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Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis

  • Zhao Na , Wei Wei , Yingfang Xu , Dong Li , Beili Yin and Weiqun Gu EMAIL logo
Published/Copyright: December 12, 2023
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Open Life Sciences
From the journal Open Life Sciences Volume 18 Issue 1

Abstract

The use of menopausal hormone therapy (MHT) has declined due to concerns about its potential side effects. However, its pivotal role in managing postmenopausal osteoporosis is gaining increased recognition. In this article, we explore how MHT assists postmenopausal women in maintaining bone health and preventing fractures. Recent research indicates that MHT significantly reduces the risk of fractures in women. This benefit is evident regardless of a woman’s bone mineral density or their use of progestogens. However, there is limited evidence suggesting that the skeletal benefits continue once the treatment is discontinued. Possible complications of MHT include heart attacks, clots, strokes, dementia, and breast cancer. The most suitable candidates for MHT are women who have recently entered menopause, are experiencing menopausal symptoms, and are below 60 years of age with a minimal baseline risk of adverse events. The treatment is available to those who meet these criteria. For women undergoing premature menopause, MHT can be considered as a means to protect bone health, especially if initiated before menopause or if accelerated bone loss is documented soon after menopause. Such decisions should be made after evaluating individual risk factors and benefits.

Keywords: osteoporosis; menopausal hormone therapy; bone health; postmenopause

1 Introduction

Over the past 30 years, osteoporosis has transformed from being perceived as a normal part of aging to being recognized as a significant non-communicable chronic illness. It now has clearly defined diagnostic criteria and effective means for early detection, risk assessment, and treatment. Osteoporosis is a skeletal disorder marked by decreased bone strength, which heightens the risk of fractures. This stems from a decline in bone density and a deterioration of bone microarchitecture. Fortunately, an array of treatment strategies aimed at increasing or preserving bone mineral density (BMD) are now accessible for osteoporosis management [1–3]. Oral bisphosphonate medication is frequently recommended for patients with diagnosed osteoporosis and a heightened fracture risk [1–3]. However, other pharmaceutical interventions such as zoledronic acid, denosumab, and teriparatide are tailored to specific stages of the risk spectrum. Identifying women who currently have a low risk but a high lifetime potential for fractures is crucial in the effective management of osteoporosis.

Inadequate bone mass or failure to achieve peak bone density can result in osteoporosis later in life (Figure 1). The attainment of optimal peak bone mass is influenced by both genetic factors and lifestyle choices, including nutrition, exercise, and abstention from bone-toxic drugs. Achieving this peak is vital in preventing osteoporosis. Factors such as poor nutrition during developmental years, lack of physical activity, coexisting medical conditions (e.g., diabetes mellitus, thyrotoxicosis, or Cushing’s syndrome), and certain medications (like corticosteroids or anticonvulsants) can contribute to a reduced peak bone mass. This peak typically develops during childhood, adolescence, and early adulthood [4]. Given its proven efficacy in fracture prevention, regardless of baseline bone density, and its potential benefits in alleviating menopausal symptoms, menopausal hormone therapy (MHT) stands out as a significant pharmaceutical intervention for osteoporosis management [5].

Figure 1 Physiology behind fractures caused by osteoporosis.
Figure 1

Physiology behind fractures caused by osteoporosis.

Hormone replacement therapy (HRT) was frequently prescribed during the 1980s and 1990s to treat menopausal symptoms such as night sweats, hot flashes, and sleep disturbances. Additionally, it was believed to confer benefits like osteoporosis prevention [6–8]. This strategy’s justification stemmed from observational studies correlating HRT with improved bone health. However, the Women’s Health Initiative (WHI) hormone therapy trials introduced skepticism. The first of these studies, published in 2002, determined that an HRT regimen combining conjugated equine estrogens (CEEs) with medroxyprogesterone acetate (MPA) did decrease fracture risk, but it also elevated the risk of cardiovascular and cerebrovascular events, breast cancer, and other health complications [9].

The evolving story of MHT serves as a cautionary tale, emphasizing the limitations of observational research and the potential for conflicting results when transitioning to randomized controlled trials [9]. Notably, re-analyses of the original observational studies using advanced pharmacoepidemiological methods – better accounting for confounding by indication – showed results more aligned with those from randomized trials [10]. Despite this, observational study outcomes inherently lack the reliability of those from randomized trials.

Further, different MHT protocols (considering the inclusion or exclusion of progestogen, the type and dosage of both estrogen and progestogen, and administration route) might lead to varying benefit–risk profiles. This notion is supported by additional re-analyses of the WHI and other studies [11]. The intent of this article is to provide a structured perspective on MHT, detailing the evidence supporting its use in preventing osteoporosis and related fractures.

2 Physiological aspects of menopause and its connection to bone

2.1 Menopausal physiology

The reduction of ovarian follicular activity leads to menopause, marking the permanent cessation of menstrual cycles. Typically, menopause is diagnosed in women in their forties or fifties, following a 12-month period of amenorrhea with no underlying physiological or pathological cause. The perimenopausal period, which usually spans 4–8 years, involves various endocrine, biochemical, and clinical changes that prepare the body for menopause [12,13].

During a regular menstrual cycle, the pituitary gland secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH), regulating the ovary’s production of estrogen, testosterone, and progesterone. However, due to ovarian reserve depletion and decreasing estrogen levels, menstrual periods may become shorter or irregular during perimenopause, even when estradiol levels remain relatively stable. When estrogen levels decline, FSH and LH levels rise in the bloodstream. Unlike estradiol, which decreases rapidly following menopause, testosterone, androstenedione, and dehydroepiandrosterone sulfate may gradually decrease with age. Postmenopausal women typically have low progesterone levels and reduced circulating estrogen levels, although local aromatization of androgen precursors may still allow for some estrogenic actions at the molecular level [10,14]. Menopausal symptoms, including hot flashes, sleep disturbances, mood swings, and urogenital changes, are attributed to these hormonal shifts and have been extensively discussed elsewhere [10].

