Menopause: Behind the Scenes

Part two of our menopause series. Last episode we established that the forecast of universal storms is wrong, most people's weather during menopause is genuinely fine. So today we're asking the follow-up question: if the forecast is wrong for most people, why is it right for some?

We're working from a systematic review that dug into the actual biology, what oestrogen fluctuations are doing to serotonin and GABA, the two systems most responsible for keeping mood stable. We get into why some people's systems are more sensitive to these changes than others, what the real risk factors look like, and how this episode's findings fit together with last episode's.

You don't need to have listened to Episode 13 first, but it'll click a lot faster if you have.

Transcript

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If you were here for episode 13, you know the forecast, the cultural story that menopause universally causes depression, anxiety, and mental health decline. And the research that says, actually, for most people, the weather is fine. The forecast was wrong. But here's the question that follows: if the storm forecast is wrong for most people, why is it right for some? What's actually happening in the atmosphere for people who did hit rough weather? Because the forecast being exaggerated doesn't mean the rain isn't real for some people. It just means that we need to understand the actual atmospheric conditions that produce it. Today we're going into the science behind why some people's weather genuinely changes, what estrogen is doing to serotonin and GABA, what that means for mood, and what the risk factors look like when you follow evidence all the way down. I'm not a clinician. I'm someone who believes that good research deserves a wider audience and that most people, given clear and honest information, are capable of doing something meaningful with it. Today's paper is Albushi et al. Does menopause elevate the risk for developing depression and anxiety? Results from a systemic review. Published in Australasian Psychiatry in 2023. Quick note on what kind of paper this is before we get into findings. This is a systemic review. That means the researchers didn't run their own study. They gathered all the published research on a question and analyzed it together. They searched major databases, including PubMed, CockTrain, Medline, Mbase, and PsychInfo covering all studies published up to December 2021 and ended up with 22 studies that met their criteria. Eight cross-sectional surveys, one retrospective cohort, and 13 prospective cohort studies. The reason this paper matters is something the researchers themselves flag at the onset. When they conducted this review, no systemic review of the psychological consequences of menopause had previously been done. For a transition that affects around half the world's population and about which enormous cultural narratives have been built and broadcasted for over a century, the evidence base had actually never been pulled together and assessed in one place. This paper does that for the first time. The menopause transition involves three stages. Perimenopause, where menstrual cycle becomes irregular as ovulation starts seizing and estrogen and progesterone begin to fall. Menopause itself, the final menstrual period, and postmenopause, defined as 12 months or more with no menstrual period. Most people reach menopause between 51 and 52 years of age on average, though the perimenopause can start considerably earlier. The psychological symptoms commonly associated with this transition include mood dysregulation, anxiety, irritability, sleeping difficulties, forgetfulness, and trouble concentrating. Those are the things the forecast is built on. And what this review asks is does the evidence actually support that association? The headline finding from this review is that menopause does increase vulnerability to depression and anxiety. This is a more direct statement than the Lancet paper from last episode, which was careful to say the risk is not universal. And it's worth thinking about why the conclusion looks slightly different, because they're actually compatible with each other. The Lancet paper was asking, does menopause universally increase the risk across the whole population? The answer is no. The evidence does support a uniform increase for everyone. This paper is asking, does menopause increase vulnerability for some people? The answer is yes. And here's the atmospheric science behind it. Both depression and anxiety are more common during menopause and post-menopause period. The prospective cohort studies in this review, which are the most methodologically reliable because they follow people over time, consistently find elevated rates during the transition and postmenopausal period compared to pre-menopausal baseline. Not in everyone, but the vulnerability is real and measurable. The two most consistently identified risk factors across the studies are vasomotor symptoms and prior history of major depression. Vasomotor symptoms, meaning hot flushes and night sweats, are significantly associated with both depression and anxiety. And prior major depressive disorder is the strongest single predictor of the depressive episodes during the transition, consistent with what the Landscape paper also found. Psychosocial factors independently increase risk as well. Adverse life events happening concurrently with the menopause transition, stressful circumstances, lack of social support, these are all confirmed as independent contributors to mood disturbance at this life stage. And neuroticism, which is a personality trait describing a tendency toward negative emotional states and emotional reactivity, is flagged as a significant risk factor. People high in neuroticism are more likely to experience depressive decompensation during the menopause transition. The atmospheric conditions are more volatile to begin with, and the transition adds pressure to a system that was already prone to instability. Episode 13 said the forecast of universal storms is wrong and creates its own harm. This paper says the storm is real for a specific subset of people, and now we're going to understand why. Both of those things can be true at once. This is the part I really want to get into because it's what makes this paper different from the last one. The Lancet paper established who is at risk. This