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Bulletin Volume 4, Issue 2, Spring 1998 Neuroendocrine
& Pituitary Center
| Referrals
| Neuroendocrine
Bulletin Archive Articles in this issue:
Testosterone Therapy in Men. Pseudo-Cushing's Syndrome in HIV-Infected Patients. Acromegalic
Heart Disease Acromegaly is associated with
an increased risk of premature death and life expectancy is
reportedly decreased by 10 years. Retrospective studies have
suggested that there is a two to four fold increase in cardiovascular
deaths in acromegaly and predictors of increased mortality
in-clude last known elevated GH level, older age at di-agnosis,
the presence of cardiovascular disease, and hypertension.
Co-morbid hypertension and diabetes mellitus may increase
the risk of atherosclerotic heart disease, and hypertension
may lead to a hypertrophic cardiomyopathy and con-gestive
heart failure. In addition, sleep apnea syn-drome is prevalent
in ac-romegalic patients and may lead to right heart failure.
Heart Disease in Patients
with Acromegaly
Studies using echo-cardiography
show evi-dence of marked left ven-tricular hypertrophy in
ap-proximately two-thirds of acromegalics. In one study, left
ventricular mass index was 60% higher than normal in acromegalics.
Studies reveal a correlation of left ventricular hypertro-phy
with duration of acro-megaly but not with serum GH levels.
Echocardiography studies suggest
that al-though systolic function is normal at rest, it is
com-promised during exertion. Therefore, ejection fraction
at baseline appears to be preserved despite the pres-ence
of left ventricular hy-pertrophy. The relatively preserved
resting systolic function may be due to GH induced increased
myocar-dial contractility. In con-trast, systolic function
in acromegalics following ex-ercise is diminished. Fur-thermore,
no difference in systolic function between hypertensive and
normo-tensive acromegalics was observed, further implicat-ing
a mechanism for car-diac dysfunction independ-ent of hypertension.
The presence of ventricular
hypertrophy and increased wall stiffness may lead to diastolic
dysfunc-tion. Such dysfunction may be prevalent in acro-megalic
patients and is as-sociated with decreased ventricular compliance
and peak filling rate, increased time to peak filling rate,
and increased isovolumic relaxation period.
Reversal of Acromegalic Heart
Disease
Data indicate that impairment
in cardiac structure and function may improve and even normal-ize
following reduction of GH and IGF-I levels. This may result
in reversal of cardiac dysfunction and congestive heart failure.
Baldwin et al. evaluated cardiac function in eleven radiation-treated
acrome-galics. Although there was a progressive reduction
in serum GH levels, a final GH concentration of less than
5mU/l was achieved in only one patient. There-fore, the lack
of improve-ment in heart disease in this study may reflect
the low rate of biochemical remis-sion achieved with radio-therapy.
It is likely that cardiovascular disease and/or cardiac risk
factors persist or worsen until bio-chemical remission occurs.
Thuesen et al. in-vestigated
the effects of twelve months of octreo-tide treatment on heart
structure in nine patients with acromegaly. A sig-nificant
decrease in left ventricular wall thickness was reported,
although values remained higher than normal. Although correlation
between the decrease in left ventricular wall thickness and
the GH level was reported at twelve months, the number of
patients achieving bio-chemical remission was not mentioned.
Similarly, Merola et al. showed a sig-nificant decrease in
left ventricular mass index and mean wall thickness in oc-treotide-treated
acrome-galics without hyperten-sion. In another study, the
reduction in left ventricular mass was greatest in those acromegalic
patients with baseline left ventricular hy-pertrophy. Of note,
the decrease in left ventricular mass in this study occurred
within one week of initia-tion of treatment and was independent
of changes in blood pressure. These data indicate that lowering
of GH/IGF-I levels leads to a significant decrease in wall
thickness which may be rapidly detected in a period of time
as short as seven days.
