When I worked in mainstream medicine, I was perplexed about why so many of my patients aged 35 and older were taking either selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs) to treat certain types of depression and anxiety. SSRIs work by blocking reuptake of serotonin by nerves, and SNRIs work by blocking the reuptake of serotonin and norepinephrine by nerves, though there is overlap between them. These brain mechanisms result in an increase in serotonin and norepinephrine concentrations in the nerve synapse (the space between two nerves). What was going on? Was norepinephrine suddenly dropping in women after 35, maybe related to postpartum, perimenopause, and menopause? The short answer is yes, norepinephrine changes substantially through the hormonal lifecycle of women and most people are unaware.
A recent review article discusses the role of norepinephrine in women, particularly in the context of its role in treating depression during the postpartum, perimenopause, and menopause periods. This review, published in 2023 in Frontiers in Endocrinology, consolidates knowledge on the interaction between hormonal changes and the hypothalamic-pituitary-adrenal (HPA) axis within the context of depressive disorders in women. It highlights the significant role of norepinephrine in stress response and its involvement in depression across these different reproductive stages.
What Are Norepinephrine, SSRIs, and SNRIs?
Norepinephrine is part of your body’s built-in alarm system—it kicks in during stress, increasing heart rate, blood pressure, and alertness to help you react quickly (think fight-or-flight mode). In terms of mood, it plays a key role in focus, motivation, and emotional resilience, but too much can lead to anxiety and agitation, while too little is linked to depression and low energy. Basically, it’s the difference between feeling ready to conquer the world and feeling stuck in Monday morning traffic. Norepinephrine interacts with other neurotransmitters such as serotonin and dopamine in complex ways during the postpartum, perimenopause, and menopause periods, influencing mood and stress responses.
SSRIs (Selective Serotonin Reuptake Inhibitors) and SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) are both antidepressants, but they work a little differently.
- SSRIs boost serotonin levels by blocking its reabsorption, making more of this “feel-good” neurotransmitter available in the brain. They’re typically the go-to for depression and anxiety. Think of them as mood-lifters with a side of emotional chill. Examples: Fluoxetine (Prozac), Sertraline (Zoloft), and Escitalopram (Lexapro) .
- SNRIs do the same for serotonin but also increase norepinephrine, which helps with both mood and energy levels. They’re often used when SSRIs aren’t enough or when more focus and motivation are needed (like in some anxiety and chronic pain conditions). Examples: Venlafaxine (Effexor), Duloxetine (Cymbalta), and Desvenlafaxine (Pristiq).
Turns out that norepinephrine changes significantly across the female lifecycle, including postpartum, perimenopause, and menopause. Welcome to the fascinating and sometimes chaotic world of hormones, where everything changes, and nothing stays the same. If you’ve ever wondered why your body seems to throw a party of its own after childbirth or during perimenopause and menopause, you’re not alone. You’ve probably seen your share of complex biological systems, but let’s dive into the intricacies of how norepinephrine—also one of your body’s “fight-or-flight” messengers along with adrenaline and cortisol—throws a tantrum during these transformative life stages. Spoiler alert: It’s not always graceful.
Postpartum and Norepinephrine
First, let’s talk about postpartum, that whirlwind period right after giving birth that can last up to a year. Imagine your body as a well-oiled machine that just finished running a marathon. You’re exhausted, you’ve produced a tiny human, and suddenly your stress response system, including norepinephrine, is like, “Okay, I’m going to take a nap, but first, let’s cause a little ruckus!” Immediately after birth, your hypothalamus (the brain’s control center) suddenly drops norepinephrine levels rapidly. The result? An increase in a byproduct called 3-methoxy-4-hydroxyphenylglycol (MHPG, which I think of as “My Hormones Plunged Gloriously), which suggests that norepinephrine is being recycled and turned over at an alarming rate. Your body isn’t having a meltdown. It’s just dealing with the emotional and physical rollercoaster that is postpartum life.
On the other hand, plasma norepinephrine levels stay elevated or continue to rise after delivery. That’s your body’s way of saying, “Hey, you’re not quite done yet!”
