| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Institute of Neuroscience and Physiology, Department of Physiology (L.M., A.H., E.S.-V.), and Institute of Medicine, Department of Molecular and Clinical Medicine (T.L., M.L.), Sahlgrenska Academy, Göteborg University, 405 30 Göteborg, Sweden; Department of Pathology and Cytology (S.C., Z.S.), Akademiska Sjukhuset, 751 85 Uppsala, Sweden; and Department of Pathology, University Clinic Center (Z.S.), Tuzla 75000, Bosnia and Hercegovina
Address all correspondence and requests for reprints to: Elisabet Stener-Victorin, Ph.D. and associate professor, Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, Göteborg University, Box 434, SE-405 30 Göteborg, Sweden. E-mail: elisabet.stener-victorin{at}neuro.gu.se.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The etiology of PCOS is unclear. One hypothesis is that PCOS is a genetically determined ovarian disorder in which excessive androgen production early in life may provide a hormonal insult that leads to PCOS in adulthood (7, 8, 9). After fetal exposure to high levels of androgens, adolescent rhesus monkeys and sheep show many features of PCOS. However, their use to study the etiology of PCOS is prohibitively expensive (10, 11, 12).
Adiposity may play a central role in generating and maintaining the syndrome. Weight reduction often improves menstrual regularity (13). A lipolytic defect in sc adipocytes may contribute to accumulation of fat and obesity (14). In addition, adipocytes of nonobese women with PCOS are 25% larger than in matched controls (14). Enlargement of abdominal sc adipocytes is associated with insulin resistance and is an independent risk factor for type 2 diabetes (15).
We and others have used a rat model in which PCOs are induced with estradiol valerate (16) to study the effects and mechanisms of electroacupuncture and exercise in the treatment of PCOS (17, 18, 19). Estradiol valerate results in acyclicity and ovarian morphology resembling PCO (16, 17, 18, 19, 20, 21), but without the typical metabolic disturbances of human PCOS (21).
In another promising rat model, PCOS is induced by daily prepubertal exposure to testosterone for 7–35 d (22). In addition to typical PCO morphology and a majority of apoptotic follicles, the rats had disturbed glucose and insulin levels, indicating that high levels of androgens can lead to insulin resistance in this model. Letrozole, a nonsteroidal aromatase inhibitor that blocks the conversion of testosterone to estradiol, also induces PCOs in 6-wk-old female rats (23). Endocrine disturbances similar to those in human PCOS were observed, but the metabolic characteristics of the syndrome were not investigated (24).
The heterogeneity of the syndrome is reflected in the many animal models of PCOS. However, few rat models have focused on the metabolic disturbances that are a major feature of human PCOS. Therefore, new rat models exhibiting not only the ovarian but also the metabolic characteristics of the syndrome would be valuable. Such models would, for example, enable further evaluation of new treatments for PCOS.
PCOS is associated with excessive androgen production during early puberty (7). In this study we sought to determine if continuous administration of the nonaromatizable androgen 5
-dihydrotestosterone (DHT), specific for the androgen receptor (AR), from before puberty to adult age, induces both PCOs and metabolic abnormalities similar to those in human PCOS. The effects of letrozole, administered in the same fashion, were evaluated to determine if it produces the metabolic effects of PCOS. Ovarian morphology, hormonal and metabolic status, body composition, and adipocyte size in abdominal fat depots were investigated in all rats.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Study procedure
At 21 d of age, rats were randomly divided into three experimental groups [control (n = 13), DHT (n = 12), and letrozole (n = 11)] and implanted sc with 90-d continuous-release pellets (Innovative Research of America, Sarasota, FL) containing 7.5 mg DHT (daily dose, 83 µg) or 36 mg of letrozole (daily dose, 400 µg) (Novartis Pharma AG, Basel, Switzerland). The dose of DHT was chosen to mimic the hyperandrogenic state in women with PCOS, whose plasma DHT levels are approximately 1.7-fold higher than those of healthy controls (24, 25). The dose of letrozole was chosen according to a previous study (23). Controls received identical pellets lacking the bioactive molecule. A microchip (American Veterinary Identification Devices; Avid Identification Systems, Inc., Norco, CA) with an identification number was inserted sc in the neck along with the pellets. Rats were weighed weekly from 21 d of age. The study was concluded after 11–13 wk of drug administration, when the rats were 14–16 wk of age.
