Hormone Therapies in Women

The evolution of hormone replacement therapy in women throughout medical history is one of the most debated topics in modern medicine. This is especially true of the paper published in 2002. Women's Health Initiative (WHI) Following this study, the approach to hormone therapy changed dramatically, creating a serious concern about hormone therapy that would last for many years among both physicians and women [1].

While WHI was an extremely important study, the way its results were presented to the public and even to a section of the medical community created significant problems. The most debated part of the study was that the treatment used was not the physiological 17β-estradiol and micronized progesterone combination that we frequently prefer today. Women were given oral conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), a synthetic progestin. Furthermore, the age range of the women included in the study was 50-79, and a significant proportion were many years after the onset of menopause. Therefore, the study was not designed as a study to evaluate the effect of modern hormone therapy on a healthy woman who has recently entered menopause [1,2].

WHI’nin kombine CEE + MPA kolunda yaklaşık 5.6 yıllık kullanım sırasında invaziv meme kanseri için relatif riskte yaklaşık %24’lük bir artış saptandı. WHI’nin kombine CEE + MPA kolunda meme kanseri açısından bildirilen sonuçlar, riskin nasıl ifade edildiğinin önemini de çok iyi göstermektedir. Çalışmada invaziv meme kanseri için relatif risk yaklaşık %24 oranında daha yüksekbulunmuştur [1]. Ancak yalnızca bu relatif oranı söylemek, gerçek risk artışını olduğundan çok daha büyük algılatabilir. Mutlak rakamlara bakıldığında yıllık meme kanseri insidansı hormon kullanan grupta yaklaşık 10.000 kadında 38, plasebo grubunda ise 10.000 kadında 30 olmuştur. Başka bir ifadeyle, fark yılda yaklaşık 10.000 kadın başına 8 ek vaka, yani yaklaşık 1.000 kadın başına 0.8 ek vaka düzeyindedir. 

Dolayısıyla “meme kanseri riskinde %24 artış” ifadesi matematiksel olarak doğru olmakla birlikte, mutlak risk belirtilmeden tek başına kullanıldığında klinik etkinin büyüklüğünü olduğundan daha dramatik gösterebilir. Üstelik bu sonuç, bugün sık kullandığımız transdermal 17β-estradiol ve mikronize progesteron ile değil, oral konjuge equine estrogen ve medroksiprogesteron asetat kombinasyonu ile elde edilmiştir. Bu nedenle WHI sonucunun yıllarca “HRT meme kanserine neden olur” şeklinde tüm hormonlara, tüm uygulama yollarına ve tüm kadınlara genellenmesi bilimsel açıdan önemli bir aşırı yorum olmuştur. 

Subsequent WHI analyses revealed a much more complex picture. In women who had undergone hysterectomy, estrogen-only treatment did not show an increase in breast cancer incidence in long-term follow-up; on the contrary, there was a significant decrease in breast cancer incidence and breast cancer-related mortality. In contrast, the increase in breast cancer incidence continued in long-term follow-up with the CEE + MPA combination [2,3]. 

This distinction is extremely important. The statement "Hormone therapy causes breast cancer" is not scientifically accurate. The risk varies depending on the type of estrogen used, the choice of progesterone/progestogen, the route of administration, the duration of treatment, the age at initiation, and the woman's individual risk profile. For example, in the E3N cohort, the combination of estrogen with synthetic progestins was associated with a higher risk of breast cancer, while the same increased risk was not observed in the combination of estrogen with micronized progesterone. This is an important finding in terms of modern HRT formulations [4]. 

Therefore, the impact of post-WHI fear on women's health needs to be re-evaluated. With the dramatic decrease in the use of hormone therapy, it is now clearer than ever that many women who could benefit from treatment live for years without adequate care, experiencing menopausal symptoms, bone loss, and other estrogen deficiency-related problems.

One of the most important indicators of this shift in approach is the FDA's recent decision. The FDA initiated the process of removing broad boxed warnings on menopausal hormone therapies in November 2025 and approved new labels for a group of menopausal hormone therapies in February 2026. Nevertheless, the treatment is not without risks, and the need for individual risk assessment has not been eliminated. 

