Is the Oral Contraceptive Pill Associated with Depression?- A Synopsis of The Impact of OC Pills on Mood

SUMMARY OF ORAL CONTRACEPTIVES - TYPES AND DOSAGES

At present, the most common hormonal contraceptive is the combination oral contraceptive (COC), which has estrogen and a progestin component to it.

Modern COCs contain much lower levels of estrogen, and progestin, and are typically deemed to have little effect on the physical and mental health of the user.

Dosage Amounts and Cycles

The COC pill typically contains between 0.02 and 0.04 milligrams of ethinylestradiol as well as different types and amounts of synthetic progestin.

The different types and concentrations have been reported to cause different estrogenic, progestational and androgenic effects. Even small decreases in dosing have been reported to cause significant improvements in premenstrual mood and depressive scores.

Monophasic or Multiphasic

Contraceptives can also be monophasic or multiphasic.

Monophasic – where the same dose of estrogen or progestin is delivered daily

Multiphasic – have varying dosages of hormones throughout a 3-4 week cycle. Multiphasic preparations were originally designed to provide effective contraception without overexposure to progestin alone.

Route of Administration

Hormonal contraceptives can be orally consumed or in the form of a contraceptive device. The route of administration may also play a role in observable adverse side effects.

For instance, users of the vaginal ring have reported less emotional lability when compared to oral contraceptive users.

However, the data in the literature is conflicting. There are as many studies showing nothing significant between different contraceptive formulations as there are studies showing differences in side effects. [Schaffir J et al.,2016 ]

Taken together, the constituents, dosage, the pattern of dosage (monophasic or multiphasic) and the ratio of progesterone to estrogen are all variables that can change the outcome on mood.

Although there is a consensus on high dosage contraceptives associated with an increase in negative moods, there is no consensus on the ratios or any other contraceptive-related variable with an increased risk of mood changes.

MECHANISM OF ACTION OF ORAL CONTRACEPTIVES

Modern hormonal contraceptives have multiple biological effects with the primary objective to manipulate events throughout the ovulatory cycle.

For some, the primary mechanism is to inhibit follicular development while for others it is to either inhibit ovulation or change the cervical mucus to inhibit sperm penetration.

Many hormonal contraceptives are designed to directly oppose androgen production through negative feedback pathways. By inhibiting secretion of hormones such as luteinizing hormone and follicle-stimulating hormone from the anterior pituitary in the brain, hormonal contraceptives effectively inhibit ovulation.

FEMALE HORMONES AND THE BRAIN

Both estrogen and progesterone influence the brain in many different ways.

The effects of ovarian hormones on the brain begin early in brain development and continue throughout adolescence and adulthood, playing an important role in learning, memory, motivation, motor control, cognition and neuroplasticity. [Gillies, G. E., & McArthur, S., 2010]

Ovarian hormones also have excitatory and inhibitory effects on various neurotransmitters. [Barth C et al., 2015]

Following are some of the key mechanisms of action of ovarian hormones on the brain: 

• Estrogen receptors ERα and ERβ are widely distributed in the brain with ERα situated in the hippocampus, hypothalamus, amygdala and brain stem.
• Estrogen facilitates glutamate transmission and suppresses GABA inhibitory input. This facilitatory effect of estrogen at glutamate NMDA receptors is responsible for plasticity, learning and memory. Progesterone suppresses the glutamate response and facilitates GABAergic neurotransmission.
• Estrogen can increase serotonin levels and decreases 5-HT reuptake. Progesterone increases serotonergic neurotransmission via the regulation of the expression of serotonin-related genes and proteins. Estrogen and progesterone are also known to modify serotonergic responsivity to SSRI administration.
• Estrogen increases dopamine release in the striatum by reducing the GABAergic inhibitory tone.
• Progesterone, as well as allopregnanolone, interacts with dopaminergic systems. In the striatum,  progesterone can stimulate dopamine release only if there has been a preexposure to estrogen which could be associated with the observed improvement in sensorimotor functions during phases of the menstrual cycle when progesterone is elevated. [Del Rio, 2018]
• These mechanisms are, thus, used therapeutically, e.g. in the case of HRT for the treatment of menopausal and post-menopausal symptoms. Prof Kulkarni covered the treatment of mood disorders in menopausal/perimenopausal women in a previous post. 
• Tibolone is a synthetic steroid hormone and an alternative to conventional HRT. View the lecture by Prof Kulkarni on Tibolone in perimenopausal depression.
• Selective estrogen receptor modulators (SERM’s) such as Tamoxifen and Raloxifene are being proposed as brain therapeutic agents in conditions such as cognitive decline, affective disorders, Alzheimer’s disease and stroke. [Arevallo M et l, 2011]

ORAL CONTRACEPTIVES AND THE BRAIN

Synthetic sex steroids that are used in hormonal contraceptives are associated with functional and structural changes in the brain that affect cognitive performance, behaviour, personality and emotion.

There are several proposed mechanisms on how hormonal contraceptives affect the brain and behaviour.

