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Combined oral contraceptive pill and depression

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Oral contraceptive pill and depression

Oestrogen and progesterone influence neurochemistry, brain function and the activity of neurotransmitters gamma-aminobutyric acid, serotonin and dopamine (1)

  • hormonal contraception is known to precipitate or perpetuate depression in some patients (1)
    • the link between oral contraceptive pills and depression relates to the amount and type of progestogen contained in these pills (1)
      • progesterone component is usually a 19-nortestosterone derivative, such as desogestrel, etynodiol diacetate, gestodene, levonorgestrel, lynestronol, norethisterone, norethisterone acetate, norgestimate or norgestrel
      • progesterone receptors alpha and beta are most abundant in the amygdala, cerebellum, cortex, hippocampus and hypothalamus

  • many of the older oral contraceptive pills, which contain ethinylestradiol, are linked to severe mood problems (1)
    • typically, the oestrogen component of oral contraceptive pills contains 20-50 micrograms ethinylestradiol, although newer oral contraceptive pills contain physiological forms of oestrogen such as estradiol and estradiol valerate.
    • newer oral contraceptive pills containing physiological forms of oestrogen may be better tolerated with a purported weaker link to mood problems
    • oestrogen receptors (ER)- alpha and ER-beta are widely distributed in the brain, with ER-alpha mainly found in the hypothalamus, hippocampus, amygdala and brainstem
    • been hypothesized that the increased risk later in life among those who used oral contraceptives during adolescence may be attributed to a greater susceptibility to gonadal hormones, including hormonal contraception, during crucial developmental periods that affect the organization of brain structures and may lead to long-lasting changes (2)

  • study evidence showed (2):
    • showed that oral contraceptive (OC) use is associated with an increased risk of depression shortly after initiation
    • study results suggest that the risk of depression is increased not only among adolescents initiating OCs but also among women older than 20 years
    • increased risk declined with continued OC use, but the lifetime risk associated with ever OC use remained significantly increased
    • results could be explained by hormonal fluctuations induced by OC initiation, which can affect women who are particularly sensitive to changes in the levels of hormones and their metabolites, such as allopregnanolone
      • fluctuations could alter GABAergic regulation of the hypothalamic-pituitary-adrenocortical in this group of women


  • Mu E, Kulkarni J. Hormonal contraception and mood disorders. Aust Prescr. 2022 Jun;45(3):75-79. doi: 10.18773/austprescr.2022.025. Epub 2022 Jun 1. Erratum in: Aust Prescr. 2022 Aug;45(4):147. PMID: 35755988; PMCID: PMC9218393.
  • Johansson, T., Vinther Larsen, S., Bui, M., Ek, W., Karlsson, T., & Johansson, Å. (2023). Population-based cohort study of oral contraceptive use and risk of depression. Epidemiology and Psychiatric Sciences, 32, E39. doi:10.1017/S2045796023000525

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