Abstract
This pilot study describes a relationship between insulin resistance and µ-opioid neurotransmission in limbic appetite and mood-regulating regions in women with polycystic ovary syndrome, suggesting that insulin-opioid interactions may contribute to behavioral and reproductive pathologies of PCOS. We found that 1) insulin resistant PCOS patients (n=7) had greater limbic µ-opioid receptor availability (non-displaceable binding potential) than controls (n=5), 2) receptor availability was correlated with severity of insulin resistance, and 3) receptor availability normalized after insulin-regulating treatment.
Keywords: Positron emission tomography, glucose regulation, mu-opioid receptors, neuroimaging, beta-endorphins, PCOS, insulin resistance
Polycystic ovary syndrome (PCOS), the most common endocrine disorder in young women(1), affects up to 18% of reproductive-aged women(2). Reproductive and metabolic disruptions include hyperandrogenism and infertility, insulin resistance (IR), and a higher prevalence of impaired glucose tolerance and type 2 diabetes(3–9).The endogenous opioid system may contribute to PCOS pathogenesis, through central effects on gonadotropin secretion and peripheral effects on glucose metabolism(10–16). Endogenous opioidsmediate insulin’s neuromodulatory effects, and almost 90% of cells containing insulin receptors are immunoreactive for the µ-opioid receptor (µOR) agonistβ-endorphin, suggesting interactions between insulin and opioid neurotransmission(17, 18).
Opioid abnormalities in PCOS and the impact of potential modulation by insulin are presently unknown, but evidence suggests decreased central opioid sensitivity in PCOS patients.Luteal phase luteinizing hormone (LH) pulsatility slowing by progesterone, which is largely absent in PCOS, is mediated by GnRH release inhibition by β-endorphin(19, 20). CNS opioid system changesin PCOS patientshave not been reported.
We evaluated IR effects on µORs in women with insulin resistant PCOS (IR-PCOS), and used positron emission tomography (PET) with the µ-receptor selective radiotracer [11C] carfentanil(21, 22) to compare receptor availabilityto non-IR controls, and to assess the ability of the hypoglycemic agent metformin to restore µOR concentrations. We hypothesized decreased opioid activity in IR-PCOS, reflected by unbound µORs, and increased opioid activity after metformin treatment, in the β-endorphin projection regions nucleus accumbens/ventral pallidum and amygdala(23).
Women aged 21 – 40 years were recruited intoIR-PCOS patients (n=7) andnon-IRcontrols (n=5) groups. PCOS criteriawere irregular menstrual cycles/amenorrhea and hyperandrogenism(24). IR was estimated using the homeostatic model (HOMA2-IR; glycemia(mmol/1) × insulinemia(µU/ml)/22.5)(25), using HOMA2-IR sensitivity ≤60%(26). Controls had regular menstrual cycles, normal androgens and glucose tolerance,no hirsutism or acne, and HOMA2-IR sensitivity ≥80%.
Participants were healthy, right-handed, nonsmokers, excluded forsignificant illness including diabetes, hormones within 2 months, pregnancy within 6 months, centrally-acting medications, substance abuse,MRI contraindications, corticosteroid, cimetidine use, and opioid allergy.
Women underwent medical histories, physical exam, and fasting glucose, insulin, 2 hour 75g dextrose oral glucose tolerance test (OGTT), free and total testosterone, dehydroepiandrosterone sulfate (DHEAS), lipids, blood count, TSH, electrolytes, and liver function screening.
Procedures were approved by the University of Michigan Institutional Review Board and Radiation Safety Review Committee. Written informed consent was obtained.
MRI and [11C]carfentanil PET scansoccurredduring the follicular phase, if cycling.. IR-PCOS patients subsequently began metformin (500mg titrated to1500mg daily). PET scan and OGTT were repeated after four months of treatment.
