Overview
Study to Assess Potential Impairments in Estradiol Augmentation of Gonadotropin Secretion in Polycystic Ovary Syndrome
Status:
Recruiting
Recruiting
Trial end date:
2025-12-01
2025-12-01
Target enrollment:
0
0
Participant gender:
Female
Female
Summary
The purpose of this study is to determine if estradiol augmentation of luteinizing hormone (LH) secretion secretion (primary endpoint) and follicle-stimulating hormone (FSH) secretion (secondary endpoint) is reduced in adult women with polycystic ovary syndrome.Phase:
Early Phase 1Accepts Healthy Volunteers?
Accepts Healthy VolunteersDetails
Lead Sponsor:
University of VirginiaTreatments:
Estradiol
Estradiol 17 beta-cypionate
Estradiol 3-benzoate
Estradiol valerate
Polyestradiol phosphate
Criteria
Inclusion Criteria:- PCOS group: post-pubertal (> 4 years post-menarche) adult woman aged 18-30 years with
PCOS, defined as clinical and/or laboratory evidence of hyperandrogenism (hirsutism
and/or elevated serum [calculated] free testosterone concentration) plus ovulatory
dysfunction (irregular menses, fewer than 9 per year), but without evidence for other
potential causes of hyperandrogenism and/or ovulatory dysfunction
- Control group: post-pubertal (> 4 years post-menarche) adult woman aged 18-30 years
with regular menstrual periods (every 26-35 days) and no evidence of hyperandrogenism
(i.e., no hirsutism, normal serum [calculated] free testosterone concentration)
- General good health (excepting overweight, obesity, PCOS, and adequately-treated
hypothyroidism)
- Capable of and willing to provide informed consent
- Willing to strictly avoid pregnancy with use of reliable non-hormonal methods during
the study period
Exclusion Criteria:
- Inability/incapacity to provide informed consent
- Males will be excluded (hyperandrogenism is unique to females)
- Age < 18 years (we do not propose to study children because we have no preliminary
data that would support this particular study in children)
- Age > 30 years (since ovarian reserve may decrease beyond age 30)
- Obesity resulting from a well-defined endocrinopathy or genetic syndrome
- Positive pregnancy test or current lactation
- Evidence for non-physiologic or non-PCOS causes of hyperandrogenism and/or anovulation
- Evidence of virilization (e.g., rapidly progressive hirsutism, deepening of the voice,
clitoromegaly)
- Total testosterone > 150 ng/dl, which suggests the possibility of virilizing ovarian
or adrenal tumor
- DHEA-S greater than upper reference range limit for controls; and DHEA-S elevation >
1.5 times the upper reference range limit for PCOS. Mild elevations may be seen in
PCOS, and will be accepted in this group.
- Early morning 17-hydroxyprogesterone > 200 ng/dl measured in the follicular phase,
which suggests the possibility of congenital adrenal hyperplasia (if elevated during
the luteal phase, the 17-hydroxyprogesterone will be repeated during the follicular
phase). NOTE: If a 17-hydroxyprogesterone > 200 ng/dl is confirmed on repeat testing,
an ACTH stimulated 17-hydroxyprogesterone < 1000 ng/dl will be required for study
participation.
- Abnormal thyroid stimulating hormone (TSH): Note that subjects with stable and
adequately treated primary hypothyroidism, reflected by normal TSH values, will not be
excluded.
- Hyperprolactinemia: Any degree of hyperprolactinemia (confirmed on repeat) will be
grounds for exclusion for subjects without PCOS. Hyperprolactinemia > 20% higher than
the upper limit of normal will be grounds for exclusion for subjects without PCOS.
Mild prolactin elevations may be seen in PCOS, and elevations within 20% higher than
the upper limit of normal will be accepted in this group.
- History and/or physical exam findings suggestive of Cushing's syndrome, adrenal
insufficiency, or acromegaly
- History and/or physical exam findings suggestive of hypogonadotropic hypogonadism
(e.g., symptoms of estrogen deficiency) including functional hypothalamic amenorrhea
(which may be suggested by a constellation of symptoms including restrictive eating
patterns, excessive exercise, psychological stress, etc.)
- Persistent hematocrit < 36% and hemoglobin < 12 g/dl
- Severe thrombocytopenia (platelets < 50,000 cells/microliter) or leukopenia (total
white blood count < 4,000 cells/microliter)
- Previous diagnosis of diabetes, fasting glucose > or = 126 mg/dl, or a hemoglobin A1c
> or = 6.5%
- Persistent liver panel abnormalities, with two exceptions. Mild bilirubin elevations
will be accepted in the setting of known Gilbert's syndrome. Also, mild transaminase
elevations may be seen in obesity/PCOS; therefore, elevations < 1.5 times the upper
limit of normal will be accepted in these groups.
- Significant history of cardiac or pulmonary dysfunction (e.g., known or suspected
congestive heart failure, asthma requiring intermittent systemic corticosteroids,
etc.)
- Decreased renal function evidenced by GFR < 60 ml/min/1.73m2
- A personal history of breast, ovarian, or endometrial cancer
- History of any other cancer diagnosis and/or treatment (with the exception of basal
cell or squamous cell skin carcinoma) unless they have remained clinically disease
free (based on appropriate surveillance) for five years
- History of allergy to transdermal estradiol patches
- BMI < 18 or > 40 kg/m2; BMI < 18 kg/m2 is considered to be underweight, while > 40
kg/m2 is considered to be class 3 obesity -- both may have marked confounding effects
for the outcomes of interest
- Menstrual cycles lasting fewer than 26 days: Cycle frequency < 26 days suggest the
possibility of relatively short follicular phases (e.g., < 12 days). If a subject with
a follicular phase shorter than 12 days participates in Aim 1c, they could experience
an endogenous gonadotropin surge under surveillance. Since we wish to capture only
experimentally-induced surges, we will exclude such subjects.