paper goes into why. What's actually happening in the atmosphere? The mechanisms the researchers propose runs like this. Estrogen fluctuations affect serotonin and GABA, and those two systems are central to mood stability. Let's start with estrogen. Over the menopause transition, estrogen doesn't just drop steadily, it fluctuates, sometimes quite dramatically, before settling at a lower level post-menopause. That variability is the key piece. It's not a single pressure change that the system adjusts to. It's repeated pressure changes across months or years that some systems handle better than others. Now, serotonin. If you've listened to the anxiety episodes, you will know serotonin from there. It's involved in mood regulation, sleep appetite, and emotional stability. Estrogen has a direct relationship with serotonin activity. It influences how serotonin is produced, how it's transported, and how sensitive the receptors are that receive it. When estrogen fluctuates significantly, serotonin function becomes less reliable. The mood regulation system loses some of its consistency. Think of estrogen as a pressure system that keeps the temperature stable. When it's functioning normally, the day is predictable. When it fluctuates, you get days where the temperature swings unexpectedly. Serotonin is what regulates how warm and stable the day feels. And when the pressure system is erratic, the temperature regulation struggles to compensate. Now let's move on to GABA. GABA is the brain's main inhibitory transmitter, the brake system. We covered it in the ADHD episode. In the context of menopause, GABA is relevant because estrogen also modulates GABA receptor sensitivity. When estrogen falls and fluctuates, GABA receptor function can become less effective. The brake system that keeps anxiety and emotional reactivity from escalating loses some of its grip. This is why the paper proposes that estrogen fluctuations affecting serotonin and GABA is the biological mechanism behind increased vulnerability to depression and anxiety during the transition. It's not that estrogen loss causes depression directly, it's that the fluctuating pressure system destabilizes the two regulatory networks, serotonin for mood stability, and GABA for emotional breaking, that normally prevent things from getting rough. And this mechanism also explains why some people are more vulnerable than others. People who are already mood sensitive to hormonal fluctuations, people whose serotonin system is already working at a lower base, people with neuroticism, people who've had depression before, all of these factors mean the atmospheric system was already less stable before the transition began. The estrogen pressure changes hit a system that has less capacity to absorb them. It's not that menopause breaks something that was working fine. It's that the atmospheric changes of the transition interact with pre-existing conditions in the system. The people who hit rough weather are the people whose conditions made them more sensitive to those pressure changes. That's not a moral failing, it's atmospheric science. So we have two papers now, two systemic reviews looking at the same question from slightly different angles. Let's put them together because I think the combination is more useful than each one on their own. Episode 13 said, the cultural forecast of universal storms is wrong. Most people's weather during the menopause transition is fine, or at least not dramatically worse than before. The widespread narrative creates a negative expectation that can themselves contribute to poor outcomes. Depression and anxiety are not inevitable features of this life stage. Episode 14 says, but menopause does increase vulnerability for a specific subset of people, and the reason is biological and identifiable. Estrogen fluctuations destabilize the serotonin and GABA symptoms. For people who are already mood sensitive, already high in neuroticism, already carrying a history of depression, or already navigating significant psychosocial stress, that destabilization can tip the system into rough weather. Both papers agree on the primary risk factors. Prior history of major depression is the strongest predictor of depressive episodes during the transition. Vasomotor symptoms, particularly when they're disrupting sleep, are a consistent driver of mood disturbance. Psychosocial stressors happening concurrently increase risk independently. And how someone frames and expects the transition, their attitudes towards it shapes how they experience it. What neither paper supports is the idea that menopause is uniformly damaging to mental health, or that distress during this period should be automatically attributed to hormones, rather to its actual identifiable causes. The forecast of universal storms has been doing real harm by creating negative expectations and by obscuring the specific treatable, modifiable factors that actually drive the rough weather. And importantly, both papers point towards the same clinical conclusion. The people who need support during this transition are identifiable. Not everyone, but a specific group whose forecast does genuinely say rainstorm, whose atmospheric conditions make them more vulnerable to pressure changes of the transition. And those people deserve accurate forecasts and targeted intervention, not a generic warning applied to everyone. So, the atmospheric science. Estrogen fluctuates across the menopause transition, and those fluctuations affect serotonin and GABA, the two systems most responsible for mood stability and emotional breaking. For people whose systems were already more sensitive, the pressure changes of the transition are enough to shift the weather. That's not a forecast error, that's a real mechanism. And understanding it changes what you can do with it. If you know your system is more sensitive to estrogen fluctuations, you know to watch your sleep and manage your vasomotor symptoms because that's where instability enters. If you have a prior history of depression, you know the transition is a higher risk period, and you can make decisions about your care accordingly. The mechanism gives you something to work with. The wrong forecast says everyone is headed into the storm. The right forecast says here are the atmospheric conditions that actually produce rough weather. Here's who has them, and here's what you can do about it. That's a forecast worth having.