A Synopsis of The Impact of Oral Contraceptive Pills on Mood

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

Authors: Dr. Sanil Rege MBBS, MRCPsych, FRANZCP,
Dr. James Graham PhD

August 23, 2017

Throughout the history of medicine, thousands of drugs have been developed, but
only one has been influential enough to earn the title of simply, the pill. Introduced in
May 1950, the oral contraceptive pill is a medical innovation that has
dramatically transformed generations. Women have gained incredible freedom
and reproductive autonomy. The birth control pill separated sexual practice from
conception, forcing re-assessment and reevaluation of social, political, and religious
viewpoints.

The first real large-scale trial of the pill was conducted in 1956 in Rio Piédras, a
Puerto Rican housing project. The 200-plus women involved in the trial received little
information about the safety of the product they were given, as there was none to
give, and no one thought that it might be necessary to provide such information. That
was the standard of the day. Women who stepped forward to describe side effects of
nausea, dizziness, headaches, and blood clots were discounted as “unreliable
historians.”Despite the substantial positive effect of the pill, its history is marked by a
lack of consent, a lack of full disclosure, a lack of true informed choice, and a lack of
clinically relevant research regarding risk. These are the pill’s cautionary tales. [1]

Hormonal contraception is available in oral pills and formulations stored within a
device such as a transdermal patch, vaginal ring or a subcutaneous implant. As
for contraceptives, they all provide an effective and safe method for the prevention of
pregnancy. Regardless of formulation, expected failure rates are <2%. However,
typical failure rates are between 3-5% due to accidental non-compliance. [2]

SUMMARY OF ORAL CONTRACEPTIVES - TYPES AND DOSAGES

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At present, the most common hormonal contraceptive is the combination oral
contraceptive (COC), which has an 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. [3]

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.

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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.

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.

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. [4]

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Ovarian hormones also have excitatory and inhibitory effects on various
neurotransmitters. [5]

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 regulation of
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.

 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 treatment of mood disorders in menopausal/perimenopausal
women in a previous post Hormones and Mental Illness in Women –
PMDD/Depression and the Pill/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. [6]

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.

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4. OCP’s suppress vitamin B6 and vitamin B12 metabolism causing a subsequent
decrease in serotonin and GABA levels in the brain. [7]

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.[5]

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.[8]

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.[9]

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). [10]

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.

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CONTRACEPTIVES AND DEPRESSION

A study published in 2016 in JAMA Psychiatry investigated whether using
hormonal contraception was associated with future use of
antidepressants.[11]

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 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.

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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)

References

1. Liao, P. V., & Dollin, J. (2012). Half a century of the oral contraceptive pill. Canadian
Family Physician, 58(12), e757-e760.

2. Frye C. An overview of oral contraceptives: mechanism of action and clinical
use. Neurology. 2006

3. Schaffir J et al., Combined hormonal contraception and its effects on mood: a critical
review. The European Journal of Contraception & Reproductive Health Care. 2016.

4. Gillies, G. E., & McArthur, S. (2010). Estrogen actions in the brain and the basis for
differential action in men and women: a case for sex-specific medicines. Pharmacological
reviews, 62(2), 155-198.

5. Barth, C., Villringer, A., & Sacher, J. (2015). Sex hormones affect neurotransmitters and
shape the adult female brain during hormonal transition periods. Frontiers in neuroscience,
9.

6. Arevalo, M. A., Santos-Galindo, M., Lagunas, N., Azcoitia, I., & Garcia-Segura, L. M.
(2011). Selective estrogen receptor modulators as brain therapeutic agents. Journal of
molecular endocrinology, 46(1), R1-R9.

7. William A et al., The role for vitamin B-6 as treatment for depression: a systematic
review. Family Practice. 2005.

8. Herzberg B et al., Depressive symptoms and oral contraceptives. British Medical Journal.
1970.

9. Westhoff C et al., Depressive symptoms and Norplant contraceptive
implants. Contraception. 1998

10. Westhoff C et al., Depressive symptoms and Depo-Provera. Contraception. 1998

11. Skovlund C et al., Association of hormonal contraception with depression. JAMA
Psychiatry. 2016

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