When the luteal phase never seems to end
Perimenopause has typically been documented to start in someone’s 40’s, but many women are experiencing it far earlier. A recent study of over 4,400 women found that more than half aged 30-35 were already experiencing perimenopause symptoms - and of those who’d seen a doctor, over a quarter received a confirmed diagnosis (1). Yet, because this is not the textbook age, many are dismissed as “too young”.
For those who have spent years managing PMDD, perimenopause can mark a devastating shift. What was once a predictable luteal phase, something you had learnt to brace and prepare for, starts to become blurred- you can’t seem to remember when luteal hell started or when it might possibly end. Everything feels like far more of a struggle, your relationships are hanging on for dear life, and you barely know yourself anymore. This is PMDD during perimenopause, and it remains one of the most under-researched and under-supported experiences in women's health.
The PMDD Brain: What’s Really Going On??
PMDD is described as a sensitivity in the brain to the natural hormonal fluctuations of the menstrual cycle. The neurobiology of PMDD points to dysfunctions in neurotransmitter systems and actual physical brain structure changes.
The leading evidence for the biology of PMDD centres on the brain's GABA system - this is our brain’s main calming system, or a neurological “brake”.
In the luteal phase, progesterone rises and then drops. Normally, in response to this, GABA receptors in our brain “shapeshift” to allow more of a calming molecule through, keeping mood stable..
In PMDD, however? This GABA receptor adjustment fails - the calming, compensation doesn’t happen, and mood destabilises as hormones shift - in a way that feels completely out of your control (2).
The same study found that this GABA receptor difference correlated with heightened activation of the amygdala - the brain's threat detection and emotion processing centre - during the luteal phase. In the context of PMDD, this maps onto what people describe: disproportionate emotional responses, anxiety, overwhelm.
On top of this, another study found that people with PMDD have increased serotonin transporter binding in the premenstrual phase, meaning serotonin gets cleared away more quickly (3). This results in less available ‘happy’ chemicals, and directly correlated with more depressive symptoms seen in PMDD luteal hell week.
Why does perimenopause make it so much worse?
Perimenopause introduces a new, unpredictable and erratic fluctuation of hormones, meaning that these neurotransmitter sensitivities seen in PMDD are activated more frequently, and not just in the luteal phase. It destabilises the entire hormonal architecture that PMDD sits within (4).
This can feel like:
◉Luteal phases are stretching longer → you’re suffering for more days each cycle
◉Cycles become chaotic → there’s no way to predict when PMDD will strike or plan around it
◉Hormones spike and crash harder → Mood symptoms intensify beyond what you’ve known before
As these fluctuations happen, estrogen and progesterone are also beginning to broadly fall.
As progesterone falls, it imitates the late luteal phase of a normally cycling woman, inducing anxiety-like effects from the lack of supportive GABA receptor adaptation (as we just described).
As estrogen declines in the perimenopausal period, it modulates serotonin receptor density, binding and transport that leads to impaired signalling. This creates a compounding effect of (1) the decreased availability of serotonin in those with PMDD, and (2) the impaired signalling of the available serotonin during perimenopause - on depressive effects (5).
On top of this, the symptoms of perimenopause themselves overlap with PMDD symptoms. Perimenopause itself brings difficulty concentrating, increased anxiety, sleep disturbances, and low mood. In someone with PMDD, it becomes sometimes impossible to separate what's perimenopause and what's PMDD, because biology is interacting at every level.
The research gap that nobody’s filling
A 2014 study of 100 perimenopausal women found that 23% met criteria for PMDD, that’s 1 in 4 women. When you compare this to the provisional 8% PMDD rate in the general reproductive-age population (6). That's a 3-fold increase.
More than a decade later, that's still the only study we can find on PMDD and perimenopause. The research simply hasn't followed to try to understand anything beyond the prevalence rate.
Why does this matter? Doctors don’t have any published evidence about how it gets worse, to quantify these experiences, to understand the ages it can exacerbate, whether there could even be new-onset PMDD as women age, and more.
This isn’t just a lack of research, it’s truly a lack of support for women. Whilst they are going through one of the most destabilising periods of life, clinicians have inadequate research to create treatment and mitigation protocols, and these women are left to fend for themselves. Too many are told there is nothing to be done about it.
What can actually help
There are options for support. On top of traditional PMDD treatment like oral contraceptives and SSRIs, which are inconsistent in their effects between different women, there is also the option of hormone replacement therapy (HRT) that can replace the hormones being lost during the perimenopausal period.
Hormone replacement therapy (HRT)
Transdermal estradiol has shown effectiveness for both physical and psychological symptoms during the perimenopausal transition (7). Oral progesterone is being talked about more to help with PMDD symptoms, though the type of progesterone seems to really matter, and evidence remains limited. Understanding is still being established, and caution and attention to detail must always be taken when managing a hormonal sensitivity disorder with hormones.