Vaginal smears
The stage of cyclicity was determined by microscopic analysis of the predominant cell type in vaginal smears obtained daily from 11 wk of age to the end of the experiment (26).
Body composition
Body composition was analyzed by dual-emission x-ray absorptiometry (DEXA) at 12 wk of age (i.e. 9 wk after implantation of the pellet) with a whole-body DEXA instrument (QDR-1000/W; Hologic, Waltham, MA). Rats were anesthetized by inhalation of isoflurane (2% in 1:1 mixture of oxygen and air; Abbott Scandinavia AB, Solna, Sweden) before scanning. Body fat, lean body mass (LBM), and bone mineral content (BMC) were determined for each rat. Body fat distribution was assessed by magnetic resonance imaging (MRI) (27). Rats were anesthetized as described previously and placed in a 7-T MRI system (Bruker BioSpin, Ettlingen, Germany). The distribution of sc and intra-abdominal fat was determined by analyzing the seventh axial slice and a coronal slice from the most caudal part of the kidney.
Blood sampling for lipid profile, leptin, and sex steroids
At 12 wk of age (9 wk after pellet implantation), tail blood was obtained after an overnight fast to assess the lipid profile and leptin concentrations. At 13–14 wk of age, blood samples were obtained in the estrus phase for analyses of progesterone, 17ß-estradiol, and testosterone. Plasma samples were stored at –20 C.
Euglycemic-hyperinsulinemic clamp
At 14–16 wk of age (11–13 wk after pellet implantation), rats were subjected to a euglycemic-hyperinsulinemic clamp (28) during the estrus phase. Rats were anesthetized with thiobutabarbital sodium (130 mg/kg ip; Inactin; Sigma, St. Louis, MO). Body temperature was maintained at 37 C with a heating blanket. Catheters were inserted into the left carotid artery for blood sampling, and into the right jugular vein for glucose and insulin infusions, and a tracheotomy was performed.
A baseline blood glucose sample was drawn directly into microcuvettes (10 µl) and analyzed with a B-glucose analyzer (HemoCue AB; Dronfield, Derbyshire, UK). Insulin (100 U/ml; Actrapid; Novo Nordisk, Bagsvaerd, Denmark) together with 0.2 ml albumin and 10 ml saline were infused at 24, 16, and 12 mU/min·kg for min 1, 2, and 3, respectively, followed by 8 mU/min·kg for the rest of the clamp. To maintain plasma glucose at a euglycemic level (6.0 mM), 20% glucose in saline was administered. The glucose infusion rate (GIR) was guided by glucose concentration measurements every 5 min. At steady-state (after 50–70 min), the mean GIR was normalized to body weight, and blood samples were taken to determine plasma insulin concentrations. An insulin sensitivity index was calculated (mean GIR/plasma insulin levels at steady-state x 102).
The rats were decapitated, and the ovaries were excised, fixed in neutral buffered 4% formaldehyde for 24 h, placed in 70% ethanol, dehydrated, and embedded in paraffin. The hind limb muscles (extensor digitorum longus, tibialis anterior, and soleus) and the parametrial, retroperitoneal, inguinal, and mesenteric fat depots were dissected and weighed.
Ovarian morphology
The ovaries were longitudinally and serially sectioned at 4 µm; every 10th section (n = 6 per ovary) was mounted on a glass slide, stained with hematoxylin and eosin, and analyzed under a conventional birefringence microscope by two persons blinded to the origin of the sections. For measurements and photographs, the slides were scanned with ScanScope (Aperio Technologies, Vista, CA) and analyzed with ImageScope virtual microscopy software (Aperio Technologies). The area of the ovary was determined with a calibrated scale tool in the virtual microscope. The area of the largest follicle and the thickness of its follicular wall, i.e. the theca cell layer and granulosa cell layer, were measured, and follicles were counted by two persons to avoid duplicate counting. The ovarian follicles and corpora lutea (CL) at different stages of development and regression, and the theca and granulosa cell layer were analyzed in detail.