Hormone therapy doesn't have to wait for menopause.

Hormonal changes in women don't begin suddenly with the last menstrual period. Perimenopause is a transitional period that can begin years before menopause, during which estrogen and progesterone production becomes increasingly irregular. During this time, menstrual irregularities, hot flashes, sleep disturbances, anxiety, mood swings, brain fog, libido changes, vaginal dryness, and changes in body composition may occur.

Therefore, it is not necessary to wait for menstruation to completely stop before performing a hormone assessment or considering treatment in suitable patients. Especially during perimenopause, hormone levels can fluctuate significantly, so it is necessary to consider not only a single laboratory result, but also the severity of symptoms, characteristics of the menstrual cycle, age, clinical findings, and repeated hormone assessments as needed.

The aim is not to view menopause as a disease. However, it is also not correct to ignore the clinical problems associated with the decrease in hormones by simply saying "a natural part of aging".

Benefits of Hormone Replacement Therapy

The most powerful and undisputed benefit of hormone therapy is the control of symptoms associated with menopause and perimenopause. Estrogen therapy is currently the most effective treatment for vasomotor symptoms, particularly hot flashes and night sweats. It also provides significant benefits for genitourinary menopausal syndrome, vaginal dryness, dyspareunia and many symptoms due to estrogen deficiency [5]. 

Kemik sağlığı açısından etkisi de oldukça güçlüdür. Menopoz sonrası östrojen kaybı kemik rezorpsiyonunu hızlandırarak kemik mineral yoğunluğunda kayba ve zaman içerisinde osteoporoz riskinde artışa neden olur. Randomize WHI verilerinde hormon tedavisi kalça ve vertebra kırıkları dahil olmak üzere osteoporotik kırıkları anlamlı ölçüde azaltmıştır. Östrojen + progestojen tedavisinde kalça ve klinik vertebral kırıklarda yaklaşık %34, toplam osteoporotik kırıklarda yaklaşık %24 azalma bildirilmiştir [6]. 

Timing is extremely important from a cardiovascular perspective. During the transition to menopause, changes in LDL and other lipoproteins, increased visceral fat, impaired insulin sensitivity, and a tendency for increased blood pressure may occur. Some of these changes are associated with the menopausal transition independently of chronological aging [7,8]. If treatment is started before these changes cause permanent damage, the cardioprotective effect of hormone replacement therapy is more clearly observed. In the ELITE randomized trial, estradiol significantly slowed the progression of carotid atherosclerosis when started within the first six years after menopause, while the same effect was not seen when started ten years or more after menopause [9]. Therefore, there are strong biological and epidemiological reasons for the role of estrogen loss in the increased cardiovascular risk in women after menopause. Early application of hormone therapy in suitable candidates will allow them to benefit from potential cardiometabolic advantages.

Estrogen has significant biological effects on synaptic function, cerebral energy metabolism, neurovascular function, and neuroplasticity in the brain. The “critical window” or “timing hypothesis,” which suggests that hormone therapy started close to menopause may show different neurological effects than therapy started many years after menopause, has gained increasing scientific support [10,12].

Nitekim uzun dönem gözlemsel çalışmalarda, hormon tedavisine menopozdan sonraki ilk yıllarda başlayan kadınlarda Alzheimer hastalığı riskinin daha düşük olduğu bildirilmiştir. Cache County çalışmasında hormon tedavisine menopozdan sonraki ilk 5 yıl içerisinde başlayan kadınlarda Alzheimer hastalığı gelişme riski yaklaşık %30 daha düşük bulunmuştur [12]. Daha büyük retrospektif veri analizlerinde de menopozal hormon tedavisi, özellikle daha uzun süreli kullanım ve 17β-estradiol ve/veya progesteron içeren tedavilerle birlikte, Alzheimer hastalığı ve diğer nörodejeneratif hastalıkların daha düşük görülme oranlarıyla ilişkilendirilmiştir [13].

