The Preliminary Phase: The Complex Definition of Perimenopause
Menopause is the stage of life when menstruation ceases due to the depletion of the ovaries’ follicular reserve for at least 12 consecutive months, marking the end of the reproductive years. According to the Spanish Association for the Study of Menopause, the average age of menopause in Spain is around 51 to 52 years old, and it is considered normal to experience menopause between the ages of 45 and 55. During menopause, the production of estrogen and progesterone decreases, as does, more gradually, the production of androgens. According to a recent study published in the journal Science, menopause is associated with up to 72 symptoms, although not all women experience them.
This period has different phases and lasts until the end of life. Before it is fully established, there is a transitional process called perimenopause, during which the first endocrine, biological, and clinical signs of the impending menopause begin to appear. Perimenopause lasts an average of four years and is characterized by persistent irregularity in the menstrual cycle, although there may be many more symptoms.
As Susan Davis, director of the Women’s Health Research Program at Monash University (Australia) and head of the Women’s Endocrinology Clinic at Alfred Hospital in Melbourne (Australia), explains to SMC Spain, perimenopause is one of the least-studied phases: “There is still limited knowledge about what the best indicators of its onset are, how its symptoms differ from those caused by psychosocial or health factors, and we do not understand what underlies the consequences it entails.” For example, why do so many symptoms and bodily changes associated with perimenopause occur at an early stage, when the ovaries are still producing estrogen?
This constant fluctuation of changes complicates its definition and diagnosis. However, a study published last year in The Lancet Diabetes & Endocrinology, conducted on more than 8,000 Australian women, found that bothersome vasomotor symptoms—such as hot flashes—and vaginal dryness were the most defining clinical characteristics of this stage.
Changes in body composition: aging or menopause?
According to a study published in Cell, of which Davis is a co-author, many changes in body composition and metabolism have been directly linked to menopause, including cardiovascular risks, osteoporosis, sarcopenia, an increased risk of diabetes, and increased body fat. “We have a fairly good understanding of the changes that occur in bones during perimenopause and postmenopause, but the effects on muscles remain unclear,” the researcher states.
The loss of bone mineral density accelerates during late perimenopause and the first few years following the last menstrual period. A study has reported approximate annual losses of 1.8–2.3% in the spine and 1–1.4% in the hip during the phases of greatest rate of loss. Nuria Marín, who holds a Ph.D. in Biomedicine and Health Sciences from the University of Cádiz, tells SMC Spain that “one of the outstanding issues is the early identification of women experiencing rapid bone loss, since bone mineral density accounts for only part of bone strength: its geometry, microarchitecture, and quality also matter.”
Sarcopenia—an age-related decline in muscle mass—also occurs during menopause, exacerbated by metabolic changes as well as by natural aging itself. Pluvio Coronado, full professor of Obstetrics and Gynecology at the Complutense University of Madrid and section chief at the Hospital Clínico San Carlos in Madrid, asks: “What is the role of menopause, and what is the role of age?” It is difficult to differentiate between the two.
The main problem is the sharp drop in estrogen levels. “Aging occurs in both premenopausal and postmenopausal women, which is why we need to conduct precise research into the impact of estrogen loss and hormonal changes—this will allow us to accurately identify the risks associated with this transition,” he adds to SMC Spain.
We have a fairly good understanding of the changes that occur in the bones during perimenopause and postmenopause, but the effects on the muscles remain unclear
Susan Davis
Marín points out that “there are estrogen receptors in cartilage, bone, muscle, tendons, and the synovial membrane, and it is biologically plausible that the decline in estrogen contributes to joint deterioration, but it cannot yet be confirmed that this is the primary cause.” With menopause, especially in the early years, there is also a decline in testosterone production, which affects muscle mass and strength, although it is difficult to distinguish these declines from those related to the natural aging process.
How does it affect the risk of diabetes and cardiovascular problems?
