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Thyroid gland dysfunction modulates ovarian response to estrogen and androgen receptors in albino rats

Abd-El Fattah, Lamiaa Ibrahim; El-Deeb, Dalia Fathy

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The Egyptian Journal of Histology: June 2011 - Volume 34 - Issue 2 - p 182-190
doi: 10.1097/01.EHX.0000396503.68755.ab
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Abstract

Introduction

Thyroid hormones act at all the levels of regulation within the reproductive system [1]. Granulosa cells and ovarian stromal cells express thyroid hormone receptors. Thus, thyroid hormones play an essential role in ovarian physiology [2]. Moreover, other investigators [3] detected that the ovarian surface epithelium is a physiologically important target for thyroid hormone.

Some researchers [4] stated that thyroid hormones might directly influence ovarian function through steroid hormone receptors, and that ovulation failure was linked with severe hypothyroidism. Association of ovarian cancer with hyperthyroidism was reported by the researchers [5]. Other reports [6] added that hypothyroidism and hyperthyroidism are more common in women than in men. Some investigators [7] clearly detected estrogen receptor (ER) and androgen receptor (AR) in granulosa and theca cells of the ovary.

This study was planned according to the facts that the mechanisms by which thyroid hormones impact ovarian function remain poorly understood [8], together with the belief of the researchers [9] that the effect of ovarian steroid hormones are mediated through interaction with specific receptors.

Our study aimed to simulate the clinical conditions of hypothyroidism and hyperthyroidism in adult female albino rats, and to detect the possible changes in ovarian estrogen and androgen hormone receptors associated with such clinical conditions.

Materials and methods

Animals

This study used 36 adult female albino rats. Their ages ranged between 3 and 4 months (mean: 3.5±0.2 months) and their mean weight ranged between 200 and 250 g (mean: 221±12g). Animals were confirmed to have regular estrous cycles.

Experimental design

The experiment was carried out in the animal house of Kasr El-Aini Hospital. Rats were divided into three groups. Each group was housed in a separate cage and received tap water and was fed ad libitum.

Control group

This group included 12 rats that received 0.5 ml saline solution once daily. Six rats received the saline orally, and the other half received it by intraperitoneal injection for 4 weeks.

Hypothyroid group

This group consisted of 12 rats that received daily orally (using a tube) propylthiouracil (Thyrocil, Amoun pharmaceutical Co., Cairo, A.R.E.) dissolved in saline solution for 4 weeks. The dose was 50 mg/kg in rabbits [10], this was adjusted according to animal species using Paget equation to be 18.75 mg/kg in rats [11]. Propylthiouracil is one of the drugs that prevent iodotyrosine formation [10].

Hyperthyroid group

This group consisted of 12 rats that received a daily intraperitoneal dose of 40 μg/kg L-thyroxine (Eltroxin, GlaxoSmithKline, Cairo, A.R.E.) dissolved in saline solution for 4 weeks [12].

Vaginal smears were performed at the end of the fourth week from the start of the experiment to all rats included in the study to select those showing predominating leukocytes over cornified and epithelial cells that coincides with the diestrus phase of the estrus cycle. An inverted phase contrast microscope (Olympus, Tokyo, Japan) was used [13]. Rats not showing the diestrus phase were excluded from the study.

Before sacrifying the selected rats, retro orbital blood samples were collected by capillary tubes. Serum thyroxine level was obtained by radioimmunoassay in the Chemical Pathology Department of Kasr El-Aini Hospital, Cairo, Egypt.

The selected rats were killed by decapitation; right-sided ovaries were obtained and transversely bisected to examine the maximum area, then fixed in 10% formol saline, embedded in paraffin, and cut at 7 μm thickness. The sections were subjected to:

  • (1) Hematoxylin and eosin stain [14].
  • (2) Immunohistochemical stains.

Ovarian sections were incubated with the primary mouse monoclonal anti-ERα antibody (Thermo Scientific, UK) [15]. Moreover, these sections were subjected to staining with rabbit polyclonal anti-AR antibody (Thermo Scientific, UK) [7]. Tissue sections were counterstained with Mayer's hematoxylin. Negative controls were obtained by skipping the step of applying the primary antibody.

