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BOR - Papers in Press, published online ahead of print October 15, 2003.
Biol Reprod 2003, 10.1095/biolreprod.103.022368
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BIOLOGY OF REPRODUCTION 70, 329–333 (2004)
DOI: 10.1095/biolreprod.103.022368
© 2004 by the Society for the Study of Reproduction, Inc.

Neuroendocrinology

Immunity and ß-Endorphin Concentrations in Hypothalamus and Plasma in Rats with Steroid-Induced Polycystic Ovaries: Effect of Low-Frequency Electroacupuncture1

Elisabet Stener-Victorin2,3,4, and Catharina Lindholm5

Department of Physiology3 Department of Obstetrics and Gynecology,4 Sahlgrenska Academy, Göteborg University, SE-413 45 Göteborg, Sweden Department of Rheumatology and Inflammation Research,5 Sahlgrenska Academy, Göteborg University, SE-405 30 Göteborg, Sweden


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The human endocrinological disorder polycystic ovary syndrome (PCOS) is a common cause of reproductive failure. Even though the cause of PCOS is unknown, hormone and immune disturbances as well as hyperactivity in the sympathetic nervous system are likely to be involved in the pathogenesis of the disease. The present study was undertaken to elucidate if rats with estradiol valerate (EV)-induced polycystic ovaries (PCO) have altered ß-endorphin concentrations in the hypothalamus and in plasma and if they have alterations in circulating immune cell populations and the activity. Repeated low-frequency (2 Hz) electroacupuncture (EA) treatments are known to modulate the release of ß-endorphin, immune responses, and the activity in the autonomic nervous system. We therefore also investigated the effect of EA treatments on the ß-endorphin and the immune systems. Low-frequency EA was given 12 times, 25 min each, over 30 days starting 2–3 days after i.m. injection of EV. The ß-endorphin concentrations in the hypothalamus and in plasma as well as the frequencies of CD4+ T cells and CD8+ T cells were significantly lower in EV-injected control rats as compared to oil-injected control rats. Repeated EA treatments in EV-injected rats significantly increased ß-endorphin concentrations in the hypothalamus. In conclusion, these findings show that both the ß-endorphinergic and the immune system are significantly impaired in rats with steroid-induced PCO and that repeated EA treatments can restore some of these disturbances.

central nervous system, female reproductive tract, hypothalamus, immunology, neuropeptides


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
One of the most common causes of reproductive failure is polycystic ovary syndrome (PCOS), a complex endocrinological disorder characterized by hyperandrogenism and ovulatory dysfunction [1]. PCOS is related to hormonal dysregulation [1] as well as hyperactivity in the sympathetic nervous system [2–5], and autoimmune disturbances have been demonstrated in some cases [6–8]. In recent years it has become evident that there is a close relationship between the endocrine system, the sympathetic nervous system, and the immune system [9]. Despite extensive research, the underlying mechanisms are still unclear. Possible mechanisms behind the beneficial effects of different treatments for PCOS in humans are for obvious reasons difficult to study since, for example, tissue samples from the central nervous system (CNS) are not obtainable in women with PCOS. The utility of murine models of PCO has been discussed [10]. However, even if it is impossible to exactly reproduce human PCOS using a rat model, it may provide important leads. We and others have used a model using a single i.m. injection of estradiol valerate (EV) independent of cycle day in normal cycling rats to induce chronic anovulation and polycystic ovaries (PCO), resembling some aspects of the human PCOS [11]. Furthermore, it is held that the EV-induced rat PCO model has an increased activity in ovarian sympathetic nerves [12].

It has previously been demonstrated that rats with EV-induced PCO have reduced hypothalamic ß-endorphin concentrations and an increased µ-opioid binding reflecting a chronic up-regulation of the receptor in response to compromised ß-endorphin input [13]. ß-Endorphin influences a variety of hypothalamic functions including reproduction, autonomic functions, and extrahypothalamic functions including immune function [14, 15]. ß-Endorphin is produced and released from the hypothalamic nucleus, the arcuate nucleus (with projections throughout the brain), and to the nucleus tractus solitarius in the brain stem. Another ß-endorphin system is found in the anterior pituitary, where ß-endorphin is coreleased with ACTH into the bloodstream and exerts its effects in different target organs [16]. Leukocytes can express opioid receptors [17] and under certain circumstances also synthesize and release ß-endorphin themselves providing the molecular mechanisms for communication with the neuroendocrine system [18].

