7 Physiological Causes of Depression in Midlife Women (That Your Doctor Might Miss)

Your Depression May Not Be What You Think It Is

If you're a midlife woman experiencing depression, you've likely heard all the typical advice: exercise more, think positive thoughts, consider antidepressants. But what if your depression isn't primarily a mental health issue at all? What if it's your body sending you a signal that something physiological has gone out of balance?

The truth is, depression is rarely just about serotonin. Depression is your nervous system's way of saying:  something needs to change.

At Urban Wellness, we've worked with many women in their 40s and 50s (and beyond) who've been told their depression is "a lack of serotonin" or "stress‑related", or who have been in and out of therapy for years. While therapy has helped to some degree, they just know something else is going on—and then perimenopause seems to compound it further.

Once we start looking at what is truly going on, they discover that underneath those symptoms lies a specific, addressable physiological dysfunction. When we identify and address the root cause, these women don't just feel better emotionally; they feel fundamentally transformed.

In this comprehensive guide, we're breaking down the seven most common physiological drivers of depression that often go undetected in conventional care. Each of these can create the exact neurological and hormonal environment that perpetuates depressive symptoms.

Why Conventional Care Often Misses These

Your GP sees depression as a mental health problem, usually triggered by a life event. They may offer medication or refer you to a psychiatrist for a prescription, but neither will investigate the underlying physiology that contributed to, or created, the depression in the first place. 

Functional medicine takes a different approach. We ask: When did this start? Were there events or health issues preceding this that may be contributing to your symptoms? What systems or imbalances created this symptom? Are genetics playing a part? Because if we don't address the possible root cause or drivers, no amount of positive thinking, therapy or medication will create lasting change. 

The Seven Physiological Drivers of Depression

 1. Circadian Rhythm Disruption

Your body runs on a 24-hour clock that governs sleep, hormone production, energy, and mood. When you are out of sync with this rhythm, perhaps through irregular sleep, late-night light exposure from your phone or laptop, or inconsistent meal timing - your nervous system becomes dysregulated. This creates the perfect environment for depression to take root.

Why it matters for midlife women:  Perimenopause and menopause further disrupt circadian rhythm through night sweats and hormonal shifts, compounding the depression risk.

Read more about Circadian Rhythm Disruption here

2.  Blood Sugar Imbalance

Skipping breakfast, relying on caffeine to power your morning, and eating the wrong type of carbs without protein can create volatile blood sugar swings throughout the day. Each dip triggers adrenaline and cortisol release – your stress hormones. Chronic adrenaline and cortisol exposure, over time, can rewire your brain toward a depressive state.

Why it's so common: Many women in midlife are either under‑eating due to restrictive diets (perhaps from too much focus on weight loss or calories), eating erratically due to busy schedules, or experiencing loss of appetite due to stress or medication. 

Read our blog 'Blood Sugar Imbalance and Depression: The Fuel Crisis Your Brain Can't Ignore' for more information

3.  Thyroid Dysfunction

Both low and high thyroid hormone levels can cause depression. Yet most doctors only check TSH, and sometimes Free T4, which is missing the real picture of thyroid function. Thyroid hormones directly impact neurotransmitter production, brain energy, and metabolism. An out-of-range thyroid often looks exactly like depression.

Why midlife is critical:  Autoimmune thyroiditis (Hashimoto's) peaks in midlife women, often triggered by chronic stress, gut dysbiosis, or nutrient deficiency.

Want to understand more about thyroid? Read our blog post on Thyroid Dysfunction here

4.  Cortisol Dysregulation

Chronic high cortisol doesn't just make you feel stressed, over time it actively rewires your brain. It hyperactivates your amygdala (fear centre), dysregulates serotonin and dopamine, and creates a state of constant vigilance. Over time, this neurological pattern becomes depression.

Why it's so common: Many women in midlife are juggling demanding careers while also managing the household, caring for children, and often supporting aging parents. Add to that perfectionism, over-functioning (saying yes to everything), and struggles with boundary-setting, and the result is relentless, chronic stress. When stress becomes constant, cortisol stays elevated, eventually leading to dysregulation, burnout, and the mood symptoms that follow.

Understand more about cortisol in our blog 'Cortisol Dysregulation and Depression: How Chronic Stress Rewires Your Brain'

5.  Compromised Methylation & Detox Pathways

Methylation is a biochemical process involved in making important neurotransmitters such as serotonin and GABA, as well as clearing stress neurotransmitters, oestrogen, and toxins from your body. When it's dysregulated, you accumulate adrenaline, norepinephrine, and dopamine in your bloodstream longer than you should. This creates anxiety, depression, and that "wired but tired" feeling. 

Why it's overlooked: This requires a detailed diet and lifestyle history, as well as functional lab testing such as genetic panels or organic acid tests, to help identify where the imbalances may be - something that is not routinely assessed by mainstream medical practitioners. 

