Estrogen, Serotonin & Mood Swings Before Your Period

ByRohan Smith
How Estrogen and Serotonin Affect Mood Swings Before a Woman's Period

Author: Rohan Smith | Functional Medicine Practitioner | Adelaide, SA

Quick Answer

Premenstrual mood swings are primarily associated with fluctuations in estrogen and their downstream effects on serotonin (5-hydroxytryptamine), a key neurotransmitter involved in emotional regulation. As estrogen declines during the late luteal phase, serotonin synthesis and signalling may decrease, contributing to symptoms such as irritability, low mood, anxiety, and emotional sensitivity commonly observed in premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) (1–3).

At a Glance

  • In primate studies, estrogen upregulates tryptophan hydroxylase (TPH2), the rate-limiting enzyme in serotonin biosynthesis, which may link hormonal fluctuations to neurotransmitter availability (6,7).
  • In macaques, estrogen lowered serotonin transporter (SERT) mRNA, so falling estrogen late in the luteal phase may affect synaptic serotonin and vulnerability to mood changes, although SERT protein findings are mixed (10,11).
  • Premenstrual dysphoric disorder (PMDD) affects an estimated 3–8% of women of reproductive age, with symptoms triggered by normal hormonal fluctuations (3,14).
  • Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have demonstrated efficacy in reducing premenstrual mood symptoms, supporting the serotonin-mediated mechanism (19).
  • Estrogen has been linked with changes in some serotonin receptors, including higher cortical 5-HT2A availability in a small human study and lower 5-HT1B autoreceptor mRNA in rats, which may influence mood and anxiety regulation (8,9).

Understanding Estrogen and Serotonin

Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter that plays a central role in regulating mood, emotional stability, anxiety, sleep, and appetite. Approximately 90% of the body’s serotonin is produced in the gastrointestinal tract, while the remainder is synthesised in the central nervous system, primarily within the dorsal raphe nucleus of the brainstem. Serotonin is closely linked to hormonal mood changes (4).

Estrogen (primarily estradiol, or E2) is a steroid hormone best known for its role in reproductive health, but it also has wide-ranging effects on brain function, neurotransmitter activity, and emotional processing. Research by Roberta Brinton and colleagues has demonstrated estrogen’s significant influence on synaptic plasticity and neuroprotection within the central nervous system (5).

How Estrogen Influences Serotonin Function

Estrogen modulates serotonin through multiple interconnected mechanisms, each of which may contribute to the mood changes observed across the menstrual cycle.

Mechanism Effect of Estrogen Impact on Mood
Tryptophan hydroxylase (TPH2) expression May upregulate serotonin synthesis Higher serotonin production may support mood stability (6,7)
5-HT2A and 5-HT1B receptors Higher 5-HT2A availability (small human study); lower 5-HT1B autoreceptor mRNA (rats) May influence serotonergic signalling and emotional regulation (8,9)
Serotonin transporter (SERT) expression Lowered SERT mRNA in macaques; protein effects varied with treatment length May change how long serotonin stays active in the synaptic cleft (10,11)
Monoamine oxidase A (MAO-A) protein Reduced after one month in macaques, not after five May preserve serotonin availability between neurons (11)

Serotonin Synthesis

Estrogen has been shown to upregulate the expression of tryptophan hydroxylase (TPH2), the rate-limiting enzyme involved in serotonin synthesis, as demonstrated in primate studies by Cynthia Bethea and colleagues at Oregon Health & Science University. Higher estrogen availability may increase serotonin production within the brain (6,7), a process that may also be influenced by serotonin synthesis and methylation pathways.

Serotonin Receptors

Estrogen can influence specific serotonin receptors, though the effect depends on the receptor and the brain region. In a small imaging study of five postmenopausal women, hormone therapy was associated with higher 5-HT2A receptor availability across the cortex. In rats, Hiroi and Neumaier found estrogen had no effect on 5-HT1A mRNA in the dorsal raphe nucleus but lowered 5-HT1B autoreceptor mRNA in one subregion, which may increase the capacity for serotonin release and has been linked with less anxiety-like behaviour (8,9).

Serotonin Reuptake and Availability

The serotonin transporter (SERT), encoded by the SLC6A4 gene, is responsible for clearing serotonin from the synaptic space. Research by Pecins-Thompson and colleagues found that estrogen lowered SERT mRNA in rhesus macaques, which could allow serotonin to remain active for longer. The picture is not settled, though. In later macaque work, SERT protein did not change after one month of estrogen and rose after five months (10,11).

The Menstrual Cycle and Premenstrual Mood Changes

Hormonal fluctuations across the approximately 28-day menstrual cycle directly influence serotonergic neurotransmission, with distinct patterns observed in each phase.

Follicular Phase: Rising Estrogen

During the follicular phase of the menstrual cycle, estradiol levels gradually rise under the influence of follicle-stimulating hormone (FSH) from the anterior pituitary gland. Primate studies suggest this rise may support serotonin production (6,7), and fluctuations in estrogen and progesterone have been linked with changes in brain function and emotional state (12).