Little is known about the immune function in human PCOS. It has been shown that women with PCOS have decreased frequencies of circulating CD8+ T cells and natural killer (NK) cells [19], altered cytokine responses, and an increased number of activated T cells in follicular fluid [20, 21]. The immune function in rats with EV-induced PCO has, to our knowledge, not previously been studied.

Acupuncture with electrical stimulation, i.e. low frequency (2 Hz) electroacupuncture (EA), excites cutaneous and muscle afferent nerve fibers, is known to activate endogenous pain-controlling systems and the release of ß-endorphin [22]. It modulates visceral functions as a reflex response via sympathetic nerves [23], psychological responses [24], and immune function [25, 26]. Acupuncture has also been shown to modulate the immune responses by increasing the CD4+ T-cell frequency in patients with allergic asthma [27] and in patients with chronic pain [28], to counteract the trauma stress-induced immunosuppression in rats [29], and to enhance the immune responses in mice [26]. Furthermore, acupuncture treatment can increase the ß-endorphin concentrations in peripheral blood mononuclear cells [30].

The present study was undertaken to determine if rats with steroid-induced PCO have alterations in their ß-endorphin and immune systems 30 days after EV injections. This is the time point when persistent estrus, permanent polycystic ovarian condition, and a characteristic abnormal plasma gonadotropin pattern develop [11, 31, 32]. In addition, we investigated the effect of repeated low-frequency EA treatments on the ß-endorphin concentrations in the hypothalamus and plasma and the effect on immune cell populations during the development of EV-induced PCO in rats.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eighty female Wistar Kyoto rats (Möllegaard, Denmark), weighing 210–236 g, with 4-day cycles, were used. The animals were kept for 1 week before the onset of the experiment. The rats were housed four to a cage at 22°C and with a 12L:12D cycle. All the animals had free access to pelleted food and tap water. Thirty-nine rats were each given a single i.m. injection of 4 mg EV (Riedeldehaen, Germany) in 0.2 ml oil (arachidis oleum; Apoteket, Umeå, Sweden). This treatment has been shown to result in persistent estrus and a permanent polycystic ovarian condition accompanied by a characteristic abnormal plasma gonadotropin pattern 4 weeks after injection [11, 31, 32]. Forty-one rats were each given a single i.m. of 0.2 ml oil alone and served as oil-injected controls. The i.m. injections were given independent of cycle day. The experiments were carried out according to the principles and procedures outlined in the NIH Guide for the Care and Use of Laboratory Animals and were approved by the local animal ethics committee at Göteborg University, Sweden.

Treatment with EA

The rats were divided into four experimental groups; oil-injected rats were referred to as the oil control group (n = 21); oil-injected, EA-treated rats were referred to as the oil-receiving EA group (n = 20); EV-injected rats were referred to as the PCO control group (n = 20); and EV-injected EA-treated rats were referred to as the PCO-receiving EA group (n = 19). All rats were anesthetized i.p. by a mixture of Ketamin (50 mg/kg; Parke-Davis, Warner Lambert Nordic AB, Solna, Sweden) and Rompun (20 mg/kg; Bayer, Bayer AG, Leverkusen, Germany) corresponding to the EA treatment given to the EA groups in order to avoid environmental factors. The control groups were also anesthetized but without acupuncture stimulation. The needles of 0.3-mm-diameter stainless steel (Xeno, Hegu, Landsbro, Sweden) were inserted obliquely in the biceps femoris muscle to a depth of 10–12 mm and perpendicular in the muscle of erector spine (in the same somatic segment as the ovaries) to a depth of 5–7 mm bilaterally. The needles were then connected to an electrical stimulator (CEFAR ACU II, Cefar, Lund, Sweden), the needle in the hind paw to the needle of the back, on each side. Stimulation frequency was a low-burst frequency of 2 Hz, with pulse duration of 0.18 msec. The intensity was adjusted until local muscle contractions were seen to reflect the activation of muscle afferents, that is, 1.5–2 mA. The acupuncture stimulation was applied for 25 min, independently of cycle day, three times a week for four weeks (12 times total) as in our previous studies [32–34].