SSRIs
They've shown benefit for psychological symptoms of PMDD and for depressive symptoms in perimenopause, particularly when combined with estrogen. Side effects including reduced libido, fatigue, and nausea are a real barrier for many. While SSRIs work and can be life changing for a proportion, they are found to fail for 39% of women with PMDD.
For those who can't use, or choose not to use, pharmaceutical options, or want to combine medical with more holistic approaches, certain nutrients and extracts have evidence behind them for both PMDD and perimenopausal symptoms. Each of these are included in DITTO Cycle Supplement for this very reason.
Saffron Extract:
In perimenopausal women, saffron extract supplementation resulted in a 33% reduction in anxiety and 32% reduction in depression (8). In those with PMDD, saffron extract significantly reduced PMDD symptoms compared to a placebo, and was comparable to the antidepressant fluoxetine in improving symptoms, with significantly fewer side effects (9).
Chamomile Extract:
Resulted in a significant reduction in menopausal symptoms, specifically vasomotor, psychological, and urological (10). In a separate study in menstrual-related mood disorders, chamomile extract supplement improved mood symptom severity compared to placebo (11).
Omega 3 fatty acids:
Reduced depression scores in women in the menopausal transition (12). Also shown to reduce severity of premenstrual symptoms (13).
References
1. Cunningham, A.C., Hewings-Martin, Y., Wickham, A.P. et al. Perimenopause symptoms, severity, and healthcare seeking in women in the US. npj Womens Health 3, 12 (2025). https://doi.org/10.1038/s44294-025-00061-3
2. Stiernman, L., Comasco, E., Johansson, M. et al. Transcription of GABAA receptor subunits in circulating monocytes and association to emotional brain function in premenstrual dysphoric disorder. Transl Psychiatry 15, 255 (2025). https://doi.org/10.1038/s41398-025-03465-6
3. Sacher J, Zsido RG, Barth C, et al. Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging Study. Biol Psychiatry. 2023;93(12):1081-1088.
4. Sander, B., Gordon, J.L. Premenstrual Mood Symptoms in the Perimenopause. Curr Psychiatry Rep 23, 73 (2021). https://doi.org/10.1007/s11920-021-01285-1
5. Barth C, Villringer A and Sacher J (2015) Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front. Neurosci. 9:37. doi: 10.3389/fnins.2015.00037
6. Chung, S. H., Kim, T. H., Lee, H. H., Lee, A., Jeon, D. S., Park, J., & Kim, Y. (2014). Premenstrual syndrome and premenstrual dysphoric disorder in perimenopausal women. Journal of menopausal medicine, 20(2), 69–74. https://doi.org/10.6118/jmm.2014.20.2.69
7. Mu, E., Chiu, L., & Kulkarni, J. (2025). Using estrogen and progesterone to treat premenstrual dysphoric disorder, postnatal depression and menopausal depression. Frontiers in pharmacology, 16, 1528544. https://doi.org/10.3389/fphar.2025.1528544
8. Lopresti AL, Smith SJ. The Effects of a Saffron Extract (affron®) on Menopausal Symptoms in Women during Perimenopause: A Randomised, Double-Blind, Placebo-Controlled Study. J Menopausal Med. 2021;27(2):66-78.
9. Rajabi F, Rahimi M, Sharbafchizadeh MR, Tarrahi MJ. Saffron for the Management of Premenstrual Dysphoric Disorder: A Randomized Controlled Trial. Adv Biomed Res. 2020 Oct 30;9:60. doi: 10.4103/abr.abr_49_20. PMID: 33457343; PMCID: PMC7792881.
10. Mohsenzadeh-Ledari F, Agajani Delavar M, Moghadamnia AA, Khafri S, Bekhradi R, Behmanesh F, Yazdani S. Efficacy and safety of Matricaria chamomilla intervention in managing menopausal symptoms: a triple-blind clinical trial. Menopause. 2025 Apr 1;32(4):353-358. doi: 10.1097/GME.0000000000002496. PMID: 39836709.
11. Najafi Mollabashi E, Ziaie T, Bostani Khalesi Z. The effect of Matricaria chamomile on menstrual related mood disorders. Eur J Obstet Gynecol Reprod Biol X. 2021 Oct 1;12:100134. doi: 10.1016/j.eurox.2021.100134. PMID: 34704015; PMCID: PMC8526954.
12. Freeman, M. P., Hibbeln, J. R., Silver, M., Hirschberg, A. M., Wang, B., Yule, A. M., Petrillo, L. F., Pascuillo, E., Economou, N. I., Joffe, H., & Cohen, L. S. (2011). Omega-3 fatty acids for major depressive disorder associated with the menopausal transition: a preliminary open trial. Menopause (New York, N.Y.), 18(3), 279–284. https://doi.org/10.1097/gme.0b013e3181f2ea2e
13. Mohammadi, M.M., Dehghan Nayeri, N., Mashhadi, M. and Varaei, S. (2022), Effect of omega-3 fatty acids on premenstrual syndrome: A systematic review and meta-analysis. J. Obstet. Gynaecol. Res., 48: 1293-1305. https://doi.org/10.1111/jog.15217