Computerized determination of adipocyte size
Parametrial and mesenteric adipose tissues were cut into small pieces and treated with collagenase (Type A; Roche, Mannheim, Germany) in minimum essential medium (1.5 mg/ml; Invitrogen, Carlsbad, CA) containing 5.5 mM glucose, 25 mM HEPES, 4% bovine albumin (Fraction V; Sigma), and 0.15 µM adenosine (pH 7.4), for 50 min at 37 C in a shaking water bath (29). After filtration through a 250-µm nylon mesh, adipocytes were washed three times and suspended in fresh medium. The mean cell size and the size distribution were determined by computerized image analysis (KS400 software; Carl Zeiss, Oberkochen, Germany) (30). In brief, the cell suspension was placed between a siliconized glass slide and a coverslip, and transferred to the microscope stage. Nine random visual fields were photographed with a CCD camera (Axiocam; Carl Zeiss). Relevant surface areas were measured automatically, and diameters of the corresponding circles calculated. Uniform microspheres (diameter, 98.00 µm; Bangs Laboratories, Fishers, IN) served as a reference.
Analytical methods
Plasma concentrations of progesterone, testosterone, and 17ß-estradiol were determined with commercial double-antibody RIA kits (progesterone RIA kit, DSL-3400; testosterone RIA kit, DSL-4100; 3rd Generation Estradiol RIA kit, DSL-39100; Diagnostic Systems Laboratories, Webster, TX). Plasma concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) were determined enzymatically with a Konelab autoanalyzer 2.0 (Thermo Clinical Labsystems, Espoo, Finland). Plasma leptin concentration was similarly determined (rat leptin RIA kit, RL-83K; Lincon Research, St. Charles, MO). Human insulin, given during the clamp, was measured with an ELISA kit (10-1113-01; Mercodia, Uppsala, Sweden). All analyses are from the same rat and assay.
The intraassay and interassay coefficients of variation and sensitivity were: 7.5%, 8.1%, and 0.05 ng/ml (testosterone); 3.6%, 6.0%, and 0.6 pg/ml (estradiol); 5.1%, 2.5%, and 0.1 ng/ml (progesterone); 1.1%, 2.0%, and 0.1 mmol/liter (TC); 1.6%, 2.2%, and 0.04 mmol/liter (HDL); 1.0%, 2.5%, and 0.02 mmol/liter (TG); 3.3%, 4.8%, and 0.5 ng/ml (leptin); and 3.4%, 3.0%, and 1 mU/liter (human insulin).
Statistical analyses
Most statistical evaluations were performed with SPSS software (version 13.0; SPSS, Inc., Chicago, IL). Effects of DHT or letrozole on body weight were analyzed by repeated-measures ANOVA, and effects on body weight, tissue weight, ovarian morphology, insulin sensitivity, body composition, adipocyte size, lipid profile, and sex steroid and leptin concentrations by one-way ANOVA. Differences between groups and controls were tested with Dunnett’s post hoc test. Values are mean ± SEM. P < 0.05 was considered significant.
Regression analyses were performed using linear regression. Adipocyte size distribution curves were compared with the Kolmogorov-Smirnov two-sample test (KS) (31). An exact P value for the comparison of two groups (A and B) was calculated through permutations. For "n" subjects in group A and "m" subjects in group B, KS statistics were calculated for all possible ways of splitting n + m subjects into two groups of sizes "n" and "m." The observed KS statistic was then ranked against the KS statistics from all of the possible permutations. The permutation P value is the percentage of possible KS statistics that are at least as extreme as the KS statistic from the original data. For these comparisons, statistical calculations were performed with the R language (http://www.R-project.org).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
). The gain was more pronounced in the letrozole group.
