الفهرس 
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Abstract
Menopause is one of the most significant events in a woman’s life and brings in a number of physiological changes that affect the life of a woman permanently. Menopause, the end of menses in woman’s life, is characterized by the exhaustion of ovarian follicles resulting in a reduction of sexual steroids (mainly estrogen) and in the occurrence of uncomfortable symptoms and serious diseases such as cardiovascular diseases (CVD) and metabolic syndrome which is a cluster of common clinical disorders including obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia.
Hormonal replacement therapy (HRT) remains the treatment of choice for alleviating menopause related symptoms which affect up to 80% of women and helps improving their health related quality of life. The addition of progesterone to estrogen for a postmenopausal woman with an intact uterus is required to protect against endometrial hyperplasia and endometrial carcinoma. Combination of estrogen and progestin therapy is recommended for all women with a uterus to prevent adverse endometrial effects.
The aim of the present study was to explore the effect of estrogen deficiency and supplementation with either estrogen alone or in combination with progesterone at low daily dose on glucose homeostasis parameters, lipid profile, liver function tests and some lipogenic genes expression in ovariectomized female rats, and the role of miR-33 in this regulation.
The study was conducted on Fifty female Wistar rats, aged 4-6 months.The animals were randomly divided into two groups: group I (Control Group) Consist of 10 female rats were anesthetized, underwent the sham surgical procedure, allowed to recover for 4 weeks and subcutaneously injected with the vehicle (olive oil/ethanol 3:2 v/v) for another 4 weeks. group II (Ovariectomized Group) consist of 40 female rats were anesthetized, bilaterally ovariectomized, allowed to recover for 4 weeks. After that rats were subdivided into four subgroups; Untreated Group: consist of 10 untreated ovx ratswere subcutaneously injectedwith the vehicle for another 4 weeks, estrogen treated group: consist of 10 ovx rats were subcutaneously injected with a daily dose of estrogen (30 µg/kg) for 4 weeks, progesterone treated group: consist of 10 ovx rats were subcutaneously injected with a daily dose of progesterone (1 mg/ kg) for 4 weeks, estrogen + progesterone Group: consist of 10 ovx rats were subcutaneously injected with a daily dose of estrogen (30 µg/kg) and progesterone (1 mg/ kg)for 4 weeks.
At the end of treatment period,the rats in all studied groups were overnight fasting, blood samples were collected to obtain serum for assessment of glucose, insulin, lipid profile, alanine amino transferase (ALT), aspartate amino transferase (AST), Gamma glutamyle transeferase(GGT), bilirubin and sterol regulatory element binding protiens 1c and 2 (SREBP1c and SREBP2). Then all rats were scarified by deep anesthesia to obtain liver for assessment of hepatic lipid content, gene expression of SREBP1c, SREBP2 and miRNA-33a. Part of liver was fixed formalin, and paraffin embedded for histopathologiacal assessment.
The results indicated that ovariectomy caused disturbance in glucose homeostasis as the levels of fasting blood glucose and insulin were elevated and insulin resistance state is established which is indicated by elevated HOMA-IR. Lipid profile is also disrupted in response to ovariectomy, as indicated by increased triglycerides, total cholesterol and LDL-C and decreased HDL-C also hepatic triglycerides were significantly elevated which increases risk of NAFLDdue to increased lipogenesis in the liver. The hepatic expression of SREBP1c at mRNA and protein levels was enhanced in OVX rats while the expression of SREBP2 showed up-regulation at mRNA level while at protein level showed down-regulation. These molecular changes were associated with down-regulation of miR-33a-5p and miR-33a-3p. The results of liver function tests and histological data confirm the hepatic manifestations of estrogen deficiency.
The OVX female rats receiving estrogen and/or progesterone corrected glucose, insulin and insulin sensitivity. Also, treatments have ameliorating effects on lipid profile, hepatic triglycerides, hepatic expression of SREBP1c and SREBP2. The expression of hepatic miR-33a (-5p and -3p) was significantly corrected in the estrogen and/or treated OVX rats with the best effects were observed in estrogen treated rats.
from the results of the present study we can conclude that:
1. Ovariectomy in rats as a model of postmenopause in human is associated with disturbed glucose homeostasis as a result of insulin resistance.
2. Ovariectomy causes dyslipidemia (increased TG, total cholesterol and LDL-C and decreased HDL-C).
3. The estrogen deficiency in OVX rats was associated with disturbed hepatic expression of SREBP1c and SREBP2 at protein and mRNA levels.
4. Ovariectomy causes significant deposition of lipids in liver which may predispose them to NAFLD as confirmed by the histological manifestations of liver.
5. These metabolic effects of estrogen deficiency may be mediated through suppression of hepatic expression of miR-33a-5p and miR-33a-3p.
6. Estrogen and/or progesterone replacement therapy of ovariectomized rats significantly improves glucose homeostasis and increases insulin sensitivity, also it corrects disturbed lipid metabolism.
7. Estrogen and/or replacement treatment have significant ameliorating effects on hepatic triglycerides while had mild or no effect on the cholesterol accumulation in the liver.
8. These ameliorating effects of estrogen (alone or in combination with progesterone) on the metabolic parameters may be mediated by up-regulating the hepatic expression of miR33a which consequently down-regulate the expression of SREBP1c; the main lipogenic transcription factor in the liver.