Follicle-Stimulating Hormone Attenuate Hepatic Low Density Protein Metabolism In Postmenopausal Women

Healthy women typically spend one third of their lives in a menopausal state. Menopause is defined as permanent cessation of ovarian function with huge endocrine changes, estrogen decrease and FSH rises sharply and persistently with menopausal state. Menopause-associated lipid change is a common healthy problem in postmenopausal women, and gives various worse influences on subsequent health and quality of life.Compare with premenopausal women, deterioration in the lipid profile is usually showed in post-menopause:total cholesterol (TC). total triglycerides (TG) and low-density lipoprotein (LDL) cholesterol levels increase, whereas high-density lipoprotein (HDL) cholesterol levels decrease. Elevated concentrations of LDL are a well established risk factor for atherosclerosis, and cholesterol found in atherosclerotic lesions is predominantly derived from LDL. In general, the menopause-associated lipid changes, especially LDL increasing, are recognized as independent factors contributing to the increasing risk of cardiovascular events in the postmenopausal years.The exact mechanism of menopause-associated lipid changes remains obscure. Studies before usually suggest that the increased incidence of lipid changes and CVD in women may be due to estrogen deficiency associated with menopause, and doctors use hormone replacement therapy (HRT) to relieve the menopause symptom, decelerate lipid changes and prevent CVD. But the role of HRT for the preventation of CVD was questioned as a result of the initial publication of the results of the randomized, double-blind, placebo-controlled Women’s Health Initiative (WHI) study in2002. Concerns were raised about the increased risk of the CVD and breast cancer associated with the use of combined therapy with conjugated equine estrogens. Although European Menopause And Andropause Society (EMAS) statements WHI trials are not substantiated, international menopause society statements not recommend to use HRT only for prevent CVD. All these results might give a suggestion that estrogen deficiency might not the only direct or important factor induce the menopause-associated lipid change.Follicle-stimulating hormone (FSH), regarded as restricted to the gonads, rise in parallel during markable endocrine transition, but were never explored.2006Sun et al. reported that FSH directly regulate the bone mass on CELL, which suggests the FSH might have functions of other organs outside gland. From that on, more and more studies are carried on the novel insights of FSH/FSH receptor in physiopathologic progress in menopause women.Meanwhile, Chu et al. investigated relationship between the basal FSH level and an established major risk and fasting lipoprotein profiles on pre-menopausal women with normal menstrual cycles. Results showed that premenopausal women with an FSH level>=7IU/1had significantly elevated TC and LDL compare with those with FSH<7IU/1. It is suggested that decreased functional ovarian reserve with FSH increasing, prior to estrogen deficiency, correlated with known CVD risk. This study focus on the function of high level FSH in postmenopausal lipid changes, and this is interesting question.This study investigates the relationship between high level FSH and postmenopausal lipid profiles. Furthermore, our study provides the first evidence that FSHR is characterized in human hepatocyte. We showed that FSH attenuate hepatic LDL by inhibiting the LDL receptor expression by animal and cell models. FSHR might regulate lipid metabolism under circumstances with abnormally high FSH in menopause. We anticipate that therapeutic inhibition of FSH level or hepatic FSHR activity in post-menopausal women will reduce menopause-associated lipid changes. Part Ⅰ: The role of follicle Stimulating Hormone in menopausal lipid profileObjectives:To investigate the relationship between follicle stimulating hormone (FSH) and postmenopausal lipid profiles. Furthermore, FSH decreasing, as receiving hormone replacement therapy (HRT), associate with the improving lipid frofiles.Materials and Methods:we obtained FSH,E2and lipid profiles on381postmenopausal women, who were not using hormonal medications or statins, with amenorrhea for at least1year and consented to participation in the study. Furthermore,124postmenopausal women with LDL>2.5mmol/L, age>40y receive the hormone replacement therapy (HRT). After6cycles, we assessed the correlation between amount of FSH decreasing and amout of lipid profiles improving.Results:1. It is showed that the LDL level increasing accompany with FSH rising;2. Meanwhile, as well as LDL elevating. FSH also showed increasing pattern;3. FSH decreased and lipid profiles improved after the postmenopausal women receiving the HRT. Especially important, as FSH decreasing more than40IU/L, the LDL decrease more significantly.Conclusions:The high level FSH after menopause participated in menopause-associated lipid change. It can be anticipated that therapeutic inhibition of FSH level might decrease the LDL level to protect cardiovascular. Meanwhile, FSH level is an good predicator for HRT effect. Part Ⅱ The role of FSH on LDL metabolism in hepatic tissue and cellObjectives:To examine the possible presence of follicle stimulating hormone receptor (FSHR) in hepatic tissue/cell. Meanwhile, we investigate the possible mechanism of FSH-FSHR signal in LDL metabolism in hepatic tissue/cell.Materials and Methods:It was assessed for the presence of FSHR of human/mouse hepatic tissue and hepatic cell line HepG2by western blot, RT-PCR and immunohistochemistry.8-week old C57BL/6mice were used to mimic the high serum FSH level in aging through ovariectomising (OVX), and castrated mice were treated with GnRH agonist to inhibit pituitary gonadotropin secretion (OVX+GnRHa), also we administered recombinant FSH together with the GnRHa to ovariectomy mice (OVX+GnRHa+FSH) to investigate the pure effect of FSH, the SHAM group as blank. The analysis of endocrine/serum lipid/hepatic lipid metabolism genes indicated high FSH levels affect lipid metabolism in animal models. Furthermore, the hepatic cell line HepG2were cultured in the presence of FSH (0-100IU/L) and different time of FSH (100IU/L) to explore the exact direct mechanism of LDL metabolism. The gene expression of LDLR was analyzed by realtime RT-PCR and WB. Finally, the effect of FSH were knocked down by si-RNA FSHR.Results:Lit was clearly demonstrated that the presence of FSHR in human/mouse hepatic tissue and cell line HepG;2. FSHR was primarily located on the membrane of hepatocyte;3. Ovariectomy/GnRHa+FSH treatment showed a higher level LDL than control/GnRHa animal group (p<0.05);4. The expression of LDLR was significantly lower in OVX/GnRHa+FSH animal group hepatic tissue versus control/GnRHa group;5. FSH suppressed LDLR expression dose-dependently and time-dependently;6. FSH inhibited the LDLR expression by FSHR.Conclusions:For the first time, FSHR was characterized in hepatic tissue/cell, FSHR was found to be localized on the membrane of hepatocyte. FSH might affect the LDL metabolism by inhibiting the LDLR through FSHR.