2.2 Menopause and its relation to the skeleton

Albright [15] reported his findings linking estrogen insufficiency due to menopause to poor bone health, establishing the idea that exogenous estrogen therapy can assist in maintaining bone mass and reducing fracture risk. Estrogen functions as an antiresorptive drug by regulating the receptor activator of nuclear factor kappa B ligand (RANKL) pathway, thus reducing osteoclast numbers [16]. The absence of estrogen diminishes matrix production, but its treatment may rejuvenate it [17].

The menopausal transition is associated with accelerated bone loss, particularly in the trabecular bone, and an increased risk of fractures later in life. Menopausal hormone therapy (MHT) has proven effective for both menopause and spinal osteoporosis, as these two conditions are interconnected. Hip and vertebral fractures become significantly more prevalent at older ages, while wrist fractures become more common around the time of menopause [10,18]. Recent menopausal women who experience a wrist fracture should undergo a comprehensive risk assessment and take necessary precautions to minimize the likelihood of further fractures [10].

2.3 A brief overview of the history of MHT as well as its various types (estrogens and progestogens)

A brief overview of MHT reveals that it involves the administration of both estrogen and progestogen to mitigate the endometrial stimulation caused by estrogen. Hysterectomy patients only take estrogen replacement therapy. In the 1890s, climacteric symptoms were first treated with desiccated ovarian estrogen. In 1929, oestrone was extracted from the urine of pregnant women [19]. Initially termed “theelin,” it was later renamed “oestrin.” By 1936, oestradiol was derived from pig ovaries [10,20]. Progynon, the first estrogenic product on the market, was an injectable hormone originally obtained from the placentas of pregnant animals. In 1941, Canada began offering oral estrogen treatment using conjugated estrogens collected from the urine of pregnant mares [20–22]. In 1942, the US joined in the medical advancements. The first isolation of crystalline progesterone occurred in 1934 [20]. It was Russell Marker who pioneered its synthesis by extracting it from diosgenin in cabeza de negro, also known as Mexican yam. Initially, there was no debate regarding the use of estrogen treatment for women. However, by the mid-1970s, it was found that using estrogen alone heightened the risk of endometrial cancer, making the addition of a progestogen essential for endometrial safety. In industrialized countries, the usage of MHT has decreased since its peak in the 1990s, when researchers first began to associate oral conjugated estrogens with MPA and an increased risk of breast cancer [20]. There have been several publications in the past 20 years that explore the various MHT formulations and routes of administration, as well as meta-analyses of the WHI conjugated estrogens and MPA research and the conjugated estrogen-alone study data [17,22–25]. The following discussion of the perks and drawbacks of MHT is made possible by the insights gained from these studies, which in turn have improved clinical decision-making.

Inadequate estrogen levels during the early stages of the menopausal transition significantly contribute to alterations in bone mass and quality, playing a substantial role in the development of postmenopausal osteoporosis. Estrogen is crucial for both bone development and maintenance, as bone is an estrogen-dependent tissue. Estrogens act on osteoblasts through specific receptors (ER) and, by extension, influence osteoclast progenitors and T-lymphocytes, leading to a substantial reduction in osteoclast growth and activity (Figure 2a). Additionally, estrogens inhibit apoptosis (cell death) in osteoblasts and osteocytes, ensuring continuous bone synthesis [26]. Estrogen deficiency during menopause primarily results in increased bone resorption and cellular-level changes, with bone formation unable to compensate for the heightened resorption activity. Rapid bone loss and alterations in microarchitecture, such as disorganization, thinning, and rupture of bone trabeculae, are associated with an elevated risk of fractures, even when bone remodeling remains robust [27,28].

Figure 2 (a) Influence that estrogens have on bone cells. (b) Alterations in cellular state brought on by estrogen fluctuations. Effects are shown with +E when estrogen is present, while effects are shown with −E when estrogen is not present. IL-1 is also known as TNF and OPG. Estrogen inhibits osteoclastogenesis and enhances osteoclast apoptosis. Estrogen inhibits osteoclastogenesis by blocking the production of IL-1 and TNF. It also increases the susceptibility of stromal cells and preosteoblasts to the effects of IL-1, which in turn blocks the production of M-CSF, RANKL, and possibly most significantly, IL-6. Furthermore, estrogen encourages the formation of OPG, which is a powerful inhibitor of osteoclastogenesis. Additionally, estrogen has the effect of making osteoclast precursors less sensitive to RANKL. Additionally, estrogen encourages osteoclastic apoptosis, which in turn shortens the lifetime of osteoclasts. It would indicate that TGF-b is the factor responsible for causing this impact [4].
Figure 2

(a) Influence that estrogens have on bone cells. (b) Alterations in cellular state brought on by estrogen fluctuations. Effects are shown with +E when estrogen is present, while effects are shown with −E when estrogen is not present. IL-1 is also known as TNF and OPG. Estrogen inhibits osteoclastogenesis and enhances osteoclast apoptosis. Estrogen inhibits osteoclastogenesis by blocking the production of IL-1 and TNF. It also increases the susceptibility of stromal cells and preosteoblasts to the effects of IL-1, which in turn blocks the production of M-CSF, RANKL, and possibly most significantly, IL-6. Furthermore, estrogen encourages the formation of OPG, which is a powerful inhibitor of osteoclastogenesis. Additionally, estrogen has the effect of making osteoclast precursors less sensitive to RANKL. Additionally, estrogen encourages osteoclastic apoptosis, which in turn shortens the lifetime of osteoclasts. It would indicate that TGF-b is the factor responsible for causing this impact [4].

Estrogen deficiency during menopause results in an increase in osteoclastic resorption activity while osteoblastic activity remains relatively constant, ultimately leading to a net loss of bone. This phenomenon was originally termed “uncoupling.” Understanding the molecular changes that occur due to estrogen deprivation (Figure 2b) has been a research priority. Cells of the stromal/osteoblastic lineage become more sensitive to interleukin-1 (IL-1) and tumor necrosis factor (TNF)-β in response to estrogen deprivation. These cells, when exposed to IL-1 and TNF, secrete various cytokines, including interleukin-6 (IL-6), interleukin-11, transforming growth factor (TGF), granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor (M-CSF). The final signaling molecule in the osteoclastogenesis process is the RANKL, produced by osteoblasts, which binds to its receptor RANK on osteoclasts [29,30].

