Ovarian Ultrasonography for the Clinical Evaluation of Polycystic Ovary Syndrome

The purpose of this study is to develop ultrasound criteria for polycystic ovaries for women
with PCOS across early, mid and late adulthood and to assess the impact of body composition
on these ultrasound criteria.. The study will also compare ultrasound features of the ovary
against or in combination with AMH (a hormonal biomarker) in predicting PCOS. This research
will help improve the diagnosis of PCOS by considering multiple markers (i.e., ultrasound
features and AMH levels) and multiple modifiers of those markers (i.e., age and adiposity).

As the name implies, the primary ultrasound feature used to diagnose PCOS is polycystic
ovaries (PCO). However, PCO have frequently been observed in healthy women, calling into
question the specificity of PCO to the condition of PCOS, as well as its ability to inform
progression of the disease and/or response to treatment. The Lujan laboratory recently showed
that the most widely accepted ultrasound criteria for PCO overlap with features of the normal
ovary, and their laboratory proposed new thresholds to redefine PCO. These new criteria
represented a significant change in the definition of PCO owing to the improved resolution of
new technology. That said, these new criteria are still limited. They do not account for
factors known or suspected to influence ovarian morphology. For example, follicle counts and
ovarian size increase at puberty and decrease with age. Additional results from the Lujan
laboratory showed that follicle number per ovary (FNPO) thresholds for women in later
adulthood (35-38y) were substantially lower than those in early (18-25y) and mid-adulthood
(26-34y). Furthermore, the new criteria for PCO do not account for a potential impact of
adiposity on ovarian morphology. In the same study, conducted by the Lujan laboratory,
overweight women exhibited more 6-9mm follicles than lean women, irrespective of androgen
status.

Lastly, there is significant interest in determining whether AMH can serve as a surrogate to
sonographic measures to define PCO. AMH is a peptide hormone produced by the granulosa cells
of growing follicles and circulating levels represent secretions by antral follicles ≤8mm.
Accordingly, serum AMH is increased in women with PCOS, reflecting the accumulation of 2-5mm
antral follicles and greater production by granulosa cells of PCO compared to normal ovaries.
Excess AMH is thought to inhibit follicle growth and selection. Unlike discrete aspects of
ovarian morphology (i.e. follicle number or size),85 AMH levels remain largely constant
throughout the normal menstrual cycle.Such stability may make AMH a more advantageous
functional and surrogate morphological indicator of ovarian status compared to morphologic
features. Further, some have argued that the variability in ultrasound assessments, and
unsuitability of transvaginal approaches in certain clinical populations, justify the pursuit
of a less onerous biomarker of PCO. However, there is significant bias across AMH assays and
a consensual threshold for AMH to define PCO has not been determined. Proposed thresholds
were hindered by heterogeneity in assay performance and in the clinical cohorts assessed.
Ultimately, the ability of AMH to serve as a surrogate marker for PCO remains unknown and
should be evaluated against sonographic measures in well-defined cohorts with improved
assays. In this study, the researchers plan to refine the sonographic definition of PCO by
establishing age-specific criteria that maintain sensitivity and specificity for PCOS in both
lean and overweight populations. They will also clarify any ability of anti-Müllerian hormone
(AMH) to better inform the diagnosis of PCOS.

To accomplish these objectives, the investigators plan to recruit 120 women with regular
ovulatory cycles and 120 women with PCOS. Within each of these categories, the investigators
plan to recruit 20 lean and 20 overweight women in each age group: 18-24y (early), 25-34y
(mid), ≥35y (later adulthood). Ultrasound scans of the ovaries will be assessed for the total
number, size, and distribution of follicles using both two- and three-dimensional imaging
techniques. Additionally, participants will have blood samples collected to determine serum
concentrations of AMH. Because features of the ovaries are expected to be different in lean
and overweight women, the researchers hope to develop ultrasound criteria that will help
healthcare providers to diagnosis specific ovulation problems in women across all body sizes
and ages. This project addresses the need to improve methods and criteria used to define PCO
across clinical populations.

Inclusion Criteria:

- Aged >18 years

- At least 2y post-menarche

- BMI >18.5kg/m2

- Good visibility of the ovaries on ultrasound

- Pelvic exam with normal results within the last 2 years

Either:

- Regular menstrual cycles (21-35 days);

- Irregular menstrual cycles (>36 days); or

- Previous diagnosis of PCOS from a primary care provider

Exclusion Criteria:

- Use of medication(s) known or suspected to interfere with reproductive function,
metabolism, and/or appetite (e.g., oral contraceptives) within the past 3 months

- Use of fertility medications in the past 2 months (e.g., Clomid)

- Current use of a non-copper intrauterine device for contraception (e.g., Mirena)

- Diagnosis of premature ovarian failure, endometriosis, or another disease/disorder
(other than PCOS) known or suspected to interfere with reproductive function

- History of ovarian surgery

- Missing uterus or an ovary

- Pregnant or breastfeeding

- Diagnosis of a bleeding disorder

- Regular use of blood thinners/anticoagulants

- Skin allergy/condition that might be aggravated by alcohol application

- Currently being treated for a vaginal infection, cervical infection, sexually
transmitted infection, or disease either with antibiotics, antifungals, or anti-viral
medication

- Abnormal vaginal discharge, pelvic pain, and/or blisters/lesions/warts/skin growths in
the genital/anal area, which have not been examined by a medical professional.

- Vaginal abnormality (e.g., vaginal atresia/hypoplasia, vaginal septation, Mullerian
agenesis, vulvar/vaginal malignancy).

- Not otherwise healthy