Reductions in car-diac mass
are associated with an improvement in systolic and diastolic
func-tion. Ten patients with ac-tive acromegaly, reported
by Giustina et al., had nor-mal systolic function but abnormal
diastolic filling pressures at rest. How-ever, following exercise,
there was a decreased workload and minute ven-tilation compared
to nor-mals. In another study, following a twenty-four hour
infusion of 500 ug of octreotide, there was an increase in
workload and minute ventilation with ex-ercise in acromegalics
compared to controls. Therefore, octreotide ad-ministration
leads to a rapid beneficial effect on cardiac function. Chanson
et al. investigated three ac-romegalics with congestive heart
failure and reduced functional capacity. Con-gestive heart
failure was severe and one of these patients had been consid-ered
for cardiac transplant. Administration of Octreo-tide resulted
in an increase in stroke volume by 24-51% and a decrease in
fill-ing pressure. Functional capacity markedly im-proved
and all three pa-tients were able to resume normal activity
and return to work without additional therapeutic modalities.
Octreotide therapy alone sustained this improvement for up
to three years in two patients. The third patient was able
to have a transsphenoidal hypophy-sectomy performed after
forty days of octreotide therapy, previously con-traindicated
due to cardiac status. These studies dem-onstrate that systolic
func-tion may improve markedly following medical therapy.
Hradec et al. observed pro-spectively seventy-eight acromegalics
treated with transsphenoidal hypophy-sectomy and, when unsuc-cessful,
adjunctive medical and/or radiotherapy. An increase in left
ventricular posterior wall thickness and left ventricular
mass was observed in patients who initially achieved bio-chemical
remission but had subsequent recurrence and in patients who
never achieved biochemical re-mission. In addition, there
was a decrease in left ven-tricular mass in patients who ultimately
achieved biochemical remission. These data show that suc-cessful
therapy of acro-megaly is associated with an improvement in
cardiac morphology.
Conclusion
Acromegalic patients have a
number of functional cardiac alterations associated with chronic
excess GH, including concentric biventricular hypertrophy,
that may be exacerbated by the presence of hypertension. Although
resting systolic function appears to be relatively unaffected,
sys-tolic function during exer-cise is impaired. In con-trast,
diastolic dysfunction at rest is seen in such pa-tients. Normalization
of serum GH and IGF-I levels are associated with a de-crease
in cardiac wall size and an improvement in cardiac performance.
Be-cause the effects of treat-ment of acromegaly on cardiac
function are related to the degree of GH and IGF-I normalization,
the goal of therapy should be to normalize hormone lev-els.
References
1. Rajasoorya C, Holdaway IM,
Wrightson P, Scott DJ, Ibbertson HK: Determinants of clinical
outcome and survival in acromegaly. Clinical Endo-crinology
1994; 41: 95-102.
Testosterone deficiency in men
is manifested typically by symptoms of hypogonadism, including
decreases in erectile function and libido. Testosterone also
has an important role in the regulation of normal growth,
bone metabolism and body composition. Specifically, testosterone
deficiency is an important risk factor for osteoporosis and
fractures in men. In men older than 65 years of age, the incidence
of hip fracture is 4-5/1000 and approximately 30% of all hip
fractures occur in men. Men with testosterone deficiency have
significant decreases in bone density, particularly in the
trabecular bone compart-ment. Testosterone defi-ciency has
been reported in over half of elderly men with a history of
hip fracture. Men with testosterone deficiency also have alterations
in body composition that include an increase in body fat.
Using quantitative CT scans to assess fat distribution, we
have shown that testosterone deficiency is associated with
an alteration in site-specific adipose deposition with increased
deposits in all areas, particularly in the subcutane-ous and
muscle areas. Be-cause truncal fat correlates with glucose
intolerance and cardiovascular risk, hypogo-nadism may have
important implications with regard to overall health and mortality.
In one study, the alteration in skeletal muscle composition
was associated with a de-crease in muscle strength. Therefore,
testosterone deficiency is associated with an enhanced risk
for osteopo-rosis, altered body composi-tion including increases
in truncal fat, and, possibly, decreases in muscle perform-ance.
Administration of testosterone
replacement therapy leads to improve-ments in libido and erectile
function. Following testos-terone replacement, men note an
increase in energy and mood, which may reflect either direct
behavioral effects of androgens, or, an elevation of hematocrit
due to rising testosterone levels. Testos-terone therapy also
leads to important beneficial effects on the skeleton and
lean tissue mass. Testosterone replace-ment increases bone
density in hypogonadal men with the most dramatic effects
seen in the trabecular bone compart-ment. These effects may
be seen as early as 6 months following initiation of testos-terone
therapy. In one recent study of the long-term bene-fits of
testosterone therapy, the greatest benefits in trab-ecular
bone were seen in the first several years of therapy. With
regard to body compo-sition, testosterone replace-ment therapy
results in a dramatic reduction in adipose content, with the
greatest effects seen in the subcutane-ous and skeletal muscle
areas. Androgen therapy leads to a significant increase in
lean skeletal muscle mass and strength. Therefore, there are
beneficial effects of testoster-one replacement on body composition
and bone mineral density in adult hypogonadal men that may
serve as indica-tions for therapy in addition to that of libido
and sexual function.
