Allison Sayre, MSN, WHNP-BC
The transition from perimenopause to menopause represents a major biological shift for the endocrine system. Although a natural stage of life, menopause is often accompanied by troublesome climacteric symptoms, leaving many women feeling like it is anything but natural. These symptoms can include vasomotor instability (i.e., hot flashes and night sweats), difficulty sleeping, cognitive and mood changes, genitourinary syndrome (i.e., vulvovaginal atrophy), and musculoskeletal discomfort, all of which can significantly impact quality of life.[1,2] It is important that healthcare practitioners understand the underlying biochemical and physiological changes that are at the root of vasomotor symptoms of hot flashes and night sweats, so that they may guide women through their unique experiences with the menopausal transition.
The Endocrine Cascade of Perimenopause to Menopause
To best understand the biology of hot flashes and night sweats, we need to review normal endocrine biology. During the reproductive years, normal menstruation is regulated by the hypothalamic-pituitary-ovarian (HPO) axis. The ovarian follicles secrete estradiol, progesterone, and small amounts of androgens, under the control of pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Sex hormones in the circulation then inhibit the production of gonadotropins, maintaining a monthly cycle, and regulating many other biological pathways throughout the body.
As a woman ages, their number of ovarian follicles decreases, leading to impaired folliculogenesis and lower hormone output. This diminished ovarian reserve eventually leads to instability in estradiol secretion, coupled with a significant reduction in progesterone due to anovulatory cycles. Progesterone typically declines first, creating a relative estrogen dominance (even as overall estrogen levels fluctuate). Eventually, estradiol levels also fall significantly, removing an important regulatory influence over multiple physiological systems, leading to troublesome climacteric symptoms including hot flashes and night sweats for many women. [1]
Vasomotor Symptoms (Hot Flashes and Night Sweats)
Hot flashes and night sweats are the most common symptoms of the menopause transition. These symptoms originate from changes in the hypothalamic thermoregulatory center and are closely linked to disruptions in the HPO axis. During a woman’s reproductive years, estradiol plays a key role in modulating the serotonergic and noradrenergic pathways that maintain a comfortable, homeostatic body temperature. Specific neuropeptides are produced in the hypothalamus that trigger heat dissipation when the core temperature increases, but they are inhibited by estrogen receptors. As estradiol levels start to decline, neuropeptides are overexpressed, meaning that small variations in core body temperature can trigger unnecessary heat-release responses such as vasodilation and sweating. This can lead to uncomfortable and unpredictable vasomotor symptoms (i.e., hot flashes and night sweats) that can significantly disrupt sleep and activities of daily life.
Neurocognitive and Mood Changes
Approximately half of all menopausal women complain of cognitive issues, particularly surrounding verbal memory delay and executive function. While there are certainly many factors that can affect cognitive function, the loss of estrogen and progesterone can account for some of them. So, why is this, you ask?
Well, estrogen has both neurotrophic and neuroprotective effects on the central nervous system, with receptors concentrated throughout the brain, particularly in areas affecting memory, attention, and emotional regulation, such as the hippocampus and amygdala.[3,4] Estradiol also modulates neurotransmitter systems, including serotonin, dopamine, and glutamate, which are all essential for a balanced mood and healthy cognitive processing.[4] During perimenopause, fluctuating estradiol disrupts these systems, leading to an increased incidence of mood changes, tension, and extended periods of sadness or apathy. Furthermore, estrogen exerts neuroprotective effects through antioxidant activity, mitochondrial effects, and increased synaptic plasticity, contributing to subtle cognitive impairments, experienced as the symptom known to many as "brain fog."[3]
Additionally, the loss of progesterone leads to reduced calming effects on the brain, as progesterone normally enhances the activity of GABA, an inhibitory neurotransmitter that helps regulate mood and reduce anxiety. Without sufficient progesterone, GABA's soothing influence weakens, potentially leading to increased anxiety, irritability, and emotional instability. [5]
Sleep Disturbances
Up to 60% of postmenopausal women will likely have experienced problematic changes to their sleep.[2] While vasomotor symptoms such as hot flashes and night sweats may contribute to waking in the night, hormonal changes can independently affect the quality and quantity of a woman’s sleep. Progesterone acts as a respiratory stimulant and has sedative effects that promote sleep continuity. Its decline may contribute to difficulties falling asleep and issues with waking in the night. Additionally, reduced estradiol alters melatonin secretion and circadian rhythms through its regulation of serotonin, further exacerbating sleep difficulties.[6]
Musculoskeletal Changes
The skeletal system is highly responsive to steroid sex hormones, particularly estradiol. Estrogen promotes osteoblastic bone formation while inhibiting osteoclastic bone resorption. Its decline leads to an imbalance favoring bone loss, contributing to low bone density, with a multifold increase in osteoporosis and vertebral and hip fractures post-menopause.
Additionally, estrogen deficiency may contribute to musculoskeletal pain and discomfort by altering collagen synthesis, promoting inflammatory cytokine responses, and affecting neuromuscular function. In fact, the menopausal transition has been linked to an increased prevalence of joint and muscle pain and discomfort, and loss of bone, cartilage, and muscle, independent of aging alone.[7]
Genitourinary Syndrome of Menopause (Vulvovaginal Atrophy)
Genitourinary syndrome of menopause (GSM), also called vulvovaginal atrophy, refers to a group of symptoms impacting the genitourinary system that arise from (you guessed it!) declining estrogen levels. Common symptoms include vaginal dryness, pain or discomfort during intercourse, frequent urges to urinate, and a higher likelihood of vaginal and urinary tract infections. So, why all of these changes?
Well, estrogen receptors are expressed abundantly throughout the vulva, vagina, pelvic floor, urethra, and bladder. When estradiol binds to these receptors, it triggers cellular pathways that promote tissue elasticity, blood flow, immune defense, and glandular secretions. A decline in estrogen disrupts these signals, causing structural and functional changes, potentially leading to lowered self-esteem, anxiety about intimacy, and even depression due to chronic discomfort and changes in sexual health.[8]
Conclusion: A Complex, Systemic Transition
The climacteric symptoms associated with perimenopause and menopause stem from a complex interplay of hormonal, neurological, musculoskeletal, and genitourinary changes. While these symptoms are a natural part of aging, they can significantly affect a woman’s health and quality of life. For healthcare practitioners, understanding the underlying physiology of the climacteric period is fundamental to designing effective, individualized management strategies, and empowering women to navigate this life stage with confidence.
Disclaimer:
The information provided is for educational purposes only. Consult your physician or healthcare practitioner if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.
Allison Sayre, MSN, WHNP specializes in women's health and functional medicine, blending both traditional and integrative approaches. With over 17 years of experience, she has empowered women to reclaim their health through personalized nutrition and supplementation, hormone balancing, and lifestyle modifications. She received her Bachelor of Science from Mount Carmel College of Nursing and her Master of Science from the University of Cincinnati. She has been a certified women’s health nurse practitioner since 2014 and has continued her education and training in functional medicine from both the Institute for Functional Medicine as well as the American Academy of Anti-Aging Medicine.