|
). Light microscopic analysis showed no structural abnormalities, follicles, and CL in different stages of development and regression, and no ovarian cysts (Fig. 2A). The theca and granulosa cell layer were normal.
|
). Vaginal smears of both groups showed leukocytes, the dominant cell type of the diestrus phase, indicating "pseudo diestrus." Ovary weight and area were lower in DHT rats and higher in letrozole rats than in controls (Table 1). The area of the largest follicle was greater in letrozole rats than controls; a trend toward follicular enlargement was observed in DHT rats. A cystic follicle was considered to be a large fluid-filled cyst with an attenuated granulosa cell layer and thickened theca interna cell layer. The number of cystic follicles was increased, and the cystic wall was thickened, characterized by a thickened theca interna cell layer and a diminished granulosa cell layer, in DHT and letrozole rats compared with controls (Table 1 and Fig. 3). Consistent with the perturbed cyclicity in both groups, the ovaries displayed atretic antral follicles, follicular cysts with a thickened theca interna cell layer, and macrophages in the cyst fluid. In addition, letrozole rats had no CL.
|
|
, B and C). Some follicles were undergoing atresia and had many apoptotic granulosa cells, mainly in the inner layers of the membrana granulosa (Fig. 3B). Occasionally, apparently healthy tertiary follicles were present.
As in human PCOs, the increased number of cysts in letrozole rats was typically orientated in the periphery of the ovary (Figs. 2C and 4A). In some cysts, the inner wall was completely vascularized, and consisted of a thick layer of large and uniform luteinized cells with rounded nuclei containing a distinct central or pericentral nucleolus; occasionally two nucleoli were seen (Fig. 4, D–F). These cells were smaller and had less cytoplasm (Fig. 3E) than luteinized cells in the CL of cycling rats but were otherwise similar (Fig. 3F). In addition, luteinized granulosa cells in the letrozole group had nuclei identical in size (10 µm) to those in CL from normally cycling rats. In other cysts, the inner wall was formed by a partly vascularized cell layer composed of granulosa cells and luteinized cells (Fig. 4F). Mitotic endothelial cells, a sign of vascularization, were occasionally observed. There were no mitotic theca interna cells in any healthy tertiary follicles, or cystic follicles in the DHT or letrozole group.
|
). Progesterone was decreased in both experimental groups; 17ß-estradiol was unaltered.
|
DEXA.
At the time of DEXA measurements, both DHT and letrozole rats were heavier than the controls. Both groups had more body fat than controls, but body fat in relation to body weight was increased only in DHT rats (Table 3). LBM was increased in both DHT and letrozole rats; however, in relation to body weight, LBM was decreased in DHT rats. BMC was increased in both DHT and letrozole rats, but BMC in relation to body weight was lower in both groups than in controls (Table 3).
|
). In relation to body weight, the weights of the inguinal, parametrial, and retroperitoneal depots were increased in DHT rats.
|
). However, the ratio of tibialis anterior weight to body weight was decreased in both DHT and letrozole rats.
MRI.
Fat distribution was visualized by MRI (Fig. 5, A and B). Consistent with the impression from the MRI, the weight of both the sc (inguinal) (P < 0.001, ANOVA) and the intra-abdominal (parametrial, retroperitoneal, and mesenteric) (P < 0.05, ANOVA) adipose tissue in relation to body weight was increased in the DHT group; in the letrozole group, the relative weights of adipose tissues did not differ from control (Fig. 5C).
|
), and the mean mesenteric adipocyte size was larger than in controls (83.8 ± 3.74 vs. 71.6 ± 1.65 µm; P < 0.05, ANOVA). In letrozole rats, the size distribution curve (Fig. 6B) and mean adipocyte size (68.1 ± 4.01 µm) in mesenteric fat were similar to those in controls. In the parametrial fat depot, mean adipocyte size (DHT, 91.3 ± 6.01 µm; letrozole, 95.2 ± 7.88 µm; and control, 93.6 ± 4.16 µm) and adipocyte size distribution (data not shown) were unaltered. In each cell population, 359-7628 cells (mean 2685 ± 268) were analyzed. The mean diameter of the reference microspheres was 97.89 ± 0.050 µm (range 97.55–98.01; n = 9).
