Introduction
Flashes of intolerable acne, endless moodiness, and brain fog often surface when recalling tween puberty, with students roaming through middle school hallways, attempting to adjust to the raging hormones that they simply cannot control. While puberty marks the beginning of the reproductive rollercoaster of a woman’s life, it is menopause that marks its finale. Menopause is a sometimes messy metamorphosis for women. Hormones face exceedingly large fluctuations in the ovaries. For some women, menopause signifies the beginning of a never-ending nightmare of uncomfortable symptoms. But for others, menopause brings forth feelings of relief: pregnancy is no longer possible, and periods conclude.
However, much like a caterpillar’s metamorphosis, the process is not completed overnight. Menopause is marked by amenorrhea, defined as the absence of a menstrual period. When this stage stretches beyond sixty days, menopause typically follows within four years; once amenorrhea lasts past ninety days, the transition often accelerates, with menopause arriving in roughly two years. Amenorrhea lasting greater than 60 days is understood as the transition between early and late menopause as defined by the Stages of Reproductive Aging Workshop (STRAW). STRAW, a clinical classification, was developed in 2001 to provide a widely applicable system for women of all lifestyles, ages, and ethnicities by dividing a woman’s adult life into three distinct phases: reproductive, transitional, and postmenopausal.
The onset of menopause certainly differs between women. In the United States, the average age of menopause is 52. Various factors may influence the start of menopause, from smoking expediting its commencement to race and ethnicity influencing the duration of symptoms. While menopause generally occurs naturally, it can also be induced by procedures like a bilateral oophorectomy, the removal of both ovaries. This surgical procedure, often performed to address ovarian cancer, cysts, or even endometriosis, results in the immediate initiation of menopause. Still, in most models, the final menstrual period (FMP) stays central to the conversation as the defining marker for menopause onset.
Hormonal Hatching: Rerouting Pathways
The hormonal shifts of menopause demand a period of adaptation, as the central nervous system (CNS) begins to rewrite itself to accommodate changes in well-established signaling pathways within the ovaries. Ovaries are the glands in the female reproductive system that contain the hormones responsible for directing menstruation and pregnancy. Therefore, as women age, their ovaries age concurrently. Studies show female fertility gradually decreases around age thirty, with a sharper decline after age thirty-five. This drop in fertility is largely due to age-related depletion of ovarian follicles. In turn, the follicle-stimulating hormone (FSH) increases, serving as a marker of ovarian aging for clinicians. Several other hormones shift during perimenopause, the transitional phase before menopause, lasting four to five years. These sex hormones range from androgen to progesterone to estrogen. For estrogen specifically, variation in concentration is not unique to menopause. When a woman is fertile, estrogen hormones facilitate the menstrual cycle. Estrogen hormones bind to an estrogen receptor (ER), causing the receptor to dimerize (activate) before entering the nucleus. In the nucleus, the activated ER binds to estrogen response elements (ERE), which are responsible for the regulation of gene expression.
One estrogen hormone, estradiol, increases during the follicular phase (the first 14 days of a typical 28-day menstrual cycle). During this period, the ovaries release an increasing amount of estradiol to thicken the lining of the uterus, in preparation for pregnancy. When pregnancy doesn’t occur, the luteal phase (the last 14 days of a typical 28-day cycle) results in menstruation. A lack of estradiol results in a weakened uterus due to insufficient development of the uterine lining. So, in the absence of estradiol, which oscillates until it eventually falls to a low level, menopause begins due to the cessation of ovulation. In addition, the loss of estradiol results in lowered feedback on luteinizing hormone (LH) and FSH. When researchers further investigated the relationship between these hormones in menstruating and non-menstruating women, they found that post-menopausal women showed FSH levels fifteen times greater and LH levels ten times greater than the menstruating women.
Understanding menopause is the key to deconstructing a slew of other mechanisms involved in the CNS. Since the female reproductive system ages earlier than most other systems in the body, menopause provides researchers with a valuable window into how aging processes in the brain and body are connected.
The effects of the aforementioned hormonal changes can present in a wide range of symptoms. Due to significant changes in both neuroendocrine and neurotransmitter pathways, menopausal symptoms directed by the CNS include mood changes and migraines. Regardless of the presence or level of anxiety before menopause, once the stage begins, women face higher levels of anxiety. Similarly, individuals are more likely to face depression, as illustrated by a group of pre-menopausal women in the Study of Women’s Health Across the Nation (SWAN). The group reported high scores for symptoms ranging from sadness to suicidal ideation.
One explanation for the stark contrast between the moods of menstruating and perimenopausal women is the inhibition of regulatory pathways for neurotransmitter release, such as serotonin and dopamine, both key to regulating mental health. When these pathways are damaged within the prefrontal cortex or limbic system of the brain, areas associated with mood control, the effects include not only mood swings but also vasomotor symptoms (hot flashes). In addition, when serotonin pathways are deregulated, thermoregulation is impaired. This obstruction results in a bodily heat response. This is because the body’s thermostat, the hypothalamus, compensates for estrogen fluctuations by increasing body temperature, causing elevated blood flow in the skin. Specifically, hot flushing, defined as vasodilation in the face accompanied by sweat or shivering, is a common vasomotor symptom for up to 80% of perimenopausal and post-menopausal women. This particular symptom varies largely amongst women, with some women feeling minor discomfort and others experiencing prolonged pain for up to 60 minutes.
Given the overlap between the origins of these symptoms, one study suggests treating both vasomotor symptoms via menopausal hormonal therapy (MHT). MHT has the capacity to address a multitude of menopause symptoms. For example, menopause puts women at risk of developing osteoporosis, a disease marked by weakened bones. Therefore, to prevent bone loss and increased instances of bone breakage, MHT can replace estrogen deficiencies. This type of therapy can come in two main forms. Systemic therapy is absorbed by the entire body via a pill or skin patch. In contrast, vaginal-estrogen therapy is lower in dosage and only treats symptoms falling under the vaginal and urinary systems. Given the multitude of available treatment options, navigating MHT may prove to be an overwhelming path. This makes it especially important to discuss the specific therapy type and dosage with a healthcare professional.
Looking Forward: Beautiful Butterflies
The direct impacts of hypoestrogenism–estrogen deficiency–including those on memory and overall cognition, have the potential to influence targeted therapy for patients. This development largely reflects the fact that the CNS was previously not considered a primary target of sex hormone therapy—an understanding that is now proving invaluable for treatments such as menopausal hormone therapy (MHT).
Still, more research must be conducted to further understand the perimenopausal transition period to the post-menopausal phase, stages where women spend nearly a third of their entire lifespan. The various effects of hormonal fluctuations play a direct role in their ability to conduct activities of daily life, including maintaining relationships and establishing a career. Still, ongoing studies show that a shift towards more women-centered research approaches benefits perimenopausal and postmenopausal women alike. This expanded perspective allows women in the coming years to emerge out of the metamorphosis with rewired pathways and a newfound understanding of the drastic and incredible changes their bodies undergo in such a short period of time.
Sources:
https://www.sciencedirect.com/science/article/pii/S0889852904000829?via%3Dihub
https://www.mdpi.com/2673-396X/2/4/36
https://www.mayoclinic.org/diseases-conditions/menopause/in-depth/hormone-therapy/art-20046372
https://www.nia.nih.gov/health/menopause/what-menopause
https://my.clevelandclinic.org/health/treatments/17800-oophorectomy
