Elevated Follicle-stimulating Hormone Induces Postmenopausal Vascular Dysfunction By Promoting Adrenal Catecholamine Synthesis

Part Ⅰ Correlation between FSH and catecholamine in the serum of postmenopausal women.Objective:To investigate the correlation between FSH and catecholamine in the serum of postmenopausal women.Materials and methods:To collect the data of women who came to Women Hospital, School of Medicine, Zhejiang University for physical examination, who had no basic diseases such as diabetes or cardiovascular diseases and taken hormone-like medicine. Their data included physique data, sex hormone, Blood lipid level, blood pressure, serum catecholamine. According to the latest women aging STRAW+10, we collected the data of three groups such as Stage+1a+1b, Stage+1c and Stage-4,-3b and analyzed their relationships between them ultimately to find the reason for increasing blood pressure in post-menopause. The specific methods as followed:reverse high performance liquid chromatography-electrochemical detector was used to detect the concentration of serum catecholamine. Immunological methods were used to detect the concentration of serum sex hormones. The blood lipid levels and height, weight, waist-hip ratio, blood pressure and heart rate were from the Laboratory Medicine from Women Hospital. The data was analyzed by SPSS19.0.It is statistically significant when P is less than0.05.Results:1. The concentration of serum catecholamine are elevated in post menopause, which are associated with serum follicle-Stimulating Hormone (FSH) and estrogen, especially with FSH elevation.2. The elevation of serum catecholamine is the most obvious during times of sex hormones volatility-Stage+la+lb, Simultaneously the elevation of blood pressure is the highest.3. The concentration of serum catecholamine is mildly associated with the concentration of serum FSH.Conclusions:Postmenopausal hypertension is due to the elevation of serum catecholamine, especially norepinephrine. The elevation of serum catecholamine is associated with estrogen loss and FSH elevation, especially the later. Part Ⅱ Corelation of follicle stimulating hormone (FSH),catecholamine and blood pressure (BP) in SD female ratsObjective:Using animal models to investigate the correlation between FSH and NE, EPI and BP.Materials and methods:Four animal models (ovariectomized, adrenalectomized, ovariectomized and adrenalectomized, and gonadotropin-releasing hormone agonist injected and ovariectomized models) were used. We designed four animal models. The first one is separated into the sham groups(S1) and bilateral ovariectomized groups; the second one included the sham groups (S2) and bilateral adrenalectomized groups implanted into physical concentration of corticosterone and aldosterone osmotic pumps; the third one is the sham groups (S3) and bilateral ovariectomized and adrenalectomized groups implanted into physical concentration of corticosterone and aldosterone osmotic pumps; the fourth group is the sham groups (S4) and bilateral ovariectomized groups injected into gonadotropin-releasing hormone agonist. Human recombinant follicle-stimulating hormone and/or estrogen were successively injected in different groups to evaluate the effect of FSH and estrogen. The blood pressure, sex hormone and serum catecholamine of All Sprague Dawley (SD) rats were measured in14days after the operation and injection. In5months after operation and injection, the mesenteric tension experiment was done for investigating the changes the systolic function of small mesenteric artery.Results:1. The postmenopausal hypertension model of SD rats models is successful. Postmenopausal hypertension of rats is relied on the existence of bilateral adrenals.2. Postmenopausal hypertension of SD rats was jointly caused by estrogen loss and follicle-stimulating hormone elevation. After bilateral ovariectomy, even estrogen is enough supplied, postmenopausal hypertension can not be completely rectified, which showed that elevated FSH is involved into regulating blood pressure in addition of estrogen loss.3. The variation tendency of FSH in SD rats was consistent with the tendency of norepinephrine and epinephrine, which showed the association of FSH and norepinephrine/epinephrine existed. In other words, when serum FSH elevated, the levels of norepinehprine/epinephrine increased, vice versa.4. The experiment of mesenteric artery function in rats showed that:whether estrogen was replaced or not, the elastical function of mesenteric artery in SD rats with high levels of serum FSH decreased.Conclusions:The four SD models demonstrated that postmenopausal hypertension is relied on the adrenal medulla. Postmenopausal hypertension is due to the elevation of catecholamine and the decrease of elastic function of small artery that caused by norepinehprine elevation. The catecholamine increase is associated with serum FSH. Part Ⅲ The intracellular mechanism of FSH promoting catecholamine synthesis in PC12and rat adrenal medulla cellsObjective:To explore the mechanism of FSH involved catecholamine synthesis in PC12cells and rat primary adrenal medulla cellse.Materials and methods:1.The expression profile of FSHR was investigated in PC12cells, rat primary adrenal medulla chromatin cells by RT-PCR, western blot and immunofluorescence staining. The effect of FSHR on the regulation of NE synthesis was evaluated by Reverse phase high performance liquid chromagraphy electrochemical technology in PC12cells and rat primary adrenal medulla chromatin cells. We explored the intracellular mechanism of FSHR involved in the NE synthesis of PC12cells in vitro.Results:1. The expression profile of FSHR was investigated in PC12cells, rat primary adrenal medulla chromatin cells.2. Different concentration of human recombinant FSH can promote the synthesis of norepinephrine and epinephrine of PC12cells and rat adrenal medulla chromaffin cells.3.FSH combined with FSHR stimulated Gsα, then activated PKA, ERK1/2, JNK ultimatedly phosphorylated CREB, c-jun, ERK and AKT that acted on response element of yrosine hydroxylase promoter to up-regulate synthesis of tyrosine hydroxylase--the rate-limiting enzyme of catecholamine synthesis, which resulted in increased synthesis of catecholamine.4. The study provides a new mechanism of postmenopausal hypertension. That is to say, elevated FSH in postmenopausal women promoted the synthesis of catecholamine by adrenal medulla chromaffin cells.Conclusions:FSH enhances tyrosine hydroxylase (TH) expression and catecholamine synthesis. FSH enhances tyrosine hydroxylase (TH) expression and catecholamine synthesis. FSHR signals activate CREB, Erk, AKT and NFκB pathways via Gsα in catecholamine synthesis.