Irregular and anovulatory cycles, weight gain, hot flashes, and sleeplessness are some of the common signs that don’t surprise anyone when a woman is moving towards menopause. These symptoms are good indicators of changes in the biological clock and reduced fertile potential. In contrast, “the other premenopause” refers to an equally important set of physiological signs, which tends to go under the radar in regards to hormonal changes. And yet! Indeed, many women experience various discomforts, which, at first glance, do not suggest a hormonal relationship, since strangely, the menstrual cycle usually remains unchanged.
Premenopause (or perimenopause) refers to the transitional period leading up to menopause when the levels of the hormones progesterone and estrogen gradually decline. The hormonal change begins sneakily in your 30s and intensifies over the years. This hormonal imbalance induces various unpleasant symptoms, sometimes strange, particularly noticeable in the forties and fifties. Let’s explore some of these less familiar, but completely normal symptoms.
Headache and migraine
Hormonal changes influence the female preponderance of headaches and migraines. Indeed, nearly two-thirds of people with migraines have hormonal triggers and the odds increase by 50% when estrogen levels, and consequently progesterone, are low (1). Since these two major hormones gradually decrease during premenopause, a proportional increase in headaches, up to 25 to 30%, are felt in women from 35 to 40 years old (2).
When estrogen and progesterone levels drop, we see a global neuroendocrine shuffle. These hormones both have an important action on the central serotoninergic receptors and on the opioid receptors involved in the sensation of pain. However, the drop in estradiol appears to be the main mechanism for hormonal migraines (3, 4).
Estrogen and Serotonin: Serotonin is the main neurotransmitter responsible for a positive attitude, but there is more to its role here. Serotonin also affects the dynamism of blood vessels (dilation and vasoconstriction), blood viscosity, the perception of pain via the trigeminal nerve and the raphe nuclei, as well as the neuroendocrine response of the hypothalamus, which is the majority of the related official causes to migraines. The involvement of serotonin is well defined, hence the relevance of drugs belonging to the category of triptans (serotonin receptor agonists), recognized as an effective treatment for migraines and headaches. In women, the perception of pain varies according to the phases of the menstrual cycle (7). In fact, estrogens are known to increase the density of serotonin receptors, which directly influences its transport in the brain. This means that with the reduction of estrogen, the participation of serotonin will also be reduced and the susceptibility to headaches will increase. The relationship between estrogen and serotonin is also the one that determines the severity of PMS (5), including mood changes and sugar cravings (through their intake of tryptophan, the precursor of serotonin) that many women experience! This suggests that the rate of hormonal changes during perimenopause may be a predictor for the development of headaches, particularly in women with a history of significant PMS during their reproductive period (6).
Estrogens and opiates: Opioid receptors are directly involved in the sensation of pain. Among the analgesic neurotransmitters belonging to this family, we find endorphins. However, estrogens promote their synthesis, which results in an inhibition of painful perception. When estrogen concentrations decrease and consequently that of endorphins, “any pain is perceived as more intense, and particularly in the case of a menstrual migraine”, underlines Dr. Calhoun, neurologist (1).
Reproductive hormones work together to ensure joint health. No wonder the increase in rheumatism and arthralgia coincides with the drop in these hormones, and is accentuated from premenopause. This is because estrogen and progesterone work by modulating inflammation downwards. The pain sets in gradually, following hormonal fluctuations during the cycle. This reality is experienced by more than half of women during perimenopause (8). Hormone replacement therapy is, in this regard, a conservative and effective measure to cope with this uncomfortable syndrome (9). In fact, arthralgia commonly occurs after stopping it suddenly, during estrogen therapy following hormone-dependent cancer and following hysterectomy, all three causing a marked drop in circulating estrogen.
Not only are estrogens anti-inflammatory and pain modulators, but they also promote the renewal of damaged chondrocytes, the cells responsible for making collagen and thus maintaining the integrity of cartilage tissue (10). Chondrocytes are cells susceptible to inflammation and hormonal disorders. In fact, they have estrogen receptors on their surface (11). During estrogen depletion, the turnover of chondrocytes is slowed down, which promotes the degradation of cartilage and bone. Several animal models have confirmed the importance of estrogen using biochemical markers of joint degradation. They have demonstrated an approximately 50% inhibition of cartilage destruction when estrogen is available (12). In women living with rheumatoid arthritis, there is pain relief when estrogen levels are higher (around ovulation) during the menstrual cycle (13, 14, 15).
Hormonal fluctuations can also lead to changes in heart rhythm. This is often most noticeable in the evening when lying down and relaxed, but can occur at any time of the day as well. The heart races without feeling nervous. Occasional and temporary palpitations may be part of the transition experience, and commonly occur during perimenopause. Heart palpitations can increase the heart rate by an average of 8 to 16 beats per minute. While premenopause can begin 8 to 10 years before menopause, it is especially during the last years of this transition that the drop in estrogen accelerates significantly and influences heart rate, increases the tendency to palpitations and non-threatening arrhythmias. The drop in estrogen is known to cause overstimulation of the heart. However, it is suggested to consult a doctor to make sure that these manifestations are indeed harmless!
Recent research shows that palpitations are a distressing problem for about 25% of women during perimenopause. The prevalence of a woman reporting distress from palpitations is higher among those with insomnia, depression and stress. In this subgroup, almost 34% reported episodes of heart palpitations (16). Since many hormonal symptoms occur due to changes in the nervous system, such as insomnia, hot flashes, and joint pain, it could be that the palpitations are explained this way (17).
