الفهرس 
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Abstract
Hyperthyroidism, one of thyroid disorders, is known to affect the oocytes, sperm, and embryo during fertilization, implantation and placentation. The association between hyperthyroidism and infertility is evidenced and scarce and sometimes conflicting. Infertility may occur in hyperthyroid females, but euthyroidism can restore these abnormalities. Up till now, there are no investigations about the effects of different stages of hyperthyroidism on the female reproductive organs; ovary and uterus. So, the present study was undertaken to fulfill the effects of mild, moderate, and severe hyperthyroidism on a) the level of female sex hormones. b) Ovarian proliferating and apoptotic markers. c) The histological abnormalities in both ovary and uterus.
The experiment was started in female rats from day 21 of weaning and were divided equally into four groups: group I (Normal Control), orally injected with sterile saline; group II (Mild Hyperthyroidism), orally injected with L-thyroxin daily for 10 consecutive days; group III (Moderate Hyperthyroidism), orally injected with L-thyroxin daily for 20 consecutive days; group IV (Severe Hyperthyroidism), orally injected with L-thyroxin daily for 30 consecutive days. Any ovarian and uterine histological alterations were evaluated microscopically using hematoxylin and eosin stain. Serum levels of thyroid stimulating hormone (TSH), free triiodotyrosine (FT3), progesterone and estradiol II were assayed. The ovarian levels of interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) were investigated. The localization and expression of both proliferating cell nuclear antigen (PCNA) and BCl-2 were evaluated in ovaries by immunohistochemistry.
The results obtained are summarized as follows:
1-Changes in the Body Weight
Induction of different stages of hyperthyroidism in rats caused significant gradual reductions in the rat body weights amounting to 4.34% (p<0.001), 13.69% (p<0.0001), and 17.86% (p<0.0001), in the three groups respectively.
2- Serum Thyroid Hormones (FT3, TSH) Levels
Induction of hyperthyroidism in groups II, III and IV revealed a significant reduction in serum TSH level in all stages (39.58, 96.52, and 98.6%, respectively, at p<0.001) together with a significant increase in serum FT3 level (23.94, 47.9, and 62%, respectively, at p<0.001), compared to the normal control rats.
3- Serum Progesterone and Estrogen Levels
Moderate and severe hyperthyroidism (groups III, IV) caused significant reductions in serum progesterone level (20.17%, 41.18 and 53%, respectively, p<0.001). The estradiol II level was significantly reduced in moderate and severe hyperthyroidism (9.38 and 14%, respectively, p<0.001), compared to the normal control rats. Serum progesterone level was significantly decreased in mild hyperthyroidism (20.17%, p<0.001), compared to the normal level. However, mild hyperthyroidism did not show any significant alteration in the level of serum estradiol II.
4-Ovarian IL-6 and IGF-1
Mild hyperthyroidism (group II) did not cause any significant disturbance in the concentration of ovarian IL-6 with a significant reduction in the ovarian IGF-1 concentration (23.89% at p<0.05), compared to the normal control group. While, moderate and severe hyperthyroidism elevated significantly the concentration of ovarian IL-6 (42.3 and 100.8%, respectively, p<0.001) and caused a significant reduction in the ovarian IGF-1 concentration (51.67 and 81%, respectively, p<0.001), compared to the normal control rats.
5- Histological Investigations
a. Ovarian Histological Examination
Induction of mild hyperthyroidism (group II) for 10 days did not show any histological alterations in the ovaries of rats. However, the ovary of the moderate hyperthyroid group (group III) showed the beginning of degeneration in the ovarian follicles as well as the presence of many apoptotic bodies in the ovarian stroma. More deleterious effects were reported in severe hyperthyroid rats (group IV) in the form of collapsed follicles and the presence of dilated and congested blood vessels in ovarian stroma. Most of the ovarian follicles in severe hyperthyroid rats were degenerated. The degeneration appeared in different forms; some follicles showed lysis of the oocyte and appearance of acidophilic material filling the cavity of the follicular antrum. The surrounding granulosa cells showed pyknosis of their nuclei and degeneration of their cytoplasm.
b. Uterine Histological Examination
Induction of mild hyperthyroidism (group II) in female rats caused vacuolations in the lumen epithelial cell and uterine glands. More histological abnormalities were seen in moderate hyperthyroid (group III) females in which congestion in uterine blood vessels and degeneration of the endometrial epithelial cells were observed. Severe hyperthyroidism (group IV) increased the thickness of endometrium lumen epithelium with the presence numerous apoptotic bodies. Moreover, many endometrium epithelial cells became apoptotic.
6- Immunohistochemical Investigation
a- Immunohistochemical Detection of PCNA
PCNA was mainly localized in granulosa cells as well as oocyte of the ovarian follicle. The intensity of PCNA immunoreactivity in the control group was moderate (++) in the granulosa cells and weak or negative in the theca interna cells. In mild and moderate hyperthyroid rats, (group II, III) PCNA was localized in granulosa cells, oocyte, and theca cells of the ovarian follicle with moderate immunoreactivity (++). The intensity of PCNA immunostaining increased to be severe (+++) in the granulosa cells and oocyte of the ovarian follicle of the hyperthyroid rats.
b- Immunohistochemical Detection of BC1-2
Results showed that the immunostaining reactivity of BCl-2 is moderate (++) in the granulosa cells of the ovarian follicle. The intensity of BCl-2 immunoreactivity in the control group was weak or negative in the theca cells and corpus lutea. The immunostaining of BCl-2 localization and intensity in the ovary of mild hyperthyroid rats (group II) were similar to that of the normal control rats. The ovary of moderate hyperthyroid rats (group III) had moderate immunoreactivity for BCl-2 in the granulosa cells and the theca cells of the ovarian follicle as well as corpus lutea. On the other hand, the ovary of severe hyperthyroid rats (group IV) showed weak immunostaining intensity of BCl-2 in the granulosa cells of the ovarian follicle and corpus lutea with weak to negative immunostaining reactivity in the theca cells.