Hormone Replacement Therapy in Menopause:  Evidence-Based Benefits, Risks, and Evolving Practice Guidelines

Pallavi Kandale, Vaibhav Shikare, Pratiksha Varhade, Anisha Awachar, Rupali Chopade, Shatrughna Nagrik, Dr. Shivshankar Mhaske,

doi:10.5281/zenodo.15529463

Review Paper | Open Access
Volume 02 | Issue 05 | Article Id IJSRT/250305127

Hormone Replacement Therapy in Menopause: Evidence-Based Benefits, Risks, and Evolving Practice Guidelines
Pallavi Kandale* Vaibhav Shikare Pratiksha Varhade Anisha Awachar Rupali Chopade Shatrughna Nagrik Dr. Shivshankar Mhaske
Satyajeet College of Pharmacy, Mehkar (MS), India

Abstract

Hormone Replacement Therapy (HRT) remains the most effective medication for treating menopausal symptoms in perimenopausal and menopausal women. When customised to individual needs, HRT gives maximum benefits with minimum hazards. A range of hormone kinds, doses, and delivery modalities are available, allowing for individualised therapy approaches. Informed decision-making, supported by reliable medical counsel, is vital for women contemplating HRT. It is particularly indicated for people with premature ovarian insufficiency, with treatment prescribed until the average age of menopause (51.4 years). This review underlines the value of tailored care, the relevance of multidisciplinary assistance, and the necessity of documented informed consent. Emphasis is centred on enhancing quality of life, especially in circumstances when prescribing HRT may include relative contraindications and little proof.

Keywords

Hormone Replacement Therapy (HRT), Menopause, Perimenopause, Premature Ovarian Insufficiency, Individualized Treatment, Quality of Life

Introduction

Menopause, which usually happens between the ages of 45 and 55, is a normal biological process that signifies the end of a woman's reproductive years. According to Nelson (2008), it is typified by a drop-in estrogen and progesterone levels, which results in a number of symptoms include mood swings, vaginal dryness, hot flashes, night sweats, and decreased bone density. One of the best ways to treat moderate to severe menopausal symptoms is with hormone replacement therapy (HRT), sometimes referred to as menopausal hormone therapy (MHT). [1] HRT involves the administration of estrogen alone or a combination of estrogen and progestogen to alleviate symptoms associated with estrogen deficiency. Estrogen therapy is typically prescribed to women who have undergone hysterectomy, while combined therapy is recommended for those with an intact uterus to reduce the risk of endometrial hyperplasia (North American Menopause Society [NAMS], 2022). [2] Over the years, the use of HRT has been subject to extensive research and debate, especially after the publication of the Women’s Health Initiative (WHI) trial in 2002, which highlighted potential risks such as increased breast cancer, cardiovascular events, and stroke (Rossouw et al., 2002). However, subsequent analyses have shown that the benefits of HRT outweigh the risks for many women, particularly when initiated in early menopause and tailored to individual health profiles (Manson et al., 2017).[3] Current clinical guidelines recommend that HRT should be considered for women with significant vasomotor symptoms or those at high risk for osteoporosis, and it should be used at the lowest effective dose for the shortest duration necessary to achieve treatment goals (British Menopause Society, 2020). [4] As research continues to evolve, it is important for healthcare providers to assess the risks and benefits of HRT on a case-by-case basis, taking into account the patient's age, time since menopause onset, symptom severity, and personal and family medical history.[5] There continues to be controversy regarding the use of menopausal therapy for women, with considerable evidence supporting the benefits of oestrogen for women,1 but with recent guidelines from the American Heart Association stating that hormone replacement therapy (HRT) and selective oestrogen-receptor modulators should not be used for the primary or secondary prevention of cardiovascular (CV) disease (CVD).2 Nevertheless, there is substantial data to support that premature menopause is associated with increased risk of coronary heart disease (CHD) and CVD events.3 The reason for this, however, remains uncertain, including the adverse effects of earlier loss of oestrogen on CHD risk factors or loss of other beneficial effects of oestrogen on the CV system. In their Heart paper, O'Keeffe and colleagues4 use data from the large United Kingdom Medical Research Counsel National Survey of Health and Development to examine the association between age at cessation of menstrual period and trajectory of CHD risk factors from ages 53–69 years in over 2500 women, where approximately 1670 had data available on blood pressure and body composition and approximately 1500 had data on lipids and glucose metabolism. These results did not demonstrate a clear impact of cessation of period on conventional CHD and CVD risk factors, therefore, suggesting that the reason for the increased CHD and CVD risk in these women with early menopause likely comes from other factors. [6] The permanent cessation of menstruation for a minimum of one year in a normally menstrual woman is referred to as menopause. The average age of menopause varies throughout different regions of the world. The average age in the European country is 51.4 years. Prevalent menopausal symptoms include vasomotor disturbances, mood fluctuations, impaired focus, vaginal dryness, atrophy of secondary sexual features, diminished libido, musculoskeletal pain, osteopenia, and osteoporosis. [7] The frequency of vasomotor symptoms varies across different geographical regions. Distressing symptoms last for 2- 3 yrs in the premenopausal period. It is prevalent in early ovarian failure and iatrogenic menopause. Vasomotor symptoms respond adequately to oestrogen replacement therapy. Hormone Replacement Therapy (HRT) utilising oestrogen analogous to normal ovarian secretion should not be conflated with the powerful ethinyl oestradiol employed in combined oral contraceptive protocols. The addition of a progestogen or micronized progesterone is important of woman still has a uterus to prevent endometrial hyperplasia and cancer. Estradiol can be administered orally (an micronized estradiol, estradiol valerate estrone, estriol or conjugated equine estrogens) or transdarmally 17beta-estradiol. Topical vaginal treatment of estrogen is utilised for localized symptoms. Various progestogen are used in combination with estradiol, either is a sequential cyclical regimen or as continuous combined therapy (CCT). Progestogen is typically taken orally. Only two formulations being accessible one is transdarmal and another one is levonorgestril intrauterine system. Tibolone is an oral synthetic steroid with estrogenic, androgenic and progestogenic effects that can be used as HRT in postmenopausal women. The role of supplementary testosterone will not be explored in this article [8]

