Metabolic syndrome (MetS) is a group of risk factors that causes cardiovascular and diabetic morbidity and mortality, which is diagnosed by central obesity, dyslipidemia, hyperglycemia, and hypertension. Increasing epidemiological data and experimental results indicate that the presence of MetS increases the incidence of common malignancies and related mortality. Epidemiological studies have previously reported an association of endometrial cancer occurrence with MetS. Aromatization of androstenedione to estrogen, insulin resistance, and diabetes can cause increased levels of free estrogen, and the detrimental effect of elevated estrogen as a carcinogen is well studied in endometrial cancer. Medications used to manage MetS such as metformin and statins are suggested to reduce endometrial cancer risk and improve survival. Some large population-based epidemiological studies have suggested that the MetS is related to an increased risk of cervical carcinoma. MetS may contribute to viral-host interactions, which lead to persistent human papilloma virus (HPV) infection, although limited epidemiological data are available. Specific effects of obesity and diabetes on the occurrence of ovarian cancer have been suggested. However, the direct correlation between MetS and ovarian cancer is still lacking. Previous retrospective studies reported that the use of metformin, statins, and beta-blockers could be associated with cancer prevention or better prognosis. Proper diagnosis and management of the MetS should be a part of the strategies undertaken to prevent and treat gynecologic cancer. So far, only limited data is available on this subject, and further clinical and fundamental research is required to further clarify the effect of these therapies on gynecologic cancer treatment.
Incidence of metabolic syndrome (MetS) is increasing worldwide and is becoming an important clinical problem and public health concern in many countries. Economic development, sedentary lifestyle, and westernized dietary patterns are factors affecting the prevalence of MetS. This environment contributes to obesity as seen in many developing and developed countries. MetS is a group of risk factors for cardiovascular complications and diabetes having insulin resistance as the major principal feature. In addition, chronic proinflammatory status is the accompanying underlying characteristic [
There is increasing epidemiological evidence suggesting that MetS elevates the risk of several common cancer types and cancer-related morbidity and mortality [
In addition to well-established breast cancer, the relationship between various gynecologic cancers and MetS has also been identified. Most of the preceding reports were related to endometrial cancer, but recent studies suggest that cervical and ovarian cancers are also associated with MetS. The purpose of this review is to present current perspectives on the epidemiological relationship between MetS and gynecologic cancer. We will also review whether specific mechanisms that distinguish them from other types of cancer affect the development of gynecologic cancer. In addition, we will explore the effects of MetS on the morbidity and mortality of this cancer.
The pathophysiological mechanisms through which obesity, dyslipidemia, and hyperglycemia contribute to carcinogenesis are clearer than the mechanism correlating hypertension to carcinogenesis. The effects of these components on the development of cancer, especially on the gynecologic cancer are briefly described in the following paragraphs.
