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Recognizing
excess cardiovascular mortality in adults with panhypopituitarism despite
adequate conventional hormone replacement therapy, the U.S. Food and Drug
Administration approved the use of recombinant human growth hormone (rhGH) replacement
for adults with GH deficiency (GHD) in 1997. Visceral adiposity, lipid
abnormalities, insulin resistance and glucose intolerance, hypertension,
increased intima-media thickness (IMT) of the major arteries and cardiac
abnormalities are associated with GHD. Sexual dimorphism in responsiveness to
GH has been observed both physiologically and in GHD treatment; females of
menstrual age have lower insulin-like growth factor (IGF)-I despite higher GH
levels than men, and require higher rhGH doses to normalize their IGF-I levels
and achieve similar improvements in body composition and bone mass.
Colao
and colleagues performed a prospective, open study of 2 years of rhGH treatment
in young adults (ages 18-45 years) to further evaluate potential sexual
differences in rhGH effects on cardiovascular risk factors. All patients had
GHD of adult onset (due to pituitary masses or craniopharyingiomas treated
surgically and not irradiated), peak GH responses to arginine-GHRH testing of
less than 9µg/L, and adequate replacement of
any concomitant pituitary hormone deficiencies. Thirty-eight healthy subjects,
matched for sex, age, and BMI were tested as controls. All patients received
rhGH starting at 4-5 µg/kg/d and titrated to normalize IGF-I levels (z-score of 0); final
doses were a median of 6.5 µcg/kg/d in
men and 7.7 µcg/kg/d in women (P<0.05). At baseline, in comparison to the controls, all GHD patients
had impaired lipid profiles; insulin resistance; increased fibrinogen and CRP
levels; increased intima-media thickness (IMT) of both common carotid arteries;
reduced cardiac size (though still within normal); and decreased cardiac
performance, exercise duration and exercise capacity. Gender specific changes
at 2 years were: significant decrease in BMI (men only), total to HDL ratio
higher in women than men, lower resting systolic blood pressure in women than
men, greater increase in peak filling rate in men (at rest and at peak
exercise), sustained increase in resting left ventricular ejection fraction
(LVEF) in men only, and greater frequency of abnormal delta LVEF at peak
exercise in women (30%) vs men (5%). Changes found equally in both sexes were:
normalization of IGF-I levels, persistence of some degree of insulin resistance
relative to controls, reduction (~10%) but not full normalization of IMT at
both common carotid arteries, failure of disappearance of well-defined
atherosclerotic plaques, normalization of LV mass indexed for body surface area
(Mi) without development of LV hypertrophy, and lower than normal exercise
performance at one year that corrected at 2 years.
Colao
A, Di Somma C, Cuocolo A, et al. Does a gender-related effect of growth hormone
(GH) replacement exist on cardiovascular risk factors, cardiac morphology,
and performance and atherosclerosis? Results of a two-year open, prospective
study in young adult men and women with severe GH deficiency.J Clin Endocrinol
Metab. 2005;90:5146-5155.
Editor’s Comment: This paper carefully evaluated multiple risk factors
of cardiovascular disease; cardiac performance and morphology; and exercise
performance in men and women. Older subjects were excluded from the study to
eliminate the effects of aging and menopause. For women requiring estrogen
replacement, route of delivery was significant. Oral estrogen replacement led
to greater GH resistance than transdermal estrogen preparations; the two
highest rhGH doses required for IGF-I normalization were in 2 women on oral
estrogen replacement. This is consistent with prior studies, as demonstrated by
clinical responsiveness1 and IGF generation testing.2 Although
the data in this paper are encouraging, the clinical efficacy of rhGH
replacement on reversing the cardiovascular risk of GHD remains unknown.
Adda Grimberg, MD
References - (linked to  )
- Mah
PM, Webster J, Jonsson P, et al. Estrogen replacement in women of fertile
years with hypopituitarism. J Clin Endocrinol Metab. 2005;90:5964-5969.
- Lissett CA, Gleeson H, Shalet SM.
The insulin-like growth factor I generation test in adults. Horm Res. 2004;62
Suppl 1:44-49.
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Current GGH - Vol. 24 No. 1
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