Collection of Blood and Tissue Samples

Animal termination was done independently of cycle day, between 0800 and 1200 h in both oil- and EV-injected rats [13]. The animals were anesthetized and killed by decapitation on Day 30 after EV injection, that is, the time when the typical PCO and the characteristic abnormal plasma gonadotropin pattern should be developed [11, 31, 32], 1–2 days after the last EA treatment. Trunk blood was collected in ice-chilled heparinized tubes for ß-endorphin analyses and for immune analyses. Blood samples for ß-endorphin analysis were centrifuged at 3000 rpm for 15 min, and the plasma was separated, frozen, and stored at -20°C until assay. Blood samples for flow cytometry were collected in heparinized tubes for immediate analyze. The hypothalamus was quickly removed and dissected on dry ice at the border -0.8–-3.8 according to rat brain stereotaxic coordinates [35] by using a brain blocker, weighed, and stored at -80°C until assay.

ß-Endorphin-Like Immunoreactivity Determined by RIA

Plasma (500 µl) was purified on Sep-pak C18 cartridges (Water Assoc. Inc. Milford, MA) and dissolved in 500 µl of assay buffer (0.05 M phosphate buffer with 1.0% BSA, pH 7.5). A combined neutral and acid extraction of dissected tissue was chosen. Frozen hypothalami were transferred to tubes containing 2 ml of boiling 0.05-mol/L phosphate buffer, pH 7.4, for 10 min and then cooled before being homogenized on a vortex mixer with a steel rod in the tube. Thereafter, the samples were centrifuged (4°C, 2800 x g) for 10 min. The supernatant was taken off and poured into other tubes. The pellet was dissolved and mixed in 2 ml of 1.0-mol/L acetic acid. The solution was boiled for 10 min. Then the centrifugation, cooling, and mixing procedure was repeated. The supernatant from the acid extract was pooled with the one from neutral extraction, and the samples were lyophilized overnight. Each lyophilized sample was dissolved in 1 ml of phosphate buffer and stored at -20°C until RIA. A standard curve of ß-endorphin RIA was prepared by serial dilutions with phosphate buffer, pH 7.4; 100 µl of standard solution or extracted sample were incubated with 200 µl of antiserum solution at 4°C for 48 h. Thereafter, 200 µl of the tracer (Eurodiagnostica, Malmö, Sweden) were added and incubated at 4°C for 24 h. Separation of the bound fraction from the unbound fraction was performed by incubating the samples together with 500 µl of a second antibody, SUSP-3 (Pharmacia & Upjohn Diagnostic AB, Uppsala, Sweden), for 30 min at room temperature. Adding 1 ml of water to the tubes interrupted the incubation of the samples. The samples were then centrifuged for 17 min (4°C, 2800 x g), and the supernatant was decanted. The radioactivity in the precipitate was measured in a gamma-counter (Wallac, Turku, Finland) for 3 min per sample. The detection limit of the assay was 3.9 pmol/L. All samples were assayed in duplicate.

Isolation of Mononuclear Cells from Peripheral Blood, Immunostaining, and Flow Cytometry Analysis

Heparinized peripheral blood was diluted in PBS and overlayed on Ficoll-Paque and centrifuged at 2000 rpm for 15 min. The cells were collected, washed once with PBS by centrifugation at 1500 rpm for 8 min, and counted. The cells isolated from the peripheral blood were immunostained with FITC-conjugated anti-rat CD4, anti-rat CD71 (transferrin receptor), and anti-rat CD68 (the rat macrophage/monocyte marker ED 1), R-PE-conjugated anti-rat CD8 (all from Serotec Ltd Scandinavia, Oslo, Norway), and PerCP-labeled anti-rat TCR{alpha} and ß (Pharmingen, BD Biosciences, San Jose, CA) diluted in PBS supplemented with 0.1% BSA, sodium azide, and 2% normal rat serum for 30 min on ice. The cells were washed and fixed in formaldehyde before analysis on a FACSCalibur (Becton-Dickinson, Mountain View, CA). Isotype-matched antibodies were always included as negative controls. For intracellular staining of CD68 (ED1), the cells were permeabilized using BD FACS permeabilizing solution prior to incubation with antibody. A total of 10 000 cells, gated for lymphocytes or monocytes, respectively, by forward and side light scatter on live cells, were analyzed for each staining.

