Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea
Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea
In women with regular menstrual cycles, antral follicles have been shown to grow in
 synchronous cohorts, called waves, 2-3 times in a menstrual cycle. It is unknown whether
 these waves of follicle growth also occur in women with amenorrhea or if there is
 abnormal/absent follicle growth. Further, oligo- or amenorrhea has been associated with
 metabolic disturbances, such as over- or under-nutrition, central obesity and insulin
 resistance. Yet, mechanisms whereby metabolic factors influence folliculogenesis in women are
 poorly understood. To understand potential mechanisms, the investigators plan to characterize
 follicle growth dynamics in women with or without regular menstrual cycles and identifying
 key metabolic differences in these women which may be important in normal follicle
 development and fertility.
In the ovaries, eggs rest in fluid filled sacs called follicles. When follicles grow they
 form small fluid-filled cysts that can be easily seen when we use ultrasound to view the
 ovaries. In women with regular menstrual cycles, groups of 10 to 20 follicles grow and
 regress at 2 or 3 different times during their cycle (usually over a 28- day period). Several
 of these follicles grow to a stage where they begin to develop the potential to ovulate - but
 in general only one follicle is chosen to ovulate. Thus, at any given time during the
 menstrual cycle, numerous fluid-filled follicles can be visualized in a woman's ovaries at
 various stages of development using transvaginal ultrasonography. In women with absent or
 infrequent menstrual cycles, very little is known about the growth patterns of their
 follicles and how factors such as metabolic hormones, might play a role in the failure to
 ovulate. Being underweight or overweight increases your chances of having irregular or absent
 menstrual cycles and that a history of abnormal reproductive function compounds a woman's
 risk for chronic diseases such as infertility, diabetes, hypertension, atherosclerosis and
 certain cancers. This is particularly the case for women with polycystic ovary syndrome
 (PCOS) that have menstrual cycles that appear to worsen or improve depending on their body
 weight and metabolic status. PCOS is an endocrine disorder that affects 6-12% of
 reproductive-aged women within the general population. The hallmark features of PCOS are
 menstrual irregularity, increased levels of androgens, and polycystic ovaries. The current
 diagnostic criteria require 2 out of 3 of these features to be present for the diagnosis,
 therefore a number of phenotypes of PCOS exist. However, the metabolic and reproductive
 differences across the phenotypic spectrum of PCOS are not well understood. Women with PCOS
 characteristically have polycystic ovaries, where up to 10 times more follicles are present
 in the ovary at any given time. Further, the follicle-size populations and overall
 distribution throughout the ovary varies in women - follicles may be situated around the
 periphery of the ovary or may be distributed throughout the ovary. Presumably these small
 follicles are arrested in development - but emerging data from the Lujan laboratory suggest
 that this is not the case. It is assumed that ovulation does not occur and that follicles do
 not grow in a normal wave pattern. In truth, no study has ever looked to see whether
 follicles are actually growing, regressing or are arrested in women with irregular/absent
 menstrual cycles. By comparing follicle wave dynamics, reproductive hormones and markers of
 metabolism in women with regular and irregular menstrual cycles, the researchers plan to
 identify what factors might explain why fertility potential and long-term health are
 compromised in some women but not in others. Further, we will determine if any of these
 metabolic factors are unique to PCOS representing specific metabolic risks or follicle growth
 impairment. The ultimate goal of this research is to understand how body composition,
 nutrition and metabolism regulate follicle development in women so we can better develop
 lifestyle and drug therapies to help women preserve their fertility and long-term health.
 Since obesity has recently become the leading cause of infertility in North America, these
 studies are especially important.

 To accomplish our objective, the investigators plan to recruit up to 40 women with regular
 menstrual cycles and up to 40 women with irregular/absent menstrual cycles. Our goal is to
 recruit an equal number of women in each group such that they are matched for age (18 - 35
 years old) and body mass index (BMI; Normal weight = 18 - 24 kg/m2; Overweight = 25 - 29
 kg/m2; Obese = 30kg/m2). Women will undergo serial ultrasonographic of their ovaries every
 other day from ovulation to ovulation in women with regular menstrual cycles or for 5 weeks
 in women with cycle irregularity. Blood samples will be collected at each visit. Ultrasound
 scans of the ovaries will be assessed for the total number, size, and distribution of
 follicles using ultrasound imaging techniques. Blood samples collected will be assayed to
 determine serum concentrations of luteinizing hormone (LH), follicle stimulating hormone
 (FSH), estradiol, progesterone, anti-müllerian hormone (AMH), and inhibin B. During day 3-5
 in women with regular menstrual cycles or at a time where no dominant follicle or corpus
 luteum is present, an early morning visit will be conducted to assess the following metabolic
 parameters : (1) 75-gram oral glucose tolerance test to characterize glucose and insulin
 dynamics at 0, 30, 60, 90, and 120 minutes post-glucose ingestion; (2) dual X-ray
 absorptiometry (DXA) scan to quantify body fat and lean muscle distribution; (3) vitals and
 anthropometry assessment to measure waist and hip circumference, height, weight, blood
 pressure, and heart rate, and (4) fasting blood tests to detect serum concentrations of
 androgens (i.e., total testosterone, androstenedione, free androgen index) and serum markers
 of metabolic syndrome (i.e., lipids and hemoglobin A1C); (5) optional subcutaneous fat biopsy
 to analyze fat cells, which represent a site of reproductive hormone synthesis.
Inclusion Criteria:

 -  Between 18 and 35 years

 -  BMI ≥ 18 kg/m2

 -  If ≥ 21 years old, must have had healthy pelvic exam w/in past 2 years

 Either:

 -  Regular menstrual cycles (21-35 days);

 -  Irregular menstrual cycles (>36 days) with or without a previous diagnosis of PCOS
 from a primary care provider

 Exclusion Criteria:

 -  Current use of medication(s) known or suspected to interfere with reproductive
 function (eg. oral contraceptives) or insulin sensitivity

 -  Pregnant or breastfeeding

 -  Not otherwise healthy