Subjects underwent one (controls) or two (PCOS patients) 70 minute PET scans (HR+ scanner;Siemens, Knoxville) in 3-dimensional mode (reconstructed full-width/half-maximum resolution, ≈5.5mm in plane, 5.0mm axially), with septa retracted and scatter correction, collecting 28 increasing duration frames. Tracer quantity [11C]carfentanil was administered (10–15mCi, ≤0.03µg/kg) via intravenous line (50% in initial bolus and remainder continuously infused for constant concentrations). [11C]carfentanil was synthesized athigh specific activity by the reactionof [11C]methyl iodide and a normethyl precursor(27).
Images were decay-corrected and reconstructed, and the dynamic frames coregistered to each other and transformed into tracer transport (K1 ratio) and receptor-related(BPND, binding potential) measures, using the occipital cortex as reference region, which lacks µORs,calculated using a modified Logan graphical analysis(28). After 5–7 minutes of radiotracer administration, the Logan plot becomes linear with slope=BPND+1, which is proportional to µORconcentration (Bmax)/receptor radiotracer affinity (Kd) (Bmax/Kd ≈ BPND).
Anatomical MR images were acquired axially with a 3T scanner (GE, Milwaukee) with a spoiled gradient recalled 3D volumetric acquisition (repetition time= 9.6, echo time=3.3, inversion recovery preparation=200ms, flip angle=17°, bandwidth=15.63, 24-cm field-of-view, 1.5mm slice thickness, 106–110 slices, 256×256 matrix, 2 excitations). T1-weighted MR and PET images were coregistered to each other and the International Consortium for Brain Mapping/Montreal Neurological Institute (ICBM/MNI) template(29).
PET images were analyzed usingSPM2(Wellcome Cognitive Neurology, London) and SPSS (SPSS Inc., Chicago). Groupcomparisons were performed using unpaired (control versus PCOS) or paired (pre- versus post-metformin) T tests on µOR BPND data extracted from the nucleus accumbens/ventral pallidum and amygdala. Significance was set at p<0.001 uncorrected with a priori hypotheses. Relationships between µORBPND and IRwere determined using Pearson correlations at p<0.05.
Demographic and clinical information is provided in Table 1A. Mean (SD)age was 26.1 (3.5). PCOS women had oligomenorrhea (cycle length>35 days), and had higher BMI, weight, waist circumference, total and free testosterone, insulin, and HOMA-IR compared to controls. Improvements following metformin treatment did not reach statistical significance.
A. Demographic and clinical measures | ||||||||
---|---|---|---|---|---|---|---|---|
Control | PCOS | pa | PCOS | pb | ||||
n: 5 controls & 7 PCOS patients |
pre- metformin |
control vs. pre- metformin |
post- metformin |
pre- vs. post- metformin |
||||
Median (IQR) | Median (IQR) | Median (IQR) | ||||||
Age (yr) | 26 | (8) | 25 | (6) | 0.742 | |||
Education (yr) | 16 | (4) | 17 | (4) | 0.743 | |||
Weight (lb) | 123.7 | (35.3) | 203.9 | (85.8) | 0.007 | 187.1 | (98.6) | 0.499 |
BMI | 23.0 | (3.1) | 35.3 | (16.2) | 0.019 | 31.7 | (15.4) | 0.108 |
Waist circumference (cm) | 72.0 | (13.5) | 102.0 | (27.6) | 0.004 | 94.5 | (27.6) | 0.176 |
Free testosterone (pg/ml) | 0.5 | (0.2) | 1.5 | (0.9) | 0.006 | |||
Total testosterone (ng/ml) | 0.36 | (0.32) | 0.70 | (0.51) | 0.073 | |||
DHEAS (ug/dL) | 189 | (88) | 200 | (88) | 0.927 | |||
Total cholesterol (mg/dl) | 179 | (60) | 157 | (46) | 0.073 | |||
HDL (mg/dl) | 76 | (24) | 47 | (17) | 0.073 | |||
