Trial Information

Effects of Physiologic Growth Hormone Administration on Cardiovascular Risk in Subjects With Growth Hormone Deficiency Following Cure of Acromegaly

The aim of the study is to evaluate the effects of physiologic growth hormone (GH)
replacement on cardiovascular risk markers, cardiac autonomic function, arterial
distensibility, body composition, and quality of life in men and women with GH deficiency
following treatment of acromegaly. We hypothesize that this population will represent a
newly identified group of patients for whom GH replacement will be of benefit.

Treatment modalities in acromegaly include transsphenoidal surgery and radiation therapy,
which can both result in hypopituitarism. A significant subset of cured acromegalics
therefore develop pituitary hormone deficiencies. Although replacement of adrenal, thyroid
and gonadal hormones is routine practice, clinicians do not replace GH in this subgroup,
even in profoundly GH deficient subjects, as there are no randomized studies proving benefit
in this population. With the accumulation of evidence on the beneficial effects of GH
replacement, this therapy is becoming standard of care in all subjects with GH deficiency
(GHD), except in this acromegaly subgroup where GH has been traditionally withheld. The GHD
syndrome is manifested by an increase in cardiovascular risk, which is potentially
reversible with GH therapy. Cardiovascular disease is the leading cause of death in
acromegalics. Although cure of acromegaly is associated with a reduction in mortality
attributable to GH excess, GHD may be a contributing factor to cardiovascular morbidity and
mortality in this group of patients, as it is in patients with other pituitary tumors. It is
therefore crucial to determine how cured acromegalics with hypopituitarism are affected by
the GHD syndrome, and it is essential to study how this particular population responds to GH
therapy. Because these patients typically have large macroadenomas and are treated with
surgery and radiation therapy, long-term management of hypopituitarism is critical. As with
all endocrine disorders, the goal of therapy is normal hormone replacement, not taking
patients from a state of hormone excess to one of permanent hormone deficiency.

Cardiovascular status in acromegaly

Acromegaly is associated with a 2-3 fold increase in mortality compared to the general
population. GH excess has been recognized to have multiple effects on the heart and
cardiovascular system. GH excess affects cardiovascular health indirectly by increasing the
prevalence of cardiovascular risk factors including hypertension, insulin resistance/type 2
diabetes, and dyslipidemia. In addition, endothelial dysfunction is more prevalent in
acromegaly than in normal controls. Impaired endothelium-dependent vasodilatation with
exaggerated sympathetic-mediated vasoconstrictor response has been recently described in
acromegalic patients. Although flow-mediated dilatation has been shown to improve in cured
acromegalics, it has not been shown to return to normal. Reports on the prevalence of
increased carotid intima-media thickness (IMT) are conflicting. Some studies have documented
an increase in IMT in active acromegaly and some have not.

A specific acromegaly-related cardiomyopathy -- independent of hypertension, diabetes and
dyslipidemia -- has been extensively described. Impairment in ejection fraction after
physical activity is observed in up to 73% of patients, which may lead to exercise
intolerance in some of them.

Morphological and functional cardiac changes are reversed with normalizing GH/IGF-I levels.
Although ventricular hypertrophy has been shown to regress, it is unclear what proportion of
patients recover a normal ventricular mass. Several echocardiographic studies have shown
that with control of disease activity diastolic filling is improved, but the effect on
ejection fraction and exercise tolerance is variable. Data on reversibility of
cardiovascular disease in acromegaly are heterogeneous due to evolving definitions of cure
for acromegaly, often short duration of studies, varying duration of disease activity,
differences in gender and gonadal status, as well as possible distinct effects of
somatostatin analogs on the heart and vessels. Dysrhythmias are also more common in
acromegaly than in controls. Some studies have shown that permanent myocardial scarring may
occur.

In our proposed study population sequelae of previous GH excess may coexist with
manifestations of GH deficiency.

Cardiovascular status in GHD

Cardiovascular morbidity and mortality in adults with GHD has been shown to be increased in
a number of retrospective studies. Increased arterial IMT, increased prevalence of
atherosclerotic plaques and endothelial dysfunction have been reported in GH deficient
adults both in childhood and adulthood onset forms.

