Perimenopause is a natural process when your ovaries gradually produce less estrogen throwing your hormonal balances out of whack. During this transition, it's common to experience symptoms like hot flashes, night sweats, and mood changes.
Literature suggests that perimenopause holds the highest risk for psychological disorders in women compared to pre-and post-menopause
Why Does Perimenopause Rage Happen?
There are many different reasons why mood disorders occur in perimenopause. (4) Among them are:
- Hormonal changes
- Structural brain changes
- Lifestyle factors
- Predisposing conditions
- Socioeconomic factors
Much of the research has suggested hormonal shifts are mainly responsible for the changes in emotions that occur during perimenopause and the menstrual cycle.
One main focus on mood disorders associated with the menopausal transition is the fluctuations in the sex hormones, estrogen, and progesterone. (8-13)
Estrogen helps produce serotonin and has many other effects on the brain, including modifying the production of endorphins. (10-18)
Estrogen levels normally range from 5 ng/dL to 35 ng/dL pre-menopause and can dip below to 1.3 ng/dL postmenopause.(4) These shifts can result in an "estrogen withdrawal," leading to mood symptoms associated with depression and anxiety.
Along with the perimenopausal estrogen decrease, a variance in menstrual regularity and ovulation occurs. These changes are related to fluctuations in follicle-stimulating hormone (FSH) and luteal progesterone. (4)
Allopregnanolone, a downstream progesterone metabolite, has been said to modulate GABAa (Gamma-aminobutyric acid) receptors resulting in anti-anxiety and antidepressant effects. (19-21). When progesterone decreases, this also lowers the activation of the calming neurotransmitter GABA.
Estrogen has many different effects on the brain, making it a probable agent for these emotional outbursts. These include: (10-18)
- Raising serotonin and serotonin receptors.
- Modifying endorphin levels, the "feel-good" chemicals
- Neuroprotection and potential nerve growth stimulation. Specifically, estrogen levels have been linked to brain-derived neurotrophic factors (BDNF) in animal studies.4 BDNF is responsible for the growth and health of nerves. It is expressed in the hippocampus, an area in the brain related to memory and emotion. (14)
- The modulation of prolactin and dopamine. (15)
Neuroscientist Lisa Mosconi explains how drops in estrogen affect the brain and further affect the symptoms of perimenopausal women:
"When estrogen doesn't activate the hypothalamus correctly, the brain cannot regulate body temperature correctly. So those hot flashes that women get - that's the hypothalamus. Then there's the brainstem in charge of sleep and wake. When estrogen doesn't activate the brainstem correctly, we have trouble sleeping. Or it's the amygdala, the emotional center of the brain, close to the hippocampus, the memory center of the brain. When estrogen levels ebb in these regions, we start getting mood swings perhaps and forget things."
Luckily for us, many of these changes are only temporary.
It has been suggested that those who already suffer from pre-menstrual symptoms (PMS) may be more likely to experience mood swings in perimenopause. In a study published in the journal, Obstetrics and Gynecology, investigators found that PMS sufferers were twice as likely to experience hot flashes and mood swings as they approached "the change" as women who did not have PMS.
