Menopause is often described simply as "the cessation of menstruation" or the end of reproductive years. However, from a woman's biological perspective, menopause is a much more significant change.

Menopause, when described as a phase, is a permanent endocrine transformation resulting from the cessation of egg-producing activity in the ovaries and a significant decrease in estrogen and progesterone production. Clinically, a diagnosis of menopause requires the absence of menstruation for 12 months after the last menstrual period. However, the hormonal transition process usually begins years before that. But it's not just the menstrual cycle that changes. Significant changes also begin in other organ systems with menopause. Therefore, women going through menopause may experience multiple symptoms.

Estrogen is not just a hormone that regulates the menstrual cycle and reproductive functions. It plays important roles in many different organs and tissues of the body. This is because estrogen receptors are found not only in the uterus and ovaries, but also in the brain, bones, heart, blood vessels, muscles, skin, bladder, and many other tissues. Estrogen helps keep bones strong and controls bone breakdown, while also playing a role in maintaining the elasticity of blood vessels, regulating body fat distribution, and maintaining muscle and skin health. In the brain, it affects mechanisms related to body temperature regulation, sleep, mood, and some cognitive functions. Therefore, the significant decrease in estrogen levels with menopause does not simply mean the cessation of menstruation or loss of fertility. This hormonal change can affect many systems in a woman's body to varying degrees. To consider menopause solely as a process concerning the reproductive system means ignoring the multifaceted role of estrogen in women's health and a significant portion of the physiological changes that can occur after menopause.

Today's women live for decades after menopause.

In the past, average life expectancy was significantly shorter than it is today. Even infections and many diseases that are easily treated today could lead to premature deaths. Furthermore, diagnostic and treatment options for chronic diseases such as hypertension, high cholesterol, cardiovascular diseases, and cancer were not as advanced as they are today. Consequently, people died at much younger ages from many health problems that we can control now.

One of the significant consequences was that the average woman's lifespan after menopause was shorter than it is today. The long-term effects of menopause and prolonged estrogen deficiency on bones, the cardiovascular system, metabolism, and other tissues were not experienced over such a long period as they are today.

Today, the picture is quite different. In the European Union, the life expectancy at birth for women is approximately 84 years. In our country, the average life expectancy for women is projected to be 84.8 years in 2024. Considering that menopause occurs on average around the age of 50-51, a woman today can live for more than 30 years after menopause. In other words, she can spend approximately one-third, or even more for some women, of her life in the post-menopausal period.

Therefore, menopause is no longer a period that can be assessed solely through a few years of hot flashes and the cessation of menstruation. We must now discuss the effects of estrogen deficiency on women's health for 30-35 years. We have succeeded in extending life expectancy; the real question now is how many of these extra years we can spend healthy and functional.

Menopause isn't just about hot flashes.

Menopoz sırasında östrojen düzeyindeki düşüş birçok fizyolojik sistemi etkiler. Sıcak basmaları ve gece terlemeleri en bilinen belirtilerdir ve çalışmalar vazomotor semptomların kadınların yaklaşık %80’ine kadarında görülebildiğini göstermektedir. Ancak tablo bununla sınırlı değildir. Uyku bozuklukları, beyin sisi, konsantrasyon ve hafıza sorunları, ruh hali değişiklikleri, vajinal kuruluk, ağrılı cinsel ilişki, libido değişiklikleri, tekrarlayan üriner yakınmalar ve kas-iskelet sistemindeki değişiklikler menopoz geçişinde sık görülür.

The changes can be quite dramatic, especially in terms of bone health. Bone loss during menopause isn't simply a natural consequence of aging; the significant drop in estrogen levels directly affects the balance between bone formation and resorption, accelerating bone breakdown. This process can actually begin before the last menstrual period and reaches its peak in the few years immediately surrounding menopause.

Long-term prospective studies clearly demonstrate the extent of this change. Data from the Study of Women's Health Across the Nation (SWAN) show that the loss of bone mineral density in the lumbar spine is approximately %1.7 per year in the two years before the last menstrual period and approximately %3.3 per year in the first two years after the last menstrual period. Although the rate of loss decreases in the later period, it does not stop completely [1].