However, the timing of hormone therapy appears to be extremely important. Starting hormone therapy for the first time at age 65 and later has not yielded the same results, and older studies such as WHIMS have even reported an increased risk of dementia in this age group [14]. In contrast, more recent neuroimaging studies have found that women who started hormone therapy more than 5 years after menopause were associated with higher tau accumulation compared to those who started earlier [15]. These findings support the idea that the effect of hormone therapy on the brain may depend not only on whether hormones are used or not, but also on which hormone is given to which woman and especially at what stage of life.

However, current randomized controlled trials have not yet definitively shown that hormone therapy started early prevents Alzheimer's disease [10,11]. Therefore, hormone replacement therapy should not be considered today as a treatment that should be started solely to prevent dementia. However, there is significant and growing scientific evidence that hormone therapy used appropriately during early menopause may provide potential long-term benefits for brain health and may be associated with a reduced risk of Alzheimer's disease [12,13,15].

What kind of assessment should be done before treatment?

The goal of hormone therapy is not simply a "low estrogen, let's replace it" approach. Understanding the woman's hormonal, metabolic, cardiovascular, and oncological risk profile as thoroughly as possible before treatment allows for safer and more personalized treatment planning.

I find it particularly meaningful to consider the following areas together in a comprehensive initial assessment: mammography and/or breast ultrasonography appropriate to age and individual risk for breast imaging; current cervical screening/Pap smear; estradiol, progesterone, total and, if necessary, free testosterone, DHEA-S and SHBG; TSH, free T4,, if necessary, free T3, anti-TPO and anti-Tg; fasting glucose, fasting insulin, HOMA-IR and HbA1c; and an extended lipid assessment including total cholesterol, LDL-C, HDL-C, triglycerides, as well as ApoB and Lp(a). All of these are not mandatory for every woman in an HRT panel. For example, current guidelines do not require a comprehensive hormone or thyroid panel for every woman before starting HRT. However, in a personalized hormone and metabolic medicine approach, this initial data can be quite valuable for later evaluation of the effects of treatment.

Dried Urine Hormone and Metabolite Analysis

Serum hormone levels show us how much hormone is circulating in the bloodstream. However, this is only one part of hormone biology. After steroid hormones are synthesized, they enter different metabolic pathways in the liver and other tissues, resulting in numerous active or inactive metabolites. Therefore, obtaining a 24-hour or multi-timepoint dried urine hormone and metabolite profile before treatment can open a completely different window compared to classic serum analysis.

Such comprehensive profiles can reveal not only estradiol levels but also different stages of estrogen metabolism, such as estrone (E1), estradiol (E2), estriol (E3), total estrogen load, and metabolites like 2-hydroxyestrone, 4-hydroxyestrone, 16α-hydroxyestrone, and methoxy-estrogen. This is an important distinction for me: two women with the same serum estradiol value may be metabolizing estrogen biochemically through completely different pathways. In one woman, 2-hydroxylation might be more dominant, while in the other, 4-hydroxylation or 16-hydroxylation might be more pronounced. Furthermore, gaining information about the conversion of hydroxy-estrogens to methoxy-estrogens can also provide insights into catechol estrogen methylation occurring via COMT.

Another important advantage is that it can assess cortisol levels not just from a single morning measurement, but throughout the day. In the sample report Cortisol levels at wakefulness, morning, afternoon, evening, and bedtime are displayed, along with total cortisol metabolites and the cortisol/metabolite ratio. This can help us evaluate the clinical picture from a broader perspective, especially in women experiencing sleep disorders, intense stress, fatigue, or significant circadian rhythm disturbances.

Therefore, in my approach, it is more accurate to view the dried urine profile not simply as "another hormone test," but as a complementary test that can create an initial metabolic map of hormone production, conversion, and elimination.

Menopause and Metabolic Performance

Menopause is not just a decrease in reproductive hormones. Significant changes in body composition and metabolic physiology can also occur during the menopausal transition. Fat distribution may shift to a more visceral pattern, maintaining lean body mass may become more difficult, insulin sensitivity may decrease, and the lipid profile may become more atherogenic. Therefore, even in a woman who maintains the same body weight, the metabolic status before and after menopause may not be the same [7,8]. 