Morphometric study

Using Leica Qwin 500 LTD (Cambridge, UK) image analysis, the number of corpora lutea in hematoxylin and eosin stained sections was counted under the microscope in 10 low-power fields. The optical density of ER-immunoreactive and AR-immunoreactive surface germinal epithelial cells and theca and granulosa lutein cells was measured using mean gray in 10 low-power fields.

Statistical analysis of the measured data was carried out using analysis of variance test followed by Bonferroni pair-wise comparison [16]. P values of less than 0.05 were considered to be statistically significant.

Results

Vaginal smears performed at the end of the experiment indicated that among the six control rats receiving oral saline, three were in the diestrus phase of the estrus cycle, and that among the other six receiving intraperitoneal saline, four showed the diestrus phase. With regard to the hypothyroid group, eight rats only were in the diestrus phase, whereas among the hyperthyroid group, seven were in the diestrus phase.

Hormonal assay results (Table 1)

The recorded means of thyroxine values were 2.9, 1.3, and 8.5 ng/dl in the control, hypothyroid, and hyperthyroid groups, respectively.

Table 1
Table 1:
Mean thyroxine values (nanogram per deciliter) in the studied groups

Hematoxylin and eosin results

Control group (Figs 1 and 2)

Examination of some ovarian sections from the control group revealed the presence of primordial follicles, atretic follicles, and corpora lutea. The ovarian medulla and blood vessels were also noted.

Figure 1
Figure 1:
Photomicrograph of a section in the ovary of a control rat demonstrating atretic follicle (A) and corpora lutea (C). Notice the ovarian medulla (arrow) and blood vessels (B). H&E ×100.
Figure 2
Figure 2:
Photomicrograph of a section in the ovary of a control rat showing primordial follicles (arrow) and a group of atretic follicles (A). H&E ×200.

Hypothyroid group (Figs 3 and 4)

Sections revealed few corpora lutea, atretic follicles, and dilated congested blood vessels. Vacuolated cells of interstitial tissue were detected.

Figure 3
Figure 3:
Photomicrograph of a section in the ovary of a hypothyroid rat showing corpus luteum (C), atretic follicles (A), and dilated congested blood vessels (B). H&E ×100.
Figure 4
Figure 4:
Photomicrograph of a section in an ovarian tissue of a hypothyroid rat demonstrating part of a corpus luteum (C), atretic follicles (A), and congested blood vessel (B). Notice the vacuolated cells (arrows) of interstitial tissue. H&E ×200.

Hyperthyroid group (Figs 5 and 6)

The ovarian sections examined showed numerous corpora lutea, atretic follicles, and markedly dilated congested blood vessels.

Figure 5
Figure 5:
Photomicrograph of a section in the ovary of a hyperthyroid rat showing many corpora lutea (C), atretic follicles (A), and markedly congested blood vessels (B). H&E ×100
Figure 6
Figure 6:
Higher magnification of the previous figure illustrating atretic follicles (A) and markedly dilated congested blood vessels (B). H&E ×200.

Immunohistochemical results

Control group

Estrogen receptor (Fig. 7): Strong ER immunoreactive nuclei of the surface germinal epithelium were recorded. The theca lutein cells exhibited strong nuclear and weak cytoplasmic immunoreactions. Weak cytoplasmic reaction was detected in the granulosa lutein cells and negative immunoreaction was detected in stromal cells.

Figure 7
Figure 7:
Photomicrograph of a section in the ovary of a control rat showing strong estrogen receptor (ER) immunoreactive nuclei of the surface germinal epithelium (arrowheads). The theca lutein cells exhibit strong nuclear and weak cytoplasmic immunoreactions (thin arrows). Weak cytoplasmic reaction is noted in the granulosa lutein cells (thick arrows). Notice the negative ER immunoreaction in stromal cells (S). ER immunostaining, ×200.

Androgen receptor (Fig. 8): The surface germinal epithelium showed negative AR immunoreaction. The theca lutein cells showed strong nuclear and cytoplasmic immunoreactions. Moderate cytoplasmic reaction was observed in the granulosa lutein cells, with negative immunoreaction in stromal cells.

Figure 8
Figure 8:
Photomicrograph of a section in the ovary of a control rat demonstrating negative immunoreaction of the surface germinal epithelium (arrowheads). The theca lutein cells show strong nuclear and cytoplasmic androgen receptor (AR) immunoreactions (thin arrows). Moderate cytoplasmic reaction is observed in the granulosa lutein cells (thick arrows). Negative AR immunoreaction in stromal cells (S) was observed. AR immunostaining, ×200.

