Psychiatr. 2011;168:386–94.

    Article  Google Scholar 

  51. 51.

    Ghaemi SN, Rosenquist KJ, Ko JY, Baldassano CF, Kontos NJ, Baldessarini RJ. Antidepressant treatment in bipolar versus unipolar depression. Am J Psychiatr. 2004;161:163–5.

    Article  Google Scholar 

  52. 52.

    Slyepchenko A, Frey BN, Lafer B, Nierenberg AA, Sachs GS, Dias RS. Increased illness burden in women with comorbid bipolar and premenstrual dysphoric disorder: data from 1099 women from STEP-BD study. Acta Psychiatr Scand. 2017;136:473–82.

    CAS  Article  Google Scholar 

  53. 53.

    Herzog AG, Blum AS, Farina EL, Maestri XE, Newman J, Garcia E, et al. Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use. Neurology. 2009;72:911–4.

    CAS  Article  Google Scholar 

  54. 54.

    Andreasen AH, Brøsen K, Damkier P. A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on cyp3a4. Epilepsia. 2007;48:490–6.

    CAS  Article  Google Scholar 

  55. 55.

    Nallani SC, Glauser TA, Hariparsad N, Setchell K, Buckley DJ, Buckley AR, et al. Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate. Epilepsia. 2003;44:1521–8.

    CAS  Article  Google Scholar 

  56. 56.

    Robakis TK, Holtzman J, Stemmle PG, Reynolds-May MF, Kenna HA, Rasgon NL. Lamotrigine and GABAA receptor modulators interact with menstrual cycle phase and oral contraceptives to regulate mood in women with bipolar disorder. J Affect Disord. 2015;175:108–15.

    CAS  Article  Google Scholar 

  57. 57.

    Kornstein SG, Harvey AT, Rush AJ, Wisniewski SR, Trivedi MH, Svikis DS, et al. Self-reported premenstrual exacerbation of depressive symptoms in patients seeking treatment for major depression. Psychol Med. 2005;35:683–92.

    CAS  Article  Google Scholar 

  58. 58.

    Kornstein SG, Toups M, Rush AJ, Wisniewski SR, Thase ME, Luther J, et al. Do menopausal status and use of hormone therapy affect antidepressant treatment response? Findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR* D) study. J Women's Health. 2013;22:121–31.

    Article  Google Scholar 

  59. 59.

    Young EA, Kornstein SG, Harvey AT, Wisniewski SR, Barkin J, Fava M, et al. Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression. Psychoneuroendocrinology. 2007;32:843–53.

    CAS  Article  Google Scholar 

  60. 60.

    Berry-Bibee EN, Kim MJ, Simmons KB, Tepper NK, Riley HE, Pagano HP, et al. Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic review. Contraception. 2016;94:650–67.

    CAS  Article  Google Scholar 

  61. 61.

    Haley CL, Sung SC, Rush AJ, Trivedi MH, Wisniewski SR, Luther JF, et al. The clinical relevance of self-reported premenstrual worsening of depressive symptoms in the management of depressed outpatients: a STAR*D Report. J Women's Health. 2013;22:219–29.

    Article  Google Scholar 

  62. 62.

    Joffe H, Petrillo LF, Viguera AC, Gottshcall H, Soares CN, Hall JE, et al. Treatment of premenstrual worsening of depression with adjunctive oral contraceptive pills: a preliminary report. The Journal of Clinical Psychiatry. 2007;68:1954–62.

    CAS  Article  Google Scholar 

  63. 63.

    Maki PM, Kornstein SG, Joffe H, Bromberger JT, Freeman EW, Athappilly G, et al. Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations. Menopause. 2018;25:1069–85.

    Article  Google Scholar 

  64. 64.

    Alonso P, Gratacos M, Segalas C, Escaramis G, Real E, Bayes M, et al. Variants in estrogen receptor alpha gene are associated with phenotypical expression of obsessive-compulsive disorder. Psychoneuroendocrinology. 2011;36:473–83.

    CAS  Article  Google Scholar 

  65. 65.

    Abramowitz JS, Schwartz SA, Moore KM, Luenzmann KR. Obsessive-compulsive symptoms in pregnancy and the puerperium: a review of the literature. J Anxiety Disord. 2003;17:461–78.