There are several modes of administration
available for testosterone replacement. The traditional form
of testosterone therapy consists of intramuscular injections
of testosterone esters given at 2 to 4 week intervals. This
mode of therapy leads to an increase in testosterone levels,
but there are marked oscillations in serum testosterone levels
with early peak, supraphysiologic levels followed by levels
that fall in the subtherapeutic range. Therefore, men may
note an improvement in sexual function only in the immediate
period following the injection. Also, men may describe mood
swings and behavioral alterations that may reflect these changing
testosterone levels. More recent advances had led to the development
of novel delivery systems for androgens such as transdermal
preparations of testosterone. The major benefit of these patches
includes the attainment of more physiologic testosterone replacement
with serum testosterone levels in the normal range throughout
the day. There are transdermal systems applied to the scro-tum
(Testoderm) and skin (Androderm) that are avail-able. Although
these patches lead to normal testosterone levels, they are
somewhat limited by difficulty with adherence and need for
shav-ing (Testoderm) and local irritation (Androderm). A new
system, Testoderm TTS (ALZA Pharmaceuticals) has been available
on the market as of March, 1998. This new form of testosterone
replace-ment consists of a single patch that is applied to
non-scrotal skin and appears be have a low incidence of local
irritation. Therefore, Testo-derm TTS may have an advantage
over currently available systems.
There are several adverse effects
of testosterone administration that need to be closely monitored,
including clinically significant benign prostatic hypertrophy
(BPH) and prostate cancer. Despite the theoretical considerations
that androgens will augment prostate size, there is no evidence
that androgen re-placement in elderly men will lead to the
development of hyperplasia or aggravate its clinical status.
There is also a concern that prostate cancer may develop during
androgen therapy. There are no data available as to whether
andro-gen therapy will enhance the progression of preclinical
to clinical cancer. However, androgens may stimulate the growth
of clinically diagnosed prostate cancer. Therefore, prior
to testosterone initiation, patients should be screened for
BPH and prostate cancer with a clinical history, digital exam,
and PSA (prostate specific antigen) level. Because androgens
may stimulate erythropoiesis and precipitate sleep-related
breathing disor-ders, a cbc should be followed and subjects
queried for the presence of sleep apnea.
References
1. Katznelson L, Finkel-stein
JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A.
1996 In-crease in bone density and lean body mass during testosterone
administration in men with acquired hy-pogonadism. J Clin
Endo-crinol Metab. 81:4358-65.
The novel occurrence of dorsocervical
fat accumulation, centripetal obesity and muscle wasting has
been described recently among a subset of HIV-infected patients.
The ex-act prevalence of the syn-drome is unknown and es-timates
vary from over 50% to only a small minor-ity of patients treated
with aggressive antiretroviral therapy. The most promi-nent
reported feature is striking fat deposition in a classical
"buffalo hump" pattern. In addition, insulin resistance, abnormal
glu-cose homeostasis and tri-glyceride elevations are also
reported in some but not all subjects. The clini-cal course
of four such pa-tients is outlined in detail in Table I and
the prominent dorsocervical fat accumu-lation in one patient
is shown in Figure 1. HIV-infected patients with this syndrome
are increasingly referred to the endocri-nologist to rule
out Cush-ing's syndrome. However, such patients are most ap-propriately
categorized as having pseudo-Cushing's syndrome because of
the absence of a known tumor resulting in hypercorti-solism
and appropriate re-sponse to standard dexa-methasone suppression
testing.
Pseudo-Cushing's syndrome is
manifested by partial or complete clinical features of cortisol
excess and characterized by nor-mal or abnormal biochemi-cal
abnormalities in gluco-corticoid testing. For ex-ample, alcoholic
patients may demonstrate clinical and biochemical features
indistinguishable from true Cushing's syndrome. In contrast,
patients with de-pression may demonstrate non-suppressibility
of corti-sol levels in the absence of a Cushingoid habitus.