HISTORY

In the 20th century, the interest in menopausal disorder has been increasing, but it took a long time to realize the real impact of hormone depletion on women’s health. The clinical conditions associated with menopause were identified as “Hormone Deficiency Syndrome” which included, besides hot flashes, other late onset chronic diseases such as osteoporosis, cardiovascular events, Alzheimer’s disease, and vaginal atrophy. At the beginning of the 20th century, the Food and Drug Administration (FDA) approved an estrogen product for the first time, Preamirin®, for the treatment of hot flashes [ The feminist movement in the 1960s changed women’s status and life expectancy, encouraging menopausal therapy, especially in European countries, with the concept of “feminine forever”. Wilson’s book, published in 1966 (“feminine forever”), became a bestseller, with its claim that “menopause is a hormone deficiency disease, curable and totally preventable, just take estrogen”. Hormone replacement therapy (HRT) was presented as a therapy that could allow women to free themselves from the malediction of estrogen loss and conserve their femininity. In the 1970s, the finding that unopposed estrogen supplements were associated with an increased risk of endometrial cancer had a bad impact on HRT’s reputation [4,5]. Ziel et al. observed a probable connection between the administration of conjugated estrogen alone and the development of endometrial cancer Nevertheless, in the following years, researchers discovered that reducing the dosage of estrogen and combining it with progesterone could reduce the risk of endometrial cancer. Such combined therapy was recommended for women with an intact uterus, raising renewed enthusiasm for HRT treatment. [9]