Triglycerides (mg/dl) | 72 | (37) | 74 | (42) | 0.416 | |||
Fasting insulin (uU/ml) | 8.1 | (0.9) | 21.4 | (5.1) | 0.004 | 18.7 | (11.5) | 0.398 |
Fasting glucose (mg/dl) | 89 | (7) | 87 | (15) | 0.683 | 94 | (14) | 0.400 |
HOMA % sensitivity | 95.4 | (12.8) | 36.6 | (9.3) | 0.004 | 43.6 | (42.2) | 0.398 |
HOMA insulin resistance | 1.0 | (0.2) | 2.7 | (0.6) | 0.004 | 2.4 | (1.5) | 0.225 |
B. In vivo µ-opioid receptor availability before and after metformin treatment | ||||
---|---|---|---|---|
PCOS pre-metformin > | ![]() |
|||
PCOS post-metforminc | ||||
Left Nucleus Accumbens |
Right Nucleus Accumbens |
Left Amygdala |
Right Amygdala |
|
µ-Opioid binding potential (mean ± SD)d | Mean ± SD | Mean ± SD | Mean ± SD | Mean ± SD |
PCOS (pre-metformin) | 1.95 ± 0.17 | 2.40 ± 0.11 | 2.28 ± 0.17 | 2.28 ± 0.23 |
PCOS (post-metformin) | 1.65 ± 0.27 | 2.11 ± 0.21 | 2.08 ± 0.19 | 2.11 ± 0.22 |
Control | 1.53 ± 0.28 | 2.05 ± 0.28 | 2.03 ± 0.07 | 2.06 ± 0.26 |
Binding potential correlation (R(p))e | R (p) | R (p) | R (p) | R (p) |
Fasting insulin (mU/mL) | .633 (.027) | .706 (.010) | .618 (.032) | .303 (.339) |
HOMA % sensitivity | −.689 (.013) | −.737 (.006) | −.610 (.035) | −.315 (.319) |
HOMA insulin resistance | .643 (.024) | .720 (.008) | .634 (.027) | .306 (.333) |
Mann-Whitney test between controls and PCOS patients pre- -metformin treatment
Wilcoxon signed ranks test between PCOS patients before and after metformin treatment
Regions with greater µ-opioid receptor binding potential in pre-treated patients (T test, compared to post-treatment)
µ-Opioid binding potential expressed as Bmax/Kd; Bmax = receptor concentration and Kd = receptor affinity for radiotracer
Pearson correlation coefficient and 2-tailed significance level across controls and PCOS patients pre-insulin regulation
Baseline µ OR BPND was greater in IR-PCOS women than controls in the nucleus accumbens/ventral pallidum (coordinates, x,y,z (mm), left −6,−4,−12, cluster size 3088mm3, p=0.009; right 10,0,−10, cluster size 2912mm3, p=0.012) and amygdala, bilaterally (left −26,−8,−24, cluster size 896mm3, p=0.045; right 18,−4,−22, cluster size 416mm3, p=0.161).
After 4 months of metformin treatment, BPND in IR-PCOS women was reduced in the nucleus accumbens/ventral pallidum by15.2(10.5)% (left, t=3.95, p=0.008) and 12.2(7.7)% (right, t=4.26, p=0.005) and in the amygdala by 8.7(7.2)% (left, t=3.07, p=0.022) and 7.1(7.7)% (right, t=2.66, p=0.038). BPND values were not statistically different from controls.
Baseline regional µORBPND was correlated with IR (fasting insulin, HOMA% sensitivity and HOMA-IR) for the nucleus accumbens/ventral pallidum bilaterally and the left amygdala (table 1b). The change in µORBPND after treatment was not significantly correlated withIR improvements.
This is the first study to evaluate the link betweenopioid neurotransmission and IR in PCOS.We focused our analysis on the amygdala and nucleus accumbens, limbicβ-endorphin neurotransmission projection areaswith reproductive, metabolic, appetite, and mood function, all of which can be disordered in PCOS(8, 30, 31). We found that IR-PCOS patientsshowed greater µORavailability in these regions thannon-IRcontrols. Four months of metformin treatment decreased receptor availability to levels similar to controls. These resultssupport insulin modulation of central opioid activity in PCOS.