Among a subset of HIV-infected patients respond-ing to aggressive
antiretro-viral therapy, striking dor-socervical fat accumula-tion,
centripetal obesity and, to a lesser degree, pe-ripheral muscle
wasting in association with insulin re-sistance, suggest a
state of partial or mild cortisol ex-cess. However, other
clas-sical features of cortisol excess, including striae,
muscle weakness and bruising are most often ab-sent, evidence
that the syn-drome is not a true state of cortisol excess.
Urine free cortisol levels may be ele-vated in some patients,
but suppress adequately during formal dexamethasone testing.
In addition, mini-mal cortisol and ACTH stimulation in response
to CRH in the combined dexamethasone-CRH test argue against
true Cush-ing's syndrome among pa-tients with elevated base-line
cortisol levels.
The mechanisms of pseudo-Cushing's
syn-drome in HIV-infection are unclear. The observed pattern
of fat accumulation, centripetal obesity and in-sulin resistance
suggest that systemic or local glu-cocorticoid excess may
play a role in the syndrome. Activation of the hypotha-lamic-pituitary
adrenal axis is known to occur in HIV-infected patients, suggest-ing
a potential mechanism of the observed phenotypic abnormalities.
HlV-infection is associated with higher than normal cortisol
levels, even in the early stages of the disease. The source
of the hypercorti-solism associated with HIV infection is
unknown and may result from the stress of the illness per
se or a cytokine effect. Variable levels of ACTH have been
reported in association with increased cortisol levels in
HIV disease suggesting that both central and pe-ripheral activation
of the hypothalamic-pituitary-adrenal axis may occur. However,
cortisol levels are often only modestly increased among HlV-infected
patients, and the diurnal rhythm of cortisol is maintained,
unlike the case in true Cushing's syndrome. Furthermore, abnormal
fat deposition and other symptoms of glucocorti-coid excess
have not previ-ously been reported among HlV-infected patients.
Notably, the recent reports
of abnormal fat deposition in HIV infection coincide with
the develop-ment of successful new strategies to rapidly and
dramatically improve the immunologic status of the HIV-infected
patient. In this regard, the syndrome is most often associated
with recovery from the wasting syndrome, weight gain and marked
improvement in immune function, suggest-ing that excess fat
deposi-tion may be related to dis-ease recovery independent
of medication usage. Alter-natively, the temporal as-sociation
of the syndrome with the use of a specific class of agents
known as protease inhibitors, sug-gests that some element
of the syndrome may be a di-rect result of this particular
therapy.
Table 1: Clinical, Hormonal
and Virologic Parameters in Four HIV-Infected Patients with
Pseudo-Cushing's Syndrome patient 1
patient 2
patient 3
patient 4
normal range
Sex
male
male
male
female
Age
44
42
46
39
Clinical signs
dorsocervical fat pad submandibular fat central obesity muscle wasting
dorsocervical fat pad submandibular fat central obesity muscle wasting facial plethora
dorsocervical fat pad subniandibular fat central obesity facial plethora
dorsocervical fat pad central obesity Weight gain (lbs)
20
20
33
11
not applicable
Predisposing factors (alcoholism,
glucocorticoid or megesterol acetate)
none
none
none
none
CD4 count (ceffs/mm3) Pre pseudo-Cushing's With pseudo-Cushing's
97 267
22 200
130 280
127 244
>800
Viral load (copies/mL) Pre pseudo-Cushing's With pseudo-Cushing's
8900 <400*
66,435 <400*
130,800 2539
122,851 <500*
undetectable
ACTH (pmol/L)
9.5
7.9
1.3-16.7
Urine free cortisol** (nmol/day)
30*** 55*** 47***
223*** 242*** 251***
361**** <14***** see footnotes below
One mg overnight dexamethasone
suppression test
<28
<33
serum cortisol <140 mnol/L
at 0800h the following morning
2-day low dose dexamethasone
suppression test
17
urine free cortisol <55
mmol/d
CRH-low dose dexamethasone
test
27.6
serum cortisol < 38.6
mmol/L excludes Cushing's syndrome
Footnotes:
The primary feature in virtually all reported cases of the pseudo-Cushing's syndrome asso-ciated with HIV-infection is a striking excess of fat deposition, primarily in a dorsocervical pattern. In the setting of weight gain, abnormal partitioning into fat may result from an al-tered steroid or cytokine milieu, or a paracrine ac-tion of the virus itself on the glucocorticoid recep-tor. For example, a direct stimulatory effect of viral proteins on the glucocorti-coid receptor has been demonstrated and may re-sult in enhanced glucocor-ticoid action and fat depo-sition during weight recov-ery. In addition, fatty acids and other liposoluble sub-stances in serum from HIV-positive patients may affect the binding of corti-sol to the glucocorticoid receptor. Tissue-specific paracrine abnormalities in cortisol metabolism may explain excess fat deposi-tion during weight recov-ery in the absence of changes in systemic steroid levels. Alternatively, pref-erential deposition of fat may occur upon recovery due to increased triglycer-ide production associated with HlV-infection.