Central obesity, defined by increased waist circumference or increased body mass index (BMI), has been related to a higher incidence of many kinds of malignancies as well as to higher morbidity and mortality in those cancers [
In addition to energy storage, the adipose tissue functions as an endocrine organ that regulates the hormones and cytokines such as sex steroids, leptin, adipokines, tumor necrosis factor (TNF)-alpha, and plasminogen activator inhibitor-1 [
An association between obesity and increased cancer incidence has been reported for female-specific cancers including ovarian, endometrial, and breast cancer. For example, a recent prospective cohort study involving 1.2 million UK women showed that higher BMI was associated with an increased incidence of endometrial cancer (relative risk [RR] per 10 units, 2.89, 95% confidence interval [CI], 2.62–3.18), ovarian cancer (RR, 1.14; 95% CI, 1.03–1.27), and breast cancer in postmenopausal women (RR, 1.40; 95% CI, 1.31–1.49) [
The mechanism by which adiposity contributes to the development of these cancers in women can be deduced as follows: in postmenopausal women, adipose tissue becomes the major organ synthesizing estrogens [
Increased adiposity in cancer patients may also have detrimental effects on treatment outcomes and mortality. For example, obesity has been reported to be a negative prognostic factor for breast cancer [
Insulin resistance is considered as the most important mechanism involved in the relationship between obesity, hyperglycemia, and carcinogenesis. Chronic hyperinsulinemia is reported to be correlated with various types of cancer including endometrial and breast cancer [
Hyperinsulinemia caused by insulin resistance and subsequent hyperglycemia triggers carcinogenesis indirectly by increasing circulating levels of free insulin-like growth factor (IGF)-1. Receptors for insulin and IGF-1 are observed in most types of cancer tissues. The insulin receptor can activate signaling pathways that stimulate cancer cell proliferation, protect cancer cells from apoptotic stimulation, and promote invasion and metastasis of cancer cells. These receptors also stimulate normal cells including vascular smooth muscle cells to proliferate and migrate, and these process can promote cancer progression [
Along with this process, impaired glucose management and hyperglycemia can promote cancer cell proliferation. This theory is supported by the increased glucose transporting proteins such as glucose transporter-1 (GLUT-1) in the cancer cells to support high glucose demands for cancer growth [
High levels of glucose promote cancer cell invasion and metastasis through stimulation of epithelial-mesenchymal transition (EMT) which acts as a crucial pathway for the acquisition of migration, invasion, and pluripotent stem cell-like phenotype [
Elevated triglyceride and suppressed HDL-cholesterol also act as risk factors for cancer. The mechanism by which hypertriglyceridemia stimulates cancer cell proliferation and promotes anti-apoptotic capacity is through the activation of ROS synthesis and DNA damage caused by this detrimental stress [
Epidemiological evidence supports the association of decreased HDL-cholesterol with certain types of cancer development. One large-scale population-based epidemiological study reported the correlation of cervical carcinoma with a low serum HDL-cholesterol level [
Epidemiologic studies have reported correlations of endometrial cancer risk with each component of the MetS, including obesity, diabetes, and hypertension. Recently, Esposito et al. [
Trabert et al. [
In addition, the effects of MetS components on the treatment of endometrial cancer were investigated, and Ko et al. [
Aromatization from androstenedione to estrogen is processed in adipose cells, and elevated free estrogen with decreased serum levels of SHBG are accompanied by obesity [
Several epidemiologic studies have suggested that medications generally prescribed to patients with MetS have a positive effect on outcomes in endometrial cancer patients besides the hypoglycemic effect [
Statins are prescribed to decrease cholesterol levels in dyslipidemia patients to manage and prevent cardiovascular diseases. These agents inhibit the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase and blocks protein prenylation through the suppression of the mevalonate pathway. These result in the suppression of the downstream cholesterol biosynthesis pathway and inhibited production of many types of isoprenoid metabolites including farnesyl pyrophosphate and geranyl pyrophosphate. Isoprenoid biosynthesis is essential for a variety of cancer cell growth-related cellular processes and for the initiation of cancer cell metastasis. As a result, statins block these pathways which contribute to the anti-cancer activity [
Cervical cancer is the second most common malignancy among women all over the world with a majority of the cases observed in the developing countries. Previous epidemiological studies have shown correlations between different types of metabolic syndrome components and the incidence of cervical cancer [
Penaranda et al. [
According to these results, women with MetS would have an increased risk of experiencing cervical cancer compared to women without MetS. In the pathophysiological aspect, estrogen, adipokine, and cytokine have been reported to be correlated with cervical cancer suggesting metabolic syndrome components could act as cofactors in the carcinogenesis of cervical carcinoma [
Previous epidemiologic studies suggested that MetS may play a role in virus and host interactions which is essential for persistent human papilloma virus (HPV) infection. This interaction is a fundamental factor in the development of cervical cancer. The causal correlation between infection with the HPV and the progress of cervical cancer has been established through decades of accumulated evidence.