How to Recognize Perimenopause Transition
The perimenopause transition can lead to a variety of symptoms. Some of the most common include: (2)
Hot flashes and Night Sweats
It is estimated that 35-50% of perimenopausal women suffer from sweating and flushing from body heat waves. Hot flashes can occur during the day or night (night sweats) and usually last 5-10 minutes. For most women, hot flashes continue for 1-2 years after menopause, although 10% of women have persistent hot flashes beyond two years. (2)
Due to falling estrogen levels, vaginal tissue can become drier and thinner in perimenopause. This can cause irritation, itching, and pain during intercourse, which can interfere with sex drive. (2)
Uterine Bleeding Problems
Progesterone, which regulates the growth of the endometrium (the inner epithelial layer of the uterus), declines in perimenopause. This can result in heavier periods. Although estrogen and progesterone fluctuations occur with perimenopause, the ratio tends to favor higher estrogen. This can fuel an increased risk for fibroids and endometriosis. (2,4)
Approximately 40% of perimenopausal women have been said to experience sleep problems. Though some studies show a relationship between night sweats and sleep disturbances, the literature is mixed. (2,24-3)6
Memory and Focus
Memory issues tend to be higher in women than men. Estradiol has been shown in several studies to have a direct impact on the memory center. (27) Due to the interactions between hormonal variations and brain function, women may complain of difficulty focusing and memory issues. (2, 4, 27, 28)
Mood swings are significant with perimenopause. Women with irritability have reported finding themselves less tolerant and more easily annoyed. (27, 28) Some women experience rage, which is a higher level of emotional upheaval than irritability. It is defined as violent and uncontrolled anger or a fit of violent wrath. (30)
If one is experiencing irritability and rage, along with these perimenopausal transition symptoms, it is likely related to "perimenopausal rage."
Functional Medicine Labs to Test for Root Cause of Perimenopausal Rage
Obtaining a baseline measurement of sex hormones and adrenal function can be helpful in addressing how one's hormonal fluctuations impact mood changes. These tests can be used to personalize nutritional and hormonal supplemental support.
Popular hormonal panels include:
- The DUTCH Complete (Dried Urine Test) is an extensive sex and adrenal hormone profile. It evaluates free cortisol patterns, organic acids, melatonin, and 8-OhdG, along with androgen, progesterone, estrogen, cortisol, and cortisone metabolites. This test is an excellent comprehensive analysis of a patient's hormone levels, giving you all the information you need for a baseline hormone assessment or monitoring hormone-replacement therapy.
- Vibrant America Hormones Panel (Serum Blood Test) assesses 13 sex hormones and related biomarkers important in women's health.
- ZRT Saliva Panel III (Saliva Test) Saliva Profile III provides a baseline assessment of four sex and adrenal hormones, plus cortisol.
Because estrogen interacts with thyroid levels, thyroid hormone function should be assessed. It is also important to monitor thyroid function with any hormone replacement therapy (HRT) because of estrogen's impact on thyroid binding globulin (TBG) and free thyroid hormone. (33)
Due to the interaction between sex hormones and neurotransmitters, a practitioner may choose to assess neurotransmitters during this transition.
The gut microbiome also plays a significant role in hormonal and mood disorders. Comprehensive stool tests offer a complete look at gut health by measuring pathogens and analyzing digestion, nutrient absorption, inflammation, and immune function.
Functional Medicine Treatment for Perimenopause Rage
Treatment for perimenopause rage will depend on the clinical history of menstrual symptoms, testing results, and mood correlations. Below are several options that are commonly used.
Hormone Replacement Therapy
Conventional treatment for menopausal systems often uses hormone replacement therapy (HRT). The available evidence suggests that the benefits may outweigh the risks in otherwise healthy women during perimenopause or early postmenopause who are experiencing moderate to severe symptoms. (35-37)
Bioidentical Hormone Replacement Therapy (BHRT) is another FDA-approved option. These include estradiol, estrone, and MP (micronized progesterone). (38) BHRT is generally viewed as a safer alternative to conventional HRT, though controversies do exist between various experts. (35-38)
HRT and BHRT can come with side effects and risks and must be personalized based on the individual.35-38
Due to their system-wide impact and the many influences hormones have, our body has complex feedback mechanisms to regulate them. (39) For these reasons, functional medicine practitioners will often focus on lifestyle, behavioral, and foundational support before assessing the need to incorporate HRT or BHRT. This starts with the less invasive and lowest risk interventions first.
A regular exercise or movement program can also enhance mood, help cope with stress, and has been shown to support health outcomes. (40)
Proper sleep and rest are also imperative for mood regulation and overall health. Since many women report sleep problems in perimenopause, it's wise to teach sleep hygiene and provide additional support for interfering factors, such as hot flashes. (41)
Mindfulness-based stress reduction (MBSR) practices develop awareness and evoke becoming aware of the present moment. They include various tools, including acceptance, mindfulness meditation, and yoga. (42)
Lavender: Lavender oil reduced hot flashes in one double-blinded 12-week clinical crossover trial of 100 women. (42)
By reducing hot flashes, some women may see improvements in sleep which could positively impact mood. Lavender, when combined with other oils, was also shown to improve psychological symptoms.