Let’s break this down without needing a PhD in biochemistry. After birth, your body does this wild hormonal cha-cha, and norepinephrine—the “fight-or-flight” chemical—gets in on the action. If your norepinephrine levels are doing the tango, you might find yourself crying over a dropped sock one minute and snapping at your partner for breathing too loudly the next. Welcome to postpartum blues, a.k.a. the emotional rollercoaster that about 30% of new moms ride.
Science shows that women with postpartum blues tend to have higher levels of MHPG. This chemical marker means your norepinephrine is working overtime, making you extra sensitive to stress and less equipped to deal with it. Translation? Your stress buffer is MIA, your patience is thinner than hospital-issue toilet paper, and even minor annoyances feel like DEFCON 1.
The result? Mood swings that make teenage angst look tame, irritability levels that could rival a sleep-deprived grizzly bear, and a general feeling of “Why…?” The good news is that the hormonal chaos and diminished stress coping are temporary. Your brain and body are recalibrating after the seismic event of childbirth, and with a little time (plus support, sleep, and maybe a good ugly cry), you’ll find your emotional sea legs again. Until then, be gentle with yourself and remember that mood disturbances such as postpartum blues and depression are common symptoms associated with changes in norepinephrine levels during the postpartum period.
During the postpartum period, the American College of Obstetricians and Gynecologists (ACOG) recommends the use of SSRIs, including escitalopram, for the treatment of perinatal depressive disorders due to their efficacy and tolerability profiles. Generally, I prefer natural approaches first like nourishing food, more sleep, exercise, and consider the latest evidence on the herbal option, saffron.
Saffron has been shown to inhibit the reuptake of norepinephrine, serotonin, and dopamine, thereby increasing their levels in the space between neurons (called the synaptic cleft) and enhancing mood. For postpartum depression, a double-blind, randomized clinical trial compared saffron (15 mg twice daily) to Prozac, a selective serotonin reuptake inhibitor (fluoxetine, 20 mg twice daily) over six weeks. The study found no significant difference in efficacy between saffron and fluoxetine in reducing depressive symptoms, suggesting that saffron is as effective as fluoxetine for treating mild to moderate postpartum depression.
Perimenopause and Norepinephrine
Fast-forward to perimenopause—or if you’re an older mother like me, postpartum and perimenopause may occur sequentially. In perimenopause, the hormonal prelude to menopause, the plot thickens. Think of perimenopause like the pre-show: It’s not the main event yet, but things are heating up. Your basal plasma norepinephrine levels during this time are higher than they were when you were still a carefree premenopausal (but not postpartum) woman. This means your body is like a pot of water slowly heating up on the stove: a little more pressure, a little more simmering, and maybe even a boil over here and there. Why the increase? Well, your brain is signaling your body to react differently as you approach menopause, preparing for the dramatic shifts ahead.
Ah, perimenopause—where the hormone levels start to resemble a rollercoaster at full speed, and norepinephrine is buckled in for the ride. During this stage, you may feel like you’re experiencing a constant low-level panic attack, but in reality, it’s just your body’s stress response ramping up. Basal plasma norepinephrine levels are notably higher during perimenopause compared to premenopausal women. It’s like your body’s stress system is cranking up the volume to 11, getting ready for what’s coming next. But here’s the plot twist: estrogen, that hormone we all know and love (even when it’s a bit moody), actually plays a role in turning the volume down a notch. When perimenopausal women receive estrogen supplementation, studies show it helps reduce the norepinephrine-induced vasoconstriction—that’s when your blood vessels tighten up like they’re squeezing the last bit of toothpaste from the tube. Estrogen also curbs the spillover of norepinephrine throughout the body, which is like trying to keep that stress-filled energy from spilling over into every aspect of your life.
Even better, estrogen has been shown to help manage norepinephrine’s overzealous response to mental stress. You know, when the smallest thing sends you into a tizzy, and you feel like you’re ready to launch into outer space? Estrogen helps to keep norepinephrine in check during those times, which is impressive when you think about it. It’s like having a personal stress manager who knows how to put the brakes on when you need it most.In perimenopause and menopause, saffron has also shown promising results. Saffron (30 mg/day) significantly improves depressive symptoms in post-menopausal women with hot flashes, which is consistent with its role in modulating norepinephrine levels. Another meta-analysis concluded that saffron is non-inferior to conventional antidepressants like fluoxetine and imipramine for treating mild to moderate depression, with fewer side effects.