Recent studies explored the influence of MetS on HPV infection among women. Huang et al., reported that the morbidity of MetS increased the risk of HPV infection in females (RR, 1.25; 95% CI, 1.09–1.46) [
There are some pathophysiological evidence indicating that MetS components could promote carcinogenesis. An increase of adipokines (e.g., resistin), inflammatory markers (e.g., soluble Fas), and cytokines (e.g. interleukin [IL]-6, TNF-α) has been observed in women with persistent HPV infection [
To investigate the effect of MetS on prognosis of cervical cancer after treatment, Ahn et al. [
Compared to other gynecologic cancers, there are relatively few studies that have directly analyzed the correlation between MetS and incidence of ovarian cancer. Although, there are some reports that analyzed the correlation between specific components of MetS and ovarian cancer.
Obesity has been reported to be correlated with the occurrence of ovarian cancer. The Collaborative Group on Epidemiological Studies of Ovarian Cancer performed a meta-analysis of 47 studies including 25,157 cases of ovarian cancer and reported a 10% increase in ovarian cancer risk per 5 kg/m2 [
Moreover, there are studies proposing that obesity may also be correlated with decreased overall survival in ovarian cancer patients. The meta-analysis of 14 studies analyzed by Protani et al. [
There is relatively little information analyzing the effects of diabetes on ovarian cancer incidence and prognosis. Shah et al. [
As described, the respective effects of obesity and diabetes on ovarian cancer risk have been analyzed, and it could be expected that MetS would increase the incidence of ovarian cancer. Although, there is still insufficient evidence on the effects of MetS on ovarian cancer risk and whether it is more obvious than the individual effects of obesity and diabetes. The process of revealing this relationship through population-based analysis is required for the future.
The etiological association between obesity, diabetes, and ovarian cancer is not clear, however, the available data provide some clues. According to a previous study, direct interactions between adipocytes and cancer cells have been suggested to stimulate tumor growth. For example, omental tissue is the most common site of ovarian cancer metastasis and secretion of cytokines such as IL-6 and IL-8 produced by adipocytes in the omentum has been reported to promote homing, migration, and invasion of ovarian cancer cells [
As described above, insulin resistance is associated with decreased serum SHBG and elevated free estrogen. A recent experimental study on the murine model suggested that elevated estrogen may play a role in promoting ovarian cancer growth [
Preceding retrospective studies reported that the use of metformin, statins, and beta-blockers is correlated with better prognosis in ovarian cancer treatment.
A meta-analysis of existing observational studies reported that metformin may decrease the incidence of ovarian cancer in diabetic patients with an odds ratio of 0.57 (95% CI, 0.16–1.99) [
As discussed in endometrial cancer, statins block the pathways related to carcinogenesis and may contribute to the anticancer activity. Lavie et al. [
Stress hormones may stimulate ovarian cancer progression through multiple mechanisms including autonomic nervous system mediators such as epinephrine and norepinephrine [
Preceding epidemiological data have reported a correlation between MetS or its diagnostic components and gynecologic cancer development and prognosis. Each component of MetS and associated metabolic disarrangements are proved to have a correlation with cancer development through experimental studies. However, it is still being debated whether the effects of each component are additive or synergistic. In this situation, further epidemiological and experimental studies are essential to clarify these findings.
Several clinical studies postulated that medications used to manage MetS have a preventive effect on cancer development. In addition, some clinical and experimental studies suggested the favorable effect of these medications on the prognosis, morbidity, and mortality of cancer treatment.
In view of these existing findings, addressing and managing MetS should be a part of the strategies undertaken to prevent and treat gynecologic cancer. So far, only limited data is available, and further clinical and fundamental research is required for robust conclusions.
The research was supported by fund from Korean Society of Obstetrics and Gynecology and grant number (03-2019-20) in Seoul Metropolitan Government-Seoul National University Boramae Medical Center.