The pill is not ‘the’ pill

We prescribed it like it was the same drug for every woman. It never was. Maybe we need to take some of the blame for the anti-pill movement?

I remember seeing post zero. At least I think it was post zero. It was one of those banal social media posts that millennials and gen x’s like me look at with a scrunched up face wondering how on earth that goes viral, missing the point entirely that that is what it’s all about.

She carefully unfolds the information insert from her pill packet in a poorly lit room, a tiny square turns into an impressive A1 sheet, covered in illegible small print: the side effects. The camera zooms in as a haunting audio of a girl screaming plays over and over.

10 seconds. No words, context or story. Millions of views. And just like that, the space women had been unknowingly waiting for had been created. Women who had been dismissed about the experiences they had had on the pill over the years, whom we had bashed down with our population based evidence like a game of complaint whack-a-mole, had validation. ‘The pill may have liberated us but it’s far from perfect and some of us feel awful on it’, was the message.

To be clear, I’m not ‘anti-pill’. Far from it; it stops me from having recurrent lung collapses and bleeding into my chest cavity from my thoracic endometriosis. It has enabled me to live a pretty ‘normal’ life, for the outsider looking in, despite having a pelvis that looks like it’s gone to war with a cheese grater and a litre of concrete. But, I’ve been on some preparations of the pill that make the thought of weeks of solitary confinement under a duvet seem desperately appealing. I can empathise with these women.

And whilst I really don’t like the way the ‘anti-pill’ rhetoric has progressed since then, dangerously so, it has made me reflect on how we, as a profession, have contributed to getting here.

When women told us they were struggling, we reached for the population data and used it to close the conversation down rather than stay curious to associations yet undiscovered. We prescribed the pill like it was the same drug for every woman. We prescribed whatever the formulary allowed, which was to be fair the safest from a clotting risk point of view, without explaining that the progestin in one pill is not the same as a progestin in another, that the oestrogen dose matters, and that the variation in chemical structure between formulations translates into meaningfully different effects in different bodies. We treated a class of drug as a single entity, when it was not.

But the evidence is now beginning to tell us that whilst this approach may be fine for many women, there are significant subsets of women who may struggle more than others and that this is further impacted by the type of pill that is given. Certain biological characteristics appear to modify how individual women respond to the pill, and we are getting better at identifying what those are.

‘The’ pill is not one drug

What we haven’t explained enough is that the pill, is not ‘the’ pill at all. There are 100s of formulations that differ by oestrogen type, oestrogen dose, type of progestin and whether the dosing changes across the month or not (monophasic or multiphasic).

And each one of these differences can change the side effect profile or be utilised to provide a benefit. For example if a woman is on a low dose oestrogen pill and experiencing breakthrough bleeding or low libido, you might up the oestrogen dose. Conversely, if she is getting lots of oestrogenic side effects on the higher oestrogen pill; nausea, breast tenderness, you might drop her to a lower dose one. A pill that has the body identical oestrogen oestradiol in it, might be more suitable for a woman in perimenopause who wants contraception and better symptom management in one pill, over the synthetic oestrogen containing pills.

Progestin type also matters. An anti-androgenic progestin may not be suitable for a woman with low libido, but might be great for a woman with acne brought on by an androgenic progestin.

And progestin type also matters for mood.

Progestin type and mood

Progestins are synthetic, lab made, versions of our own natural progesterone hormone. They are very similar to progesterone, enough to attach to its receptors and create progesterone like effects, but they’re not exactly the same and can also attach to other receptors.

First and second-generation progestins (the earlier versions), including levonorgestrel and norethisterone, have some androgenic activity and that can worsen acne, cause weight gain and affect mood in some women.

Third and fourth-generation progestins either have a neutral effect on androgen receptors or are actually anti-androgenic, like drosperinone, making them useful for women with acne, hirsutism, or fluid retention. Drosperinone is also the progestin in the only combined pill formulation licensed specifically for PMDD. However, the trade-off here is they tend to have higher clotting risk profiles so usually aren’t given as first line.