Insulin receptorsare expressed in proopiomelanocortin (POMC) containing neurons, the precursor of β-endorphin. Arcuate nucleus POMC neurons project to the amygdala, nucleus accumbens and hypothalamus, where they regulate mood, reward processing, including food reward, and the hypothalamic-adrenal and hypothalamic-gonadal axes(32–35). Detection of altered opioid receptor measures in IR-PCOS patients in these regions provides information about PCOS pathophysiology, and suggests a mechanism to explain neuroendocrine dysregulation, increased incidence of depression, and appetite dysregulation and obesity associated with PCOS(8, 30, 36).
A classic neuroendocrine feature of PCOS is rapid and high amplitude LH pulses(37, 38). Opioids are believed to mediate sex steroids negative feedback on gonadotropin release via the hypothalamus and amygdala(21, 39).Although we did not test for presynaptic opioid release, altered µORavailability in the IR-PCOS subjects may indicate reduced central opioid activity and compensatory receptor upregulation. Consistent with the hypothesized relationships between µORavailability and insulin, we observed positive correlations between baseline µORBPND andIR.Metformin treatment normalized µORBPND in IR-PCOS patients, suggesting that improved insulin sensitivity restores dysregulated opioid neurotransmission, consistent with research showing that chronic opioid receptor antagonism has metabolic and reproductive effects only in PCOS patients with IR(10–12, 40–43).
Altered opioid function in IR-PCOS may contribute to appetite and mood difficulties observed in PCOS(8, 30, 36, 44). Opioid transmission in the ventral pallidum/nucleus accumbens regulates reward processing and hedonic function/motivation, and µORagonistsstimulate food-intake and appetite for high-fat/high-glucose foods through amygdala and nucleus accumbens reward circuitry(34, 35, 45–47). The ventral basal ganglia and amygdala’s rich population of µORsregulate affective states(32). In women, major depression is associated with opioid system dysregulation in the amygdala(33). Abnormal glucose metabolism is also linked to depression, and diabetesprevalence is 2–3 times higher in depressed individuals (48–50).
Study strengths include intrasubject design and control comparison.Limitationsare sample size, lack of placebo, and no comparison with non-IR PCOS women.Hypothalamic nucleiare not easily assessed with PET because of size, limitedresolution,and averaging of activity with surrounding areas. In future studies, a challenge intervention to induce endogenous opioid release would allow presynaptic function evaluation, and distinguish isolated changes in receptor availability from alterations in presynaptic endogenous opioid tone(22, 29, 51).
The endogenous opioid systemmay represent an essential link in the interface between the reproductive and metabolic systems. While further study is required to understand the complex relationship between insulin function and opioid transmission in PCOS, this pilot study provides strong initial evidence of altered metabolic-opioid system interactions in IR women with PCOS. We found altered µORavailability prior to metformin treatment in regions that regulate appetite and mood, and modulation of receptor sites after metformin treatment. Our results suggest that insulin-opioid interactions contribute to behavioral and reproductive pathologies of PCOS, which should be explored in comprehensive larger-scale studies.
ACKNOWLEDGEMENTS
We thank the University of Michigan PET Center and fMRI laboratory, Anne Tkaczyk for study coordination, and especially the participants of our study.
Grants and fellowships supporting the writing of this paper:
This work was supported by the National Center for Research Resources (UL1RR024896), the University of Michigan Office of the Vice President for Research and the fMRI Laboratory Pilot Program, and for investigator support, by the National Institute for Child Health and Human Development (5T32HD007048), the University of Michigan Postdoctoral Translational Scholars Program,and the Phil F. Jenkins Research Fund. This work utilized Chemistry Laboratory Core of the Michigan Diabetes Research and Training Center funded by DK020572 from the National Institute of Diabetes and Digestive and Kidney Diseases.
Footnotes
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