Daha uzun süreli SWAN takiplerinde de benzer bir tablo görülmektedir. Son adet tarihinin beş yıl öncesinden beş yıl sonrasına kadar olan 10 yıllık dönemde lomber omurgada toplam kemik mineral yoğunluğu kaybı yaklaşık %10,6 olarak hesaplanmış; dikkat çekici biçimde bunun yaklaşık %7,4’ü menopoz geçişinin birkaç yıllık hızlanmış döneminde meydana gelmiştir. Femur boynunda da aynı dönemde anlamlı kemik kaybı görülmektedir [2].

In short, it is incorrect to view postmenopausal osteoporosis (bone loss) as a problem that only occurs in old age. One of the periods when bone loss is most rapid is the years immediately before and after a woman's menopause. One of the main biological reasons for this acceleration is estrogen deficiency; decreased estrogen leads to increased bone resorption and, over time, a decrease in bone strength. This is a fact we know for sure.

The cardiovascular system is not independent of this hormonal transformation. During the menopausal transition, some cardiometabolic changes occur that cannot be attributed solely to chronological aging. Large prospective studies have detected significant increases in total cholesterol, LDL-cholesterol and ApoB levels, especially in the period around the last menstrual period [3]. In other words, women transitioning to menopause experience significant increases in cholesterol levels and ApoB levels, which we call atherogenic and are associated with heart attacks.

In addition, the distribution of body fat changes. During menopausal transition, the tendency for fat tissue to accumulate, especially in the abdominal and visceral regions, increases. SWAN data have shown that the acceleration of visceral fat accumulation begins approximately two years before the last menstrual period [4].

The changes are not limited to cholesterol or body composition. Impairment of endothelial (vascular wall) function and increased arterial stiffness have also been associated with the menopausal transition. For example, the SWAN Heart study showed that the increase in arterial stiffness accelerated particularly in the one-year period around the last menstrual period [5]. Therefore, the American Heart Association also defines the menopausal transition as a period of particular attention in terms of cardiovascular protection in women [6].

In women, coronary heart disease typically occurs at a later age than in men; however, cardiovascular risk increases significantly during and after menopausal transition, and the protective difference between women and men gradually narrows [6,7]. It is not correct to attribute this increase solely to estrogen loss; aging, blood pressure, body composition, insulin resistance, lipid changes, smoking, and other individual risk factors also contribute to the picture, but when the relationship of many of these other factors with menopause is evaluated, menopause emerges as a factor that equalizes the coronary heart disease risks observed in women and men.

The effects of menopause are not limited to the bone and cardiovascular systems. The brain is also an estrogen-sensitive organ. Estrogen receptors are found in many brain regions important for memory, learning, and cognitive function, including the hippocampus and prefrontal cortex. Estrogen is associated with important processes for brain health such as neuronal energy metabolism, synaptic plasticity, mitochondrial function, cerebral blood flow, and neuroinflammation. Therefore, the relationship between the significant decrease in estrogen levels during menopause and brain aging and neurodegenerative processes has long been investigated [8,9].

This issue is particularly important because Alzheimer's disease is more common in women than in men, and it is thought that the menopausal transition may be one of the biological factors contributing to this gender difference. Of course, it is also wrong to create the perception that women get Alzheimer's simply because they go through menopause, because there are many environmental factors and especially genetic predispositions such as APOE ε4 carrier status [9,10].

Studies on age of menopause and duration of estrogen exposure throughout life suggest a possible link between the hormonal environment and cognitive aging. While some studies have associated a longer reproductive period and later menopause with better cognitive performance or slower cognitive decline, current data do not definitively show that longer natural estrogen exposure reduces the risk of dementia [11].

