الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 213 |  |  |
| | | from | 213 | | |
Abstract
PCOS is a multifactorial disease that is primarily characterized by ovulatory dysfunction and hyperandrogenism. It can not only cause female subfertility with ovarian disorders but also may be one of the factors associated with an increased rate of early pregnancy failure. Even though the etiology of PCOS is not fully understood, several pathways have been implicated.
There is increasing evidence that the TGF-β signaling pathway plays a critical role in developing PCOS. Moreover, recent discoveries demonstrate a significant role of autophagy in the pathogenesis of PCOS. However, the relationship between TGF-β1 and autophagy has not been studied in PCOS as yet.
Therefore, this study was designed to investigate the relationship between TGF-β1 and Beclin-1, as a cellular autophagy marker, in a letrozole-induced PCOS model.
The experimental study was carried out on 45 female adult albino Wistar rats aged 12 weeks and with average weights of
180 g. Animals were randomly divided into three groups; group I served as a normal control group, group II (vehicle
control group) received 1% of CMC aqueous solution at a dose of 2.0 ml/kg B.W once daily per oral route (p.o.) for three successive weeks, and group III (PCO group) administered letrozole dissolved in 1% CMC at a dose of 1.0 mg/kg B.W once daily p.o. for three successive weeks.
At the end of the experimental period, blood and ovarian tissue samples were collected. Blood samples were used to determine serum levels of gonadotropins, FSH and LH, as well as gonadal hormones including total testosterone, E2, and progesterone. Ovaries were excised, immediately cleaned of fat, washed with saline, dried with filter papers, and divided into three parts as follows
• One was homogenized and used for the estimation of TAC, PC content, Beclin-1,TGF-β1 and protein levels.
• A small part of the ovaries was fixed in aqueous Bouin’s fluid for histopathological examination.
• The third part was cut into " ~ "1 mm sections and fixed in 4 % buffered glutaraldehyde solution for electron microscopy.
The results of the study can be summarized as follows
• Serum levels of LH and testosterone were significantly elevated in letrozole-treated animals compared to normal control and CMC vehicle groups.
• Serum levels of FSH, progesterone, and estradiol were significantly decreased in letrozole-treated animals compared to both the control group and the CMC vehicle group.
• Ovarian PC content was significantly increased in letozole-treated rats in comparison with normal and CMC vehicle groups.
• The treatment of animals with letozole produced a slightly significant decrease in ovarian TAC compared to normal and CMC vehicle groups.
• Ovarian levels of Beclin-1 and TGF-β1 were significantly increased in letozole-treated rats compared to control and CMC vehicle groups.
• The increased Beclin-1 level in ovarian tissue of PCOS animals correlated positively and significantly with TGF-β1 whereas, it showed a negative significant correlation with TAC.
• When a significant crude correlation was found, multiple linear regression models with a subsequent backward stepwise procedure were used to assess the association between Beclin-1 and different parameters. The final model of the multiple linear regression models revealed just one
relationship; it was a positive relationship between Beclin-1 and TGF-β1 that explained the 62.3% variance in Beclin-1.
• The histopathological examination showed that ovaries of the control and vehicle groups exhibited a typically normal appearance with follicles and corpora lutea in different stages of development and regression. On the other hand, the ovaries of the treated group displayed typical PCO-like changes and follicular cysts in the ovarian surface were evident macroscopically.
• Transmission electron microscope revealed that the oocytes in the control and CMC vehicle groups conserved their junctions and maintained a close relationship with the granulosa. The oocytes’ cytoplasm was homogeneous and contained mitochondria, endoplasmic reticulum, microtubules, and a nucleus with prominent nucleolus.
• In the PCO group, the oocytes in the cell death process had altered junctions with granulosa cells leading to the detachment of the latter from the wall of the former. Moreover, the chromatin in the nucleus began to condense. An interesting ultrastructural characteristic in the altered oocytes was the presence of numerous dispersed autophagic vesicles in the cytoplasm, which contain cytoplasmic structures in different phases of degradation.
In conclusion, this work highlights the relationship between TGF-β1 and Beclin-1 ovarian levels in a letrozole-induced PCOS model indicating that TGF-β1 might be a determinant factor of Beclin-1 in a letrozole-induced PCOS model and the increased level of the latter appears to be associated with the high level of the former. Thus, there is a need for additional studies to explore therapeutic strategies targeting TGF-β1 signaling that may regulate autophagy and subsequently present promising remedies in the treatment of PCOS.