Clary Sage: In one small trial with 22 women, clary sage oil decreased cortisol levels and increased 5-hydroxytryptamine (5-HT). It also improved depression ratings. (43)
Geranium and Rose: In one trial, salivary estrogen concentration was elevated upon inhalation exposure to geranium and rose oil. Together with previous studies, this study supports the notion that olfactory exposure to some essential oils can influence the salivary concentration of estrogen.
Neroli (Bitter Orange): In one study with 63 healthy postmenopausal women, inhalation of neroli oil for five days for five minutes twice daily improved serum estrogen and cortisol concentrations. It also enhanced sexual desire, blood pressure, and heart rate. (45)
Various herbals have been found to be supportive of menopausal symptoms through a variety of mechanisms. (46)
Jia Wei Xiao Yao San, (modified Xiao Yao San) a Traditional Chinese Herbal formula, is commonly used to help alleviate mood disorders associated with women's hormones. This formula is one of the most commonly studied Chinese formulas due to its positive effects on mood disorders. The Chinese Medicine mechanism of Xiao Yao San (XYS), is that it soothes the liver, invigorates the spleen, nourishes the blood to restore the normal menstruation, and clears away the liver fire due to blood deficiency.
Biochemically, the XYS decoction also reversed CIS-induced decreases in brain-derived neurotrophic factor (BDNF) and increases in tyroxine hydroxylase (TrkB), and neurotrophin 3 (NT-3) in the frontal cortex, and the hippocampal CA subregion. This helped to decrease depression symptoms.
In an RCT comparing isopropanolic black cohosh extract and ethanolic St John's wort among 301 women, scores on the Menopause Rating Scale decreased by 50% in the treatment group and depression symptoms significantly reduced.
Phytoestrogens are plant-derived compounds commonly sourced from soy and red clover (isoflavones)) flaxseed (lignans), and hops (Humulus lupulus). They are frequently used to reduce hot flashes in perimenopausal and menopausal women. Reducing hot flashes improved perimenopausal women's quality of life and mood.
What you eat can directly influence your mood by providing micronutrients needed to make neurotransmitters, regulating hormone levels, and providing energy throughout the day.
Various studies have supported a link between plant foods and Phytoestrogens and mood enhancement. Increasing phytoestrogens has been shown to significantly promote positive mood in menopausal women with depression and anxiety disorder.
Thyroid- Gut Axis Treatment
Other interventions based on the functional medicine matrix, such as supporting the thyroid-gut axis and other systems, should also be considered. The interaction between estrogen and progesterone can be positively influenced by addressing gut and thyroid function.
Many practitioners support patients during perimenopause by prescribing a Mediterranean-based diet to help patients increase their plant and micronutrient intake while lowering systemic inflammation and enhancing mood.
The transition to menopause encompasses changes in hormones, mood, and social and physiological effects. These shifts can negatively impact many aspects of the mind-body, and those with underlying mood disorders and who have experienced hormonal issues throughout their lifespan are likely more vulnerable.
The variations in sex hormones that occur with perimenopause profoundly affect the brain and mood. Estrogen and progesterone impact neurotransmitters, neurosteroid signaling, and overall brain functioning. This can result in irritability and lead to rage.
Understanding the underlying mechanisms and using a functional medicine approach that focuses on lifestyle, including balancing stress, mind-body approaches, aromatherapy, nutrition, and herbal support, can help balance the hormones and improve brain health and overall mood.
Hormone replacement is also an option; however, personalizing dosages specifically to an individual's symptoms and lab results is important for monitoring safety and avoiding side effects.