Statistics

All statistics were measured using SPSS 10.0 software for Macintosh. All group comparisons were made by two-way ANOVA followed by Bonferroni multiple post hoc comparison tests. All data were expressed as mean ± standard error of mean (SEM). A P value less than 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The impact of EV-induced PCO on the opioid system was evaluated by comparing the ß-endorphin concentrations in the central nervous system (CNS) and plasma in EV-injected and oil-injected control rats. The PCO control group had significantly lower ß-endorphin concentrations in both hypothalamus and in plasma as compared to the oil control group (Fig. 1). The effect of repeated EA treatments on ß-endorphin concentrations was evaluated. After 12 EA treatments, the hypothalamic ß-endorphin concentrations were significantly increased in rats with EV-induced PCO (Fig. 1). ß-Endorphin concentrations in hypothalamus and plasma following repeated EA treatments were not significantly different from the oil control group (Fig. 1). In contrast to rats with EV-induced PCO, EA treatment did not affect ß-endorphin concentrations in oil-injected rats.



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  		FIG. 1. ß-Endorphin concentrations in hypothalamus and in plasma in the four experimental groups. Data are expressed as mean ± SEM. Two-way ANOVA followed by Bonferroni multiple post hoc comparison tests was used to compare differences between the groups. aP < 0.001 oil control group versus PCO control group. bP < 0.05 PCO control group versus PCO group receiving EA. cP < 0.05 oil control group versus PCO control group

To evaluate the impact of EV-induced PCO on circulating T-lymphocyte populations, the frequencies of CD4+ and CD8+ T cells in peripheral blood were analyzed by flow cytometry. The frequency of CD4+ T cells and CD8+ T cells were significantly lower in the PCO control group compared to the oil control group (Fig. 2). The frequencies of CD4+ and CD8+ T cells following repeated EA treatments in rats with EV-induced PCO were not significantly different from the oil control group (Fig. 2).



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  		FIG. 2. CD4, CD8, transferrin T cells, transferrin non-T cells, monocytes/macrophage, and NK cells in the four experimental groups. Data are expressed as mean ± SEM. Two-way ANOVA followed by Bonferroni multiple post hoc comparison tests was used to compare differences between the groups. aP < 0.05 oil control group versus PCO control group. b+cP < 0.001 oil control group versus PCO control group. dP < 0.001 oil control group versus PCO group receiving EA

The expression of the transferrin receptor (CD71) on T cells, a good marker of activated T cells [36], was also studied. The frequency of transferrin receptor positive T cells in the PCO control group was not significantly different as compared with the oil control group. Repeated EA treatments decreased, although not significantly, the percentage of transferrin receptor expressing T cells in both oil- and EV-injected rats (Fig. 2). The frequency of transferrin receptor positive non-T cells, that is, B lymphocytes, natural killer (NK) cells, and monocytes, was significantly higher in the PCO control group as compared to the oil control group. Repeated EA treatment had no effect on the transferrin receptor expression on these cells (Fig. 2).

The frequency of monocytes/macrophages (ED1 + cells) was not significantly changed in the PCO control group as compared to the oil control group. Repeated EA treatments decreased, although not significantly, the frequency of monocytes/macrophages in EV-induced PCO rats.

The frequencies of NK cells were similar in oil- and EV-injected rats, and repeated EA treatment did not change the NK cell frequencies (Fig. 2).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main findings of the present study are that rats with EV-induced PCO have decreased ß-endorphin concentrations in the hypothalamus and plasma as well as decreased frequencies of circulating CD4+ and CD8+ T cells as compared to oil-injected control rats. Furthermore, repeated low-frequency EA treatments normalized the ß-endorphin concentrations and increased the T-lymphocyte frequencies in rats with EV-induced PCO and did not differ from oil-injected control rats.

The etiology of human PCOS is unknown, but hypotheses that the endocrine system, the sympathetic nervous system, and the immune system are involved in the pathogenesis of human PCOS are emerging. It has been suggested that human PCOS is an autoimmune disease [8]. Furthermore, ß-endorphin may play a role in the pathogenesis of autoimmune diseases since increased cytokine production in autoimmune disorders induces ß-endorphin secretion from the pituitary gland and lymphocytes [15]. Interestingly, the ß-endorphin production and release is disturbed both in human PCOS as well as in EV-induced PCO in rats [13, 37, 38]. It is well known that ß-endorphin exerts a tonic inhibitory control on the GnRH pulse generator and on pituitary LH release [38]. The finding in the present study of decreased ß-endorphin concentrations in the hypothalamus and in plasma in rats with EV-induced PCO indicates a disturbed ß-endorphin production. It has been postulated that such a reduction in ß-endorphin concentrations could lead to the suppression of the plasma LH pattern that characterizes the EV-induced PCO [13].