During this period, in addition to classic glucose, insulin, and lipid measurements, a broader Metabolic Performance Profile (MPP) may offer a useful complementary assessment for some patients. The attached image shows a female MPP. This example evaluates metabolism not through a single parameter, but across different areas such as gut-related metabolites, essential and non-essential amino acids, inflammation and oxidative stress, B-vitamin/methylation cofactors, cellular energy production, and muscle metabolism. 

This type of assessment is not mandatory for HRT and does not directly diagnose menopause. However, considering that the menopausal transition is also a period of remodeling of metabolic elasticity, muscle tissue, mitochondrial energy production, glucose metabolism, and cardiometabolic risk, it can provide a valuable starting profile, especially for women seeking a more comprehensive longevity and metabolic health approach.

How should treatment begin?

One of the key principles in hormone replacement therapy is to start with a low dose and progress gradually. The goal is not to achieve a specific laboratory result, but to provide physiological hormone support with the lowest possible effective dose.

After treatment begins, clinical responses such as hot flashes, sleep, mood, cognitive complaints, energy levels, libido, and vaginal and urinary symptoms are monitored. After an appropriate period, hormone levels and necessary metabolic parameters are re-evaluated; the dose or method of administration may be adjusted according to the clinical response and laboratory findings.

Forcing a lab value to an “optimal” number is not the goal of treatment. How the patient feels, how much their symptoms have improved, and whether they tolerate the treatment safely are often more valuable than a single hormone result. Lab tests are tools that guide treatment; they are not treatment itself.

***

All information presented here is for general informational and educational purposes only. This content is not intended to diagnose any disease, provide personalized medical assessments, or initiate, modify, or discontinue any treatment.

The information provided does not replace a doctor's examination, personal medical evaluation, or professional healthcare. Because health conditions and treatment needs vary from person to person, it is recommended that you consult your own doctor or relevant healthcare professional before starting any medication, supplement, treatment, or medical practice, or making any changes to your current treatment.

Because medical information and scientific data can change over time, the information presented here should not be assumed to be applicable to every individual or every clinical situation.

I wish you healthy days,

Dr. Ahmet Özyiğit, MD, MSc, PgDip, FAAMM, ABAARM
Longevity Physician

Elite Research and Surgical Hospital

References

1. Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288:321-333. DOI: 10.1001/jama.288.3.321
   
2. Manson JE, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310:1353-1368. DOI:10.1001/jama.2013.278040
   
3. Chlebowski RT, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials. JAMA. 2020. DOI:10.1001/jama.2020.9482
   
4. Fournier A, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114:448-454. DOI: 10.1002/ijc.20710
   
5. The North American Menopause Society Advisory Panel. The 2022 Hormone Therapy Position Statement of The North American Menopause Society. menopause 2022;29:767-794. DOI: 10.1097/GME.0000000000002028
   
6. Cauley JA, et al. Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density: The Women's Health Initiative Randomized Trial. JAMA. 2003;290:1729-1738. DOI: 10.1001/jama.290.13.1729
   
7. Uddenberg ER, et al. Menopause transition and cardiovascular disease risk. Maturitas. 2024. DOI:10.1016/j.maturitas.2024.107974
   
8. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab. 2003;88:2404-2411. DOI: 10.1210/jc.2003-030242
   
9. Hodis HN, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016;374:1221-1231. DOI: 10.1056/NEJMoa1505241
   
10. Henderson VW, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis.Neurology. 2016;87:699-708. DOI: 10.1212/WNL.0000000000002980
    
11. Gleason CE, et al. Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study. PLoS Med. 2024;21:e1004435. DOI: 10.1371/journal.pmed.1004435
    
12. Shao H, et al. Hormone therapy and Alzheimer's disease dementia: new findings from the Cache County Study.Neurology. 2012;79:1846-1852. DOI: 10.1212/WNL.0b013e318271f823
    
13. Kim YJ, et al. Association between menopausal hormone therapy and risk of neurodegenerative diseases: implications for precision hormone therapy. Alzheimer's Dementia (NY). 2021;7:e12174. DOI: 10.1002/trc2.12174
    
14. Shumaker SA, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291:2947-2958. DOI:10.1001/jama.291.24.2947
    
15. Coughlan GT, et al. Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography. JAMA Neurol. 2023;80:462-473. DOI: 10.1001/jamaneurol.2023.0455