Anxiety can happen to anyone.
Regardless of age, gender, socioeconomic status, culture, ethnic background, or life circumstances, anxiety can affect anyone.
And I have to tell you, anxiety can be the worst.
Give me a physical injury any day. At least with a broken bone, sprained ankle, or cut, you know what is wrong. You can see it. You can point to it. You can make a plan to heal it.
Anxiety is different.
It can make you question yourself, your judgment, your decisions, and sometimes even your sanity. It can convince you that something terrible is about to happen, even when your rational mind knows otherwise.
But what I have found in my 20+ years of clinical experience is that hormonal change can seriously exacerbate or even trigger anxiety for the very first time.
These women aren't necessarily facing a crisis. Their jobs may be stable. Their marriages may be solid. Their kids may be doing well. Yet suddenly they find themselves lying awake worrying, overwhelmed, impatient, on edge, and unable to relax.
They start wondering, ‘What is going on? Why am I feeling this way? What is happening to me?’
There is nothing ‘wrong’ with them. We are amazing, healthy women.
It’s about hormones.
Because the hormonal changes in perimenopause and menopause are so vastly different, this article is about perimenopause and anxiety.
I have to say, perimenopause is not ‘baby-menopause.’
In many women, perimenopause can affect the body, brain, and emotional well-being very differently than menopause itself.
Okay, off my soapbox, and let’s talk about anxiety and peri!
Flaky-Friends (AKA: Inconsistent Ovarian Function)
In perimenopause, your ovaries are, well… They are flaky.
They haven’t always been so unreliable. In fact, your ovaries used to be so hyperresponsible. They showed up for work every day, on time, and dropped the ball (ovulation) right on time.
But in perimenopause, they act like they are on island time.
- They might not ovulate (drop the ball)
- Might ovulate earlier or later in the cycle.
- Might do a half-ass job ovulating
- Might ovulate right on time
But the key here is that they are unpredictable, unreliable, and yes, flaky.
Like that friend who said they were going to pick up from the airport but is way late (love that Uber exists now).
Are they just burnt out at this stage of the game? Have your poor ovaries been carrying too much for too long, and their mental bandwidth finally runs out? Is it an ovarian rebellion?
If the ovaries start taking too much PTO, what happens?
When the egg leaves the ovary (ovulation), there is a spot on the ovary that becomes the corpus luteum.
- The corpus luteum will secrete progesterone.
If there is a lack of ovulation or a half-ass corpus luteum (suboptimal corpus luteum), there is less progesterone.
If there is less progesterone, there is less allopregnanolone. Allopregnanolone is a metabolite of progesterone.
Why is allopregnanolone so important?
Allopregnanolone plays an important role in helping the brain regulate:
It does this by enhancing GABA (the brain’s main inhibitory neurotransmitter).
Now, allopregnanolone doesn’t ‘make’ GABA. It helps GABA work more efficiently by increasing GABA-A receptor activity in the brain.
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Less allopregnanolone (from less progesterone in perimenopause) can make women more vulnerable to:
- Anxiety
- Poor sleep
- Irritability
- Harder to drown out excess stimuli
- Way more sensitive to any kind of stress.
Estrogen, Behave!
Estrogen Up! Estrogen Down! Down! Down Estrogen! Now Up, Up!
Why is estrogen (estradiol) up and down in perimenopause?
One day it's high and the next it drops. Why can’t estrogen behave herself?!
In perimenopause, it feels like estradiol takes on a mind of her own.
Well, it isn't exactly estradiol that is the culprit.
The sneaky offender is: Inhibin B
Who is Inhibin B?
There are granulosa cells around the eggs in the ovary. Those granulosa cells make Inhibin B.
Inhibin B is a protein hormone that has one main job:
- Suppress FSH (Follicle-stimulating hormone).
Backup a bit: What is FSH?
In a nutshell (bc you know I could go on and on and on…), FSH is secreted by the pituitary gland.
- Lower FSH levels (under 10) indicate adequate ovarian function.
- High FSH levels point to lower ovarian function or no ovarian function (perimenopause and menopause).
Inhibin B will lower FSH.
As the number of eggs (follicles) declines, there are fewer granulosa cells, which means less inhibin B.
Less inhibin B = higher FSH levels
This is so interesting to me bc everyone talks about estrogen decline suppressing FSH. Which is true.
Less estradiol = higher FSH.
But this is the key to why a woman in perimenopause can have ginormous spikes of estradiol throughout her cycle.
- Her inhibin B is lower (bc of fewer follicles and fewer granulosa cells), which makes FSH rise.
Key point in perimenopause:
- FSH elevation in perimenopause can cause the ovary (granulosa cells) to release a bunch of estradiol into the bloodstream.
- And other times, there is a drop in estradiol bc fewer follicles are responding to FSH.
↓ Inhibin B = ↑ FSH → exaggerated follicular stimulation → very high estradiol
This is one reason some perimenopausal women have estradiol levels of 300, 400, or even 500+ pg/mL at times.