Lab Tests in This Article
1. Menopause and Mood Disorders. Medscape. January 30, 2019. https://emedicine.medscape.com/article/295382-overview
2. Perimenopause: A Rocky Road to Menopause. Harvard Health Publishing: Harvard Medical School. August 9, 2022. https://www.health.harvard.edu/womens-health/perimenopause-rocky-road-to-menopause
3. Born L, Koren G, Lin E, Steiner M. A new, female-specific irritability rating scale. J Psychiatry Neurosci. 2008 Jul;33(4):344-54. PMID: 18592028
4. Musial N, Ali Z, Grbevski J, Veerakumar A, Sharma P. Perimenopause and First-Onset Mood Disorders: A Closer Look. Focus (Am Psychiatr Publ). 2021 Jul;19(3):330-337. doi: 10.1176/appi.focus.20200041. Epub 2021 Jul 9. PMID: 34690602
5. Office of Women’s Health. Premenstrual Syndrome. Updated February 22, 2021. https://www.womenshealth.gov/menstrual-cycle/premenstrual-syndrome
6. Sander B, Gordon JL. Premenstrual Mood Symptoms in the Perimenopause. Curr Psychiatry Rep. 2021 Oct 6;23(11):73. doi: 10.1007/s11920-021-01285-1. PMID: 34613495.
7. Gordon JL, Girdler SS, Meltzer-Brody SE, Stika CS, Thurston RC, Clark CT, Prairie BA, Moses-Kolko E, Joffe H, Wisner KL. Ovarian hormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: a novel heuristic model. Am J Psychiatry. 2015 Mar 1;172(3):227-36. Doi: 10.1176/appi.ajp.2014.14070918. Epub 2015 Jan 13. PMID: 25585035;
8. Gordon JL, Girdler SS, Meltzer-Brody SE, Stika CS, Thurston RC, Clark CT, Prairie BA, Moses-Kolko E, Joffe H, Wisner KL. Ovarian hormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: a novel heuristic model. Am J Psychiatry. 2015 Mar 1;172(3):227-36. doi: 10.1176/appi.ajp.2014.14070918. PMID: 25585035.
9. National Institute of Mental Health (NIMH). The Effects of Estrogen Withdrawal on Mood Symptoms in Women. Clinical Trial. April 27, 2016. ClinicalTrials.gov Identifier: NCT00060736. Available at: https://clinicaltrials.gov/ct2/show/NCT00060736, Published study: Schmidt PJ, Ben Dor R, Martinez PE, et al. Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2015;72(7):714–726. doi:10.1001/jamapsychiatry.2015.0111.
10. Hoffman, M. Estrogen and Women’s Emotions. WebMD. August 1, 2021. https://www.webmd.com/women/guide/estrogen-and-womens-emotions
11. Freeman EW, Sammel MD, Lin H, Gracia CR, Kapoor S. Symptoms in the menopausal transition: hormone and behavioral correlates. Obstet Gynecol. 2008 Jan;111(1):127-36. doi: 10.1097/01.AOG.0000295867.06184.b1. PMID: 18165401.
12. Sander B, Gordon JL. Premenstrual Mood Symptoms in the Perimenopause. Curr Psychiatry Rep. 2021 Oct 6;23(11):73. doi: 10.1007/s11920-021-01285-1. PMID: 34613495.
13. Amin Z, Canli T, Epperson CN. Effect of estrogen-serotonin interactions on mood and cognition. Behav Cogn Neurosci Rev. 2005 Mar;4(1):43-58. doi: 10.1177/1534582305277152. PMID: 15886402.