Menopause increases the risk of developing type 2 diabetes by up to 47%. The transition to this stage is often accompanied by increased fat accumulation, especially in the abdominal area. Due to metabolic changes, the body expends less energy, which contributes to weight gain. This weight gain triggers the production of inflammatory molecules and increases circulating free fatty acids, which contributes to the development of greater insulin resistance.
As Coronado explains, although insulin resistance naturally increases with age, the decline in estradiol—a type of estrogen—that accompanies the menopausal transition is associated with this increased risk of diabetes. A study published in Maturitas confirmed that hormone therapy has a beneficial effect on glucose metabolism, thereby helping to reduce the incidence of type 2 diabetes in postmenopausal women. However, “there is still a great deal to be studied in this regard,” adds the expert.
Another risk associated with this stage is cardiovascular problems, which are linked to estrogen deficiency. The age at which this period begins and the type of symptoms influence its onset, according to a review co-authored by Coronado. A meta-analysis recently published in the European Journal of Preventive Cardiology found that experiencing menopause at a later age minimized the risk of cardiovascular events. However, the authors state that longer-term follow-up studies are still needed and that the evidence remains insufficient for some factors.
Does the risk of developing dementia and other neurological problems increase? How does the brain change?
Many women going through menopause experience cognitive changes such as difficulty remembering information or finding the right words. Approximately 60% of middle-aged women report having memory problems during this stage, according to the Study of Women's Health Across the Nation.
In addition to being a reproductive transition, menopause is also accompanied by a neurological transition, which is why many of its symptoms are neurological in nature, such as sleep disturbances, mood swings, and forgetfulness. Sophia R. van’t Hof, a doctoral candidate in psychiatry at the University of Amsterdam (Netherlands), explains to SMC Spain that “most aspects of brain remodeling remain a mystery.” Although some cross-sectional studies—which measure a single point in time—have already been conducted, until now there have been virtually no longitudinal studies—in which more than one brain scan of the same woman is available. “We are taking the first steps toward understanding the structural changes in the brain throughout this stage,” adds the researcher.
Most aspects of brain remodeling remain a mystery
Sophia R. van’t Hof
Van’t Hof is the lead author of a recent study published in Nature Communications, in which she demonstrated that menopause is the only hormonal transition in women that does not involve a decrease in gray matter or brain volume, unlike the transitions of puberty and pregnancy, which do cause a reduction in cortical gray matter. “We need to conduct large longitudinal studies that track not only structural changes in the brain but also cognition, mental health, and hormones. In addition, I would love to see research into functional changes in the brain,” says Van’t Hof.
The direct link between declining estrogen levels and cognition and the risk of dementia remains controversial, as these symptoms could also be side effects of poor sleep quality or mood changes. Furthermore, it takes a long time for dementia to manifest, as it typically appears in one’s 70s or 80s, and “a cohort study of this scale is complex to conduct,” adds Coronado.
What role does it play in pelvic floor disorders?
The pelvic floor supports the pelvic organs, and its dysfunction can lead to disorders such as urinary and fecal incontinence, pelvic organ prolapse, or pelvic pain syndrome. According to a study conducted on more than 1,000 Spanish women, more than half suffer from some form of urinary incontinence, and menopause is one of the factors that increase the likelihood of developing it. Although estrogen and progesterone receptors have been detected in key structures of the pelvic floor, it is difficult to determine the specific role of menopause in the development or progression of pelvic floor disorders, as it cannot be easily separated from aging or other associated diseases. With regard to pelvic organ prolapse, a systematic review showed that aging is a risk factor, but menopause is not.
Urinary tract infections are also a common problem during this stage. Hormonal changes and aging alter the urogenital microbiome, weakening the body’s natural defenses against these infections. Studies have shown that lower estrogen levels raise the vaginal pH and reduce the vaginal microbiota dominated by lactobacilli, which increases the likelihood that uropathogenic microbes such as Escherichia coli or Enterococcus will colonize the area. However, it is not yet fully understood exactly how these changes affect the urobiome, so studying them could help prevent recurrent urinary tract infections and improve their treatment in menopausal women.