Epidemiology-

Mean age of menopause is different in different region of the world. Median age of 42.1-49.5 years South Asian countries but in European countries median age is (50.1- 52.8) is 51.4 years. Vasomotor symptoms (hot flushes and night sweats) are common, affecting about 70% of women (severely in about 20%), for a median duration of 5.2 years, but may continue for many more years in about 10% of women [10]. Menopausal symptoms adversely affect quality of life. In the 1970s epidemiological studies identified that the most common cause of death in women with early onset of menopause is cardiovascular diseases (CVD). The possibility that estrogens may be protective to the female cardiovascular system led to much research into looking at the effect of estrogen on the cardiovascular system [5-6]. Since epidemiological studies was the heart and estrogen/ progesterone replacement study designed to identify of HRT prevented recurrence of coronary heart disease in women with established coronary heart. Hormone Replacement Therapy (HRT) usage patterns among menopausal women have varied significantly over time and across regions, influenced by evolving scientific evidence, public perception, and clinical guidelines. Historically, HRT was widely prescribed during the latter half of the 20th century to manage menopausal symptoms and prevent chronic conditions such as osteoporosis and cardiovascular disease. By the late 1990s, it was estimated that up to 40% of postmenopausal women in developed countries such as the United States and the United Kingdom had used HRT at some point. [11] However, the release of the Women’s Health Initiative (WHI) trial findings in 2002 led to a dramatic decline in HRT use. The study raised concerns about increased risks of breast cancer, stroke, and cardiovascular events associated with combined estrogen-progestin therapy. [12] As a result, prescription rates fell sharply worldwide. For example, in the United States, the prevalence of HRT use among women aged 50–74 dropped from 41% in 2001 to around 16%. [13] Subsequent re-analyses of the WHI data and newer research have led to a more nuanced understanding of HRT. These studies have shown that the timing of initiation relative to menopause onset, the type of hormones used, and the route of administration significantly influence risk profiles. [14] This has prompted professional bodies to revisit guidelines, and in some regions, HRT use has stabilized or slightly increased, particularly among younger menopausal women with severe symptoms. Current estimates suggest that HRT use remains relatively low. In the UK, about 14% of women aged 50–64 used HRT as of the mid-2010, [15] although recent trends show a resurgence in use due to increased awareness and advocacy around menopause. In contrast, usage in developing countries remains much lower due to limited access, awareness, and differing cultural attitudes toward menopause and aging [16]

Pathophysiology:

Menopause is related to the depletion of ovarian follicles subsequent to apoptosis or programmed cell death together with alterations in the hypothalamus and pituitary hormones, the ovary ceases to respond to the pituitary hormones. Menopause also occurs owing to premature ovarian insufficiency which includes genetic, infection, autoimmune and metabolic causes or due to surgery. Women born with roughly seven million oocytes yet over their reproductive lifespan only release up to 500 oocytes. Therefore, ovarian insufficiency may be owing to fewer number of follicles present in the ovary or increasing rate of follicle loss. Another hypothesis is that improper pairing during meiosis may result in oocytes apoptosis. Surgical menopause occurs owing to surgical removal of ovaries, typically ovarian malignancy, cervical cancer radical hysterectomy or severe endometriosis. It also arise owing to chemotherapy (Anthraycline, cyclophosphamide) and perhaps radiotherapy. Randomized control trial on post-menopausal women (an average age of 66.7 years) with conjugate equine estrogen and medroxy progesterone acetate did not demonstrated any advantage but increase different thromboembolism most prominent is the first year of therapy and gall bladder illness. [17]. Menopause is marked by a decline in ovarian follicular function, leading to reduced production of estrogen and progesterone. This hormonal deficiency affects multiple physiological systems, producing vasomotor symptoms (e.g., hot flashes), genitourinary atrophy, mood disturbances, and increased risk of osteoporosis and cardiovascular disease). [18] Hormone Replacement Therapy (HRT) aims to correct this estrogen deficiency, thereby alleviating symptoms and preventing long-term complications.

Estrogen Deficiency and Menopausal Symptoms

In premenopausal women, estrogen regulates thermoregulation, maintains the integrity of the urogenital tract, modulates bone metabolism, and plays a role in cardiovascular and neurological functions. When estrogen levels decline during menopause, these regulatory effects diminish:

Vasomotor symptoms arise due to hypothalamic dysregulation of thermoregulatory centers, believed to be linked to changes in neurotransmitter levels (e.g., norepinephrine, serotonin) affected by estrogen withdrawal. [19]
Urogenital atrophy occurs as estrogen maintains epithelial integrity and collagen synthesis in the vagina and urinary tract. Estrogen deficiency leads to thinning of the epithelium, decreased lubrication, and increased susceptibility to infections and dyspareunia. [20]
Bone loss accelerates postmenopause due to increased osteoclast activity, which estrogen normally suppresses. This results in decreased bone mineral density and increased fracture risk. [21]
Cardiovascular changes include unfavorable shifts in lipid profiles and vascular function, potentially increasing atherosclerotic risk. [22]
Mechanism of Action of HRT HRT involves the exogenous administration of estrogens (with or without progestogens) to compensate for endogenous hormone loss:
Estrogen binds to estrogen receptors (ERα and ERβ) found in various tissues—e.g., brain, bone, vasculature, and urogenital tract—restoring function. It improves vasomotor stability, enhances vaginal health, and reduces bone resorption by inhibiting osteoclast activity.
Progestogen, when added, opposes estrogen’s proliferative effects on the endometrium, reducing the risk of endometrial hyperplasia and cancer in women with an intact uterus [23]
Different formulations (oral, transdermal, vaginal) and types of estrogen (e.g., estradiol, conjugated equine estrogens) may have distinct metabolic effects. For instance, transdermal estrogen avoids first-pass hepatic metabolism, leading to less impact on clotting factors and lipid metabolism compared to oral routes. [24]

