Progesterone & Oestrogen Imbalance: The Hormonal Depression Trap in Midlife Women
- urbanwellnessuk
- 7 hours ago
- 6 min read
Most women know about oestrogen and understand that menopause involves hormone changes. But progesterone is one of the most overlooked hormones that may be the most critical for your mental health.
Progesterone is nature's anti-anxiety, mood-stabilizing hormone. It increases GABA (the calming neurotransmitter), reduces the stress response, and creates a sense of calm and safety in your nervous system. For decades of your reproductive life, progesterone was your built-in mood stabilizer.
Then perimenopause arrives.
Progesterone begins to decline, often dramatically and erratically. And as it declines, you lose that biological anti-anxiety protection. Simultaneously, oestrogen fluctuates wildly. The combination of low progesterone and dysregulated oestrogen creates the perfect neurological environment for depression.
This is why depression is so common in perimenopause and menopause. It's not a character flaw. It's a predictable neurological response to hormone dysregulation.
Why Progesterone is Your Brain's Best Friend
Progesterone & GABA (The Calming Neurotransmitter)
Progesterone is metabolized into a compound called allopregnanolone, which is one of the most potent GABA modulators in your brain. GABA is your nervous system's calming neurotransmitter.
When progesterone is adequate, your brain has abundant GABA signalling. You feel calm, grounded, and able to handle stress.
When progesterone declines, GABA signaling drops. Your nervous system loses its calming brake. You feel anxious, hypervigilant, and unable to relax. Depression often follows.
Progesterone & the Amygdala (Fear Center)
The amygdala is your brain's threat-detection centre. Progesterone directly dampens amygdala reactivity. When progesterone is adequate, your amygdala doesn't overreact to threats.
When progesterone declines, the amygdala becomes hyperactive (similar to what happens with chronically high cortisol, see ‘Cortisol Dysregulation and Depression: How Chronic Stress Rewires Your Brain’). You perceive danger where there is none. Your nervous system is on constant alert. Depression and anxiety become the default state.
Progesterone & Serotonin
Progesterone enhances serotonin receptor sensitivity. This means your brain is more responsive to available serotonin. When progesterone declines, your brain becomes less responsive to serotonin—even if serotonin levels are adequate.
This is why women often report SSRIs stop working during perimenopause. It's not that the serotonin is gone. It's that without adequate progesterone, your brain isn't responsive to it.
The Oestrogen Dysregulation Piece
While progesterone is declining, oestrogen is doing something worse: it's erratic.
Early perimenopause is often characterized by relative oestrogen dominance (high oestrogen relative to declining progesterone). Later perimenopause involves declining oestrogen with chaotic fluctuations.
Both patterns dysregulate mood because:
Oestrogen Dysregulates Serotonin & Dopamine
Oestrogen affects the production and reuptake of serotonin and dopamine. Fluctuating oestrogen creates chaotic neurotransmitter levels.
High oestrogen can temporarily boost mood (the "good" perimenopause days where you feel great). Then as it crashes, mood crashes simultaneously. This boom-bust pattern is characteristic of perimenopause depression.
Impaired Oestrogen Clearance
As methylation declines (see Blog 5) during midlife, your ability to clear oestrogen also declines. Excess oestrogen accumulates, creating:
Neuroinflammation
Progesterone receptor blocking (excess oestrogen blocks where progesterone would bind)
Neurotransmitter dysregulation
This is why some midlife women are actually oestrogen-dominant (too much oestrogen relative to progesterone), not oestrogen-deficient.
Oestrogen & Progesterone Ratio
What matters most isn't the absolute levels of each hormone. It's the ratio.
A healthy ratio is progesterone approximately 300:1 relative to oestrogen (in the luteal phase of the cycle, or steady-state in menopause).
As you approach menopause, this ratio inverts. You might have low progesterone and high-or-fluctuating oestrogen. This dysbalanced ratio is what creates depression.
Why Midlife Compounds the Problem
Declining Progesterone Synthesis
In your reproductive years, your ovaries make progesterone in a predictable, reliable way. In perimenopause, ovulation becomes irregular. Some months you ovulate (and make progesterone). Some months you don't (and make no progesterone).
This erratic progesterone production creates chaotic mood swings.
Methylation Decline
As we age, methylation naturally becomes less efficient (see ‘Methylation, Detoxification & Depression: The Hidden Biochemical Block’). This affects your ability to clear excess oestrogen. Oestrogen accumulates, worsening the progesterone/oestrogen imbalance.
Accumulation of Xenooestrogens
Over decades, you've been exposed to xenooestrogens—environmental chemicals that mimic oestrogen (e.g. plastics, pesticides, personal care products). These accumulate in your body and add to your oestrogen burden.
Gut Dysbiosis
The estrobolome (oestrogen-metabolizing bacteria in your gut, see ‘The Gut-Brain Depression Axis: How Dysbiosis Inflames Your Brain’) becomes dysbiotic as you age. Your ability to clear oestrogen through the gut declines, further raising circulating oestrogen.
Nutrient Depletion
Hormone metabolism requires B vitamins, magnesium, and other nutrients. Many midlife women are depleted in these, impairing hormone clearance.