There is a lack of studies on the impact of hormone treatments
Menopausal symptoms can be treated, although not all women need specific treatment. Various studies show that women who do need treatment face multiple barriers, the main one being a lack of knowledge about menopause and the risks and benefits of hormone replacement therapy.
In Spain, thousands of women are facing a shortage of medications containing estradiol in transdermal form due to a sharp increase in demand. The Spanish Agency for Medicines and Health Products (AEMPS) published its latest update on October 2, explaining that the pharmaceutical company Gedeon Richter—the only manufacturer of estradiol in this form, known as Lenzetto—had run out of stock. The company has informed them that it will gradually resume supply in November and in 2027. The shortage of this drug has led to the purchase of alternative medications, such as patches, which has also caused stock shortages.
In total, there are more than 200 types of hormone therapy, which differ in dosage, the formulation of estrogens and progestins, and the timing of administration. They are usually administered orally or via transdermal patches. Coronado explains: “There is so much heterogeneity in hormone therapies that the results are contradictory; there are not enough studies to demonstrate the benefits or impacts.”
There is so much heterogeneity in hormone therapies that the results are contradictory; there are not enough studies to demonstrate the benefits or impacts
Pluvio Coronado
A large body of scientific literature demonstrates that hormone therapy has significant beneficial effects on skeletal muscle mass, strength, and protection against injury in older women, as well as on cognition. However, there is no clear consensus on whether the risks of hormone therapy outweigh those of untreated menopause, as it has side effects such as thrombosis or the development of breast or endometrial cancer.
Current evidence shows that the risks are lower when therapy is initiated in women under 60 years of age or within 10 years of menopause. In Europe, the latest recommendation from the European Medicines Agency (EMA) dates from May 2020 and is based on a meta-analysis of prospective studies published in The Lancet in 2019 that linked several of these treatments to a higher incidence of breast cancer. Based on this study, the EMA recommends that “women should only use hormone replacement therapy to treat menopausal symptoms at the lowest dose and for the shortest possible time that is effective for them.”
That said, the risks and benefits differ for each person and must be evaluated on an individual basis. However, as Davis explains, “there are no data on the safety of hormone therapy for women in perimenopause, and at this time, prescribing standard menopausal hormone therapy—intended for postmenopausal women—to women in perimenopause constitutes an experiment on human subjects.”
Tailoring treatments
To treat the symptoms of this stage, experts agree that the best approach is to tailor treatment to each person’s characteristics and needs. Personalized medicine makes it possible to identify women who are most likely to respond favorably to various hormone therapies, taking into account age, the time elapsed since menopause, symptom severity, breast cancer risk, and genetic predisposition. This makes it possible to tailor the dose, formulation, and route of administration of the treatment. “But to do that, you have to know the patient well—her medical history and her circumstances—which is very difficult in quick consultations,” Coronado points out.
Beyond hormone therapy, Marín focuses on preventing premature aging through physical exercise: “It can simultaneously improve strength and functional capacity, stimulate bone health, reduce visceral fat, increase insulin sensitivity, and protect cardiovascular and mental health—but it does not replace estrogen and should not be presented as a substitute for hormone therapy.”
She adds: “The question at hand is no longer simply whether exercise is beneficial. We must determine which type, intensity, and level of supervision each woman needs; when it is best to start; how to adapt the program to symptoms and to bone, joint, or cardiovascular risk; since perimenopause could represent a window of opportunity to preserve muscle, bone, metabolism, and functional capacity before deterioration becomes more difficult to reverse, but longitudinal studies to demonstrate this are still lacking,” adds Marín.
The question that remains is no longer simply whether exercise is beneficial; we need to find out what type, amount and level of supervision each woman requires
Nuria Marín
Therefore, there is still a great deal of research to be done that requires funding. “During the first fifteen years after the publication of the first article from the Women’s Health Initiative, it was nearly impossible to secure funding for any research in this field. We had studies on hormone therapy for menopause that were very difficult to publish, since no one wanted to publish data from clinical trials related to this stage of life. I’ve continued to conduct research in this field over the years, but securing funding has been a nightmare until recently,” Davis concludes.
