In this study DHEA (one of the androgens) was used to induce PCOS causing metabolic disturbances as increase in plasma glucose, cholesterol and triglycerides levels. This pointed out by Iuhas  who reported that both insulin resistance and hyperandrogenemia contribute to this abnormal lipid profile, where androgen decreases lipoprotein lipase activity in abdominal fat cells, and insulin resistance impairs the ability of insulin to exert its antilipolytic effects. Also disturbance in hormonal profile (DHEA group) and this could be ascribed to adrenocorticotrophic hormone (ACTH) which reduces LH secretion. This is unusual result in PCOS but it occurs in women who suffering from PCOS over 20 years, and also for women which have a decrease in ovary size .
The sex hormones dehydroepiandrostenedione (DHEA) is produced in the adrenal glands, the gonads, and in numerous peripheral sites. Although adrenal androgen secretion increases in response to adrenocorticotropic hormone (ACTH), androgens do not influence ACTH secretion, and ACTH plays a primarily permissive role in the adrenal androgen physiology. ACTH stimulates ovaries tissue to secrete FSH . As well as DHEA could induce the over production of active oxygen in ovarian tissue. This lead to a very high significance decrease in the levels of GSH and SOD and remakable significance increase in MDA tissues content. Our results were in harmony with Kandasamy who have documented an increased oxidative stress in patients with PCOS. Elevations in MDA (a byproduct of lipid peroxidation), have been previously reported in PCOS patients . Significantly, all abnormalities were ameliorated in Met + DHEA treated group, where Met decrease both hepatic glucose assembly and its intestinal absorption, and cause an increase in peripheral uptake and its utilization and thus resulting in improved insulin sensitivity. This assumption is in consistent with Heibashy.
Metformin suppresses androstenedione production by a direct effect on ovarian theca cells and decreases FSH . Recently, it has been demonstrated that metformin treatment increased AMPK activity in rat granulosa cells, leading to subsequent reduction of steroid synthesis However, it is still unclear whether this effect is AMPK-dependent or not.
Oxidation parameters analysis revealed that metformin can antagonize the action of DHEA and prevent damage of ovarian tissues  and produced an enhanced chronic activation of AMPK which is necessary to increase the ovarian GSH content. It is also evident that metformin treatment, significantly attenuates the increase in malondialdehyde (MDA) content and total reactive oxygen species generation and restores the decrease in both enzymatic and non-enzymatic antioxidants .
VAC has an estrogenic like effect  which is in accordance to van Die who reported that increase the level of luteinizing hormone (LH) while gently suppressing the secretion of FSH follicle stimulating hormone due to its dopaminergic nature which attributed to the highest quantity of its diterpenes .
Also, VAC can act as opiate system, decreasing the gonadotropic releasing hormone (GnRH) which acts on the pituitary gland lead to decrease the release of LH and FSH .
The aforementioned results of Met + VAC + DHEA treated group, which showed a very high significance amelioration in oxidative parameters were in harmony to Malta??, who stated that VAC has potential natural antioxidant activity .
The Met + VAC +DHEA combination remedy have higher significant amelioration than Met + DHEA, which supported by ROC analysis and revealed lower AUC regarding FSH and PRL but higher AUC regarding LH than those of Met + DHEA group. Worthy mentioning, VAC has a synergistic effect with metformin in PCOS treatment.
Metformin and vitex mixture showed beneficial and synergistic effect in treatment of PCOS as they together give improvements in most of the parameters estimated, in addition to increase the antioxidant potency and amending histological changes of ovaries tissues produced by metformin. Further investigations to find out the mechanism of the herbal extracts effect are needed to complete our understanding of the reproductive endocrinological effects for herbal medicine for these common conditions.
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