Luteal Phase: Estrogen Withdrawal

In the luteal phase, particularly in the days leading up to menstruation, estrogen levels decline following the breakdown of the corpus luteum. This withdrawal may reduce serotonin activity and increase vulnerability to mood symptoms such as irritability, sadness, anxiety, and emotional reactivity. These mood symptoms are commonly observed in premenstrual syndrome (PMS) and tend to be more pronounced in premenstrual dysphoric disorder (PMDD), which a review led by C. Neill Epperson for the DSM-5 work group concluded had enough evidence behind it to qualify as a full diagnostic category (13,14).

Cognitive Function and Neuroprotection

Estrogen’s effects extend beyond mood regulation to cognitive processes including memory and learning. A review by Yuko Hara and colleagues, published in Physiological Reviews, described how estrogen supports synapse structure and function in the hippocampus and prefrontal cortex. Karyn Frick’s review of rodent research further described how estradiol modulates hippocampal memory in young and ageing females (15,16).

Menopause and Mood Vulnerability

During the menopausal transition (perimenopause), circulating estradiol levels can become more variable. Research by Claudio Soares and Ellen Freeman suggests this hormonal change may contribute to the increased risk of depressive symptoms reported by some women during perimenopause and postmenopause, even in those with no prior history of depression (17,18).

Why This Matters Clinically

Understanding how estrogen modulates serotonin through tryptophan hydroxylase, serotonin receptors, and the serotonin transporter may help explain why mood symptoms often follow predictable hormonal patterns across the menstrual cycle. It also provides insight into why broader hormonal imbalances may further influence mood regulation and emotional wellbeing. This understanding also helps explain why certain interventions—such as selective serotonin reuptake inhibitors (SSRIs) or hormone-based therapies—may reduce premenstrual mood symptoms in some individuals, as demonstrated in the landmark fluoxetine trial by Meir Steiner and colleagues (19,20).

When to Consider Further Support

Premenstrual mood changes that are severe, persistent, or disruptive to daily functioning may warrant further assessment by a qualified healthcare practitioner.

Symptom Pattern Possible Consideration
Mood changes occurring predictably in the luteal phase PMS or PMDD assessment
Severe irritability, anxiety, or depressive episodes premenstrually Hormonal and neurotransmitter evaluation
Emotional symptoms alongside fatigue and sleep disruption Comprehensive hormonal and nutritional testing
Worsening mood symptoms during perimenopause Estrogen metabolism and adrenal function review

Next Steps

  1. Track your cycle and symptoms: Record mood changes, energy levels, and emotional patterns across your menstrual cycle to identify whether symptoms align with hormonal phases.
  2. Assess hormonal and nutritional status: Consider comprehensive hormone testing to evaluate estrogen metabolism, cortisol patterns, and serotonin-supporting nutrient levels including vitamin B6, folate, zinc, and tryptophan.
  3. Seek personalised support: If premenstrual mood changes are severe or disruptive, a functional medicine assessment can help identify the hormonal and neurochemical patterns driving your symptoms.

Frequently Asked Questions

Why do mood swings happen before a woman’s period?
Mood swings before a period are commonly linked to fluctuations in estrogen and their effects on serotonin, a neurotransmitter involved in mood regulation. As estrogen levels fall in the late luteal phase, serotonin production and availability may decrease, increasing vulnerability to irritability, low mood, anxiety, and emotional sensitivity.

Is premenstrual low mood a psychological issue or a hormonal one?
Premenstrual mood changes are driven primarily by physiological processes rather than personal weakness or poor coping. Hormonal fluctuations influence brain chemistry, particularly serotonergic signalling, which can affect emotional regulation even in individuals with otherwise stable mental health.

When should premenstrual mood changes be investigated further?
Further assessment may be appropriate when mood symptoms are severe, persistent, or interfere with daily functioning, particularly if they occur predictably across the menstrual cycle. This includes symptoms suggestive of PMS or PMDD, or mood changes accompanied by fatigue, sleep disruption, or other hormonal irregularities.

Key Insights

  • Estrogen plays a regulatory role in serotonin production, receptors, and reuptake via tryptophan hydroxylase, 5-HT receptors, and the serotonin transporter (SERT)
  • Declining estrogen levels in the luteal phase may reduce serotonin activity in the dorsal raphe nucleus and prefrontal cortex
  • These neurochemical changes help explain common premenstrual mood symptoms including irritability, anxiety, and low mood
  • Hormonal mood shifts reflect physiological processes, not personal weakness

Citable Takeaways

  1. Estrogen increased tryptophan hydroxylase gene expression in the dorsal raphe of rhesus macaques, as demonstrated by Pecins-Thompson et al., which may increase serotonin synthesis (6).
  2. Severe premenstrual syndrome affects about 5–8% of women, most of whom also meet criteria for PMDD, with symptoms triggered by fluctuations in gonadal hormone levels, according to Yonkers et al. in The Lancet (3).
  3. Estrogen lowered serotonin transporter (SERT) mRNA in the raphe of rhesus macaques, as reported by Pecins-Thompson et al. in Molecular Brain Research (10).
  4. Fluoxetine (an SSRI) demonstrated significant efficacy in reducing premenstrual dysphoric symptoms in a controlled trial by Steiner et al. published in Archives of General Psychiatry (19).
  5. Research by Schmidt et al. in the New England Journal of Medicine showed that women with PMS may have differential behavioural sensitivity to gonadal steroid fluctuations compared to women without PMS (20).
  6. A DSM-5 work group review by Epperson et al. in the American Journal of Psychiatry concluded that the evidence on premenstrual dysphoric disorder had matured enough for it to qualify as a full diagnostic category (13).