Hypothyroid group

Estrogen receptor (Fig. 9): Moderate ER immunoreactive nuclei of the surface germinal epithelium were recorded. The theca lutein cells revealed strong nuclear and weak cytoplasmic immunoreactions. Very weak cytoplasmic reaction was noted in the granulosa lutein cells, whereas stromal cells revealed negative immunoreaction.

Figure 9
Figure 9:
Photomicrograph of an ovarian section in a hypothyroid rat showing moderate estrogen receptor immunoreactive nuclei of the surface germinal epithelium (arrowheads). The theca lutein cells show strong nuclear and weak cytoplasmic immunoreactions (thin arrows). Very weak cytoplasmic reaction is noted in the granulosa lutein cells (thick arrows) with negative immunoreaction of stromal cells (S). Estrogen receptor immunostaining, ×200.

Androgen receptor (Fig. 10): The surface germinal epithelium showed negative AR immunoreaction. Strong nuclear and cytoplasmic immunoreactions were observed in the theca lutein cells. The granulosa lutein cells exhibited strong cytoplasmic reaction. Negative immunoreaction was detected in stromal cells.

Figure 10
Figure 10:
Photomicrograph of a section in the ovary of a hypothyroid rat illustrating negative immunoreaction of the surface germinal epithelium (arrowheads). Strong nuclear and cytoplasmic androgen receptor immunoreactions (thin arrows) are shown in the theca lutein cells. Strong cytoplasmic reaction is recorded in the granulosa lutein cells (thick arrows) and negative immunoreaction in stromal cells (S). Androgen receptor immunostaining, ×200.

Hyperthyroid group

Estrogen receptor (Fig. 11): Strong ER immunoreactive nuclei of the surface germinal epithelium were observed. The theca lutein cells revealed strong nuclear and weak cytoplasmic immunoreactions. Moderate nuclear and cytoplasmic reactions were noted in the granulosa lutein cells, with negative immunoreaction in stromal cells.

Figure 11
Figure 11:
Photomicrograph of a section in the ovary of a hyperthyroid rat demonstrating strong estrogen receptor immunoreactive nuclei of the surface germinal epithelium (arrow heads). The theca lutein cells reveal strong nuclear and weak cytoplasmic immunoreactions (thin arrows). Moderate nuclear and cytoplasmic reactions are noted in the granulosa lutein cells (thick arrows). Negative immunoreaction in stromal cells (S) was detected. Estrogen receptor immunostaining, ×200.

Androgen receptor (Fig. 12): Nuclei of the surface germinal epithelium showed strong AR immunoreaction. Strong nuclear and cytoplasmic immunoreactions were observed in the theca lutein cells. Moderate cytoplasmic reaction was noted in the granulosa lutein cells, whereas stromal cells revealed negative immunoreaction.

Figure 12
Figure 12:
Photomicrograph of an ovarian section in a hyperthyroid rat showing strong nuclear androgen receptor (AR) immunoreaction of the surface germinal epithelium (arrow heads). Strong nuclear and cytoplasmic AR immunoreactions (thin arrows) are observed in the theca lutein cells. Moderate cytoplasmic reaction is noted in the granulosa lutein cells (thick arrows) and negative immunoreaction in stromal cells (S). AR immunostaining, ×200.

Morphometric results

The mean number of corpora lutea revealed a high significant increase (P<0.0005) in the hyperthyroid group versus the control and the hypothyroid groups (Table 2 and Histogram 1). With regard to ER immunoreactivity in the surface germinal epithelial cells, a high significant decrease (P<0.007) in the mean optical density of ER immunoreactive nuclei was recorded in the hypothyroid group versus the control group with a nonsignificant difference between the hyperthyroid and control groups. A high significant increase (P<0.008) and a high significant decrease (P<0.012) in the mean optical density of ER immunoreactivity in the theca lutein cells were recorded in hyperthyroid and hypothyroid groups, respectively versus the control group. A high significant decrease (P<0.0005) in the mean optical density of ER immunoreactivity in the granulosa lutein cells was estimated in both the hypothyroid and hyperthyroid groups versus the control group with a nonsignificant difference between both experimental groups (Table 3 and Histogram 2). In contrast, AR immunoreactive nuclei of the surface germinal epithelial cells were observed only in the hyperthyroid group. The mean optical density of AR immunoreactivity of the theca lutein cells showed a high significant increase (P<0.004) and a high significant decrease (P<0.004) in the hypothyroid and hyperthyroid groups, respectively versus the control group. The mean optical density of AR immunoreactivity of the granulosa lutein cells revealed a high significant increase (P<0.0005 and 0.015) in both the hypothyroid and hyperthyroid groups, respectively versus the control group (Table 4and Histogram 3). Therefore, a negative correlation was documented between ER and AR immunoreactivity in the hypothyroid and hyperthyroid groups (Histogram 4).