14. BDNF gene. Brain derived neurotrophic factor. Medline Plus. Updated March 1, 2013. https://medlineplus.gov/genetics/gene/bdnf/
15. Al-Chalabi M, Bass AN, Alsalman I. Physiology, Prolactin. [Updated 2021 Jul 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507829/
16. Komesaroff PA, Esler MD, Sudhir K. Estrogen supplementation attenuates glucocorticoid and catecholamine responses to mental stress in perimenopausal women. J Clin Endocrinol Metab. 1999 Feb;84(2):606-10. doi: 10.1210/jcem.84.2.5447. PMID: 10022424. https://pubmed.ncbi.nlm.nih.gov/10022424/
18. Rekkas PV, Wilson AA, Lee VWH, et al. Greater Monoamine Oxidase A Binding in Perimenopausal Age as Measured With Carbon 11–Labeled Harmine Positron Emission Tomography. JAMA Psychiatry. 2014;71(8):873–879. doi:10.1001/jamapsychiatry.2014.250
19. Walton N, Maguire J. Allopregnanolone-based treatments for postpartum depression: Why/how do they work? Neurobiol Stress. 2019 Oct 24;11:100198. doi: 10.1016/j.ynstr.2019.100198. PMID: 31709278.
20. Glick ID, Bennett SE. Psychiatric complications of progesterone and oral contraceptives. J Clin Psychopharmacol. 1981 Nov;1(6):350-67. doi: 10.1097/00004714-198111000-00003. PMID: 7037875.
21. Hantoushzadeh S, Sheikh M, Shariat M, Mansouri R, Ghamari A, Golshahi F. The effects of progesterone therapy in pregnancy: vaginal and intramuscular administration. J Matern Fetal Neonatal Med. 2021 Jul;34(13):2033-2040. doi: 10.1080/14767058.2019.1656190. Epub 2019 Aug 28. PMID: 31409166.
22. Young SN. The effect of raising and lowering tryptophan levels on human mood and social behaviour. Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368(1615):20110375. doi: 10.1098/rstb.2011.0375. PMID: 23440461. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638380/
22. Dury, Julien. Study on serotonin and depression sparks fierce debate. Yahoo News. August 11, 2022. https://news.yahoo.com/study-serotonin-depression-sparks-fierce-100736982.html
23. Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2022 Jul 20. doi: 10.1038/s41380-022-01661-0.
24. Lee J, Han Y, Cho HH, Kim MR. Sleep Disorders and Menopause. J Menopausal Med. 2019 Aug;25(2):83-87. doi: 10.6118/jmm.19192. Epub 2019 Aug 5. Erratum in: J Menopausal Med. 2019 Dec;25(3):172. PMID: 31497577.
25. Schaedel Z, Holloway D, Bruce D, Rymer J. Management of sleep disorders in the menopausal transition. Post Reprod Health. 2021 Dec;27(4):209-214. doi: 10.1177/20533691211039151. PMID: 34748453.
26. Moreno-Frías C, Figueroa-Vega N, Malacara JM. Relationship of sleep alterations with perimenopausal and postmenopausal symptoms. Menopause. 2014 Sep;21(9):1017-22. doi: 10.1097/GME.0000000000000206. PMID: 24569619.
27. Goldstein, J. Menopause and memory: Know the facts. Women’s Health. Harvard Health Publishing. Harvard Medical School. November 3, 2021.https://www.health.harvard.edu/blog/menopause-and-memory-know-the-facts-202111032630
28. Dresden, D. What causes mood swings during menopause? Medical News Today. May 22, 2017. Accessed at: https://www.medicalnewstoday.com/articles/317566. Retrieved August 16, 2022.
29. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.
30. Rage. https://www.merriam-webster.com/dictionary/rage
31. Hofman, L. Human Saliva as a Diagnostic Specimen, The Journal of Nutrition. May 2001. 131: 5. Pages 1621S–1625S, https://doi.org/10.1093/jn/131.5.1621S
32. Newman M, Curran DA. Reliability of a dried urine test for comprehensive assessment of urine hormones and metabolites. BMC Chem. 2021 Mar 15;15(1):18. doi: 10.1186/s13065-021-00744-3. PMID: 33722278.
33. Mazer NA. Interaction of estrogen therapy and thyroid hormone replacement in postmenopausal women. Thyroid. 2004;14 Suppl 1:S27-34. doi: 10.1089/105072504323024561. PMID: 15142374.