|
Decreased insulin sensitivity in DHT rats
The mean GIR was lower in DHT rats than in controls (14.0 ± 1.5 vs. 18.3 ± 1.5 mg/kg·min; P < 0.01), determined by a euglycemic-hyperinsulinemic clamp. Furthermore, insulin sensitivity index (ratio of mean GIR to steady-state plasma insulin level) was lower in DHT rats (ANOVA, P < 0.001) than in controls, indicating insulin resistance (Fig. 7). The mean GIR (21.4 ± 1.7 mg/kg·min) and the insulin sensitivity index (Fig. 7) were similar in letrozole rats and controls. At steady-state, the plasma glucose level was approximately 6 mmol/liter, and the plasma insulin levels were 193 ± 9 mU/liter (control), 270 ± 15 mU/liter (DHT), and 228 ± 11 mU/liter (letrozole).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
summarizes similarities and dissimilarities between DHT and letrozole exposed rats vs. controls and PCOS women vs. controls.
|
DHT rats had irregular cycles. Their ovaries had large, atretic antral follicles, follicular cysts with a thickened theca interna cell layer, a diminished granulosa cell compartment, and few fresh CL, as in PCOs. Androgens may facilitate early follicular differentiation (33). In subhuman primates, androgens promote the differentiation of primordial to primary follicles; oocyte-derived IGF-I has been implicated in this activation (34). The findings in our models are in line with these observations, indicating that androgens are the major cause of PCOs.
Ovarian morphology
In both experimental groups, ovarian cysts had a flattened epithelioid cell layer facing the antrum, similar to that in rat models of PCOs induced by dehydroepiandrosterone (35) or letrozole (36). This "epithelialization" of inner cell layers may reflect the transformation of outer granulosa cells during atresia (35, 36). Alternatively, dying apoptotic cells in atretic follicles may secrete soluble factors that recruit macrophages (37), which appear in the follicular fluid during atresia. The macrophages must cross and, therefore, disrupt the basement membrane separating the vascular membrana granulosa from the theca cell layer. Growth factors and cytokines from macrophages contribute to angiogenesis and proliferation of fibroblasts and smooth muscle cells (38), and may be involved in the vascularization of the atretic granulosa layer we observed. Therefore, the flat epithelial-like cells could be a new population of cells accompanying the endothelial cells at vascularization. We hypothesize that vascularization of the remaining healthy granulosa cells causes luteinization of those cells, as in the letrozole group; however, the molecular mechanism remains to be elucidated.
The cysts in letrozole-exposed rats resembled those in human PCO cysts described by Green and Goldzieher (39). The cyst wall in Fig. 3 is nearly identical to the vascularized wall they saw in an atretic follicle and interpreted as a thickened theca interna. We believe the thickened cyst wall consists of theca interna cells and a vascularized layer of luteinized granulosa cells. An "intermediate" stage of this process is suggested by the presence of granulosa cells imbedded in the cyst wall (Fig. 4). Therefore, the thickened "hyperplastic" theca interna in the cyst wall described in a letrozole PCO rat model similar to ours (23) may reflect luteinized granulosa cells rather than true hyperplasia.
Sex steroid concentrations
The plasma sex steroid profile of letrozole-exposed rats is consistent with findings in other rat models of letrozole-induced PCOs (23, 36). Testosterone levels were markedly higher in the letrozole rats than in controls, presumably because letrozole blocks the conversion of androgen substrates to estrogen, reflecting endogenous androgen accumulation. In both letrozole and DHT rats, progesterone production was decreased, indicating anovulation, as in human PCOS (40) and other rat models of letrozole-induced PCOs (23, 36). Estrogen levels were similar in all rats. Lower estradiol levels were expected because letrozole blocks aromatization of testosterone to estradiol, but were not observed. Estradiol levels vary considerably during the estrous cycle. We obtained blood samples for sex steroid measurements in the estrus phase in controls and in experimental rats with cyclic changes. Because estradiol levels are lowest in the estrus phase, this might explain the lack of difference between controls and letrozole-exposed rats.
