Endothelial Dysfunction in Adolescents and Women With PCOS
Although adult women with PCOS demonstrate evidence of endothelial dysfunction, little is
known regarding alterations in the number of pro-inflammatory monocytes, CEC, CPC, and ECFC
(endothelial injury/repair profile) among affected women. For many women, the clinical
manifestations of PCOS emerge during adolescence. Based on studies documenting the increased
prevalence of MetS and inflammatory markers in adolescent girls with PCOS, and non-invasive
studies documenting the presence of endothelial dysfunction in children with traditional
cardiovascular risk factors, it is likely adolescent girls with PCOS already manifest
evidence of early vascular dysfunction, which may in turn impair follicular development and
contribute to the development of infertility.
Consequently, we hypothesize that perturbations in the balance between circulating
inflammatory and progenitor cells contribute to the endothelial dysfunction observed in
adult women with PCOS. Specifically, we anticipate that PCOS women will manifest greater
evidence of vascular injury (increased numbers of inflammatory monocytes, CEC, and ECFC) and
impaired endothelial repair (decreased levels of CPC) compared with control women. Moreover,
we propose that, in adolescent girls with PCOS, endothelial dysfunction and corresponding
alterations in the endothelial injury/repair profile are already present.
Specific Aim 1: Determine if the endothelial injury/repair profile (inflammatory monocytes,
CEC, CPC, and ECFC) assessed by flow cytometry (PFC) and endothelial function (assessed by
flow-mediated vasodilation (FMD) of the brachial artery) are altered in treatment-naïve
adult (18-40 years of age) women with PCOS (n=15) compared with age and body mass index
(BMI)-matched control women (n=15).
Specific Aim 2: Determine if the endothelial injury/repair profile assessed by PFC, AGE
levels, and endothelial function (assessed by FMD of the brachial artery) are altered in
treatment-naïve adolescents (14-17 years of age) with PCOS (n=15) compared with age and
BMI-Z-score-matched control girls (n=15).
Specific Aim 3: Determine if observed alterations in the endothelial injury/repair profile
(pro-inflammatory monocytes, CEC, CPC and ECFC) or levels of AGE correlate with endothelial
function (assessed by FMD of the brachial artery) in adolescent and adult women with (n=30)
and without PCOS (n=30), and whether androgens, insulin resistance, or other cardiovascular
risk factors influence these relationships.
This is a cross-sectional study design involving 30 post-menarchal adolescents and 30 adult
female subjects. Specifically, the adolescent population will include 15 treatment-naïve
adolescent females (ages 14-17 years) with PCOS and 15 age- and BMI-percentile-matched
control adolescent subjects. Similarly, the adult study population will include 15
treatment-naïve adult females (ages 18-40 years) with PCOS and 15 age- and BMI-matched
control women. All study procedures will be conducted at the Clinical Research Services Unit
(CRSU) at Virginia Commonwealth University (VCU) during a single visit (~3.5 hrs).
Subjects will be admitted to the CRSU after a 12-hour overnight fast. Subjects will also be
instructed to refrain from vigorous physical activity for 24 hours prior to the visit. All
participants will undergo a detailed medical history (including a menstrual history) and a
complete physical examination (including assessments of Tanner Staging for breast and pubic
hair development). Hirsutism will be assessed using the modified Ferriman-Gallwey scoring
At the study visit, the following anthropometric measurements with be performed on all
- Blood pressure obtained in left arm - 3 readings at 5 minute intervals
- Height (2 measurements)
- Weight (2 measurements)
- Waist/umbilicus/hip circumference measurements (2 measurements)
At the study visit a resting electrocardiogram (ECG) will be obtained for all subjects.
At the study visit, the following labs will be obtained on all subjects:
- Comprehensive metabolic panel
- Lipid panel
- Urine pregnancy
- Testosterone* *These analyses are to be performed only when additional eligibility
screening is needed and only at PI request.
All subjects will undergo measurement of brachial artery flow-mediated vasodilation (FMD).
FMD testing will be performed by the PI or Co-Investigator in the CRSU Peripheral Vascular
Lab with the assistance of a trained technician using an ultrasound peripheral vascular
imaging system. Adult subjects only will also undergo brachial artery reactivity testing for
the assessment of non-endothelial dependent (NED) vessel dilation following the
administration of nitroglycerin. NED testing will be performed following a rest period of at
least 15 minutes from completion of the FMD testing. 400 μg of nitroglycerin will be
administered sublingually, and images will be recorded for at least 3 minutes following the
administration of nitroglycerin.
Following the FMD testing (allow 30 minute interval), all subjects are to undergo a 2-hour
75 g oral glucose tolerance test.
• Samples collected at baseline (-15 and 0) and 30 minute intervals for glucose, insulin
Observational Model: Case Control, Time Perspective: Cross-Sectional
Peripheral vascular imaging via ultrasonography during brachial artery flow-mediated vasodilation (FMD)
A blood pressure cuff is placed on right forearm. A 7-12MHz linear array ultrasound transducer is placed on upper arm. 2-D and Doppler images are acquired. Forearm cuff is inflated to ~ 50 mmHg above resting systolic blood pressure (max 300 mmHg) for 4.5 minutes, then deflated. Blood flow velocity via Doppler is recorded for 15 seconds; 2D-images of the brachial artery are collected for 3 minutes. Brachial artery diameter is measured at end diastole (R-wave on ECG).FMD is determined: %FMD=(LDp-LDb)/LDbx100, where LDp=luminal diameter after inflation and LDb=luminal diameter at baseline
~ 30 minutes
Edmond Wickham, MD
Virginia Commonwealth University
United States: Federal Government
U54HD034449- Wickham Pilot
|Virginia Commonwealth University||Richmond, Virginia|