Menopause and Norepinephrine
Next up is menopause, the grand finale of the hormonal symphony. By the time you’ve officially entered menopause, norepinephrine’s antics are not yet over. Postmenopausal women exhibit higher baseline plasma norepinephrine levels compared to premenopausal women—again, it’s like that stress button never quite gets turned off. This increased norepinephrine is linked to higher systemic vascular resistance, which means your blood vessels are working harder than ever, not necessarily a good thing. Combine that with reduced responsiveness of your beta-adrenergic receptors (basically, the body’s “brake system” for norepinephrine), and you get altered cardiovascular function—your heart and blood vessels just aren’t handling things like they used to. It’s the hormonal equivalent of driving a car with a malfunctioning brake.But don’t despair just yet—there’s a silver lining. Estrogen replacement therapy in postmenopausal women can improve the way your body handles norepinephrine-induced vasoconstriction. In other words, estrogen helps take the edge off those tight, stressed-out blood vessels, showing that estrogen’s absence during menopause isn’t just a hormonal change—it’s like leaving the brakes off a car and letting the stress drive you. With estrogen back in the mix, it helps the body regain some control over these runaway responses, making menopause a little more manageable.
Back to SSRIs and SNRIs
As some of the most prescribed medications for women navigating the hormonal rollercoaster of perimenopause and menopause, SSRIs and SNRIs can impact norepinephrine levels, contributing to its ability to help stabilize mood and manage symptoms of anxiety and depression. For many women dealing with the emotional and physical challenges of hormonal changes, this can be a game changer. In fact, it’s estimated that about 12-15% of women aged 40 to 60 take SSRIs like Lexapro, often to help ease the mood swings, irritability, and anxiety that can come with perimenopause and menopause.
However, while antidepressant pharmaceuticals can be a life-saver, they are not without its side effects. Some women experience headaches, nausea, insomnia, weird yawning, or sexual side effects like decreased libido or difficulty reaching orgasm—because hormones and neurotransmitters just love to make things complicated. It’s also worth noting that starting Lexapro can cause a bit of an initial “adjustment period,” where you might feel a little off as your body gets used to the medication. For some, the medication can lead to weight gain or sleep disturbances, though these effects aren’t universal.
To sum up: postpartum, perimenopause, and menopause all bring their own unique challenges to the norepinephrine party. From the sharp drop right after childbirth to the gradual increase during perimenopause and menopause, your stress hormones are on a wild ride. Thankfully, estrogen plays a key role in modulating norepinephrine’s effects and you may want to talk to your healthcare professional about treatment with estrogen therapy. Lifestyle medicine can help too, starting first with what you eat and how you move. Exercise has been shown to support norepinephrine levels throughout the female lifecycle, making the wild ride less bumpy. My wish is that more women are offered lifestyle medicine first to cope with the sometimes dramatic norepinephrine fluctuations when under stress as we age.
Now it’s your turn. Have you had challenges with mood when postpartum, or in perimenopause or menopause? What helped?
References:
1. Hantsoo, L., et al. 2023. “The Role of the Hypothalamic-Pituitary-Adrenal Axis in Depression Across the Female Reproductive Lifecycle: Current Knowledge and Future Directions.” Frontiers in Endocrinology 14: 1295261. https://doi.org/10.3389/fendo.2023.1295261.
2. Moltz, H., et al. 1975. “Hypothalamic Norepinephrine: Concentration and Metabolism During Pregnancy and Lactation in the Rat.” Neuroendocrinology 19, no. 3: 252–58. https://doi.org/10.1159/000122445.
3. Doornbos, B., et al. 2008. “Sequential Serotonin and Noradrenalin Associated Processes Involved in Postpartum Blues.” Progress in Neuro-Psychopharmacology & Biological Psychiatry32, no. 5: 1320–25. https://doi.org/10.1016/j.pnpbp.2008.04.010.
4. Lederman, R. P., et al. 1977. “Endogenous Plasma Epinephrine and Norepinephrine in Last-Trimester Pregnancy and Labor.” American Journal of Obstetrics and Gynecology 129, no. 1: 5–8. https://doi.org/10.1016/0002-9378(77)90809-2.
