Role of Endogenous Estrogen in Growth-Hormone Regulation in Postmenopausal Women

NCT01186796 | Completed Phase 1 Results DMC

• 1 other identifier: 07-003036
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Participants are being asked to take part in this research study to learn why growth hormone(GH) levels decline when estrogen production falls at the time of menopause. GH is a hormone released from the pituitary gland that affects bone, muscle, and fat. Estrogen is a female hormone. Doctors believe that lower estrogen is one of the reasons that GH diminishes in postmenopausal women. However, estrogen does not fall completely. This raises the question whether the little bit of estrogen that is left is doing anything. Lack of GH makes bones thinner, muscles weaker, and fat stores larger. To learn whether the low amount of the body's own estrogen maintains GH secretion after menopause, the investigators need to stop any estrogen you might be taking and then partially block the effect, if any, of your own estrogen. The investigators will use a new estrogen-blocking drug (fulvestrant). Fulvestrant(which also goes by the tradename, Faslodex) was recently approved by the Food and Drug Administration (FDA) to treat breast cancer. Fulvestrant is being used in a non-FDA approved manner in this study (not to treat breast cancer, but to study the effect on Growth Hormone secretion). The drug interferes with how estrogen works in the body, except in the brain. The study that you are considering now tests whether your own estrogen works outside the brain to maintain GH secretion in postmenopausal women. This concept is important, because the brain controls how the pituitary gland secretes GH.

Conditions

Healthy

Keywords

Women; Fulvestrant Study; Post Menopausal Women; Hormones; Healthy Adult Women

Outcome Measures

Primary Outcomes (1)

• Mean Baseline GH Concentration

  Averaged over 90-min baseline on the saline day.

  Withdrawal of blood samples (2.5 mL each) every 10 min for 6 hr. Sampling will begin at 0800 h and conclude at 1400 h.

Secondary Outcomes (4)

• Mean GH Concentration (Pulsatile) in Response to Secretagogue

  Withdrawal of blood samples (2.5 mL each) every 10 min for 6 hr. Sampling will begin at 0800 h and conclude at 1400 h.

• Mean Mass of GH Released Per Burst in Response to Secretagogue

  Withdrawal of blood samples (2.5 mL each) every 10 min for 6 hr. Sampling will begin at 0800 h and conclude at 1400 h.

• Mean Duration of GH Bursts (Mode) in Response to Secretagogue

  Withdrawal of blood samples (2.5 mL each) every 10 min for 6 hr. Sampling will begin at 0800 h and conclude at 1400 h.

• Mean GH Half-Life in Response to Secretagogue

  Withdrawal of blood samples (2.5 mL each) every 10 min for 6 hr. Sampling will begin at 0800 h and conclude at 1400 h.

Study Arms (1)

Fulvestrant

EXPERIMENTAL

Drug: Fulvestrant

Interventions

Fulvestrant DRUG

Secretagogue combinations are assigned in randomized double-blind order within-subject to include the following four conditions: (i)L-arginine (30 gm i.v. over 30 min from 0930 h to 1000 h) followed by 5 mL bolus of NS at 1000 h; (ii) L-arginine (30 gm i.v. over 30 min from 0930 h to 1000 h) followed by GHRH and Ghrelin (both at dose of 0.3 mcg/kg bolus i.v.) at 1000 h; (iii) L-arginine (30 gm i.v. over 30 min from 0930 h to 1000 h) followed by GHRH (0.3 μg/kg bolus i.v.) at 1000 h; (iv) L-arginine infusion (30 gm i.v. over 30 min from 0930 h to 1000 h) followed by Ghrelin (0.3 μg/kg bolus i.v.) at 1000 h. \*\*Ghrelin dosage is based on 70 kg subject.Total exposure of Ghrelin will be 42 mcg total dose for 2 subject visits (21 mcg per visit).

Fulvestrant

Eligibility Criteria

• Age: 50 Years - 80 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• healthy postmenopausal women (ages 50 to 80 y), wherein menopause is defined by the absence of spontaneous menses for 1 y and a serum concentration of FSH \> 30 IU/L and of (ultrasensitive) estradiol \< 20 pg/mL and verified by medical history and screening blood work;
• normal hemoglobin of \>11.0 g/dL in women (a ferritin level will be drawn, and must be normal, if Hgb is 11.0 - 11.5) , Platelets greater than 200 x 109/L, AST 8-48 U/L.
• Subjects (age 50 and above) will have a screening baseline ECG if not on record from the past year.

You may not qualify if:

• exposure to psychotropic or neuroactive drug within five biological half- lives;
• undesirability, disinclination or ill advisability of withholding estrogen supplements (e.g. under treatment for symptomatic hot flushes; primary physician recommendation);
• BMI \< 19 or \> 35
• drug or alcohol abuse; psychosis, depression, mania or anorexia nervosa;
• acute or chronic organ or systemic inflammatory disease;
• endocrinopathy, other than primary thyroidal failure receiving replacement;
• although fulvestrant has no known intrinsic estrogenicity, for safety reasons we include contraindication to short-term estrogen exposure; e.g.,estrogen-sensitive neoplasia, undiagnosed vaginal bleeding, deep-venous thrombosis, stroke or threatened stroke, clinical evidence of atherosclerotic heart disease, including myocardial infarction and/or angina, refractory high blood pressure, severe type IV hyperlipidemia:
• nightshift work or recent transmeridian travel (exceeding 3 time zones within 5 days of admission);
• systemic anticoagulation other than anti platelet therapy (in view of i.m. injections of fulvestrant); history of bleeding diathesis (ie; disseminated coagulation (DIC), clotting factor deficiency
• acute weight change (\> 3 kg in 6 weeks); and/or
• unwillingness to provide written informed consent.
• Platelets less than 200 x 109 /L
• International normalization ratio(INR) (Prothrombin time) greater than 1.6
• Total bilirubin greater than 1.5 x ULRR
• ALT or AST greater than 2.5 xULRR if no demonstrable liver metastases or greater

Sponsors & Collaborators

• Mayo Clinic: lead
• National Institutes of Health (NIH): collaborator
• AstraZeneca: collaborator

Study Sites (1)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

MeSH Terms

Interventions

Fulvestrant

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Limitations and Caveats

Strengths and limitations of the study include the potentially confounding effects of body composition (not studied here except at the level of BMI), underlying physical fitness of subjects, size of the cohort, and the brevity of the study (2 months)

Results Point of Contact

• Title: Johannes. D. Veldhuis, M.D.
• Organization: Mayo Clinic

Veldhuis.Johannes@mayo.edu

507-255-0902

Study Officials

• Johannes Veldhuis, M.D.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Johannes D. Veldhuis, MD

Study Record Dates

• First Submitted: August 16, 2010
• First Posted: August 23, 2010
• Study Start: June 1, 2009
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: March 27, 2015
• Results First Posted: March 27, 2015

Record last verified: 2015-03

Locations

US (1)