How to Recognize Hormone-Driven Depression
Perimenopause-pattern symptoms:
Mood swings that track with cycle (if still cycling)
Worse mood in luteal phase (after ovulation, when progesterone declines)
Temporary mood improvement when oestrogen rises
Mood worsens closer to period
Dramatic mood shift month-to-month
Brain fog that fluctuates
Sleep that worsens in luteal phase or during low-hormone times
Progesterone-deficiency symptoms:
Anxiety that's worse in luteal phase
Inability to relax
Hypervigilance
Difficulty sleeping (especially second half of cycle)
Irritability
Difficulty with change or uncertainty
Tremor or shakiness
Panic attacks
Oestrogen-dysregulation symptoms:
Migraines (often correlate with oestrogen fluctuations)
Hot flashes, night sweats (obvious sign of dysregulation)
Breast tenderness, bloating (signs of oestrogen dysregulation)
Mood crashes associated with oestrogen drops
Low mood mixed with physical symptoms
Poor oestrogen clearance symptoms:
Elevated oestrogen despite being menopausal (continued symptoms)
Persistent bloating, breast tenderness, puffiness
Continued hormonal acne despite age
Difficulty losing weight (oestrogen promotes fat storage)
Persistent mood dysregulation in menopause (not just perimenopause)
Important Note: Antidepressants & Hormones
Many women are on SSRIs for depression driven by hormone dysregulation. Here's the issue:
SSRIs can worsen hormone balance by:
Affecting oestrogen metabolism
Interfering with sexual function and arousal (needed for hormone production)
Creating additional side effects on top of hormone dysregulation
That said: do not stop SSRIs abruptly. Work with your practitioner about:
Whether hormone optimization alone might allow dose reduction
Whether adding hormone support allows better SSRI response
Potential for gradual SSRI tapering as hormone balance improves
Whether different antidepressant classes work better with hormone support
Many women find that once their hormones are optimized, they need less SSRI or none. But this must be done carefully with professional guidance.
If this resonates, and you suspect there's more going on beneath the surface, you're probably right. Discover how we work with women who are ready to go beyond symptom management and address what's really driving their depression.
The Bottom Line
Your depression may not be a serotonin problem. It may be a progesterone-deficiency problem or an oestrogen-dysregulation problem.
The good news? These are highly addressable through a combination of nutrient support, lifestyle optimization, stress management, and—in many cases—bioidentical hormone supplementation.
By the time you finish this seven blog series, you should understand that depression in midlife women is rarely "just depression." It's a physiological dysregulation that has multiple, interconnected drivers.
And every single one of them is addressable.
Ready to Find Out What's Really Going On?
At Urban Wellness, we use comprehensive hormone testing - such as the DUTCH test (Dried Urine Test for Comprehensive Hormones) or HUMAP (Human Methylation and Physiology panel) - to assess your oestrogen, progesterone, cortisol, and metabolite levels in detail. These tests go far beyond what standard NHS blood tests measure, giving us a complete picture of your hormonal balance, how well you're metabolizing and clearing hormones, and whether stress or methylation issues are contributing to your symptoms.
If you're struggling with low mood, anxiety, insomnia, or exhaustion in midlife and suspect your hormones are playing a role, let's talk. Book a free 20-minute discovery call to discuss your symptoms, what testing might be right for you, and how we can create a personalised plan to help you feel like yourself again.
Summary: The Complete Picture
We have a whole series on the seven physiological drivers of depression in midlife women:
1. Circadian Rhythm Disruption → Impairs cortisol, melatonin, and energy production
2. Blood Sugar Imbalance → Triggers stress response and depletes neurotransmitters
3. Thyroid Dysfunction → Reduces brain energy and neurotransmitter production
4. Cortisol Dysregulation → Rewires brain toward fear and depression
5. Methylation & Detox Issues → Prevents clearance of stress chemicals
6. Neuroinflammation & Gut Dysbiosis → Stops serotonin production and inflames brain
7. Hormone Imbalance → Removes progesterone protection and dysregulates neurotransmitters
These seven factors rarely exist in isolation. They're interconnected, each amplifying the others.
Your depression is likely driven by a combination of these, not just one.
The path forward: identify which factors are present for you, then address them systematically. Start with foundation (circadian rhythm and blood sugar), then layer in targeted support for your specific dysregulations.
This is functional medicine approach: not "what disease do you have?" but "what is broken, and how can we fix it?"
Your depression can heal. Your brain can rewire. Your physiology can rebalance.
It just requires understanding what's actually wrong.
At Urban Wellness, that's exactly what we do—identify the root causes driving your depression and create a personalised plan to address them. If you're ready to stop managing symptoms and start healing, book a free 20-minute discovery call and let's figure out what your body has been trying to tell you.
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Reference Research:
- Journal of Affective Disorders - progesterone and depression in perimenopause
- Psychoneuroendocrinology - allopregnanolone and mood regulation
- NCBI/PMC - "Oestrogen and Serotonin: Interactions in Mood and Cognition"
- Mayo Clinic - hormone changes in midlife women
- Frontiers in Endocrinology - progesterone as neuroprotective agent
- Functional Medicine Research Foundation - hormone optimization in midlife