Osteoprotegerin (OPG), secreted by cells of the stromal osteoblast lineage, acts as a natural antagonist to RANKL [31]. It has been found that estrogen increases the synthesis of OPG [31]. RANKL, identified as the uncoupling factor secreted by osteoblasts, and other factors increase the quantity of pre-osteoclasts in the bone marrow, accelerating bone resorption. Estrogen plays a pivotal role by enhancing OPG secretion and reducing M-CSF and RANK, as previously highlighted [29–32]. The simplest form of MHT is the use of estrogen either alone (in the event of a hysterectomy) or in conjunction with a progestogen. Researchers in the WHI used a combination of MPA 2.5 mg/day and CEE 0.625 mg/day. There are now a plethora of options, including oral micronized 17-oestradiol (often at a dose of 1–2 mg/day) and additional progestogens such dydrogesterone, micronized progesterone or norethisterone acetate. There are several dose and delivery strategies, including transdermal and percutaneous formulations [20]. Transdermal application of 25–50 pg/day of 17-oestradiol is one such example. Transdermal administration of estrogen, which bypasses the liver’s first-pass metabolism, appears to have a lower risk of venous thromboembolic disease and stroke compared to oral administration [33,34]. While the addition of progestogen in MHT is recommended to reduce the possibility of developing endometrial cancer, it is important to note that the benefit–risk profiles of mimic estrogen MHT and anti-estrogen MHT differ significantly. Additionally, tissue selective estrogen complex (including CEE and bazedoxifene) and tibolone (a synthetic steroid with mixed estrogenic, androgenic, and progestogenic action) [35] may be used to alleviate the symptoms of menopause. However, their use and availability vary widely across countries. As a result of these challenges, it is crucial to assess each MHT formulation independently and personalize treatment as much as possible within the bounds of the available information. Additional information on dosage and administration methods may be found in Rozenberg et al. [20,10].

3 Role of MHT in disease prevention

Weight gain is not directly caused by menopause; however, low estrogen levels can promote a shift in fat distribution from the hips and thighs to the abdomen and torso. Abdominal obesity increases the likelihood of chronic inflammation, which in turn elevates the risk of developing diseases such as heart disease, diabetes, and certain forms of cancer [36].

3.1 Cardiovascular diseases (CVD) risk

Figure 3 illustrates the various mechanisms by which a deficient supply of estrogen elevates the risk of CVD. CVD encompasses disorders of the heart and blood vessels, including common types such as coronary artery disease, strokes, and hypertension. Risk factors, including high blood pressure, smoking, and obesity, contribute to their onset. Insufficient estrogen levels can result in adverse lipid changes, such as increased levels of triglycerides and LDL cholesterol, along with decreased levels of HDL cholesterol. Additionally, low estrogen can activate the renin-angiotensin system and contribute to a decline in arterial endothelial function.

Figure 3 There are several ways in which estrogen decline during menopause might have a negative impact on cardiometabolic health. The decrease in estrogen that occurs during menopause is thought to have direct impacts on the brain, including the potential to lessen satiety and, as a result, increase food intake; it also causes sleep disturbances and lessens muscle’s sensitivity to insulin. In addition, the melanocortin 4 receptor and the estrogen receptor- in the brain are responsible for estrogen’s ability to boost physical activity. This function may be lost after menopause. These alterations, taken together, are a contributor to the rise in visceral adiposity that is associated with menopause, as well as the risk of fatty liver disease. These, in turn, contribute to insulin resistance, which in turn leads to type 2 diabetes mellitus, a higher atherogenic lipid profile (lower HDL cholesterol, increased LDL cholesterol, and triglycerides), and systemic inflammation. Estrogen deficiency has been shown to directly affect arterial endothelial function, which, when combined with a lower lipid profile, raises the risk of CVD [20].
Figure 3

There are several ways in which estrogen decline during menopause might have a negative impact on cardiometabolic health. The decrease in estrogen that occurs during menopause is thought to have direct impacts on the brain, including the potential to lessen satiety and, as a result, increase food intake; it also causes sleep disturbances and lessens muscle’s sensitivity to insulin. In addition, the melanocortin 4 receptor and the estrogen receptor- in the brain are responsible for estrogen’s ability to boost physical activity. This function may be lost after menopause. These alterations, taken together, are a contributor to the rise in visceral adiposity that is associated with menopause, as well as the risk of fatty liver disease. These, in turn, contribute to insulin resistance, which in turn leads to type 2 diabetes mellitus, a higher atherogenic lipid profile (lower HDL cholesterol, increased LDL cholesterol, and triglycerides), and systemic inflammation. Estrogen deficiency has been shown to directly affect arterial endothelial function, which, when combined with a lower lipid profile, raises the risk of CVD [20].

Furthermore, estrogen insufficiency is associated with risk factors for insulin resistance and type 2 diabetes. These factors include impaired glucose clearance in muscles, increased food intake, and decreased physical activity, as reported [20,37,38]. Animal studies have demonstrated that sleep deprivation during menopause exacerbates insulin resistance and leads to an accumulation of visceral adipose tissue [20,38].

MHT based on estrogen has been found beneficial in various ways. These benefits encompass reduced accumulation of central adipose tissue, improved endothelial function, and lower levels of total and LDL cholesterol. They also include increased levels of HDL cholesterol and triglycerides. However, oral estrogen formulations were associated with a threefold increase in the incidence of venous thromboembolic events [39–49]. Since transdermal estradiol is not subject to first-pass metabolism in the liver, it does not elevate the risk of venous thromboembolic disease or stroke [33,34]. Treatment with estrogen also reduces the risk of developing type 2 diabetes in women without a family history of the disease [20,40]. Despite evidence that estrogen directly improves glucose clearance in muscle and decreases pancreatic β-cell endoplasmic reticulum stress by reducing the buildup of misfolded proinsulin, women might not experience these benefits until later in postmenopause.