    Article  Google Scholar 

  66. 66.

    Hill RA, McInnes KJ, Gong EC, Jones ME, Simpson ER, Boon WC. Estrogen deficient male mice develop compulsive behavior. Biol Psychiatry. 2007;61:359–66.

    CAS  Article  Google Scholar 

  67. 67.

    Williams KE, Koran LM. Obsessive-compulsive disorder in pregnancy, the puerperium, and the premenstruum. The Journal of Clinical Psychiatry. 1997;58:330–4.

    CAS  Article  Google Scholar 

  68. 68.

    Vulink NC, Denys D, Bus L, Westenberg HG. Female hormones affect symptom severity in obsessive–compulsive disorder. Int Clin Psychopharmacol. 2006;21:171–5.

    Article  Google Scholar 

  69. 69.

    Labad J, Menchón JM, Alonso P, Segalàs C, Jiménez S, Vallejo J. Oral contraceptive pill use and changes in obsessive–compulsive symptoms. J Psychosom Res. 2006;60:647–8.

    Article  Google Scholar 

  70. 70.

    Guiloff E, Ibarra-Polo A, Zanartu J, Tascanini C, Mischler TW, Gomez-Rogers C. Effect of contraception on lactation. Am J Obstet Gynecol. 1974;118:42–5. https://doi.org/10.1016/S0002-9378(16)33643-2.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Roberts TA, Hansen S. Association of hormonal contraception with depression in the postpartum period. Contraception. 2017;96:446–52.

    CAS  Article  Google Scholar 

  72. 72.

    Toffoletto S, Lanzenberger R, Gingnell M, Sundstrom-Poromaa I, Comasco E. Emotional and cognitive functional imaging of estrogen and progesterone effects in the female human brain: a systematic review. Psychoneuroendocrinology. 2014;50:28–52.

    CAS  Article  Google Scholar 

  73. 73.

    Pluchino N, Cubeddu A, Giannini A, Merlini S, Cela V, Angioni S, et al. Progestogens and brain: an update. Maturitas. 2009;62:349–55.

    CAS  Article  Google Scholar 

  74. 74.

    Gingnell M, Engman J, Frick A, Moby L, Wikstrom J, Fredrikson M, et al. Oral contraceptive use changes brain activity and mood in women with previous negative affect on the pill — a double-blinded, placebo-controlled randomized trial of a levonorgestrel-containing combined oral contraceptive. Psychoneuroendocrinology. 2013b;38:1133–44.

    CAS  Article  Google Scholar 

  75. 75.

    Lisofsky N, Riediger M, Gallinat J, Lindenberger U, Kühn S. Hormonal contraceptive use is associated with neural and affective changes in healthy young women. Neuroimage. 2016;134:597–606.

    CAS  Article  Google Scholar 

  76. 76.

    Petersen N, Cahill L. Amygdala reactivity to negative stimuli is influenced by oral contraceptive use. Soc Cogn Affect Neurosci. 2015;10(9):1266–72.

    Article  Google Scholar 

  77. 77.

    Rohleder N, Wolf JM, Piel M, Kirschbaum C. Impact of oral contraceptive use on glucocorticoid sensitivity of pro-inflammatory cytokine production after psychosocial stress. Psychoneuroendocrinology. 2003;28(3):261–73.

    CAS  Article  Google Scholar 

  78. 78.

    Montoya ER, Bos PA. How oral contraceptives impact social-emotional behavior and brain function. Trends Cogn Sci. 2017;21(2):125–36.

    Article  Google Scholar 

  79. 79.

    Aleknaviciute J, Tulen JHM, De Rijke YB, Bouwkamp CG, van der Kroeg M, Timmermans M, et al. The levonorgestrel-releasing intrauterine device potentiates stress reactivity. Psychoneuroendocrinology. 2017;80:39–45.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Thalia Robakis.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Reproductive Psychiatry and Women's Health

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Robakis, T., Williams, K.E., Nutkiewicz, L. et al. Hormonal Contraceptives and Mood: Review of the Literature and Implications for Future Research. Curr Psychiatry Rep 21, 57 (2019). https://doi.org/10.1007/s11920-019-1034-z

Download citation

Keywords

  • Oral contraceptive
  • Mood
  • Depressive disorders
  • Anxiety disorders
  • PCOS