Perimenopause is a state of endocrine variability rather than endocrine deficiency.
Menopause = deficiency.
Perimenopause = variability.
Side note: This is also why, when a menopausal woman is on adequate levels of HRT or even rhythmic dosing, she might still have a higher FSH, even though the estradiol levels are perfect.
There just really are no more granulosa cells left to make inhibin B.
Now, if you are still with me after that physiology rabbit hole, why does it matter?
Estradiol (E2) also has profound effects on the brain, in particular, neurotransmitters:
- Serotonin: Mood and well-being
- Dopamine: Motivation and reward
- Norepinephrine: Alertness and focus
- Glutamate: Excitation and learning
- GABA: Calm and relaxation
In perimenopause, when the estradiol levels are spiking and then falling and then normal, it can make a woman feel anxious, overwhelmed, irritable, and unfocused.
BUT not all the time, it's pretty random.
That is why women in perimenopause feel so perplexed (to put it mildly), one day you're happy and the next you're a grumpy, anxious, stress ball.
This may help explain why many women describe feeling emotionally stable one week and completely different the next.
Overreacting
The Sky Is Falling!!
Estrogen and progesterone affect more than just neurotransmitters in the brain. They can directly influence other parts of your brain, in particular, your Limbic System:
Your limbic system consists of your amygdala, hippocampus, and prefrontal cortex.
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Amygdala: Threat detection and fear processing
- When estrogen and progesterone are fluctuating dramatically, the amygdala becomes more reactive. Leading to more worry, and minor stressors can feel like major threats.
- Hippocampus: Memory and stress regulation. Also helps regulate cortisol levels. The ups and downs of estradiol in perimenopause can cause cortisol signals to linger longer. This can make stressful experiences feel more intense and harder to ‘move on from.’
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Prefrontal cortex: Executive function and self-control (basically the ‘adult in the room’)
- When estradiol is spiking and diving while progesterone has left the building, the emotional brain becomes louder than the rational brain. This can lead to overthinking, ruminating, and repetitive thoughts. Worries from that amygdala become hard to dismiss.
This is where a woman may find herself worrying excessively about situations that she would have handled with ease just a few years earlier.
A minor problem can suddenly feel like a major crisis, and she may recognize that she is overreacting while simultaneously feeling unable to turn off the alarm bells in her brain.
Many women describe it as their stress threshold is narrowed considerably, feeling uncertain, and just feeling like, ‘don’t give one more thing to deal with!’
Get Ready To Rumble! HPA Has Entered the Octagon:
HPA stands for hypothalamic-pituitary-adrenal axis, which is basically the communication between your brain (hypothalamus and pituitary) and your adrenal glands.
Amid the ups and downs of estradiol and the decline in progesterone during perimenopause, your limbic system becomes highly reactive (see above).
This stimulates the HPA axis to jump into action.
Back up a bit. In a perfect world, if a stressor occurs, the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary to release adrenocorticotropic hormone (ACTH), which tells the adrenal glands to release cortisol.
When cortisol is released, it sends a signal (via a negative feedback loop) back to the hypothalamus to shut off the system.
Hypothalamus → CRH → Pituitary gland → ACTH → Adrenals → Cortisol → feedback back to the hypothalamus = shut off.
But this doesn't happen in perimenopause. What happens in perimenopause, you ask?
During perimenopause, fluctuating estradiol and declining progesterone can make the brain's stress circuits more reactive. Although the normal cortisol feedback system remains present, it becomes less effective at shutting off the stress response, leaving women feeling more anxious, overwhelmed, wired, or emotionally reactive.
PERI:
Hypothalamus → CRH → Pituitary gland → ACTH → Adrenals → Cortisol → feedback back to the hypothalamus = stays on longer or takes longer to shut off = anxiety
Then you throw in sleep deprivation that can happen in perimenopause, along with the perceived chronic stress, the HPA axis is ready to rumble, and there is no tapping out.
Cortisol My Frenemy
I say this over and over in my articles. We need cortisol to live.
But if cortisol is dysregulated, chronically elevated, up and down all day long, as it can be in perimenopause, it can mess with your neurotransmitters.
Elevated cortisol:
- Decreases GABA activity = more anxious, reactive, and easily overwhelmed
- Increases glutamate activity = more wired, harder to drown out extra stimuli, harder to relax
- Alters serotonin signaling = lower mood, more worry-prone, more sensitive
- Alters dopamine signaling = less motivation, less pleasure, less drive
Perimenopause can be the perfect recipe for anxiety
Now that you know the physiology behind what is happening with perimenopause and anxiety, what can we do about it?
This next part of the article will focus on:
- Hormone Stabilization (progesterone and estradiol)
- Supporting GABA/allopregnanolone
- Calming the limbic system
- Lowering HPA-axis activation/cortisol
- When to consider HRT
In fact, this is the order I would start when working with anxiety and peri.
Now that you understand the "why," let's talk about the "what next?"
Perimenopausal anxiety is often the result of real physiologic changes involving your hormones, brain, and stress-response system.