Effect of HRT

Premature ovarian insufficiency

In the developed world menopause under 45 years in defined as premature ovarian failure [ 25]. Women with early ovarian insufficiency have an earlier development of both CVD and osteoporosis. They are also recognised to have reduced breast cancer risk compared with their menstrual friends. The risk of breast cancer with HRT use in these women in regarded to be not more than population risk for their age, while the benefits are greater by prevention of long-term morbidity. Hence it is strongly urged that these women should consider taking HRT, at least until the age of 50

Effect of HRT on cardiovascular events in recently post-menopausal women:

A randomized trial by Schaerbeek et al.10 that was carried out in Denmark in 1990-1993, has been the first one to examine the correct timing and the long term effect of HRT on CVD in recently postmenopausal women. After 10 years women on HRT were shown to have had a significant reduction in mortality and CVD associated events, with no apparent increased risk of VTE, stroke or cancer. The health benefits were seen up to 6 years after ceasing. 2012 Cochrane collaboration comprehensive review. [26] examined the clinical consequences of using HRT for 1 year or more. Twenty-three randomized double-blind studies were included with 42830 women aged 26-91 yrs. Since 70% of data were gathered from the women’s health initiative and HTRS most participants were post-menopausal. This review included that there was no indication to use HRT for primary or secondary prevention of CVD or dementia or for protection of cognitive function. There was a significant improvement and reduction in the risk of bone fracture after 5 years use. So no one prescription for optimum length of therapy or safe upper age limit for usage of HRT is therefore achievable because they will be customized to every woman’s circumstances. For most women, short term treatment will be adequate to relieve vasomotor symptoms for others; HRT may need to be continued for longer. For all women the lowest effective dose should be used for the shortest possible duration and the need to continue HRT should be reassessed at least yearly.

Practical guidelines on prescribing HRT: HRT in Low risk women

There are few women in whom HRT is an unequivocal contraindication. The worry of increased breast cancer risk is prominent for most women and clinicians. The risk as a result of taking HRT is substantially lower than the risk associated with obesity, moderate alcohol use or deferring first conception until beyond 35 years. [27] The absolute increase in breast cancer risk is 6 times per 1000 women for 5 years of estrogen and progestogen and reverts back to the population risk 5 years after stopping13. Three months trial of HRT will enable a women to assess her quality of life, whether HRT has been of help or not and the decision on length, having been made aware that the breast cancer risk will be duration dependent. A detailed history will show any existing medical problems or family history or CVD or cancer. This information will direct the clinician to the optimal regimen, dose and route of administration. Baseline measurement of body mass index (BMI) and blood pressure give information as to the need for further inquiry. There is no necessity for a preoperative mammogram or breast examination pelvic examination, cervical smear or endometrial thickness measurement by transvaginal scan. Once established on HRT a lady should not cease abruptly but should wean of treatment gradually. Continuing or resuming on HRT is a decision based on quality of life. Troublesome menopausal symptoms can develop in the perimenopausal state. To minimise unnecessary examination or unscheduled bleeds these women should be begun on sequential (cycle) HRT for 12-14 days per months. If periods are reasonably regular, the HRT should start with the next bleed, but if uncommon (more than three months apart) the HRT can be began without awaiting a period. The most common unpleasant effects include headache breast tenderness, bloating and muscular cramps. Weight gain is not a harmful effect of HRT [28]. Adverse effects are brief and usually resolve after 3 months. Any unscheduled bleeding should be investigated. Persistent progestogen adverse effects can be addressed by changing the progestogen or by employing an intrauterine device. This will give the benefit of contraceptive, reducing to periods and endometrial protection with chronic estrogen usage. Once started on HRT an annual assessment is all that is necessary. HRT does not elevate blood pressure and there is no evidence to monitor more regularly. Women who intend to be on HRT for more than 5 years should be advised to switch to combination contraception to avoid an elevated risk to endometrial hyperplasia seen in women on long term sequential therapy. Lower doses may be tested prior to switching and if tolerated. Then the women can transition to a lesser dose of CCT by finishing the month of sequential treatment. So that the withdrawal bleeding begins before commencing the CCT. As a general, women aged 54 years would be urged to switch as 80% of women at this age will be postmenopausal. CCT (continuous combination therapy) or Tibolone are used in postmenopausal women (amenorrhea for 12 months). Such women will have been estrogen deficient for this time and starting with a low dose combination will limit side effects and breakthrough bleeding. The dose can be increased after 3 months if menopausal symptoms linger. Initial breakthrough bleeding is typical but normally lessens and ends with time. Persistent bleeding should be explored after 6 months with an ultrasound scan and / or endometrial biopsy. The risk of endometrial cancer is lower in people using CCT than in those not using HRT. If bleeding occurs after a time of amenorrhea, then research is still required even if a causative factor is recognised Contributing factors included:

Forgotten tablets, poor patch adherence, low compliance.
Introduction of new medication or over the counter predations.
All other cases of post-menopausal bleeding. [29]

Patients with relative contraindication to HRT could be referred to expert service for consultation. Quality of life may be the decisive factor for women with contraindication and in such case a written declaration from the women in helpful and may avoid any future medico-legal difficulty.

Thrombosis risk:

According to Canadian society incidence of VTE and PE increased from 0.12 % (in general population) to 0.2% in HRT user. The risk of VTE related with HRT therapy is largely apparent after utilising 12 months. This risk varies upon kind of HRT, dosage of medicines and mode of delivery. Transdermal HRT is associated with a reduced risk of VTE than oral however smaller doses may be less likely to induce this risk. Women who are sedentary, overweight and smoker higher risk of VTE [30-31.]

Benefits of Hormone replacement Therapy

1. Relief from Menopausal Symptoms

HRT is effective in alleviating common menopausal symptoms, including:

Hot flashes and night sweats
Vaginal dryness and discomfort during intercourse
Mood swings, irritability, and sleep disturbances
Cognitive issues like "brain fog"
The Menopause Society

These improvements can significantly enhance quality of life during menopause. Canadian Cancer Society

2. Bone Health

Estrogen plays a crucial role in maintaining bone density. HRT helps prevent osteoporosis and reduces the risk of fractures, particularly in women who experience early menopause or have low estrogen levels.

3. Cardiovascular Health

Initiating HRT before the age of 60 or within 10 years of menopause onset may offer cardiovascular benefits, such as improved cholesterol profiles and reduced risk of heart disease.

4. Mood and Cognitive Function

HRT may alleviate mood swings, depression, and cognitive difficulties associated with menopause, contributing to improved mental well-being.

5. Sexual Health

By addressing vaginal dryness and discomfort, HRT can enhance sexual function and libido, improving overall sexual health. [32]

Other benefits of HRT:

Other identified benefits of HRT other than those altering vasomotor symptoms, include alleviation of poor mood and protection against loss of tooth. Several studies have found a risk reduction of bowel cancer in women using HRT, but this is not recognised to be as indication to prescribe HRT as prophylactic for this illness. Some forms of Estrogen replacement therapy appear to be neuroprotective, protecting cognitive function and reducing the incidence of Alzheimer’s disease. Some protection against Parkinsonism disease has also been reported. It is believed that there may be a ‘Window of opportunity’ for retaining cognitive function if HRT is used early in the menopause. [18] HRT is useful in reducing the bone loss generally occurs with the menopause. [33]

Fig.-1: Guidance on HRT prescribing with permission from the West Midlands Menopause society.

Topical vaginal estrogen

Atrophic vaginitis is treated with topical estrogen, resulting in cornification and regeneration of the vaginal epithelium. This enhances lubrication and sexual function. Systemic absorption is negligible with low- dosage topical estrogen. Additional systemic progestogen is not necessary. Vaginal estrogen may alleviate symptoms of urgency of micturition and recurring urinary tract infections. Vaginal symptoms can remain even while on enough systemic HRT; in such circumstances both topical and systemic are required. The safety of topical vaginal estrogen has not been studied in individuals with breast cancer, where presumably the risks are small. The benefits to the genitourinary tract together with greater sexual intimacy may outweigh the risk. [34]

HRT after breast cancer [35-36]

Breast cancer is a frequent disorder that affects people of all ages. The great majority of breast tumours are estrogen receptor positive (ER+) and require adjuvant tamoxifen or aromatase inhibitors, the adverse consequences of which can include worsened and debilitating menopausal symptoms. Many breast cancers and precancerous alteration (ductal carcinoma in situ) are screen discovered and caught at an early stage, with great prognosis. Adequate studies have not been done where such individuals have stayed on adjuvant treatment with the addition of HRT. Some case-control studies 3S have revealed no defrayment to the mortality rate or recurrence rate with HRT. Therefore, HRT use is a patient choice. There is limited information on the hazards and benefits of herbal and alterative over-the-counter medications.