The GHD syndrome is characterized by a cluster of factors that are associated with increased
cardiovascular risk, such as central adiposity, increased visceral fat, insulin resistance,
dyslipoproteinemia and decreased plasma fibrinolytic activity. GH administration has
beneficial 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. GHD is also associated with cardiac autonomic dysfunction that may
contribute to cardiovascular mortality and improves with GH replacement therapy. Of
particular importance regarding patients with acromegaly, it has been shown that twelve
months of GH replacement improves left ventricular mass and cardiac performance in young
adults with GHD. Therefore, hypopituitary patients with a history of acromegaly who are now
GH deficient may be particularly good candidates to benefit from physiologic GH replacement.

Adipose tissue has receptors for GH, which has lipolytic activity. A decrease in central fat
as assessed by waist-to-hip ratio have been reported in some studies, but not in others.
Consequences of increased abdominal adiposity include increased risk of cardiovascular
disease, type 2 diabetes and cerebrovascular disease. Long-term GH treatment decreases total
body fat including visceral fat. Lean body mass and muscle function are improved with GH
therapy in adults with GHD. GH increases lean body mass and decreases adipose tissue mass
when given to adults with GHD or the elderly. Administration of GH causes insulin
resistance acutely but long-term therapy may restore glucose sensitivity through its effects
on body composition.

GH treatment increases lipoprotein (a) (Lp (a)) levels but its effects on other lipoproteins
are still controversial. Some studies have reported decreases in low-density lipoprotein
cholesterol (LDL) with or without increases in high-density lipoprotein cholesterol (HDL)
with GH administration, while others have not. Key factors likely involved in the
discrepant findings include heterogeneity of patients studied in terms of age of onset of
the GHD (childhood versus adulthood), gender, severity of GHD and methodological issues such
as dose and duration of GH administration. In addition, many of the studies have no control
period. There is a decrease in the hepatic expression of LDL receptors in GHD, which is
reversed by GH therapy. This phenomenon could be linked to the exaggerated postprandial
increase in triglycerides-rich particles observed in GHD, which is also normalized by the
administration of GH.

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. Among those, high-sensitivity testing for C-reactive protein
(CRP) is one of the best validated. Several prospective studies support a strong link
between levels of CRP and future risk of coronary events. CRP adds considerable value to
the total and HDL cholesterol measurement in the prediction of cardiovascular risk.

These distal markers reflect the consequences of elevated proinflammatory cytokines such as
interleukin-6 (IL-6). GH is known to have important immunomodulatory effects. 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. 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. Other emerging inflammatory markers include
intercellular adhesion molecule-1 (ICAM-1), P-selectin and CD 40 ligand (CD40L), which is
thought to reflect platelet activation and may promote atheromatous plaque destabilization.
Myeloperoxidase was recently shown to predict the early risk of myocardial infarction and
the risk of major adverse cardiac events in the following six months. And lately placental
growth factor (PlGF) has been found to be an independent marker of adverse outcome in
patients with acute coronary syndromes. The effect of the GH-IGF-I axis on these markers is
unknown.

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 atherosclerosis in this population. In addition to inflammatory
markers, thrombogenic cardiovascular risk markers such as fibrinogen, tissue-type
plasminogen activator (tPA) and plasminogen activator-inhibitor 1 (PAI-1) are thought to be
surrogate markers of vascular health. It will be critical to determine whether physiologic
GH replacement has beneficial effects in patients with a history of acromegaly, and to
define the influence of GH and gonadal status on these risk factors.

Quality of life has been shown to be poorer in GH deficient females treated for acromegaly
than in females with other causes of GHD. Short-term GH replacement caused a non-significant
improvement in quality of life scores in subjects with GHD following cure of acromegaly, but
the effects of longer GH treatment duration have not been published in this specific
subgroup. Our study will provide more data on the quality of life of subjects following cure
of acromegaly (GH deficient versus GH sufficient) and on the effects of GH therapy in the GH
deficient group.

Data on body composition and cardiovascular risk markers in patients with cured acromegaly
are rare. No studies have yet been published comparing these endpoints in GH sufficient and
GH deficient subjects with a history of acromegaly. Our hypothesis is that GH sufficient
subjects have a more favorable profile than GH deficient subjects. Several studies have
shown a normalization of mortality rates in subjects with cured acromegaly compared to
subjects with active acromegaly. However it has not been demonstrated that this improvement
was mediated by a normalization of the cardiovascular risk factors. Collecting
cross-sectional data in this patient population may contribute to answer this question.