Estrogen Deficiency and Mechanisms of Fat Accumulation
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 79
- 试验地点
- 1
- 主要终点
- Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression
研究概览
简要总结
The purpose of this study is to evaluate potential mechanisms by which estradiol deficiency accelerates fat gain and abdominal fat accumulation in women.
详细描述
Many factors contribute to the current epidemic of obesity. Although estrogen status is not commonly recognized as a determinant of obesity risk in women, there is strong evidence from large randomized controlled trials that estradiol (E2)-based hormone therapy (HT) reduces weight gain by about 40% in postmenopausal women. Importantly, there is also strong evidence that E2 reduces abdominal fat accumulation, a fundamental component of the Metabolic Syndrome. Some studies suggest risks of HT outweigh the benefits for some women. However, this does not negate the importance of learning the mechanisms by which E2 influences energy balance and fat patterning.
This study uses gonadotropin releasing hormone (GnRH) analog therapy to determine the effects of chronic (5-month) sex hormone suppression on resting energy expenditure (REE), altered hypothalamic-pituitary-adrenal (HPA) axis activity, and fat gain.
It is hypothesized that REE will be reduced in response to chronic sex hormone suppression, promoting fat gain. It is also hypothesized that stress-induced hypothalamic-pituitary-adrenal (HPA)axis activity will be amplified during sex hormone suppression; altered HPA axis activity leading to cortisol excess causes abdominal fat accumulation. Finally, it is hypothesized that E2 add-back therapy will lessen these responses.
Participants will be randomized so that half of the women in each treatment arm will participate in an exercise training program, consisting of progressive resistance exercise to prevent the decline in fat-free mass (FFM) and the increase in fat mass that has been observed in young women in response to GnRH analog therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 49 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Healthy premenopausal women, aged 18 to 49 years
- •Regular menses (no missed cycles in previous year; cycle length 25-35 days)
- •Positive luteinizing hormone test or a mid-luteal serum progesterone greater than 3 ng/mL
- •Nonsmokers
- •Willing to receive all study interventions
- •Physically able and willing to be randomized to participate in a supervised resistance exercise training program
排除标准
- •Already performing high-intensity resistance exercise training more than 1 day per week
- •On diabetes medications
- •Use of hormonal contraception in the past 3 months
- •On oral or inhaled glucocorticoids
- •Positive pregnancy test
- •Intention to become pregnant or start hormonal contraceptive therapy during the period of study
- •Lactation
- •Hypersensitivity to extrinsic peptide hormones, mannitol, Gonadotropin-releasing hormone (GnRH), leuprolide acetate, benzyl alcohol (the vehicle for injection of leuprolide acetate), or transdermal patch
- •Score greater than 16 on the Center for Epidemiologic Studies Depression Scale and Beck Depression Inventory-II score greater than 18, or clinician recommendation to exclude
- •Severe osteopenia or osteoporosis (proximal femur or lumbar spine t scores < -2.0)
- •BMI greater than 40 kg/m2, weight change of more than ± 2 kg in last 6 months, or weight-reduced by more than 5 kg from maximal body weight
- •Abnormal vaginal bleeding
- •History of breast cancer or other estrogen-dependent neoplasms
- •History of venous thromboembolic events
- •Moderate or severe renal impairment (creatinine clearance <50 mL/min by Cockcroft-Gault)
- •Chronic hepatobiliary disease, defined as liver function tests (AST, ALT, alkaline phosphatase, total bilirubin) greater than 1.5 times the upper limit of normal
- •Thyroid dysfunction, defined as ultra sensitive TSH less than 0.5 or greater than 5.0 mU/L
- •Uncontrolled hypertension, defined as resting BP greater than 150/90 mmHg
- •Cardiovascular disease, including indicators of ischemic heart disease or serious arrhythmias at rest or during the graded exercise test; follow-up diagnostic testing to rule out cardiovascular disease by a cardiologist will be allowed
- •Orthopedic or other problems that would interfere with participation in the exercise program
研究组 & 干预措施
1
GnRH agonist + placebo
干预措施: leuprolide acetate (Drug)
2
GnRH agonist + placebo + exercise
干预措施: leuprolide acetate (Drug)
2
GnRH agonist + placebo + exercise
干预措施: progressive resistance exercise training (Behavioral)
3
GnRH agonist + Estradiol
干预措施: leuprolide acetate (Drug)
3
GnRH agonist + Estradiol
干预措施: Estradiol Transdermal (Drug)
4
GnRH agonist + Estradiol + exercise
干预措施: leuprolide acetate (Drug)
4
GnRH agonist + Estradiol + exercise
干预措施: Estradiol Transdermal (Drug)
4
GnRH agonist + Estradiol + exercise
干预措施: progressive resistance exercise training (Behavioral)
结局指标
主要结局
Cortisol Response (Area Under the Curve) to CRH Under DEX Suppression
时间窗: Before and after 5 months of treatment
Cortisol response to corticotropin releasing hormone (CRH) during dexamethasone (DEX) suppression; DEX/CRH stimulation test
Resting Energy Expenditure (REE)
时间窗: Before and after 5 months of treatment
Resting energy expenditure measured by indirect calorimeter at baseline and after 5 months of treatment.
次要结局
- Total Energy Expenditure (TEE)(Before and after 5 months of treatment)
- Fat-free Mass(Before and after 5 months of treatment)
- Fat Mass(Before and after 5 months of treatment)