Table 2
Table 2:
Mean number of corpora lutea in the studied groups
Table 3
Table 3:
Mean (±SD) optical density of ER immunoreaction in the surface germinal epithelium, theca, and granulosa lutein cells of the studied groups
Table 4
Table 4:
Mean (±SD) optical density of AR immunoreaction in the theca and granulosa lutein cells of the studied groups
Histogram 1
Histogram 1:
Histogram 1. Mean±standard deviation number of corpora lutea in the studied groups.
Histogram 2
Histogram 2:
Histogram 2. Mean±standard deviation optical density of estrogen receptor immunoreaction in the surface germinal epithelium, theca, and granulosa lutein cells of the studied groups.
Histogram 3
Histogram 3:
Histogram 3. Mean±standard deviation optical density of androgen receptor immunoreaction in the theca and granulosa lutein cells of the studied groups.
Histogram 4
Histogram 4:
Histogram 4. Negative correlation between estrogen receptor (ER) and androgen receptor (AR) immunoreactivity in the studied groups.

Discussion

This study simulates the clinical conditions of hypothyroidism and hyperthyroidism, and records the changes occurring in the ovary of female adult albino rats in the diestrus phase, this phase was chosen because some studies [17] mentioned that granulosa cells at early stages of follicular development do not actively participate in thyroid hormone binding. The histological and immunohistochemical findings of this study will be discussed.

Dilated congested blood vessels were observed in both hypothyroid and hyperthyroid rats; this finding could be attributed to the increased vascular supply needed for the growing corpora lutea and the increase in their functional activity [18].

Numerous corpora lutea were detected in the hyperthyroid group that was significantly increased versus control and hypothyroid groups. Similar to the previous finding, investigators [19] detected inhibition of folliculogenesis and ovulation with corpora lutea that are smaller in number and diameter in hypothyroidism. Other researchers [20] added that in thyroidectomy, there was decreased responsiveness of ovarian granulosa cells to follicle stimulating hormone that increased serum prolactin level consequently inhibiting normal luteinizing hormone secretion. However, recent investigators [21] recorded that hypothyroidism did not influence the number of corpora lutea. Therefore, it could be suggested that the reverse might occur in hyperthyroid conditions stimulating ovulation, and hence corpora lutea formation.

In both hypothyroid and hyperthyroid groups, many atretic follicles were seen. This could be explained by the researchers [19] who reported that ovarian follicles were not well developed in hypothyroid animals, suggesting that thyroid hormones could have a direct effect on growth of ovarian follicles. In hyperthyroidism, the ovaries contained follicles of abnormal size, form, and number [22].

In the hypothyroid group, vacuolated stromal cells were detected most probably representing those of the interstitial gland. This finding was explained by the researchers [23] as stromal hyperthecosis; microscopically, it was noted as hypercellular stroma with luteinization of stromal cells that appear with a vacuolated cytoplasm. This is a disorder of ovarian stroma and was recorded in women with polycystic ovarian disease (PCOD).

With regard to the immunohistochemical results, the control group demonstrated strong ER immunoreactivity in nuclei of the surface germinal epithelium and theca lutein cells; weak cytoplasmic immunoreaction was recorded in both theca and granulosa lutein cells. This was in part supported by the researchers [24] who reported that ERα was detected in the germinal epithelium. Other investigators [25] observed no immunostaining in rat ovary with anti-ERα antibody.