Similar to statins, the effects of MHT on the development of atherosclerosis and CVD are believed to be time-dependent [41–43]. Observational studies on symptomatic menopausal women have shown that up to 10 years of MHT usage can have a significant beneficial effect on CVD risk. Thus, for bone protection and fracture prevention, MHT should be primarily considered for treating menopausal symptoms in newly postmenopausal women with a low baseline risk of CVD, cerebrovascular disease, thromboembolic disease, and breast cancer. However, randomized controlled trials that involved asymptomatic women more than 10 years postmenopause found no benefit or potential harm, leading to skepticism regarding the primary prevention of CVD with MHT in a meta-analysis. Nonetheless, according to [20,44], MHT use was associated with a decreased risk of coronary heart disease and overall mortality among women who are less than 10 years past their last menstrual period. For postmenopausal women less than 6 years after their last menstrual cycle, transdermal MHT might offer cardiovascular benefits without elevating the risk of venous thromboembolic events. However, current guidelines do not recommend its use for primary or secondary prevention. Therefore, MHT is not presently advised for the prevention of CVD [20,43].

3.2 Other complications

Except for premenopausal women undergoing surgical menopause, menopause is typically not linked with memory loss. Nevertheless, evidence from longitudinal cohort studies suggests that many women undergo a decline in cognitive function after menopause, with memory experiencing the most noticeable drop. Beyond vasomotor symptoms (VMS), sleep disturbances, mood fluctuations, and anxiety, changes in sex steroid hormone levels play a crucial role in memory function during the menopausal transition. Although the role of estrogen in cognitive health is biologically conceivable, there are conflicting results from observational studies and randomized controlled trials. These findings can be both beneficial and detrimental.

Two WHI studies presented evidence of an age-related effect. In WHI substudies, MHT use showed neither harm nor benefit for women who started treatment between the ages of 50 and 55. However, it was associated with negative cognitive effects in women aged 65 and older [44,45]. Two subsequent clinical studies found no positive impact of MHT on cognition [44,45]. Women within 2 years of menopause taking oral hormones reported improved mood and anxiety compared to those using transdermal hormones. Despite the potential of estrogen medication to maintain cognitive function post-surgical menopause, MHT should not be used to enhance cognitive performance in postmenopausal women. Yet, short-term MHT has shown promise in addressing menopausal depression [46,47].

Globally, as many as 12% of women experience early ovarian insufficiency (pre-40 ovarian failure), and up to 4% undergo menopause before age 45. Women with ovaries that cease to function before age 45 face heightened risks of developing type 2 diabetes, early CVD, and premature death, especially if they gain weight and have dyslipidemia [48,49]. According to two meta-analyses [48,49] and most observational studies, oral MHT users possess a reduced risk of developing colorectal cancer. The WHI trials indicated that women who took both MPA and oral conjugated estrogen had a lower risk of colorectal cancer than those taking conjugated estrogen alone [20]. Still, using MHT primarily to prevent colorectal cancer is not recommended. The relative safety of different formulations requires more extensive research [50].

4 Effectiveness of MHT in the prevention of fractures

Initial intervention studies were conducted on small groups of women using single or dual-photon absorptiometry to showcase the preservation of bone mass by estrogen, either alone or in conjunction with progestogen [24]. Additionally, US-based studies indicated that the treatment influenced bone histomorphometric parameters [24,51]. The Postmenopausal Estrogen or Progestin Intervention study [12] was the pioneering randomized trial to illustrate that MHT preserves BMD postmenopause using dual-energy X-ray absorptiometry. The WHI determined that MHT reduced the occurrence of hip fractures and other osteoporosis-related fractures in a non-selected sample with low BMD. Over an average follow-up of 5.2 years, a randomized trial with around 16,000 women aged 50–79 years – all of whom had an intact uterus at baseline – revealed a 34% reduction in hip fracture incidence for those who received CEE + MPA compared to a matching control group. Beyond the drop in hip fracture incidence, the WHI study also noted a decline in clinical vertebral fractures and other osteoporotic fractures in the CEE + MPA group in contrast to the placebo [52]. Furthermore, after an added 5.6 years of therapy, the CEE + MPA group maintained a statistically significant reduction in fracture risk. The MHT’s broad efficacy for fracture prevention was underscored by the observation that this risk reduction was uninfluenced by factors such as age, body mass index, smoking habits, personal or family history of falls or fractures, total calcium intake, or prior hormone therapy usage [52]. After 3 years of treatment, the active group experienced a 3.7% increase in total hip BMD, contrasting with a mere 0.14% in the control group [10,53].

The bone-protective effect of MHT must be evaluated when deciding its inclusion in osteoporosis therapy. Women (n = 347) from four placebo-controlled MHT trials were followed up 5, 11, and 15 years after completing treatment [54]. While bone loss rates reverted to typical postmenopausal levels after ceasing MHT, the BMD of MHT-treated women remained higher than that of placebo-treated women for several years. Additionally, those previously treated with MHT had a reduced frequency of all osteoporotic fractures compared to the placebo group [54].

However, other research, both mechanistic and population-based, has challenged the alleged preventative benefits of MHT for bone health. Postmenopausal women in the US National Osteoporosis Risk Assessment study, who had discontinued MHT within the past 5 years, had a similar hip fracture risk as those who had never been on MHT [55]. Another study using data from the Kaiser Permanente health management organization in Southern California monitored 80,955 postmenopausal women who had been on MHT for approximately 6.5 years [56]. Compared to continuous MHT users, those who abruptly stopped had a 55% increased risk of hip fracture within the following 2 years. Observational studies, in contrast to randomized trials, tend to be more susceptible to bias and confounding. Three years post-intervention, the WHI trial detected no lasting benefit from MHT use [57]. Yet, during both the intervention and post-intervention periods, the hip fracture rates were lower in the intervention group. Women assigned to either MHT or placebo, then observed for 5 years post-intervention, showed no signs of decreased fracture risk among former MHT users compared to those who had taken a placebo. While the CEE + MPA trial did not observe a significant reduction in overall fractures among past MHT users, the CEE-alone study (focused on women who had undergone hysterectomy before the study) did find some evidence of a lasting effect on total fractures [58–61].

In the WHI trial, 16,089 women were randomly assigned to receive MHT or a placebo and either calcium + vitamin D supplementation or a placebo. This was to ascertain the effectiveness of combining these two interventions to reduce hip fractures. The combination of MHT and calcium + vitamin D supplements proved more effective in preventing hip fractures compared to either treatment alone. A notable reduction in hip fractures was observed among women who received the calcium and vitamin D supplements, as opposed to those given a placebo or hormone treatment alone. However, the combination therapy appeared to accelerate fracture healing [60], but did not influence variations in BMD in the hips and spine.