Energy and interest: low tolerance to physical and mental effort
With the decrease in sex hormones, many women experience brain fog, loss of mental clarity, difficulty concentrating and remembering. This is not surprising, since estrogens, as modulators of several neurotransmitters, influence executive function and the speed of information processing. This is well listed as a symptom of falling hormones, but let’s explore another lesser-known facet of dopamine.
Dopamine is one of the circulating estrogen-sensitive neurotransmitters. It controls muscle activity and modulates our level of attention and motivation. This explains why women have varying cognitive and athletic abilities at different times of their menstrual cycle. Scientists have known for decades that working memory (short-term information processing) depends on dopamine. A few years ago, a team of neuroscientists at the University of California at Berkeley explored how hormonal fluctuations during a woman’s menstrual cycle can affect the brain. The researchers found that this hormone worked as powerfully as caffeine, methamphetamines, or the popular attention drug Ritalin. Indeed, women who had a low production of estrogen, and consequently dopamine, had more difficulty performing the proposed tasks. This came to confirm the relationship between estrogen and dopamine release. This finding would only be observed in women, and not in men. It may also mean that caffeine, which triggers a release of dopamine, like drugs such as Ritalin, is less effective at certain times of the month for some women (18).
Estrogens undoubtedly modulate behavior through their impact on dopamine. This being recognized as the main molecule of pleasure and satisfaction; many women feel a decrease in motivation during perimenopause. This results in varying disinterest and reduced initiative. The greater the drop in hormones, the more dopamine will be affected and the lower the enthusiasm will be. Premenopause can thus become a disturbing period and even take on the scale of a major mental crisis for some women.
Sex hormones, especially estrogen, influence the individual far beyond the reproductive aspect. Perimenopause is a necessary step that transforms the lives of all women. Clinical signs differ from woman to woman. Some well-documented symptoms, such as missed periods and hot flashes, unequivocally signal the onset of this transitional period. However, several other devious and less characterized manifestations begin years well before menopause. They affect the quality of life and are not automatically interpreted in light of intensifying hormonal fluctuations. Recognizing that these symptoms are normal and transient helps reduce their anxiety-inducing nature. Perimenopause is an evolutionary process that starts earlier for some women than others, be aware!
Originally published in the journal Vitalité QC: https://vitalitequebec-magazine.com/
- Calhoun A, Ford S. Elimination of menstrual-related migraine beneficially impacts chronification and medication overuse. Headache. 2008;48(8):1186-1193;
- Low estrogene levels trigger menstrual migraine, Neurology Review, 2009 may 17;
- Nater, J. Bougousslavsky, Migraine et hormones. Rev Med Suisse 2002, volume 2;
- B W Somerville, The role of progesterone in menstrual migraine, Neurology, 1971 Aug;21(8):853-9;
- Rémy C. Martin-Du-Pan. Syndrome prémenstruel, envie de sucre et sérotonine. Rev Med Suisse 2010; volume 6. 1517-1517;
- Faubion S, Batur P, Calhoun AH. Migraine Throughout the Female Reproductive Life Cycle. Mayo Clinic Proceedings. 2018 May;93(5):639–645;
- International Association for the Study of Pain, September 2007. iasppain.org;
- Magliano M. Menopausal arthralgia: Fact or fiction. 2010 Sep 1;67(1):29-33;
- Rowan T Chlebowski, Dominic J Cirillo et al. Estrogen alone and joint symptoms in the Women’s Health Initiative randomized trial, Menopause, 2018 Nov;25(11):1313-1320;
- Reena M TalwarB, rendan S Wong et al. Effects of estrogen on chondrocyte proliferation and collagen synthesis in skeletally mature articular cartilage, J Oral Maxillofac Surg, 2006 Apr;64(4):600-9;
- Anita Breu, Benedikt Sprinzing et al. Estrogen reduces cellular aging in human mesenchymal stem cells and chondrocytes, J Orthop Res, 2011 Oct;29(10):1563-71;
- M A Karsdal, A C Bay-Jensen, K Henriksen, C Christiansen, The pathogenesis of osteoarthritis involves bone, cartilage and synovial inflammation: may estrogen be a magic bullet? Menopause Int, 2012 Dec;18(4):139-46;
- J E McDonagh, M M Singh, I D Griffiths. Menstrual arthritis. Ann Rheum Dis, 1993;
- N S Latman, Relation of menstrual cycle phase to symptoms of rheumatoid arthritis, Am J Med, 1983 Jun;74(6):957-60;
- Rowan T. Chlebowski, Dominic J. Cirillo et al. Estrogen Alone and Joint Symptoms in the Women’s Health Initiative Randomized Trial, 2013 Jun;
- Jenet Carpenter, PhD, distinguished professor, Audrey Geisel Endowed Chair in Innovation, associate dean of research, Indiana University School of Nursing, Indianapolis;
- Stephanie Faubion, MD, medical director, North American Menopause Society, and director, Center for Women’s Health, Mayo Clinic, Rochester, Minn.; Journal of Women’s Health, 20, 2020, online;
- Jacobs, Emily Christine, Estrogen shapes dopamine-dependent cognitive processes: Implications for women’s health. Berkeley, University of California, 2010.