34. Gwak MG, Chang SY. Gut-Brain Connection: Microbiome, Gut Barrier, and Environmental Sensors. Immune Netw. 2021 Jun 16;21(3):e20. doi: 10.4110/in.2021.21.e20. PMID: 34277110. PMCID: PMC8263213.
35. Vigneswaran K, Hamoda H. Hormone replacement therapy - Current recommendations. Best Pract Res Clin Obstet Gynaecol. 2022 May;81:8-21. doi: 10.1016/j.bpobgyn.2021.12.001. Epub 2021 Dec 14. PMID: 35000809.
36. NAMS Position Statement: The 2022 hormone therapy position statement of The North American Menopause Society. Menopause: The Journal of The North American Menopause Society. 29(7): 767-794. DOI: 10.1097/GME.0000000000002028
37. Johnson, T. What are Hot Flashes. WebMD. July 3, 2022. https://www.webmd.com/menopause/guide/menopause-hot-flashes
38. Stanczyk FZ, Matharu H, Winer SA. Bioidentical hormones. Climacteric. 2021 Feb;24(1):38-45. doi: 10.1080/13697137.2020.1862079. Epub 2021 Jan 6. PMID: 33403887.
39. Nussey S, Whitehead S. Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 1, Principles of endocrinology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK20/
40. Hamer M, Endrighi R, Poole L. Physical activity, stress reduction, and mood: insight into immunological mechanisms. Methods Mol Biol. 2012;934:89-102. doi: 10.1007/978-1-62703-071-7_5. PMID: 22933142.
41. American Sleep Association. Sleep hygiene. https://www.sleepassociation.org/about-sleep/sleep-hygiene-tips/sleep-hygiene/
42. Johnson A, Roberts L, Elkins G. Complementary and Alternative Medicine for Menopause. J Evid Based Integr Med. 2019 Jan-Dec;24:2515690X19829380. doi: 10.1177/2515690X19829380. PMID: 3086892.
43. Lee KB, Cho E, Kang YS. Changes in 5-hydroxytryptamine and cortisol plasma levels in menopausal women after inhalation of clary sage oil. Phytother Res. 2014 Nov;28(11):1599-605. doi: 10.1002/ptr.5163.
44. Shinohara K, Doi H, Kumagai C, Sawano E, Tarumi W. Effects of essential oil exposure on salivary estrogen concentration in perimenopausal women. Neuro Endocrinol Lett. 2017 Jan;37(8):567-572. PMID: 28326753.
45. Choi SY, Kang P, Lee HS, Seol GH. Effects of Inhalation of Essential oil of citrus aurantium L. var. amara on menopausal symptoms, stress, and estrogen in postmenopausal women: A randomized controlled trial. Evid Based Complement Alternat Med. 2014;2014:796518. doi:10.1155/2014/796518.
46. Kargozar R, Azizi H, Salari R. A review of effective herbal medicines in controlling menopausal symptoms. Electron Physician. 2017 Nov 25;9(11):5826-5833. doi: 10.19082/5826. PMID: 29403626; PMCID: PMC5783135.
47. Geller SE, Studee L. Botanical and dietary supplements for menopausal symptoms: what works, what does not. J Womens Health (Larchmt). 2005 Sep;14(7):634-49. doi: 10.1089/jwh.2005.14.634. PMID: 16181020.
48. Głąbska D, Guzek D, Groele B, Gutkowska K. Fruit and Vegetable Intake and Mental Health in Adults: A Systematic Review. Nutrients. 2020 Jan 1;12(1):115. doi: 10.3390/nu12010115. PMID: 31906271; PMCID: PMC7019743.
49. Burgess, L. What are phytoestrogens? Benefits and foods. Medical News Today. January 17, 2018. https://www.medicalnewstoday.com/articles/320630
50. Fattah A. Effect of Phytoestrogen on Depression and Anxiety in Menopausal Women: A Systematic Review. J Menopausal Med. 2017 Dec;23(3):160-165. doi: 10.6118/jmm.2017.23.3.160. Epub 2017 Dec 29. PMCID: PMC5770525.