Our finding of significantly decreased frequencies of circulating CD4+ and CD8+ T cells in EV-injected rats shows that the immune system is affected in the present steroid-induced PCO model. The effect of ß-endorphin on immune responses is unclear. Some investigators report a tonic inhibitory effect of ß-endorphin on immune responses [39, 40], whereas others have found a stimulatory effect [41]. In our study we found that the frequencies of activated, that is, transferrin receptor expressing, non-T cells, were significantly higher in the EV-injected than in the oil-injected controls. This suggests an inhibitory function of ß-endorphin on proliferative responses of both T cells and other lymphocyte subsets in EV-induced PCO. However, since the expression of endorphin receptors on the lymphocytes or their endogenous ß-endorphin production were not studied in the present study, one might speculate that these changes of the endorphin and immune systems are directly connected, and the possible correlation remains to be elucidated. In contrast to the suggested inhibitory effect of ß-endorphin on proliferative T-cell responses, a stimulatory effect of ß-endorphin has been demonstrated on the lytic activity of NK cells [42]. In our study there were no differences in the frequencies of NK cells between EV-injected and oil-injected rats found, but since the activity of NK cells was not specifically studied, possible changes in the NK cell population in the EV-injected rats cannot be ruled out.

It has also been suggested that human PCOS is associated with stress [3] and increased activity in the sympathetic nervous system [2, 4, 5]. During stress, ACTH and ß-endorphin are produced by lymphocytes and appear to interfere with T-lymphocyte function [43]. In addition, the central ß-endorphin system modulates the activity in the sympathetic nervous system shown by modulation of the central cardiovascular system [44]. It is assumed that rats with EV-induced PCO have increased activity in ovarian sympathetic nerves [12, 45]. The increased ovarian sympathetic nerve activity in EV-injected rats is related to an augmented production of ovarian nerve growth factor (NGF) [12, 45]. Interestingly, NGF has been shown to be elevated in a number of inflammatory and autoimmune states [46]. Since activated CD4+ T-cell clones and resting peritoneal mast cells not only express TrkA but also synthesize and release active NGF, this suggests that NGF is an autocrine or paracrine factor (or both) in the development and regulation of immune response states [46]. This further supports a close interaction between the immune and the sympathetic nervous system.

In the present study we found that repeated EA treatments restore the disturbed ß-endorphin concentrations in the hypothalamus and tended to restore the plasma and the T-lymphocyte frequencies in EV-injected rats. Recently we found that repeated low-frequency EA treatments significantly reduced increased ovarian NGF concentrations in rats with steroid-induced PCO [32, 34]. We have also shown that ovarian concentrations of corticotrophin-releasing factor, a stress-related peptide, and endothelin-1, a potent vasoconstrictor peptide, were significantly decreased in rats with PCO after repeated low-frequency EA stimulation [33, 34]. We and others have shown that repeated EA treatments induce ovulation in women with PCOS and anovulation and exert normalizing effects on endocrinological and neuroendocrinological disturbances [47, 48]. The effect of repeated EA in both the experimental and the clinical studies has been attributed to an inhibition of a high activity in the autonomic nervous system.

Taken together, the present EV-induced rat PCO model likely reflects several aspects of human PCOS. The present study shows that the opioid and immune systems are impaired in the steroid-induced PCO model and that repeated EA treatments restore some of these functions.


   FOOTNOTES
 
1 This study was supported by grants from Wilhelm and Martina Lundgrens's Science Fund, Jubileumsfonden, Göteborg University, Hjalmar Svensson Foundation, the Royal Society of Art and Sciences in Göteborg, and the Swedish Society of Medicine. Back

2 Correspondence: Elisabet Stener-Victorin, Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska, Sahlgrenska Academy, Göteborg University, SE-413 45 Göteborg, Sweden. FAX:46 34 067 6732; elsv{at}fhs.gu.se Back

Received: 15 August 2003.

First decision: 18 September 2003.

Accepted: 30 September 2003.


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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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