DHT and letrozole could induce a hyperandrogenic status. But DHT rats had low plasma testosterone concentrations. However, because DHT was administered continuously, the endogenous production of androgens or testosterone was probably reduced in DHT-exposed rats; in men, androgen injections reduce endogenous androgen production (41). Furthermore, the DHT dose was chosen to initiate an androgenic status high enough to evoke a biological response.
We speculate that the effects in DHT rats are mediated by direct AR activation in target tissues, whereas those in letrozole rats are mediated by the accumulation of endogenous testosterone, which also results in pronounced activation and/or up-regulation of the AR.
Growth and body composition
In human PCOS, adiposity correlates with symptom severity (42, 43). DHT significantly increased the body weight of the rats, reflecting increased body fat, as well as intra-abdominal and sc adipose tissue depots in relation to body weight. Consistent with these findings, specific activation of the AR by DHT increases fat mass in orchidectomized (orx) male mice (44). As expected, the amount of body fat correlated with plasma leptin levels in pooled and individual groups of rats.
Sex steroids appear to be important in regulating adiposity and fat distribution. Visceral fat tends to accumulate in hyperandrogenic women (45), and fat mass, especially abdominal, in adolescents with PCOS is reduced by insulin-sensitizing treatment with metformin and specific AR blockade (46). PCOS women have increased fat mass and central adiposity related to hyperinsulinemia and hyperandrogenemia from prepuberty to postmenarche (47). These findings are consistent with the effects of DHT exposure in our study.
The increased body weight in letrozole rats was not related to relative changes in body fat or LBM. Thus, letrozole may stimulate general growth without affecting relative body composition. In combination with an aromatase inhibitor, testosterone increases the retroperitoneal fat mass in orx male mice, while testosterone itself does not (44).
Adipocyte size
Adipose tissue mass increases as a result of increased adipocyte size or number. The risk of metabolic complications is elevated by the amount and location of adipose tissue and adipocyte size. Adipocyte enlargement is associated with insulin resistance and is an independent predictor of type 2 diabetes (15, 48). In nonobese women with PCOS, sc adipocytes are about 25% larger, possibly as a result of lipolytic catecholamine resistance, than in healthy controls matched for body mass index (BMI) and body fat (14).
To analyze intra-abdominal adipose tissue depots, we used computerized image analysis that allows detailed assessment of mean adipocyte diameter and adipocyte size distribution (30). In parametrial adipose tissue, neither DHT nor letrozole influenced the mean size or size distribution of adipocytes. Thus, the increases in this depot likely reflect an increased number of adipocytes. However, in mesenteric adipose tissue, DHT increased mean adipocyte size. The borderline significance of the increase in mesenteric fat was probably mainly due to increased adipocyte size; however, we cannot exclude an increased number of adipocytes. Letrozole also tended to increase the mesenteric depot but did not influence adipocyte size, indicating that it, too, may increase the number of adipocytes in mesenteric fat.
In sum, in our rat model of DHT-induced PCOS, mesenteric adipocytes were larger than in controls or in letrozole rats with a similar amount of mesenteric fat. This enlargement may be analogous to the enlarged sc fat cells in nonobese women with PCOS (14).
Insulin sensitivity, leptin concentration, and lipid profile
In women with PCOS, insulin sensitivity is decreased by 35–40%, independently of obesity, although obesity further exacerbates insulin resistance (49), and an association between androgen and insulin levels has been suggested (50). DHT induced insulin resistance and increased abdominal fat mass and adipocyte size, as in women with PCOS and hyperandrogenemia (14, 49); both are independently associated with insulin resistance and prediction of type 2 diabetes (5). In female rats (51), testosterone administration induces insulin resistance, attributed to effects on glucose transport (52, 53); another finding was reduced capillary density in the muscle, despite increased muscle weight (51). Because DHT rats became insulin resistant, with increased body and muscle weight, they also might have had reduced capillary density in muscle. In line with our findings in DHT-exposed rats, elevated androgen levels are partly responsible for insulin resistance in muscle in PCOS women (54).
