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5-ALA dehydratase-deficient porphyria; 5-aminolaevulinic dehydratase deficiency porphyria; ADP; ALA dehydratase porphyria; ALA-D porphyria; Amino levulinic acid dehydratase deficiency; Delta-aminolevulinate dehydratase deficiency porphyria; Plumboporphyria; Porphobilinogen synthase deficiency |
Clinical Trial: Growth Hormone Administration and Its Effects on Cardiovascular Risk Factors in Growth Hormone Deficient Women
This study is currently recruiting patients.
Verified by Massachusetts General Hospital August 2005
|
Purpose
The purpose of the study is to evaluate the effects of growth hormone replacement on women with growth hormone deficiency. Growth hormone deficiency means your body no longer produces growth hormone due to a tumor or some kind of disease of your brain in an area called the pituitary/hypothalamic region. This is the area of the brain where growth hormone is normally produced. We will establish the effects of growth hormone replacement on cardiovascular parameters (laboratory tests, the flexibility the arteries, changes in heart rate) in women with growth hormone deficiency. Our goal is to see if this therapy:
- has effects on women’s cardiovascular risk markers (special blood tests which indicate how healthy your heart and arteries are
- has effects on women’s types and levels of various substances circulating in their blood
- in women affects the stiffness of their arteries and heart rate variability in parallel with changes in cardiovascular risk markers
- has different effects depending on whether you are pre or post menopausal.
Your participation in this study is expected to last approximately 12 months.
| Condition | Intervention |
|---|---|
| Growth Hormone Deficiency Pituitary Tumor Pituitary Disease | Drug: Genotropin |
MedlinePlus related topics: Brain Cancer; Brain Diseases; Cancer; Cancer Alternative Therapies; Dwarfism; Endocrine Diseases; Pituitary Disorders
Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Crossover Assignment, Efficacy Study
Official Title: Gender-Specific Effects of Physiologic GH Administration on Cardiovascular Risk Factors in Women with Growth Hormone Deficiency
Expected Total Enrollment: 60
Study start: January 2002
The aim of the study is to evaluate the gender specific effects of physiologic Growth Hormone (GH) replacement in women with GH deficiency on the basis of pituitary/hypothalamic region tumors, radiation, or surgery on cardiovascular risk markers and arterial distensibility. Cardiovascular mortality in growth hormone (GH) deficient adults has been shown to be increased in a number of retrospective studies [1-4]. Increased arterial intima-media thickness, increased prevalence of atherosclerotic plaques and endothelial dysfunction have been reported in growth hormone deficient adults both in childhood and adulthood onset forms [5-8] The growth hormone deficiency (GHD) syndrome is associated with a cluster of cardiovascular-risk factors such as central adiposity [9-11], increased visceral fat [12], insulin resistance [13], dyslipoproteinemia [3, 14] and decreased plasma fibrinolytic activity [15]. GH administration has effects on a number of these factors, but it is unknown which mechanisms are implicated in GH action on the process of atherosclerosis. In addition to alterations in atherosclerotic markers, abnormalities in cardiac function and structure have been reported among patients with GHD possibly contributing to the increased cardiovascular mortality [16-17]. In addition, GHD is associated with cardiac autonomic dysfunction that may also contribute to cardiovascular mortality and improves with GH replacement therapy [19].
The vast majority of studies have focused primarily on men and the gender-specific effects of GH replacement on cardiovascular risk factors remain unknown. In addition to being of interest in terms of understanding the physiologic effects of GH therapy, there are important therapeutic implications regarding data in women. Cardiovascular disease is the leading cause of mortality in women. Effects of GH replacement on bone density may be less pronounced in women and because specific GH effects on cardiovascular risk factors in women are unknown, many adult women with GHD are untreated.
Long-term GH treatment decreases total body fat [12, 20-24] including visceral fat [22]. Decreases in central fat as assessed by waist to hip ratio have been reported in some studies [12, 20, 22, 24], but not in others [21, 25, 26]. Administration of GH causes insulin resistance acutely [12] but long-term therapy may restore glucose sensitivity [27]. GH treatment increases lipoprotein (a) (Lp (a)) levels but its effects on other lipoproteins are still controversial. Some studies have reported decreases in LDL cholesterol with or without increases in HDL cholesterol [20, 28-30] with GH administration, while others have not [6, 31, 32]. Twelve months of GH replacement improves left ventricular mass and cardiac performance in young adults with GHD [30]. Key factors likely involved in the discrepant findings include heterogeneity of patients studied in terms of age of onset of the GH deficiency (childhood versus adulthood), gender, severity of GHD and methodologic issues such as dose and duration of GH administration. In addition, many of the studies have no control period.