The specialist needs to examine the following criteria while discussing management in order to anticipate prognosis:

Stage of the disease at diagnosis (size, ER status, grade of tumor and lymphnode status). This gives a guide to the prognosis.
Type of adjuvant therapy now or previously utilised.
Time since diagnosis.
The woman’s approach to her symptoms.
The woman’s worry of recurrence/fear of using hormones.
What she has tried already. [43]

Non-hormonal therapies

Women in need of treatment may be offered clonidine, selective serotonin reuptake inhibition (SSRI)(if not on tamoxifen) or selective nor adrenaline reuptake inhibitors(SNRI) (unlicensed use for vasomotor symptoms), or gabapentin, coupled with self-help recommendations for a trial period of 3-4 months. If this is ineffective, then the next approach may be evaluated. When all other prescription medications have been tried, then a conversation concerning quality of life and survival is relevant. Should the patient choose to use HRT, it is recommended that this is discussed with her oncologist and care providers. [44]

Tibolone

Tibilone, a selective tissue estrogenic activity regulator, is useful in alleviating symptoms in postmenopausal women. The discovery of a lower stimulatory effect on breast tissue compared with other HRT preparations indicated that it was feasible to test its safety in a randomized controlled study in women with recently diagnosed breast cancer [45]. Quality of life was better in the therapy group, although a greater rate of breast cancer recurrence was seen exclusively in the women with ER+ illness. There are no data on whether it is safe to use in disease-free survivors who still have menopausal symptoms several years after their initial therapy.

Family history of breast cancer [37]

As observed in the Nurses’ Health study HRT did not increase the risk of breast cancer in those women with a family history. Therefore, a family history of breast cancer is not a contraindication to HRT, rather an opportunity for the doctor to evaluate whether the history is relevant and warranting a referral to ‘the clinical geneticist and extra screening under 50 years of age.

Carriers of BRCA mutations

BRCAI and BRCA2 mutation carriers are at greater risk of breast and ovarian cancer. Risk-reducing surgery including mastectomies and bilateral salpingooophorectomy (BSD) is normally carried done after the family is complete26. Surgical menopause in these premenopausal women generates abrupt and severe symptoms. Preoperative counseling will help the patient select between BSO solely, or hysterectomy plus BSO. The progestogen necessary when the uterus remains may impact the decision. HRT is indicated in these young women to avoid the early onset of osteoporosis and CVD associated with a premature menopause. The use of HRT following risk-reducing surgery appears to be safe with no significant increase of breast cancer, especially if estrogen-only therapy is employed. [38-39]

FIGO guideline in menopausal syndrome, 2017 [40]

Certain sort of HRT may protect memory loss
Biphosphonate continue considerably prevent hip fracture in compare with no user or stop use more than 2 years
Soya protein a reduce coronary heart diseases.
Avoidance of coffee dramatically lowers menopausal symptoms.
HRT does not shorten the lives.
American menopausal society guideline of HRT [41]

The 2017 hormone therapy position statement of the north American menopause society recommend that hormone therapy remains the most effective treatment for vasomotor symptoms and genitourinary syndrome of menopause and has prevent bone loss and fracture. The danger of hormone treatment varied based on type, dose, duration of usage, mode of administration, timing of beginning and whether a progestogen is utilised. [46] For women aged younger than 60 years or who are within 10 years of menopause start and have no contraindications, the benefit risk ratio is most favorable for treatment of troublesome VMS and for those at elevated risk for bone loss or fracture. For women who commence hormone treatment more than 10- or 20-years following menopause onset or aged 60 years or older, the benefit risk ratio appears less favorable because of increasing risk of coronary heart diseases, stroke VTE, and dementia. Longer length of therapy must be periodic reevaluation. [42 -47]

Risks of Hormone Replacement Therapy [48-49]

1. Breast Cancer

Combined estrogen-progestin therapy has been linked to an increased risk of breast cancer. The risk becomes more pronounced with long-term use (typically beyond 5 years). This association was notably highlighted in large studies like the Women's Health Initiative (WHI) and the Million Women Study.