Understand Your Hormonal Mood Patterns

Premenstrual mood changes can be distressing, especially when they recur predictably each month or begin to affect relationships, work, or overall wellbeing. At Elemental Health and Nutrition, we take an evidence-informed functional medicine approach that considers hormonal rhythms, nervous system regulation, nutritional status, and lifestyle factors together to help clarify contributing drivers and guide appropriate next steps.

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References

  1. Albert PR. Why is depression more prevalent in women?. Journal of Psychiatry and Neuroscience. 2015;40(4):219-221. https://doi.org/10.1503/jpn.150205
  2. Bethea CL et al. Diverse actions of ovarian steroids in the serotonin neural system. Front Neuroendocrinol. 2002;23(1):41-100. https://doi.org/10.1006/frne.2001.0225
  3. Yonkers KA et al. Premenstrual syndrome. Lancet. 2008;371(9619):1200-10. https://doi.org/10.1016/s0140-6736(08)60527-9
  4. Young SN. How to increase serotonin in the human brain without drugs. J Psychiatry Neurosci. 2007 Nov;32(6):394-9. https://pubmed.ncbi.nlm.nih.gov/18043762/
  5. Brinton RD. Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends in Pharmacological Sciences. 2009;30(4):212-222. https://doi.org/10.1016/j.tips.2008.12.006
  6. Pecins-Thompson M et al. Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques. J Neurosci. 1996;16(21):7021-9. https://doi.org/10.1523/jneurosci.16-21-07021.1996
  7. Sanchez RL et al. A second tryptophan hydroxylase isoform, TPH-2 mRNA, is increased by ovarian steroids in the raphe region of macaques. Brain Res Mol Brain Res. 2005;135(1-2):194-203. https://doi.org/10.1016/j.molbrainres.2004.12.011
  8. Moses-Kolko EL et al. Widespread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women. Fertil Steril. 2003;80(3):554-9. https://doi.org/10.1016/s0015-0282(03)00973-7
  9. Hiroi R, Neumaier JF. Estrogen decreases 5-HT1B autoreceptor mRNA in selective subregion of rat dorsal raphe nucleus: inverse association between gene expression and anxiety behavior in the open field. Neuroscience. 2009;158(2):456-64. https://doi.org/10.1016/j.neuroscience.2008.10.016
  10. Pecins-Thompson M et al. Regulation of serotonin re-uptake transporter mRNA expression by ovarian steroids in rhesus macaques. Brain Res Mol Brain Res. 1998;53(1-2):120-9. https://doi.org/10.1016/s0169-328x(97)00286-6
  11. Smith LJ et al. Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of macaques. Neuropsychopharmacology. 2004;29(11):2035-45. https://doi.org/10.1038/sj.npp.1300510
  12. Farage MA et al. Cognitive, sensory, and emotional changes associated with the menstrual cycle: a review. Arch Gynecol Obstet. 2008;278(4):299-307. https://doi.org/10.1007/s00404-008-0708-2
  13. Epperson CN et al. Premenstrual dysphoric disorder: evidence for a new category for DSM-5. Am J Psychiatry. 2012;169(5):465-75. https://doi.org/10.1176/appi.ajp.2012.11081302
  14. Halbreich U et al. The prevalence, impairment, impact, and burden of premenstrual dysphoric disorder (PMS/PMDD). Psychoneuroendocrinology. 2003;28 Suppl 3:1-23. https://doi.org/10.1016/s0306-4530(03)00098-2
  15. Hara Y et al. Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse. Physiol Rev. 2015;95(3):785-807. https://doi.org/10.1152/physrev.00036.2014
  16. Frick KM. Estrogens and age-related memory decline in rodents: what have we learned and where do we go from here?. Horm Behav. 2009;55(1):2-23. https://doi.org/10.1016/j.yhbeh.2008.08.015
  17. Soares CN. Depression in Peri- and Postmenopausal Women: Prevalence, Pathophysiology and Pharmacological Management. Drugs & Aging. 2013;30(9):677-685. https://doi.org/10.1007/s40266-013-0100-1
  18. Freeman EW et al. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006;63(4):375-82. https://doi.org/10.1001/archpsyc.63.4.375
  19. Steiner M et al. Fluoxetine in the Treatment of Premenstrual Dysphoria. Obstetrical & Gynecological Survey. 1995:785-787. https://doi.org/10.1097/00006254-199511000-00015
  20. Schmidt PJ et al. Differential behavioral effects of gonadal steroids in women with and without premenstrual syndrome. N Engl J Med. 1998 Jan 22;338(4):209-16. https://doi.org/10.1056/NEJM199801223380401

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