Dive further into understanding Methylation in our blog here

6.  Neuroinflammation & Gut Dysbiosis

Your gut produces 90% of your serotonin. When your gut microbiome is imbalanced or your intestinal barrier is compromised, bacteria, undigested food particles, and toxins can leak into your bloodstream. Your immune system recognizes these as threats and triggers an inflammatory response, and that inflammation doesn't stay in your gut. It travels through your bloodstream and can cross into your brain, causing neuroinflammation that disrupts mood-regulating neurotransmitters. But gut dysfunction isn't the only culprit—chronic stress activating the kynurenine pathway, mould exposure, infections, blood sugar dysregulation, and nutrient deficiencies can all drive neuroinflammation. This neuroinflammation is now recognized as a primary driver of depression. 

The gut-brain connection is real:  An inflamed gut = an inflamed brain = depression symptoms.

Why it's overlooked: Doctors don't assess gut health, microbiome balance, or markers of inflammation when treating depression, even though neuroinflammation is now recognized as a primary driver of mood disorders—and standard mental health assessments don't include stool testing, inflammatory markers, or gut barrier function.

Read 'The Gut-Brain Depression Axis: How Dysbiosis Inflames Your Brain' to find out more about gut health and the impact it has on mood

7.  Progesterone & Oestrogen Imbalance

Progesterone is nature's calming hormone. As it declines in perimenopause and menopause, many women lose their biological "anti-anxiety" protection. Progesterone acts on GABA receptors in the brain—GABA is your brain's main calming neurotransmitter, responsible for slowing down racing thoughts, easing tension, and promoting relaxation. When progesterone levels drop, GABA activity decreases, leaving you more vulnerable to anxiety, insomnia, irritability, and that "wired but can't calm down" feeling—even if nothing stressful is happening.  Additionally, impaired oestrogen clearance (due to poor methylation or gut dysbiosis) can create excess oestrogen, which dysregulates mood.

But here's where it gets worse: chronic stress accelerates progesterone loss. When you're under constant stress, your body prioritises making cortisol (your stress hormone) over progesterone. Both hormones are made from the same raw material (pregnenolone), and when your body is in survival mode, it diverts resources away from calming, reproductive hormones like progesterone and toward cortisol production. So if you're a midlife woman juggling chronic stress and perimenopause, you're getting hit twice: declining progesterone from hormonal transition plus further depletion from high cortisol. This double hit leaves your GABA system severely compromised, making anxiety and low mood even harder to manage.

This makes it clear that the hormonal shift in perimenopause isn't just about hot flashes—it's fundamentally changing brain chemistry in a way that directly impacts mood and anxiety regulation. And chronic stress makes it significantly worse..

Why it's overlooked: GPs rarely check progesterone levels (they typically only test FSH and sometimes oestradiol), and even when they do, they're looking for fertility or menopause status—not whether hormone levels are optimal for mood, sleep, and nervous system regulation. We often write to GPs and get them to test our client's progetserone level if we feel it is warranted.

Learn more about the role our hormones splay in our mood in 'Progesterone & Oestrogen Imbalance: The Hormonal Depression Trap in Midlife Women'

How These Seven Factors Work Together

Here's the critical insight:  These factors are interconnected.  Circadian disruption drives blood sugar imbalance. Blood sugar imbalance elevates cortisol. High cortisol damages gut barrier, creating dysbiosis. Dysbiosis increases inflammation in the brain. Neuroinflammation dysregulates hormones. And compromised methylation prevents you from clearing the excess stress hormones and inflammatory markers.

One dysfunction rarely exists in isolation. That's why treating depression with a single antidepressant often feels like putting a band-aid on a broken system.

The Urban Wellness Approach

At Urban Wellness, we use functional lab testing and root cause analysis to identify which of these seven factors are driving your depression. Then we create a personalized protocol that addresses the physiological imbalances—not just the symptom.

 This might include:

• Nutritional support to stabilize blood sugar and support neurotransmitter production

• Circadian rhythm optimization through light, meal timing, and sleep protocols

• Gut healing to reduce neuroinflammation

• Stress-resilience practices to regulate the nervous system

• Targeted supplementation based on lab findings

• Hormone balancing through nutrition and lifestyle

  
  

What You'll Find in This Series

Over the next seven blogs, we're diving deep into each physiological driver. For each one, you'll discover:

-  The science behind how this factor creates depression

-  How to recognize it in your own experience

-  Practical first steps  you can take immediately

By the time you finish this series, you'll have a comprehensive understanding of your body's language. You'll know which questions to ask your doctor. And most importantly, you'll have a roadmap toward addressing the real reasons behind your depression.

Your Next Step

Ready to move beyond the assumption that your depression is "just mental"?

Start with Blog 1: Circadian Rhythm Disruption—the most foundational driver of mood and the easiest to address first.

Note:  This blog series is educational and not a substitute for professional medical advice. If you're currently on antidepressants, please work with your prescribing doctor before making changes. Many of these physiological imbalances can be addressed alongside medication, and a functional medicine approach can support optimization of your overall protocol.

If you're ready to identify your specific root causes of depression and want personalized support, book your complimentary call with Nicola today