2. Endometrial (Uterine) Cancer

Estrogen-only therapy can increase the risk of endometrial cancer in women who have not had a hysterectomy. To mitigate this risk, a progestogen is usually added to the regimen for women with an intact uterus.

3. Ovarian Cancer

Some studies suggest a slight increase in the risk of ovarian cancer with both estrogen-only and combined HRT. However, the absolute risk remains low.

4. Cardiovascular Events

HRT may elevate the risk of heart disease, stroke, and blood clots, especially when initiated in women over 60 or more than 10 years post-menopause. Starting HRT closer to the onset of menopause may reduce these risks.

5. Gallbladder Disease

HRT, particularly oral estrogen, has been associated with an increased risk of gallbladder disease, including gallstones.

6. Dementia and Cognitive Decline

Initiating HRT in women aged 65 or older may increase the risk of dementia. The timing of therapy initiation appears to be a crucial factor.

7. Venous Thromboembolism (Blood Clots)

Oral estrogen therapy has been linked to a higher risk of blood clots. Transdermal (patch) estrogen may present a lower risk in this regard. [48-49]

Future Aspect:

A] Scientific Advances and Safer Therapies

Reevaluated Safety: Recent studies indicate that HRT is safe for many women under 60 or within 10 years of menopause onset, effectively alleviating symptoms like hot flashes and night sweats.
Innovative Delivery Methods: New hydrogel-based systems are being developed to provide consistent hormone levels with less frequent dosing, enhancing convenience and reducing side effects.
Transdermal Options: Transdermal estradiol and oral progesterone are gaining popularity due to their favorable safety profiles, particularly concerning cardiovascular risks.

B] Personalized and Extended Care

Individualized Therapy: Advancements in hormone monitoring, such as dried urine testing, are enabling more personalized HRT plans tailored to individual hormonal profiles.plminstitute.org
Extended Use Beyond 65: Emerging research suggests that with proper risk assessment, some women may benefit from continued HRT use into their 70s and 80s, potentially reducing risks of mortality, certain cancers, and cardiovascular diseases. Lippincott Journals [50]

C] Non-Hormonal and Alternative Therapies

New Medications: Fezolinetant, an NK3 receptor antagonist, has shown promise in reducing menopausal hot flashes without affecting estrogen levels, offering an alternative for those who cannot undergo traditional HRT. IQVIA+2Wikipedia+2The Australian+2
Natural Supplements: Products like Femarelle, containing plant-based compounds, are being explored for their potential to alleviate menopausal symptoms, though more extensive studies are needed to confirm efficacy.

D] Global Accessibility and Policy Changes

Policy Initiatives: Countries like Ireland are implementing programs to provide free HRT treatments, reflecting a growing recognition of menopause care as a public health priority.

E] Cognitive Health Considerations

Timing Matters: Research indicates that initiating estrogen-only therapy during midlife may reduce the risk of Alzheimer's disease, whereas starting combined therapies later in life may have variable outcomes.

F] Ethical and Societal Implications

Delaying Menopause: Innovations like ovarian tissue preservation and medications such as rapamycin are being investigated to potentially delay menopause, raising discussions about the medicalization of natural aging processes. [51]

CONCLUSION:

Hormone Replacement Therapy (HRT) gives significant benefits to symptomatic postmenopausal women, notably in relieving painful menopausal symptoms such as hot flashes and vaginal dryness, especially when alternative therapy proves ineffective. While there are no absolute contraindications of HRT, caution is advised in women with a personal or family history of venous thromboembolism (VTE) or cardiovascular illness, which are considered relative contraindications. Combined HRT should not be routinely advised for all postmenopausal women. Its use should be customised based on symptom intensity and patient risk profile. HRT may be explored for the prevention of osteoporotic hip fractures but should not be administered for the prevention of cardiovascular disease, breast cancer, or colorectal disorders. Alternative therapies remain restricted in both effectiveness and safety, supporting the necessity for thorough, case-by-case assessment before commencing HRT. HRT offers substantial relief from menopausal symptoms and can provide additional health benefits when initiated appropriately. However, it's essential to weigh these benefits against potential risks, which vary based on individual factors such as age, health history, and the timing of therapy initiation. Engaging in a thorough discussion with a healthcare provider can help determine the most suitable approach to managing menopause.

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