The bone-protective benefits observed in the WHI trial were supported by a meta-analysis of 28 studies encompassing 33,426 participants and 2,516 fracture cases. The hazard ratio for all fractures (MHT vs placebo) was found to be statistically significant. Zhu et al. [62] reported that the magnitude of effect for hip and spinal fractures was similar. While studies on lower dosages and transdermal applications have shown positive effects on BMD, definitive fracture outcomes remain under-researched [25]. These dosages include oral conjugated estrogens at 0.3 mg/day, micronized 17-estradiol at 0.25 mg/day, and transdermal estradiol at 14 g/day. Estrogen therapy aims to mimic the functions of natural estrogens, namely oestradiol, oestrone, and oestriol. The most frequently prescribed forms of estrogen are available in oral formulations (Table 1) [20,63,64].

Table 1

MHT and standard dose per day

Compound Dose per day
estrogens CEEs 0.625 mg
Micronized 17β-oestradiol 2.0 mg
Oestradiol valerate 2.0 mg
Piperazine oestrone sulfate (oestropipate) 0.625 mg
Transdermal 17β-oestradiol 50 μg
Subcutaneous implant oestradiol 50 mg
Oestradiol gel 1 mg
Oestradiol hemihydrate gel 1.5–2.25 mg
Progestogens Micronized progesterone 100 mg
Dydrogesterone 5–10 mg
Drospirenone 1–2 mg
Norethisterone acetate 1.0 mg
MPA 2.5–5 mg
Levonorgestrel intrauterine device 20 μg levonorgestrel every 24 h initially
Other Tibolone 2.5 mg
Conjugated estrogens plus bazedoxifene 0.45 mg plus 20 mg
Drospirenone 4 mg for 24–28 days for perimenopausal cycle control and contraception

5 Incorporating MHT into routine maintenance for bone health

5.1 Economics of health care provisioning

Researchers have studied the cost-effectiveness of menopausal hormone therapy (MHT) in treating menopausal symptoms and preventing fragility fractures in asymptomatic women at high risk. Zethraeus et al. [64] examined the societal perspective in Sweden for women between the ages of 50 and 60, integrating efficacy and side effect data from the WHI into an individual state transition model. Lekander et al. [65] conducted a parallel analysis for the UK population using a Markov cohort simulation model for women aged 50 and older. Both investigations, which were based on WHI data, confirmed the cost-effectiveness of MHT [65]. It was shown that cost-effectiveness was largely influenced by the severity of menopausal symptoms, with MHT being deemed cost-effective even for those with moderate symptoms [64].

The studies encompassed women from Sweden, the United States, and the United Kingdom who were at high risk but did not have menopausal symptoms. In the state transition model, fracture, cancer, and CVD were all considered terminal conditions. The evidence for cost-effectiveness was less compelling for women who had never sustained a uterine fracture. However, the data suggested that MHT was more cost-effective than no treatment for those who had undergone a hysterectomy. The pivotal determinant in evaluating cost-effectiveness was the fracture risk. Economically, women who had experienced a hysterectomy and had no prior vertebral fracture seemed to benefit from MHT. Only women with a pristine history of vertebral fracture and an intact uterus were advised against MHT. These results support the use of MHT for alleviating menopausal symptoms but raise questions about its role in fracture prevention, especially for those at a lower risk. The analyses did not account for the duration since menopause, a factor generally believed to enhance cost-effectiveness.

5.2 Recommendation and guidelines for MHT

Several international guidelines endorse MHT as a potential first-line therapy to maintain bone health in women just entering menopause. EMAS members concur that the “administration of systemic MHT possesses a favorable risk–benefit profile for women under the age of 60 years or within 10 years postmenopause for both menopausal symptoms and osteoporosis” [66]. The North American Menopause Society asserts that the benefit–risk ratio is optimal for treating prominent VMS and for women under 60, or within 10 years of menopause onset, especially those at high risk for bone loss or fracture and with no contraindications. Recommendations from the International Menopause Society (IMS) [67] mirror this stance. While the American Association of Clinical Endocrinologists highlights that “MHT should be administered at the lowest dose and shortest duration needed to manage menopausal symptoms,” they also stress its use for osteoporosis prevention and treatment within an overall benefit-versus-risk assessment for each patient [68]. The US Endocrine Society notes the lack of consensus regarding MHT’s efficacy in preventing CVD, breast cancer, or dementia but acknowledges its uncertain benefit in fracture prevention [69]. The American College of Obstetricians and Gynecologists emphasizes treating menopausal symptoms, advocating for the “lowest dosage, shortest duration” approach. A Global Consensus Statement from 2016 states: “MHT can commence in postmenopausal women at fracture or osteoporosis risk before age 60 or within 10 years postmenopause.” This sentiment was backed by prominent organizations like the Endocrine Society, the European Menopause Society, the International Osteoporosis Foundation (IOF), the Federation of Latin American Menopause Societies, and the IMS dose [70], the optimal benefits of MHT might be reaped at the lowest feasible dose. The UK’s National Institute for Health and Care Excellence (NICE) champions MHT for postmenopausal symptoms, noting the subdued risks of CVD with estrogen-only MHT and negligible or slightly elevated coronary heart disease risks with combined MHT for those below 60. When devising a treatment strategy, factors like baseline cardiovascular risk, breast cancer status, and history of thromboembolic disease should be considered [10]. The US Preventive Services Taskforce Report stands as a credible source for evidence-based guidance in clinical preventive services, offering a window into the most recent trends in US preventive healthcare, crucial for MHT decisions. With healthcare’s ongoing evolution, such insights are invaluable. The influence of NICE guidelines in the UK and their alignment with European healthcare perspectives provides a broader international context. Their continual updates, capturing the latest in medical science, render them an essential tool for clinicians and patients navigating MHT choices in Europe and beyond.