In the hypothyroid group, moderate ER immunoreaction was recorded in nuclei of the surface epithelium. There was a significant decrease in ER immunoreactivity in the hypothyroid group versus control in all the studied compartments namely surface germinal epithelium, theca, and granulosa lutein cells. Studies [20,26] recorded a decrease in serum levels of estrogen in thyroidectomy and hypothyroidism. On the contrary, other researchers [21,27] observed increased serum concentration of estradiol in hypothyroidism with increasing expression of ER.

In the hyperthyroid group, strong ER immunoreactivity was observed in nuclei of the surface germinal epithelium. A significant increase in ER immunoreactivity of the theca lutein cells and decrease in the granulosa lutein cells versus control group were confirmed. These findings were in agreement with some investigators [28] who detected that excess thyroid hormone increased expression of ERα in the ovarian surface epithelium that was strongly associated with ovarian cancer. Moreover, other researchers [29] reported upregulation of ERα by thyroid hormone in rat pituitary cell line. A recent review [26] added that serum estrogen and ovarian conversions of androgen-to-estrogen were increased in thyrotoxicosis. On the contrary, other investigators [30] reported that thyroid hormone inhibited estradiol production in all culture conditions. The recorded changes in hyperthyroidism might clinically give rise to oligomenorrhea, which may progress to amenorrhea as reported by some researchers [31].

With regard to AR immunoreactivity of the control group, negative AR immunoreaction was reported in the surface germinal epithelium, whereas strong nuclear and cytoplasmic immunoreactions were detected in theca lutein cells and only moderate cytoplasmic immunoreaction of granulosa lutein cells was observed. In agreement with the previously mentioned results, some investigators [7,24] recorded AR immunoreactivity in the nuclei of ovarian cells, principally the granulosa and theca cells, and suggested that thecal androgen could be a paracrine modulator of granulosa cell function.

AR immunoreactivity of the hypothyroid group revealed negative immunoreaction in the surface germinal epithelium. Morphometrically, AR immunoreactivity was proved to be significantly increased versus the control group. This finding was consistent with the researchers [32] who suggested that AR upregulation could be mediated by the accumulation of endogenous testosterone. This accumulation might be attributed to inhibition of the aromatase enzyme and blockade of androgen conversion to estrogen. Such explanation was supported by the investigators [33] who reported that thecal cells synthesize androstenedione that is converted to estradiol by the cytochrome P450 aromatase enzyme of the granulosa cells. In contrast, some investigators [20] reported low testosterone levels in hypothyroid rats that could be associated with decreased AR on the basis of the suggestions of the other researchers [32].

The suggestion of testosterone accumulation in the hypothyroid group might give rise clinically to manifestations of PCOD reported by the researchers [31] including hirsutism, acne, and male pattern alopecia. Microscopically, follicular atresia, follicular cysts, and anovulation with stromal hyperthecosis are changes of PCOD that were recorded in the hypothyroid group of this study.

With regard to AR immunoreactivity of hyperthyroid rats, strong immunoreactions were recorded in both surface germinal epithelia. AR immunoreactions were significantly decreased in the theca cells and significantly increased in the granulosa lutein cells versus the controls. The decrease in AR immunoreactivity could be explained by increased conversion of androgen-to-estrogen by the aromatase enzyme, which could also explain the increased AR immunoexpression in granulosa lutein cells, as it is going to be converted to estrogen by aromatase. On the contrary, other investigators [34] demonstrated that thyroid hormone increased basal androgen secretion, with consequent increase in AR based on the results of some researchers [32].

With regard to stromal cells, they were negative for both ER and AR immunoreactivity in all the studied groups including the control group. This was consistent with the researchers [7] who detected ER and AR immunoreactivity only in granulosa and theca cells.

Conclusion

In conclusion, our data clearly demonstrated a negative correlation between ER and AR immunoreactivity in the experimental groups. In other words, a decrease in ER and an increase in AR immunoreactivities were detected in hypothyroid rats, which was vice versa in hyperthyroid rats. Therefore, it could be suggested that thyroid hormones are important to maintain normal estrous cycle and hence in the regulation of ovarian hormones. The mechanism by which thyroid hormones influence ovarian function remain to be elucidated. However, it might be through their effect on aromatase enzyme, which is the key regulator in ovarian hormone production reflected on the level of steroid hormone receptor expression.

Table
Table:
No title available.

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Keywords:

androgen receptor; estrogen receptor; ovary; thyroid hormone

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