1. Synthetic hormonal contraceptives act on estrogen and progesterone receptors, and this has many downstream actions covered earlier.
2. Hormonal contraceptives can reduce endogenous testosterone possibly by increasing sex hormone binding globulin, which reduces the availability of testosterone and leads to estrogen dominance or a feminising effect on the brain.
3. Alternatively, hormonal contraceptives can also result in a reduction of endogenous estradiol and progesterone. In some cases, this can lead to more physiologically active testosterone and thereby facilitates a masculinising effect on the brain.
4. OCP’s suppress vitamin B6 and vitamin B12 metabolism causing a subsequent decrease in serotonin and GABA levels in the brain. [William A et al.,2005]
5. Oral contraceptives reduce the levels of serotonin primarily through increasing MAO activity. However, in contrast, hormonal contraceptives have also been reported to improve and stabilise mood and that this is likely to involve an increase in serotonin through inhibition of MAO.[Barth C et al., 2015]

CONTRACEPTIVES AND MENTAL HEALTH

Hormonal contraceptives have been on the market since 1960 and have been prescribed to at least 100 million women worldwide. However, the effect of sex steroid contraceptives on mental health is under-researched and what has been published shows conflicting evidence.

This is in contrast to anabolic steroids, which have been well researched and show significant structural and functional changes to the brains of steroid users.

Early studies on the first generation of hormonal contraceptives showed that oral contraceptives with high progestin content could cause depression in healthy women. Herzberg B et al.,1970

Progestin-only forms were originally more favourable because they were longer acting and required less compliance from the user.

Today, newer formulations of progestin-only contraceptives contain synthetic progestins that are similar to progesterone but have a higher specificity and fewer reported side effects.

In one study researchers analysed the effect of progestin-only contraceptives on the mental health of women.[Westhoff C et al.,1998]

Results showed that 93 of 910 women in the study dropped out due to significant negative health issues. Further analysis of these women six months later showed that they had higher depression scores than those who remained in the study.

In another similar study, by the same researchers, 218 out of 495 women dropped out of the study while testing another progestin-only contraceptive (Depo-Provera containing medroxyprogesterone acetate). [Westhoff C et al., 1998]

The reason for dropping out was attributed to higher depressive scores. In contrast, those that remained in the study had a positive change in mood scores on follow-up. Thus, it appears that for some, progestin-only contraceptives may worsen mood but only in women who are susceptible to it.

CONTRACEPTIVES AND DEPRESSION

A study published in 2016 in JAMA Psychiatry investigated whether using hormonal contraception was associated with future use of antidepressants.[Skovlund C et al.,2016]

This was a very large prospective cohort study that included 1,061,997 women with an average age of 24 years. By comparing users of hormonal contraception with non-users, the researchers found contraceptive users were 23% more likely to be prescribed antidepressants at a later date.

Compared with nonusers, users of combined oral contraceptives had an RR of first use of an antidepressant of 1.23 (95% CI, 1.22-1.25). Users of progestogen-only pills had an RR for first use of an antidepressant of 1.34 (95% CI, 1.27-1.40); users of a patch (norgestrolmin), 2.0 (95% CI, 1.76-2.18); users of a vaginal ring (etonogestrel), 1.6 (95% CI, 1.55-1.69); and users of a levonorgestrel intrauterine system, 1.4 (95% CI, 1.31-1.42). For depression diagnoses, similar or slightly lower estimates were found. The relative risks generally decreased with increasing age. Adolescents (age range, 15-19 years) using combined oral contraceptives had an RR of a first use of an antidepressant of 1.8 (95% CI, 1.75-1.84) and those using progestin-only pills, 2.2 (95% CI, 1.99-2.52). Six months after starting use of hormonal contraceptives, the RR of antidepressant use peaked at 1.4 (95% CI, 1.34-1.46). When the reference group was changed to those who never used hormonal contraception, the RR estimates for users of combined oral contraceptives increased to 1.7 (95% CI, 1.66-1.71).

Although it is difficult to draw firm conclusions from the literature as a whole, these new findings are suggestive of a clinical association between hormonal contraceptive use and future adverse mood affects.

The most recent published study examined 1,236 women in the United States National Health and Nutrition Examination Survey compared women who reported first use of oral contraceptives in adolescence to women who had never used oral contraceptives and women who had first used oral contraceptives in adulthood on 1‐year prevalence of major depressive disorder (MDD) assessed by trained interviewers.

The study showed a long‐term association between adolescent oral contraceptive use and depression risk in adulthood regardless of current oral contraceptive use.

Our findings suggest that adolescence may be a sensitive period during which OC use could increase women’s risk for depression, years after first exposure. [Anderl C et al., 2019]

THE BIG PICTURE

The literature at present describes many benefits and risks to hormonal contraceptives. Low-dose oral prescriptions offer relative safety and efficacy when compared to first generation higher dose oral contraceptives.

They prevent unwanted pregnancies, exert improvements in the menstrual cycle, and in some cases, reducing mood swings and may relieve mental health issues such as anxiety.

However, the literature also presents many health risks of oral contraceptives. Concerns are primarily about an increased risk of cardiovascular diseases and increased risk of affective mood disorders and depression.

Overall, family planning is key to safe population growth, but healthcare professionals should be mindful of the risk of adverse effects when prescribing hormonal contraceptives.

Identification of patients that are vulnerable to these risks through measuring baseline hormonal levels, assessing hormone sensitivity through menstrual cycle mood history and a history of previous mental health issues is critical.

As we celebrate the more than half a century of the pill, we can reflect on its legacy and its importance for patients, their families, and the planet, which logged its 7 billionth inhabitant in the fall of 2011. We can recall the cautionary tales it told from its origins to its current variations. The pill led the way but we need creative exploration of choice, access, and safety in controlling fertility for the future. (Liao, 2010)

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