5.3 Therapeutic methodology of MHT

The diagnosis of osteoporosis is now feasible thanks to well-established criteria and advanced technology. The disease can also be effectively addressed using a range of established methods. The IOF, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases, and the European Guidance for Assessment and Treatment of Postmenopausal Osteoporosis (2019) have recently released comprehensive guidelines for categorizing and evaluating individuals at low, high, and very high risk of osteoporotic fractures. Given the diverse pharmaceutical options available, including calcium and vitamin D supplements, bisphosphonates, and anabolic therapy, a risk-based management strategy is crucial. Although the FRAX® algorithm [71] might indicate a reduced risk of fragility fracture over the next decade for postmenopausal women, these women may still face a significantly higher residual lifetime risk (Figure 4). Consequently, MHT might be considered a preventive measure in the initial phase of a broader treatment strategy, especially in situations where a targeted bone therapy, like bisphosphonates, might not be appropriate. The question then arises: should MHT be recommended primarily for the preservation of bone health and fracture prevention, or should the reduction in fracture risk be viewed as a secondary benefit of a medication primarily used to treat menopausal symptoms?

Figure 4 (a and b) An infographic that provides an overview of the classification of fracture risk based on the FRAX major osteoporotic fracture probability in postmenopausal women. The FRAX model is used for the first risk assessment, which only considers clinical risk variables. When the FRAX probability is in the red zone, this indicates a very high risk, and suggests that an initial course of anabolic medication followed by antiresorptive therapy would be warranted. If the FRAX probability is in the green zone, this indicates a low risk, and the patient should be counseled on how to improve their lifestyle, as well as their consumption of calcium and vitamin D, and the therapy of menopausal hormones. If the FRAX probability is in the intermediate (orange) zone, then a BMD examination and recalculation of the FRAX probability should be performed, including taking into account the femoral neck BMD. After recalculation, the risk may fall into the red zone (very high risk), the orange zone (high risk, which indicates starting antiresorptive treatment), or the green zone (low risk, either in the original green zone or in the original orange zone but below the intervention threshold). The red zone represents a very high risk, while the orange zone and green zone both advise initial antiresorptive therapy. Take note that individuals who have had a previous fracture due to fragility are classified as having at least a high risk, and depending on the FRAX likelihood, maybe even a very high risk. (c). Different treatment options are based on the classification of the patient’s risk of fracture. Regarding the various therapeutic approaches (such as bone resorption inhibitors, anabolic medicines, etc.) [71].
Figure 4

(a and b) An infographic that provides an overview of the classification of fracture risk based on the FRAX major osteoporotic fracture probability in postmenopausal women. The FRAX model is used for the first risk assessment, which only considers clinical risk variables. When the FRAX probability is in the red zone, this indicates a very high risk, and suggests that an initial course of anabolic medication followed by antiresorptive therapy would be warranted. If the FRAX probability is in the green zone, this indicates a low risk, and the patient should be counseled on how to improve their lifestyle, as well as their consumption of calcium and vitamin D, and the therapy of menopausal hormones. If the FRAX probability is in the intermediate (orange) zone, then a BMD examination and recalculation of the FRAX probability should be performed, including taking into account the femoral neck BMD. After recalculation, the risk may fall into the red zone (very high risk), the orange zone (high risk, which indicates starting antiresorptive treatment), or the green zone (low risk, either in the original green zone or in the original orange zone but below the intervention threshold). The red zone represents a very high risk, while the orange zone and green zone both advise initial antiresorptive therapy. Take note that individuals who have had a previous fracture due to fragility are classified as having at least a high risk, and depending on the FRAX likelihood, maybe even a very high risk. (c). Different treatment options are based on the classification of the patient’s risk of fracture. Regarding the various therapeutic approaches (such as bone resorption inhibitors, anabolic medicines, etc.) [71].

MHT appears beneficial in preventing fractures in individuals with low BMD, regardless of concurrent progestogen use. However, it remains uncertain if the benefits will persist once the medication is discontinued. Various factors, including age, duration of use, dosage, and administration method, might influence the risks and benefits associated with MHT. The KEEPS trial suggested that the potential cardiovascular benefits of unopposed estrogen, initiated within 10 years postmenopause, outweigh those of opposed estrogen. However, there are potential adverse outcomes, including deep vein thrombosis, stroke, and gallbladder disease. The risk of breast cancer has also been highlighted as a potential side effect of combined MHT in the study conducted by Rozenberg et al. [10].

In assessing the potential risks associated with MHT, both the absolute risks of side effects in the menopausal population and the benefit–risk balance of other osteoporosis treatments must be considered. In the United Kingdom, a 50-year-old woman with no known risk factors for CVD has a 2% probability of developing the disease over the next decade. According to the WHI, women with an intact uterus treated with combined MHT face a 34% increased risk of CHD. However, this increase might not be clinically significant (final absolute risk = 2.68%) [8]. Postmenopausal women with modest cardiovascular risk might benefit from a 5-year course of MHT starting at menopause, but the long-term effects remain uncertain. Besides rare yet severe side effects like osteonecrosis of the jaw and atypical femoral fractures, intravenous administration of bisphosphonates and denosumab can lead to symptomatic hypocalcaemia [2,3,72]. Due to the heightened risk of myocardial infarction, the European Medicines Agency imposed restrictions on strontium ranelate’s license. Though the drug was voluntarily withdrawn from the market, it has since returned as a generic. Conversely, romosozumab has been associated with an increased risk of cardiovascular adverse events. Exposure to strontium ranelate has been demonstrated to elevate the risk of DVT [23,72].

More broadly, the challenges and risks of improperly administering oral bisphosphonates should be considered. Therefore, a comprehensive evaluation of MHT’s pros and cons is essential. MHT can mitigate the risk of bone loss and fractures and is also effective in alleviating menopausal symptoms. While the benefit–risk ratio of using MHT primarily for fracture prevention is less established, further exploration of MHT within the framework of a long-term osteoporosis treatment strategy is warranted. Nonetheless, MHT should be viewed as a first-line treatment for women who have recently entered menopause, especially if the primary therapeutic goal is preserving skeletal health and they have a low risk of CVD, thromboembolic disease, and breast cancer. This article does not delve into the clinical assessment of menopausal symptoms or the specific management of these symptoms, including potential risks. All the international and national entities whose recommendations we have referenced provide comprehensive guidance on managing menopause.

