In women older than 55 with a high probability of postmenopause, we discovered that subjects with lower FSH had lower HDL-C, higher TG, TC/HDL-C ratio and LDL-C/HDL-C ratio. Metabolic factors including diabetes, BMI and hypertension mostly explained the association of FSH with TG and LDL-C/HDL-C ratio but only partially explained the associations of FSH with HDL-C and TC/HDL-C ratio. As far as we know, this is the first study to detect the association between FSH and lipid profile in detail in a large population sample.
Dyslipidemia is a well-known independent risk factor for CVD and cerebral ischemic stroke.24 With rapid socioeconomic development, urbanization, and lifestyle and diet changes, the prevalence of dyslipidemia has also been rapidly increasing.25 Dyslipidemia is closely related to other metabolic comorbidities such as diabetes, obesity and fatty liver. For example, the features of diabetic dyslipidemia are elevated TG concentration, reduced HDL-C concentration, and increased LDL-C concentration.26 NAFLD is also characterized by atherogenic dyslipidemia and HDL dysfunction.27 According to recent studies, FSH was found to be significantly associated with metabolic diseases.13–15, 28 Our previous studies showed, compared with postmenopausal women in the highest quartile of FSH, the odds of diabetes and non-alcoholic fatty liver disease in postmenopausal women in the lowest quartile of FSH increased 96% and 84–194%, respectively.14,15 In this study, we further demonstrated lower FSH was significantly associated with lower HDL-C, and higher TG, TC/HDL-C ratio and LDL-C/HDL-C ratio after adjusting for age, total T, E2 and LH. These results accord with recent studies about the association of FSH with metabolic syndrome.28,29 The above information lends credibility to the findings on FSH and lipid profile.
FSH is mainly secreted by the pituitary gland and it regulates development and function of reproductive organ after being released into the blood, therefore it is not surprising that FSH receptor (FSHR) is mainly expressed in the reproductive system.30 However, FSHR has also been found to be expressed in non-reproductive organs and tissues such as mouse osteoclasts,31 human blood vessel,32 chicken adipose tissue33 and human liver,13 exerting extra-reproduction function. Interestingly, a recent study showed FSH interacted with FSHR in hepatocytes and reduced LDL receptors levels, which subsequently attenuated the endocytosis of LDL-C in mouse model. This might lead to an elevated circulating LDL-C level in postmenopausal women with a mean age of 48.6 years.13 In chicken and mouse model, studies also found FSH promoted lipid biosynthesis in adipose tissue and visceral fat accumulation through upregulating FSHR mRNA expression and the Gai/Ca2+/cAMP-response-element-binding protein pathway.33,34 These results seem to be contradictory to previous epidemiological studies. A negative correlation between FSH concentration and BMI was observed.22,35−37 Also, every 1 standard deviation decrement of FSH is associated with a 3.83-fold increased risk of metabolic syndrome, in which adiposity is the core element.28 Moreover, in observational cohort studies, in obese women the rise of FSH was significantly attenuated, especially after the final menstrual period., and weight loss would increase FSH among overweight and obese postmenopausal women.38 In regard of opposite study results, here is one explanation: FSH may induce fat accumulation and lipid biosynthesis in early stage of postmenopause, but the development of metabolic diseases especially obesity would conversely suppress the release of FSH and LH. This hypothesis needs further investigations to confirm.
It is not surprising that common metabolic factors including diabetes, BMI and hypertension largely mediated the association between FSH and lipid profile. Other endogenous sex hormones may also have a role in this association. For example, total testosterone may induce rise of TC, LDL-C or TG, and fall of HDL-C,10,39 though some studies found no such effect.11,40 Estrogen hormone replacement therapy usually ameliorated lipid profile.41,42 However, it is worth mentioning that in our study, even after adjustment for total T, E2 and LH, FSH was still significantly associated with some elements of lipid profile. Also, considering the independent association of FSH and HDL-C, some internal relationship might exist which needs further exploration.
Our study had some strengths. First, the novelty, it presented in detail the association between FSH and lipid profile for the first time in a large sample, and focus on several possible explanatory factors. Second, the study was performed in a general population as opposed to a clinic-based population. However, our study also has some limitations. Because the nature of this study is cross-sectional, causal relationship could not be confirmed. Moreover, final menstruation information was not obtained, so based on previous studies18,19 and natural menopause age in Chinese women,20 we used an age proxy 55 years to define postmenopause.
In conclusion, lower FSH was associated with lower HDL-C, higher TG, TC/HDL-C ratio and LDL-C/HDL-C ratio in women older than 55 with a high probability of postmenopause. Diabetes, BMI and hypertension mostly explained the association of FSH with TG and LDL-C/HDL-C ratio but only partially explained the associations of FSH with HDL-C and TC/HDL-C ratio. Further prospective trials and animal studies are needed to clarify this association.