Unfortunately, personalised prescribing of the pill has not always been routine practice. In the UK for example, the most commonly prescribed combined pills contain androgenic 1^st or 2^nd generation progestins (e.g. Microgynon, Rigevidon, Ovranette, Brevinor). They carry the lowest clotting risk and are the cheapest making them the perfect first line option. However, these androgenic containing progestins are also known to negatively affect mood in some women.

The reason progestin type influences mood is thought to be partly due to the effect of their metabolites on the brain. Progesterone is metabolised in the brain into neuroactive steroids, the most important of which is allopregnanolone: a natural calming agent that acts on the same receptors targeted by sedatives. Fluctuations in its levels are now understood to be central to mood disorders including PMDD (premenstrual dysphoric disorder, a severe form of PMS) and, potentially, to the mood sensitivity some women experience on hormonal contraception.

Natural progesterone is readily converted to allopregnanolone. Synthetic progestins, however, vary considerably in how readily this conversion occurs, meaning different progestins produce different levels in the brain. Progestins also appear to differ in their effects on other mood-regulating neurotransmitter systems, including serotonin, though the exact mechanisms aren’t fully understood. But what we do know is that androgenic and anti-androgenic progestins seem to differ in their neurological effects, with the former seeming to have more negative impacts.

Having said that, we also know that there are some women who are simply intolerant to all progestogens (synthetic or natural), which is referred to as progesterone intolerance.

Who reacts differently, and why

Mood disturbance is one of the commonest reasons for a woman to discontinue hormonal contraception and yet, not all women will experience mood problems. We now know there are some risk factors that make it more likely.

Adolescents

Emerging evidence suggests that adolescents may be particularly vulnerable to mood effects from hormonal contraception. Large population studies have found significant associations between hormonal contraception and depression or psychotropic drug use in adolescent girls, while finding little or no significant association in adult women. The type of progestin also appears to be relevant.

The increase in absolute risk is small though; 1 in 100 risk of being prescribed an antidepressant for a 12-14 year old not on the pill, versus 4 in 100 on the pill. So not an insignificant increase but nor is it deterministic. And of course this risk needs to be considered in context; her medical history, risks of not using reliable contraception, risk of unintended pregnancy with its own profound effects on mental and physical health.

Women with pre-existing PMS or mood disorders

A 2021 Swedish study found that women with a previous or ongoing mental health problem had nearly double the odds of experiencing mood side effects from hormonal contraception compared to women without any mental health history. This is supported by a placebo-controlled trial from 2018, which found that women with a history of mood, anxiety, or eating disorders who took a combined oral contraceptive had significantly worse mood scores than those given a placebo. Women without pre-existing mental health problems showed no mood difference between the pill and placebo at all. This suggests that the mood effects attributed to the pill at a population level may be largely driven by a subgroup of women who are biologically predisposed to them, rather than being a universal effect of the drug.

A 2026 UK study of 1,133 contraceptive users found that women with pre-existing PMS were 2.5 times more likely to stop the combined pill due to side effects, and 2.3 times more likely to stop the progestogen-only pill. Women with a history of anxiety or mood disorders were also more likely to discontinue the combined pill. Mood problems were the most commonly reported reason for stopping overall.

Notably, this pattern was not seen with the hormonal IUD, which works locally at much lower systemic hormone levels and avoids the daily hormonal peaks and troughs of oral methods. This may matter: it suggests that for women with pre-existing PMS or mood disorders, it is not necessarily progestogen itself that is the problem, but the way oral methods deliver it.

Women with ADHD

There is growing evidence that women with ADHD represent a specific subgroup with heightened sensitivity to oral hormonal contraception. A large Swedish national register study covering nearly 30,000 girls and young women with ADHD and over 760,000 without, found that women with ADHD already carry a threefold higher baseline risk of depression irrespective of contraceptive use. When taking a combined oral contraceptive, their risk of depression was substantially elevated further, with women with ADHD on the pill showing approximately five times the depression risk of non-ADHD women not using hormonal contraception. The progestogen-only pill produced a similarly elevated risk. Non-oral hormonal methods, including the implant and hormonal IUD, appeared to carry a lower excess risk in preliminary analysis, leading researchers to speculate that daily hormonal fluctuation from pill-taking may be a contributing factor, though this finding requires confirmation in larger studies.