6 Limitation of MHT

MHT, while beneficial for many individuals, comes with several limitations. First, it is associated with an increased risk of serious health issues, including breast cancer, dementia, stroke, and CVD, particularly with prolonged use [73–83]. This necessitates careful consideration and ongoing monitoring during the treatment process. Second, MHT might not be suitable for all individuals; those with a history of certain types of cancers, blood clots, or liver disease are generally advised against it. Moreover, it can cause side effects such as nausea, headaches, and vaginal bleeding, which can significantly affect the quality of life. The therapeutic regimen of MHT can be complex and may require trial and error to find the most suitable hormone combination and dosage for an individual, which can be time-consuming and potentially frustrating. Furthermore, the beneficial effects of MHT often reverse once the therapy is halted, which can lead to the recurrence of menopausal symptoms. Lastly, there is also the challenge of adherence to therapy (Collaborative Group on Hormonal Factors in Breast Cancer, 2019). The necessity for continuous use and potential side effects can discourage individuals from sticking to the therapy in the long run. It is essential to have a thorough discussion with healthcare providers to understand the potential risks and benefits fully, and to ensure informed decision-making regarding the therapy [75] (Collaborative Group on Hormonal Factors in Breast Cancer, 2019). This underscores the necessity for individualized treatment approaches and the active involvement of patients in managing their health choices.

7 Conclusion

Research on MHT is complex, as observational studies and randomized trials have yielded inconsistent results. While subsequent studies have largely exonerated MHT, lingering controversy after the initial WHI findings resulted in a sharp decline in its usage. Postmenopausal women under 60 looking to protect their bone health might opt to initiate MHT around the onset of menopause or shortly thereafter, rather than waiting until they need specific bone-active medications. This decision is informed by MHT’s proven efficacy in alleviating menopausal symptoms. In making this choice, it is crucial to weigh not just the risk of breast cancer but also the potential for CVD, stroke, pulmonary embolism, and bone fracture. This evaluation should encompass the entirety of the patient’s menopausal experience and include a comprehensive discussion of benefits and risks. The outcome of hysterectomy can be influenced by various factors, such as the type, dosage, and administration method of estrogen and progestogen, and the potential presence of estrogen resistance. It is paramount to employ treatments proven to reduce fracture risk and to tailor therapies according to each patient’s unique benefit–risk profile, aiming to prevent fractures and maintain bone integrity. Our research indicates that postmenopausal women with a low risk of CVD and breast cancer may derive the most benefit from MHT for treating menopausal symptoms, with the added advantages of ensuring bone protection and reducing fracture risk.

# Zhao Na and Wei Wei contributed equally to the article.

  1. Funding information: Authors state no funding involved.

  2. Author contributions: Zhao Na and Wei Wei equally contributed for the literature collection and preparation of the manuscript. Yingfang Xu, Dong Li, and Beili Yin were involved in the manuscript preparation and validation. Weiqun Gu involved in designing the work, preparation, validation, and revision of the manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2023-06-14
Revised: 2023-09-08
Accepted: 2023-10-02
Published Online: 2023-12-12

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0759
Keywords for this article
osteoporosis; menopausal hormone therapy; bone health; postmenopause
Creative Commons
BY 4.0