An important distinction should be made here regarding menopausal hormone replacement therapy (HRT). The biological effects of estrogen on the brain do not mean that hormone therapy prevents dementia. In fact, randomized studies examining the initiation of hormone therapy at an advanced age, especially after 65, have failed to demonstrate a protective effect against dementia. In contrast, studies examining women who started treatment close to the menopausal period have reported a lower risk of Alzheimer's or dementia. This difference has led to the emergence of what is called the "critical window" or "timing hypothesis": it is thought that the effect of estrogen on the brain may depend not only on whether it is given or not, but also on the age at which it is started and how long after menopause it is initiated [9,12].

However, it is too early to draw a definitive conclusion on this matter. A large systematic review and meta-analysis published in 2025 reported an association between HRT started within the first five years after menopause and a lower risk of Alzheimer's disease [13]. Nevertheless, we do not yet have enough data to prescribe hormone therapy to protect against Alzheimer's and other neurodegenerative diseases.

The decision to initiate menopausal hormone replacement therapy should be made considering vasomotor symptoms, bone health, genitourinary symptoms, the woman's age, time elapsed since menopause, and her individual cardiovascular and oncological risk profile. Potential long-term effects on brain health are still being actively investigated, and the timing of treatment is particularly important [9,12–14].

Sleep problems can occur during menopause.

During menopause, some women may experience sleep problems such as difficulty falling asleep, frequent awakenings during the night, or early morning awakenings. One of the important reasons for this is vasomotor symptoms; hot flashes and night sweats, especially those occurring at night, can lead to sleep disruption. In addition, hormonal changes, mood swings, and the increased risk of obstructive sleep apnea with age can also negatively affect sleep quality [18].

This situation is not only important in terms of quality of life. Sleep is a fundamental component of brain, metabolic and cardiovascular health. Insufficient or fragmented sleep has been associated with impaired cognitive function, cerebrovascular diseases and neurodegenerative diseases including Alzheimer's disease [19,20]. Similarly, poor sleep health is also associated with cardiometabolic risks such as hypertension, impaired glucose metabolism, obesity, coronary heart disease and stroke [21].

Daha da önemlisi, uyku süresi ve kalitesi yaşam süresiyle de ilişkilidir. Yaklaşık 1,4 milyon kişiyi ve 112 binden fazla ölümü kapsayan prospektif çalışmaların meta-analizinde, kısa uyuyan kişilerde tüm nedenlere bağlı ölüm riskinin normal uyku süresine sahip kişilere kıyasla yaklaşık %12 daha yüksek olduğu gösterilmiştir [22]. Daha geniş bir başka meta-analizde ise 5 milyondan fazla katılımcının verileri değerlendirilmiş ve kısa uyku; tüm nedenlere bağlı mortalitenin yanı sıra diyabet, hipertansiyon, kardiyovasküler hastalık ve koroner kalp hastalığı riskinde artışla ilişkilendirilmiştir [23]. Uyku süresinden bağımsız olarak insomnia belirtileri de önem taşımaktadır: yaklaşık 1,6 milyon kişiyi kapsayan prospektif çalışmaların meta-analizinde uykuya dalma güçlüğü ve dinlendirici olmayan uyku hem tüm nedenlere bağlı mortalite hem de kardiyovasküler mortalite riskinde artışla ilişkili bulunmuştur [24]. Kısacası mevcut veriler kronik olarak yetersiz ve kalitesiz uykunun uzun dönem sağlık açısından göz ardı edilmemesi gereken bir risk göstergesi olduğunu güçlü biçimde desteklemektedir.

Therefore, sleep disturbances that occur during menopause should not be dismissed simply as "a normal part of menopause." Menopause is already a significant period in which the bone, metabolic, neurological, and cardiovascular risk profiles begin to change; adding chronic sleep disturbances to this can create an additional long-term health risk burden. For this reason, in menopause management, in addition to controlling hot flashes and night sweats, evaluating sleep quality and investigating specific sleep disorders such as insomnia and sleep apnea when necessary should be an important part of a healthy aging approach.

Some women may experience a significant decrease in sexual desire after menopause.