5. Dormal, V., et al. 2025. “The Effects of Combined Scutellaria and Saffron Supplementation on Mood Regulation in Participants With Mild-to-Moderate Depressive Symptoms: A Randomized, Double-Blind, Placebo-Controlled Study.” Nutrients 17, no. 5: 809. https://doi.org/10.3390/nu17050809.
6. Monchaux De Oliveira, et al. 2021. “Saffron Extract-Induced Improvement of Depressive-Like Behavior in Mice Is Associated with Modulation of Monoaminergic Neurotransmission.” Nutrients 13, no. 3: 904. https://doi.org/10.3390/nu13030904; Monchaux De Oliveira, C., et al. 2021. “Prevention of Stress-Induced Depressive-Like Behavior by Saffron Extract Is Associated with Modulation of Kynurenine Pathway and Monoamine Neurotransmission.” Pharmaceutics 13, no. 12: 2155. https://doi.org/10.3390/pharmaceutics13122155; Siddiqui, S. A., et al. 2022. “Anti-Depressant Properties of Crocin Molecules in Saffron.” Molecules 27, no. 7: 2076. https://doi.org/10.3390/molecules27072076.
7. Kashani, L., et al. 2017. “Comparison of Saffron Versus Fluoxetine in Treatment of Mild to Moderate Postpartum Depression: A Double-Blind, Randomized Clinical Trial.” Pharmacopsychiatry 50, no. 2: 64–68. https://doi.org/10.1055/s-0042-115306.
8. Del Rio, G., et al. “Alpha-2 Adrenergic Activity in Perimenopausal Women.” Journal of Endocrinological Investigation 20, no. 10 (1997): 603-10. https://doi.org/10.1007/BF03346917.
9. Kashani, L., et al. 2018. “Efficacy of Crocus Sativus (Saffron) in Treatment of Major Depressive Disorder Associated With Post-Menopausal Hot Flashes: A Double-Blind, Randomized, Placebo-Controlled Trial.” Archives of Gynecology and Obstetrics 297, no. 3: 717–24. https://doi.org/10.1007/s00404-018-4655-2.
10. Tóth, B., et al. 2019. “The Efficacy of Saffron in the Treatment of Mild to Moderate Depression: A Meta-Analysis.” Planta Medica 85, no. 1: 24–31. https://doi.org/10.1055/a-0660-9565; Dai, L., et al. 2020. “Safety and Efficacy of Saffron (Crocus Sativus L.) for Treating Mild to Moderate Depression: A Systematic Review and Meta-Analysis.” The Journal of Nervous and Mental Disease 208, no. 4: 269–76. https://doi.org/10.1097/NMD.0000000000001118.
11. Sherwood, A., et al. 2010. “Cardiovascular Hemodynamics During Stress in Premenopausal Versus Postmenopausal Women.” Menopause 17, no. 2: 403–9. https://doi.org/10.1097/gme.0b013e3181b9b061.
12. Sudhir, K., et al. “Estrogen Supplementation Decreases Norepinephrine-Induced Vasoconstriction and Total Body Norepinephrine Spillover in Perimenopausal Women.” Hypertension 30, no. 6 (1997): 1538-43. https://doi.org/10.1161/01.hyp.30.6.1538; Komesaroff, P. A., et al. 1999. “Estrogen Supplementation Attenuates Glucocorticoid and Catecholamine Responses to Mental Stress in Perimenopausal Women.” The Journal of Clinical Endocrinology & Metabolism 84, no. 2: 606–10. https://doi.org/10.1210/jcem.84.2.5447; Sung, B. H., et al. 1999. “Estrogen Improves Abnormal Norepinephrine-Induced Vasoconstriction in Postmenopausal Women.” Journal of Hypertension 17, no. 4: 523–28. https://doi.org/10.1097/00004872-199917040-00010.
13. Smith, J. R., et al. 2019. “Influence of Sex, Menstrual Cycle, and Menopause Status on the Exercise Pressor Reflex.” Medicine and Science in Sports and Exercise 51, no. 5: 874–81. https://doi.org/10.1249/MSS.0000000000001877; Wenner, M. M., et al. 2022. “Influence of Age and Estradiol on Sympathetic Nerve Activity Responses to Exercise in Women.” Medicine and Science in Sports and Exercise 54, no. 3: 408–16. https://doi.org/10.1249/MSS.0000000000002823.