Women with ADHD are also at substantially elevated risk of PMDD: a 2025 British Journal of Psychiatry study found that over 40% of women meeting an ADHD symptom threshold met criteria for provisional PMDD, compared to under 10% of controls. And as we see above, women with PMS symptoms have a higher risk of side effects with the pill.

A call for more personalised prescribing

A history of PMS, a mood disorder, ADHD, progesterone intolerance or being an adolescent is not necessarily a reason to not take hormonal contraception at all if there are other reasons that make taking it compelling, but it is a reason to prescribe it differently. The type, the dose and route of the contraception may need to be carefully considered, and these women will need more thorough counselling, earlier follow-up, and a lower threshold for switching formulation or method if symptoms occur.

The pill is such a useful medication for so many things. A cure? No. But an effective treatment? Absolutely! I hate to see 60 years of development and a solid evidence base for its contraceptive and therapeutic efficacy be completely trashed by what the ‘anti-pill’ movement has become. The women being steered away from it entirely by social media without consideration for each woman’s own context, sometimes into fertility awareness apps with no clinical validation or unintended pregnancy, are not being better served.

But we also have to be honest about where we went wrong. The women whose side effects were dismissed with population statistics were not being well served either. What the evidence is now giving us is something more valuable than a blanket verdict: the tools to identify which women are likely to do well on which formulation, to have a different conversation with an adolescent than with a 30-year-old, to recognise ADHD or a history of progesterone sensitivity as signals for a different approach.

We should have been saying this for years. The pill is not ‘the’ pill. And its prescription needs a personalised approach.

 

References

· Douxfils J et al. Are natural estrogens used in contraception at lower risk of venous thromboembolism than synthetic ones? A systematic literature review and meta-analysis. Frontiers in Endocrinology. 2024.

· Didembourg M et al. Lower reporting of venous thromboembolism events with natural estrogen-based COCs compared to ethinylestradiol containing pills: A disproportionality analysis of the Eudravigilance database. Contraception. 2024.

· Stegeman BH et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ. 2013.

· Zettermark S et al. 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.

· Kraft MZ et al. Symptoms of mental disorders and oral contraception use: A systematic review and meta-analysis. Frontiers in Neuroendocrinology. 2023.

· Pletzer B et al. Progesterone and contraceptive progestin actions on the brain: A systematic review of animal studies and comparison to human neuroimaging studies. Frontiers in Neuroendocrinology. 2023.

· Bengtsdotter H et al. Ongoing or previous mental disorders predispose to adverse mood reporting during combined oral contraceptive use. European Journal of Contraception and Reproductive Health Care. 2018.

· Lundin C et al. Towards individualised contraceptive counselling: clinical and reproductive factors associated with self-reported hormonal contraceptive-induced adverse mood symptoms. BMJ Sexual and Reproductive Health. 2021.

· Lundin C et al. Hormonal Contraceptive Use and Risk of Depression Among Young Women With Attention-Deficit/Hyperactivity Disorder. Journal of the American Academy of Child and Adolescent Psychiatry. 2022.

· Broughton T et al. Increased risk of provisional premenstrual dysphoric disorder (PMDD) among females with attention-deficit hyperactivity disorder (ADHD): cross-sectional survey study. The British Journal of Psychiatry. 2025.

· Wynchank D et al. Menstrual Cycle-Related Hormonal Fluctuations in ADHD: Effect on Cognitive Functioning: A Narrative Review. Journal of Clinical Medicine. 2025.

· Stevens R et al. Patterns of contraceptive side-effect variation: assessing medical and lifestyle factors associated with side-effects among those using hormonal contraception in the United Kingdom. European Journal of Obstetrics and Gynaecology and Reproductive Biology. 2026.