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  3. Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis
  4. Identifying two pathogenic variants in a patient with pigmented paravenous retinochoroidal atrophy
  5. Effects of phytoestrogens combined with cold stress on sperm parameters and testicular proteomics in rats
  6. A case of pulmonary embolism with bad warfarin anticoagulant effects caused by E. coli infection
  7. Neutrophilia with subclinical Cushing’s disease: A case report and literature review
  8. Isoimperatorin alleviates lipopolysaccharide-induced periodontitis by downregulating ERK1/2 and NF-κB pathways
  9. Immunoregulation of synovial macrophages for the treatment of osteoarthritis
  10. Novel CPLANE1 c.8948dupT (p.P2984Tfs*7) variant in a child patient with Joubert syndrome
  11. Antiphospholipid antibodies and the risk of thrombosis in myeloproliferative neoplasms
  12. Immunological responses of septic rats to combination therapy with thymosin α1 and vitamin C
  13. High glucose and high lipid induced mitochondrial dysfunction in JEG-3 cells through oxidative stress
  14. Pharmacological inhibition of the ubiquitin-specific protease 8 effectively suppresses glioblastoma cell growth
  15. Levocarnitine regulates the growth of angiotensin II-induced myocardial fibrosis cells via TIMP-1
  16. Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study
  17. Single-cell transcription analysis reveals the tumor origin and heterogeneity of human bilateral renal clear cell carcinoma
  18. Identification of iron metabolism-related genes as diagnostic signatures in sepsis by blood transcriptomic analysis
  19. Long noncoding RNA ACART knockdown decreases 3T3-L1 preadipocyte proliferation and differentiation
  20. Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report
  21. Dosimetry comparison with helical tomotherapy, volumetric modulated arc therapy, and intensity-modulated radiotherapy for grade II gliomas: A single‑institution case series
  22. Soy isoflavone reduces LPS-induced acute lung injury via increasing aquaporin 1 and aquaporin 5 in rats
  23. Refractory hypokalemia with sexual dysplasia and infertility caused by 17α-hydroxylase deficiency and triple X syndrome: A case report
  24. Meta-analysis of cancer risk among end stage renal disease undergoing maintenance dialysis
  25. 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress
  26. Experimental study on the optimization of ANM33 release in foam cells
  27. Primary retroperitoneal angiosarcoma: A case report
  28. Metabolomic analysis-identified 2-hydroxybutyric acid might be a key metabolite of severe preeclampsia
  29. Malignant pleural effusion diagnosis and therapy
  30. Effect of spaceflight on the phenotype and proteome of Escherichia coli
  31. Comparison of immunotherapy combined with stereotactic radiotherapy and targeted therapy for patients with brain metastases: A systemic review and meta-analysis
  32. Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation
  33. Association between the VEGFR-2 -604T/C polymorphism (rs2071559) and type 2 diabetic retinopathy
  34. The role of IL-31 and IL-34 in the diagnosis and treatment of chronic periodontitis
  35. Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features
  36. mNGS facilitates the accurate diagnosis and antibiotic treatment of suspicious critical CNS infection in real practice: A retrospective study
  37. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC
  38. Radiotherapy for primary thyroid adenoid cystic carcinoma
  39. Design and functional preliminary investigation of recombinant antigen EgG1Y162–EgG1Y162 against Echinococcus granulosus
  40. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial
  41. Bibliometric analysis of METTL3: Current perspectives, highlights, and trending topics
  42. Performance comparison of three scaling algorithms in NMR-based metabolomics analysis
  43. PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer
  44. The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy
  45. Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor
  46. Prostatitis as initial manifestation of Chlamydia psittaci pneumonia diagnosed by metagenome next-generation sequencing: A case report
  47. NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2
  48. Association of interleukin-10 rs1800896, rs1800872, and interleukin-6 rs1800795 polymorphisms with squamous cell carcinoma risk: A meta-analysis
  49. Exosomal HBV-DNA for diagnosis and treatment monitoring of chronic hepatitis B
  50. Shear stress leads to the dysfunction of endothelial cells through the Cav-1-mediated KLF2/eNOS/ERK signaling pathway under physiological conditions
  51. Interaction between the PI3K/AKT pathway and mitochondrial autophagy in macrophages and the leukocyte count in rats with LPS-induced pulmonary infection
  52. Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves’ disease in children
  53. Cloning, subcellular localization and expression of phosphate transporter gene HvPT6 of hulless barley
  54. Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome
  55. Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis
  56. Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation
  57. Gemella morbillorum infective endocarditis: A case report and literature review
  58. An unusual ectopic thymoma clonal evolution analysis: A case report
  59. Severe cumulative skin toxicity during toripalimab combined with vemurafenib following toripalimab alone
  60. Detection of V. vulnificus septic shock with ARDS using mNGS
  61. Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
  62. The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology
  63. Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review
  64. ctDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis
  65. Diagnosis of primary amoebic meningoencephalitis by metagenomic next-generation sequencing: A case report
  66. Phylogenetic analysis of promoter regions of human Dolichol kinase (DOLK) and orthologous genes using bioinformatics tools
  67. Collagen changes in rabbit conjunctiva after conjunctival crosslinking
  68. Effects of NM23 transfection of human gastric carcinoma cells in mice
  69. Oral nifedipine and phytosterol, intravenous nicardipine, and oral nifedipine only: Three-arm, retrospective, cohort study for management of severe preeclampsia
  70. Case report of hepatic retiform hemangioendothelioma: A rare tumor treated with ultrasound-guided microwave ablation
  71. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling
  72. Rare presentation of double-clonal Waldenström macroglobulinemia with pulmonary embolism: A case report
  73. Giant duplication of the transverse colon in an adult: A case report and literature review
  74. Ectopic thyroid tissue in the breast: A case report
  75. SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer
  76. Vaginal metastasis from breast cancer: A case report
  77. Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine
  78. Inhibition of TAZ impairs the migration ability of melanoma cells
  79. Molecular complexity analysis of the diagnosis of Gitelman syndrome in China
  80. Effects of maternal calcium and protein intake on the development and bone metabolism of offspring mice
  81. Identification of winter wheat pests and diseases based on improved convolutional neural network
  82. Ultra-multiplex PCR technique to guide treatment of Aspergillus-infected aortic valve prostheses
  83. Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2
  84. Immune checkpoint inhibitors in cancer patients with COVID-19
  85. Utility of methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses
  86. Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma
  87. Berberine suppressed sarcopenia insulin resistance through SIRT1-mediated mitophagy
  88. DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway
  89. Lung abscess by Fusobacterium nucleatum and Streptococcus spp. co-infection by mNGS: A case series
  90. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis
  91. Granulomatous polyangiitis involving the fourth ventricle: Report of a rare case and a literature review
  92. Studying infant mortality: A demographic analysis based on data mining models
  93. Metaplastic breast carcinoma with osseous differentiation: A report of a rare case and literature review
  94. Protein Z modulates the metastasis of lung adenocarcinoma cells
  95. Inhibition of pyroptosis and apoptosis by capsaicin protects against LPS-induced acute kidney injury through TRPV1/UCP2 axis in vitro
  96. TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats
  97. Primary mediastinum Ewing’s sarcoma with pleural effusion: A case report and literature review
  98. Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents
  99. Tanshinone IIA alleviates chondrocyte apoptosis and extracellular matrix degeneration by inhibiting ferroptosis
  100. Study on the cytokines related to SARS-Cov-2 in testicular cells and the interaction network between cells based on scRNA-seq data
  101. Effect of periostin on bone metabolic and autophagy factors during tooth eruption in mice
  102. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy
  103. Intravaginal estrogen management in postmenopausal patients with vaginal squamous intraepithelial lesions along with CO2 laser ablation: A retrospective study
  104. Hepatocellular carcinoma cell differentiation trajectory predicts immunotherapy, potential therapeutic drugs, and prognosis of patients
  105. Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials
  106. Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer
  107. Development of an instrument-free and low-cost ELISA dot-blot test to detect antibodies against SARS-CoV-2
  108. Research progress on gas signal molecular therapy for Parkinson’s disease
  109. Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway
  110. The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma
  111. α-Fetoprotein contributes to the malignant biological properties of AFP-producing gastric cancer
  112. CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa
  113. Association between thyroid stimulating hormone levels and papillary thyroid cancer risk: A meta-analysis
  114. Significance of sTREM-1 and sST2 combined diagnosis for sepsis detection and prognosis prediction
  115. Diagnostic value of serum neuroactive substances in the acute exacerbation of chronic obstructive pulmonary disease complicated with depression
  116. Research progress of AMP-activated protein kinase and cardiac aging
  117. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5
  118. Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target
  119. Metastasis from small cell lung cancer to ovary: A case report
  120. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury
  121. The effect of NK cell therapy on sepsis secondary to lung cancer: A case report
  122. Erianin alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation
  123. Loss of ACOX1 in clear cell renal cell carcinoma and its correlation with clinical features
  124. Signalling pathways in the osteogenic differentiation of periodontal ligament stem cells
  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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