Inflammation plays a central role in the pathophysiology of atherosclerosis. Each atherosclerotic lesion represents a different stage of a chronic inflammatory process in the arterial wall and different markers along the inflammatory cascade have been reported to predict cardiovascular risk [34]. Among those, high-sensitivity testing for C-reactive protein (CRP) is one of the best validated [35]. Several prospective studies support a strong link between levels of CRP and future risk of coronary events [36-40]. [36-40]. CRP adds considerable value to the total and HDL cholesterol measurement in the prediction of cardiovascular risk [41]. Other distal indicators of inflammation such as serum-amyloid polypeptide A (SAA) likewise predict coronary risk [42]. These distal markers reflect the consequences of elevated proinflammatory cytokines like interleukin-6 (IL-6). GH is known to have important immunomodulatory effects [43-45]. We therefore hypothesized that the effects of GH on the process of atherosclerosis might be mediated through the cytokine-inflammatory pathway. We have recently investigated the effects of physiologic GH replacement in cardiovascular risk markers in men with GHD [46]. In this study we found that CRP and IL-6 levels decreased in GH treated men compared to controls despite no significant change in serum lipid levels. We also recently have investigated levels of inflammatory markers in women with hypopituitarism compared with healthy controls. We found that women with hypopituitarism have increased levels of IL-6 and CRP suggesting that chronic inflammation may be involved in the pathogenesis of atheroscelerosis in this population [47]. It will be critical to determine whether physiologic GH replacement has beneficial effects in women, and whether these effects are influenced by estrogen.
We will investigate the effect of long-term physiologic GH administration on IL-6, CRP, SAA as well as other classic cardiovascular risk factors in women with GHD in a randomized, placebo-controlled study. In addition, we will evaluate structural/function correlates in women by measuring arterial wall distensibility and heart rate variability in parallel with cardiovascular risk markers.
We will establish the gender-specific effects of physiologic GH replacement on cardiovascular risk in women with GHD by investigating whether this therapy:
- has gender-specific effects on cardiovascular risk markers
- has gender-specific effects on lipid profiles
- alters heart rate variability and arterial distensibility in parallel with changes in cardiovascular risk markers
- has different effects depending upon gonadal status
Eligibility
Inclusion Criteria:
- GH deficiency due to pituitary or hypothalamic tumors or disease affecting this area. Subjects will have been treated with medication, surgery, radiation, or a combination of these. GH deficiency will be defined as a peak plasma GH of less than 5 ng/ml in response to insulin tolerance testing or GHRH plus arginine stimulation test. In subjects with suspected hypothalamic dysfunction the arginine plus L-dopa stimulation test may be used, with a cutoff of 1.7 ng/ml for diagnosis of GH deficiency. Partial GH deficiency will be defined as a GH peak of 5 to 9 ng/ml (inclusive) during insulin tolerance testing or GHRH plus arginine testing.
- GH deficiency will also be diagnosed if IGF-I levels are below 2 standard deviations for the age-sex normal range in a patient with at least two documented hormone deficiencies.
- Subjects must have evidence of a stable pituitary mass (for at least 12 months) if there is a history of a tumor except in the case of ACTH-producing microadenomas, where no follow-up imaging is required after cure.
- Subjects age 40 and over must have a screening mammogram if they have not already had one within one year prior to their baseline visit
Exclusion Criteria:
- Active Cushing’s disease within 1 year
- History of acromegaly
- Untreated thyroid or adrenal insufficiency. Subjects on replacement therapy must be stable for at least 3 months prior to entry into the study.
- History of malignancy except for skin cancer and except for childhood solid malignancy with documented cure for > 10 years prior to starting the study
- Hemoglobin <10.0 gm/dl
- Hepatic or renal disease (SGPT/SGOT > 3x ULN or Creatinine levels >2.5 mg/dl)
- Congestive heart failure (New York Heart Association’s classification system Class II-IV CHF will be excluded)
- History of unstable cardiovascular disease (coronary artery or cerebrovascular disease) or symptoms within one year prior to entry into the study
- Diabetes mellitus
- Pregnancy or nursing
- Active carpal tunnel syndrome
Location and Contact Information
Amber E Schaub, BS 617-724-1579 aschaub@partners.org
Massachusetts
Massachusetts General Hospital, Boston, Massachusetts, 02114, United States; Recruiting
Amber Schaub, BS 617-724-1579 aschaub@partners.org
Anne Klibanski, M.D., Principal Investigator
Anne Klibanski, M.D, Principal Investigator, Massachusetts General Hospital
More Information
Publications
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Leong KS, Mann P, Wallymahmed M, MacFarlane IA, Wilding JP. Abnormal heart rate variability in adults with growth hormone deficiency. J Clin Endocrinol Metab. 2000 Feb;85(2):628-33.
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Jarrar D, Wolf SE, Jeschke MG, Ramirez RJ, DebRoy M, Ogle CK, Papaconstaninou J, Herndon DN. Growth hormone attenuates the acute-phase response to thermal injury. Arch Surg. 1997 Nov;132(11):1171-5; discussion 1175-6.
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Last Updated: August 25, 2005
Record first received: August 24, 2005
ClinicalTrials.gov Identifier: NCT00136032
Health Authority: United States: Institutional Review Board
ClinicalTrials.gov processed this record on 2005-08-30
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