In this change, vaginal dryness and painful intercourse due to estrogen deficiency, sleep disturbances, psychological and relational factors, as well as changes in androgens, may play a role. Although testosterone levels decrease with age in women, the relationship between blood testosterone levels and sexual desire is not one-to-one, and low testosterone levels alone do not diagnose “testosterone deficiency” or hypoactive sexual desire disorder (HSDD) [15,16]. However, if persistent decreased sexual desire, i.e., HSDD, is present in the postmenopausal period after other causes have been evaluated, testosterone therapy is an evidence-based treatment option.

Evaluation of randomized controlled trials shows that testosterone used in doses not exceeding the physiological range for women can increase sexual desire, arousal, orgasmic function, and sexual satisfaction, and reduce distress associated with sexual dysfunction [15–17]. According to current international consensus, the primary evidence-based indication for testosterone therapy in women is postmenopausal HSDD; the aim of treatment is not to raise testosterone to the levels used in men, but to keep it within the physiological range of premenopausal women [15,16]. Therefore, treatment should be implemented with appropriate patient selection, initial testosterone measurement, and regular clinical and biochemical follow-up; and should be monitored for acne, increased hair growth, and other androgenic side effects. Safety data at physiological doses are quite positive.

Of course, not every woman will experience all of these effects. Some women don't experience any additional symptoms during the onset of menopause and go through this transition very smoothly. On the other hand, some women experience effects that seriously reduce their quality of life. Since this process varies from person to person, it cannot be managed with a single recommendation or method. It is important to evaluate and manage the menopause process in the most appropriate way by considering the individual's risk factors, symptoms, and overall health status.

Hormone Replacement Therapy in Menopause

Menopausal hormone replacement therapy (HRT) is a treatment aimed at replacing hormones, particularly estrogen, that decrease with menopause in suitable women. In women with a uterus, progesterone is also used alongside estrogen to protect the uterine lining. My preferred approach today is to use bioequivalent hormones whenever possible. By bioequivalent, we mean that the hormone used has the same structure as the hormone naturally produced by the female body. For example, estradiol is one of the main estrogens naturally produced by our body; micronized progesterone has the same structure as the progesterone produced by the body. These hormones can be used in different forms such as gels, patches, sprays, capsules, or tablets, depending on the individual's needs.

While estrogen use was previously accepted in tablet form, oral estrogens are no longer considered suitable for HRT purposes. Instead, estrogen is preferred to be administered topically as a gel, spray, or patch. In this way, estrogen enters the bloodstream directly and does not have to pass through the liver first, as is the case with orally administered estrogen. This provides a more advantageous safety profile, especially in terms of blood clotting. Progesterone, on the other hand, is generally available orally in capsule form.

The goal of HRT is not to "rejuvenate" women or stop aging. The aim is to reduce symptoms such as hot flashes, night sweats, sleep problems, vaginal dryness, and in some women, sexual dysfunction, all of which are caused by the hormone deficiency that occurs with menopause. This will improve quality of life, protect against accelerated bone loss after menopause, and lower the cardiovascular risk profile. Because every woman's needs are different, the hormones and dosages used must be tailored to the individual. Therefore, the basis of the modern HRT approach is to give the right woman the right hormones at the right time, in the appropriate doses.

Why are most women still afraid when HRT is mentioned?

A significant part of the answer to this question goes back to 2002. When the initial results of a study conducted by the Women's Health Initiative (WHI) were published, news that hormone replacement therapy increased the risk of breast cancer and cardiovascular disease caused a major stir worldwide.

Çalışmanın yayınlanan sonucuna göre kombine hormon tedavisi gören kadınlarda invaziv meme kanseri için bildirilen relatif risk yaklaşık %26 daha yüksek bulundu (HR 1.26). “%26 daha fazla meme kanseri” doğal olarak son derece korkutucu bir manşet olarak ciddi bir yankı getirdi. Fakat bu çalışmanın ve bu sonuçların daha yakınen takibinde ciddi sorunlar vardı:

1- Relatif risk %26 dendiği zaman, kanser olgusunun %26 daha fazla yaşandığı algısı oluşuyor. Fakat relatif risk tek başına hikâyenin tamamını göstermiyor. Mutlak rakamlara baktığımızda placebo grubunda yılda her 10.000 kadın başına yaklaşık 30 invaziv meme kanserigörülürken hormon grubunda bu sayı 38 idi. Yani 10.000 kadının bir yıl tedavi edilmesiyle yaklaşık 8 ek vaka. Bu risk sıfır değildir ve önemsiz diye geçiştirilemez. Ancak “%26 risk artışı” ile “Yüzde 0.08 risk artışı” aynı verinin iki farklı anlatım biçimidir. Hastaların karar verirken her ikisini de bilmeye hakkı vardır.

2- The average age of the women in the study was approximately 63. This means that a significant portion of the women participating in the study were at least 10 years away from the onset of menopause. We know that hormone replacement therapy yields more positive results when started within the first 10 years. But the problem isn't limited to that.

3- The combination used was not the transdermal 17β-estradiol and micronized progesterone that we frequently prefer today. The study used oral conjugated equine estrogen (CEE) and synthetic medroxyprogesterone acetate (MPA). Oral estrogens are not used today due to certain health risks associated with their use. Therefore, the hormones used in this study are not the same as those currently accepted and used.

Başka bir ifadeyle, 2002 WHI çalışması “bütün hormon replasman tedavileri tehlikelidir” sorusunu test etmedi. Belirli bir hasta grubunda, belirli bir yaşta ve belirli bir hormon kombinasyonunu test etti. Bunun daha da ötesinde, bilim 2002’de durmadı. WHI katılımcılarının 20 yıldan uzun süre takip edildiği sonraki analizlerde, rahmi alınmış kadınlarda yalnız östrojen (CEE) verilen grupta placebo ile karşılaştırıldığında meme kanseri görülme riski yaklaşık %22 daha düşük bulundu (HR 0.78). Yani, sentetik progesteron işin içerisine katıldığı zaman meme kanseri riskinin artmış olduğu gözlemlendi.

In the French E3N study, in which approximately 80,000 women were followed for an average of 8 years, the use of estrogen in combination with natural progesterone was not associated with a significant increase in breast cancer risk, while the use of estrogen in combination with some synthetic progestins was associated with a significant increase in risk [25]. Similarly, in a large British study evaluating more than 43,000 breast cancer cases, no significant increase in risk was found with the use of micronized progesterone, while the risk of breast cancer was higher with the use of synthetic progestins [26].

In short, we have no data from large cohort studies that modern HRT approaches increase the risk of breast cancer [27]. That is why the FDA (Drug and Pharmaceutical Administration) has removed the 'Black Box Warning' it previously issued for hormone replacement therapy, which drew attention to the risk of breast cancer, by 2025.

Of course, caution is still necessary in women with a history of hormone-sensitive cancer or a family history of this type of cancer, and all women should undergo the necessary tests before starting treatment.

Important tests to perform before starting HRT:

• A thorough medical and family history.
• Mammography / Breast Ultrasound
• Pap smear
• Blood lipids - Apo B, Lp(a), total cholesterol, HDL, LDL and triglycerides
• Glucose metabolism - Fasting blood glucose, Insulin, Homa-IR and HbA1c
• Inflammation markers - hsCRP, CBC
• Hormones: Estradiol, prolactin, progesterone, total testosterone, SHBG, DHEA-s.

Some doctors argue that menopause is a natural process and therefore hormone therapy is unnecessary. Yes, menopause is a natural process. However, the fact that a process is natural does not mean we should ignore its negative effects on health. It is also natural for our vision to weaken as we age. So, should we just accept vision loss without wearing glasses? It is also natural for bone density to decrease with age. So why do we try to prevent and treat osteoporosis?

The aim of medicine is not to interfere with every process in nature. However, preventing and, when necessary, treating the consequences of natural processes that reduce quality of life or negatively affect health is one of the fundamental tasks of modern medicine.

Hormone replacement therapy is not necessary or suitable for every woman. However, simply because menopause is a natural process, it is not a scientific approach to deny women who could benefit from it this option.

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