Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea
Condition: Oligomenorrhea; Amenorrhea; Polycystic Ovary Syndrome (PCOS)
MeSH terms: Polycystic Ovary Syndrome; Amenorrhea; Oligomenorrhea
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Women must be able to transport to Cornell University in Ithaca, NY. Eligible participants
        are between 18-35 years with a BMI of 18 kg/m2 or higher. Women are screened and enrolled
        following consent based on their response to our advertisements. Enrollment is restricted
        to the geographical area.
      
Biospecimen description: 
      Blood serum, subcutaneous fat
    
Keywords: Polycystic Ovary Syndrome (PCOS); Nutrition; Metabolism; Antral follicle growth; Menstrual Cyclicity