In addition, fat deposition may be the re-sult of altered P450 me-tabolism of endogenous glucocorticoid or other as yet unknown effects of protease inhibitor therapy. A significant number of patients described in recent reports were taking combi-nations of new antiretrovi-ral therapies, most often including indinavir, and had experienced dramatic im-provements in disease status and significant dec-rements in viral load in as-sociation with the devel-opment of pseudo-Cushing's syndrome. A dramatic effect of protease inhibitors on P450 metabo-lism has recently been demonstrated. Such medi-cines may also have tissue-specific paracrine effects to increase glucocorticoid concentration in fat cells, independent of any meas-urable change in circulating steroid hormone levels. Protease inhibitors and/or other new antiretroviral agents may therefore alter metabolism in such a way that patients preferentially gain fat mass during weight recovery. There is no known treatment for the pseudo-Cushing's syndrome asso-ciated with HIV-infection. Anecdotal evidence sug-gest that discontinuation of protease inhibitor therapy in some cases will result in decreased symptomatolgy. Liposuction of the poste-rior cervical fat pad is a cosmetic alternative that may allow significant im-provement in appearance as well as functional en-hancement of neck exten-sion in some patients. In addition, ketoconazole, a medication which inhibits adrenal steroidogenesis and is used to treat Cushing's syndrome may poentially be of some utility in a sub-set of patients with HIV-associated pseudo-Cushing's syndrome. For example, moderate im-provement in dorsocervical fat was recently described in one patient receiving ketoconazole. In this case, the patient had an elevated baseline urine free cortisol level, suggesting that keto-conazole might be of po-tential benefit. However, the use of ketoconazole for this indication should be considered experimental and most appropriately re-served for patients with increased urine free cortisol levels. It must be empha-sized that ketoconazole administration is associated with adrenal insufficiency, hypogonadism and poten-tial liver function abnor-malities and should be used with caution in such pa-tients. Controlled pro-spective studies are needed to establish the efficacy of ketoconazole administra-tion and/or other therapies in this population. The development of pseudo-Cushing's syn-drome among a relatively large subset of HIV-infected patients treated with aggressive antiretrovi-ral therapy is an important and unexpected new devel-opment which may be a direct result of improve-ment in the immunologic and clinical status of such patients. The striking similarities in phenotypic expression of the syndrome among affected patients suggests a common, but still unknown, etiologic factor which may relate to specific medication effects or more generally to dis-ease recovery. Clinicians treating patients with HIV disease are increasingly likely to encounter patients with these symptoms as ever more powerful antivi-ral therapies are used to improve immune function. Important, as yet unan-swered, questions exist as to the mechanism of syn-drome and its clinical im-plications in terms of re-covery from the wasting syndrome and the potential prohibitive effect of potent new antiretroviral therapies in this regard. Is the syn-drome simply a cosmetic issue, or do the associated metabolic and phenotypic abnormalities have real im-plications for the long-term health of such patients? Finally, the potential treat-ment of such patients is now limited but may in-clude potential endocrine manipulation with steroid inhibitors in the near fu-ture. Further research into the mechanisms of HIV-associated pseudo-Cushing's syndrome is needed to allow treatment and/or prevention of this syndrome in the future. References 1. Carr A, Samaras K, Law M, Freund
J, Chisholm DJ, Cooper DA. A Syndrome of peripheral lipodystrophy,
hyperlipi-demia, and insulin resis-tance in patients receiving
HIV protease inhibitors. AIDS. 1998 (In Press).
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