In contrast, letrozole did not decrease insulin sensitivity despite increasing testosterone levels. DHT might have a stronger, more direct effect than letrozole on insulin-signaling pathways. A challenge for future studies will be to elucidate the mechanisms.
Do women with PCOS have increased leptin levels? In one study, they had higher leptin levels than controls after adjustment for BMI (55). However, subsequent studies showed that leptin levels were similar in PCOS women and controls matched for age and weight or for BMI (56, 57). In our study, plasma leptin levels were higher in DHT rats than in controls and correlated with the amount of body fat. Hyperleptinemia is thought to indicate leptin resistance, which may contribute to the pathogenesis of obesity (58) and is strongly connected to insulin resistance (59).
Women with PCOS exhibit an abnormal lipoprotein profile, characterized by dyslipidemia (60); however, the results are not consistent. In orx mice, AR activation by DHT alters the serum lipid profile and increases fat mass (44). In the present study, both DHT and letrozole exposure increased fat mass but did not affect the lipid profile.
Conclusions
We believe the DHT model is preferable for studies of both ovarian and metabolic features, whereas the letrozole model is suitable for studies of the ovarian features of PCOS. Although none of the models address the etiology of PCOS, both models may be useful for assessing new treatments.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Disclosure Statement: The authors have nothing to disclose.
First Published Online May 10, 2007
Abbreviations: AR, Androgen receptor; BMC, bone mineral content; BMI, body mass index; CL, corpora lutea; DEXA, dual-emission x-ray absorptiometry; DHT, dihydrotestosterone; GIR, glucose infusion rate; HDL-C, high-density lipoprotein cholesterol; KS, Kolmogorov-Smirnov two-sample test; LBM, lean body mass; MRI, magnetic resonance imaging; orx, orchidectomized; PCO, polycystic ovary; PCOS, polycystic ovary syndrome; TC, total cholesterol; TG, triglyceride.
Received February 6, 2007.
Accepted for publication April 30, 2007.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1- and ß2-adrenergic receptors in rats with steroid-induced polycystic ovaries. J Neuroendocrinol 17:846–858[Medline]-reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88:2760–2766This article has been cited by other articles:
 |
|
 |
|
  S. Franks Do Animal Models of Polycystic Ovary Syndrome Help to Understand Its Pathogenesis and Management? Yes, but Their Limitations Should be Recognized Endocrinology, September 1, 2009; 150(9): 3983 - 3985. [Full Text] [PDF]
|
|
|
|
|
|
D. Shi, M. K. Dyck, R. R. E. Uwiera, J. C. Russell, S. D. Proctor, and D. F. Vine A Unique Rodent Model of Cardiometabolic Risk Associated with the Metabolic Syndrome and Polycystic Ovary Syndrome Endocrinology, September 1, 2009; 150(9): 4425 - 4436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Homburg Androgen circle of polycystic ovary syndrome Hum. Reprod., July 1, 2009; 24(7): 1548 - 1555. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Manneras, S. Cajander, M. Lonn, and E. Stener-Victorin Acupuncture and exercise restore adipose tissue expression of sympathetic markers and improve ovarian morphology in rats with dihydrotestosterone-induced PCOS Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2009; 296(4): R1124 - R1131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Demissie, M. Lazic, E. M. Foecking, F. Aird, A. Dunaif, and J. E. Levine Transient prenatal androgen exposure produces metabolic syndrome in adult female rats Am J Physiol Endocrinol Metab, August 1, 2008; 295(2): E262 - E268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Manneras, I. H. Jonsdottir, A. Holmang, M. Lonn, and E. Stener-Victorin Low-Frequency Electro-Acupuncture and Physical Exercise Improve Metabolic Disturbances and Modulate Gene Expression in Adipose Tissue in Rats with Dihydrotestosterone-Induced Polycystic Ovary Syndrome Endocrinology, July 1, 2008; 149(7): 3559 - 3568. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
