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Nonfatal Stroke, Cardiac Disease, and Diabetes Mellitus
in Hypopituitary Patients on Hormone Replacement
Including Growth Hormone
Helene Holmer, Johan Svensson, Lars Rylander, Gudmundur Johannsson, Thord Rose´n,
Bengt-Åke Bengtsson, Marja Thore´n, Charlotte Ho¨ybye, Marie Degerblad, Margareta Bramnert,
Erik Ha¨gg, Britt Ede´n Engstro¨m, Bertil Ekman, Bo Norrving, Lars Hagmar, and Eva-Marie Erfurth
Department of Internal Medicine (H.H.), Centralsjukhuset, SE-291 85, Kristianstad, Sweden; Endocrine Unit (H.H.,
E.-M.E.), Departments of Medicine and Neurology (B.N.), Lund University Hospital, SE-221 85 Lund, Sweden; Research
Centre for Endocrinology and Metabolism (J.S., G.J., T.R., B.-A.B.), Sahlgrenska University Hospital, SE-413 45 Go¨teborg,
Sweden; Division of Occupational and Environmental Medicine and Psychiatric Epidemiology (L.R., L.H.), Lund University,
SE-221 00 Lund, Sweden; Department of Endocrinology, Metabolism and Diabetes (M.T., C.H., M.D.), Karolinska
University Hospital Solna, SE-141 86 Stockholm, Sweden; Department of Endocrinology (M.B.), University Hospital, SE-205
02 Malmo¨, Sweden; Department of Medicine (E.H.), University Hospital, SE-901 87 Umeå, Sweden; Department of Medical
Sciences (B.E.E.), Internal Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden; and Internal Medicine
(B.E.), Department of Medicine and Care, University Hospital, SE-581 83 Linko¨ping, Sweden
Context: The impact of long-term GH replacement on cerebrovas-
cular and cardiovascular diseases and diabetes mellitus in hypopi-
tuitary patients is unknown.
Objective: The incidence of nonfatal stroke and cardiac events, and
prevalence of type 2 diabetes mellitus (T2D) and cardioprotective
medication were compared between cohorts of GH-deficient (GHD)
patients and population controls.
Design and Participants: The incidence of nonfatal stroke and
cardiac events was estimated retrospectively from questionnaires in
750 GHD patients and 2314 matched population controls. A preva-
lence of T2D and cardioprotective medication was recorded at the
distribution of questionnaires. Time since first pituitary deficiency to
start of GH therapy was 4 and 2 yr, and time on GH therapy was 6
yr for GHD women and men, respectively.
Results: Lifelong incidence of nonfatal stroke was tripled in GHD
women and doubled in GHD men, but a decline was seen in both
genders during periods after first pituitary hormone deficiency and
GHD, during which most patients had GH therapy. The lifelong in-
cidence of nonfatal cardiac events declined in GHD men during first
pituitary hormone deficiency and GHD periods. GHD women had a
higher prevalence of T2D and lipid-lowering medication, whereas
GHD men had a higher prevalence of antihypertensive medication.
Conclusions: The declined risks of nonfatal stroke in both genders
and of nonfatal cardiac events in GHD men during periods on GH
replacement may be caused by prescription of cardioprotective drugs
and 6-yr GH replacement. GHD women had an increased prevalence
of T2D, partly attributed to higher body mass index and lower phys-
ical activity. (J Clin Endocrinol Metab 92: 3560 –3567, 2007)
E
PIDEMIOLOGICAL STUDIES HAVE revealed in-
creased cerebrovascular and cardiovascular mortal-
ity in patients with hypopituitarism on conventional hor-
mone treatment, but without GH therapy (1–3). The
greatest increase was seen in cerebrovascular disease (2, 3),
with a more pronounced risk in women, but without gen-
der difference in cardiac mortality (2). Furthermore, an
increased incidence of nonfatal cerebrovascular and car-
diovascular events (4) was recorded among GH-deficient
(GHD) patients, along with higher prescription of cardio-
protective medication in GHD women (5). Untreated GHD
has been assumed to be responsible for early atherogenesis
in hypopituitarism because cardiovascular risk factors
have been improved on GH therapy (6).
Hypertension is an important risk factor for myocardial
infarction (MI) and stroke (7, 8). In unsubstituted GHD an
increased prevalence of treated hypertension has been re-
corded (9). It is noteworthy that GH treatment has decreased
diastolic blood pressure (10), but the risk ratio for nonfatal
cerebrovascular events tends to increase in GHD patients,
even after 5-yr GH therapy (4).
A high prevalence of impaired glucose tolerance (11, 12)
and type 2 diabetes mellitus (T2D) has been shown in GHD
patients (13). GH treatment may further increase insulin and
glucose levels (14), and even lead to diabetes mellitus (DM)
in GHD children (15), which is most likely explained by the
insulin antagonistic effect of GH (15). In GHD adults,
6-month low-dose GH replacement showed impairment of
insulin sensitivity (16), but it has also been suggested that GH
therapy decreases insulin resistance because of reduction in
fat mass (17, 18). However, an actual prevalence of DM
among GH-treated GHD patients is unknown.
First Published Online July 10, 2007
Abbreviations: AO, Adult-onset; BMI, body mass index; CI, confi-
dence interval; CRT, cranial radiotherapy; DM, diabetes mellitus; FHD,
first confirmed pituitary hormone deficiency; GHD, GH deficient; IRR,
incidence rate ratio; MI, myocardial infarction; POR, prevalence odds
ratio; PTCA, percutaneous transluminal coronary angioplasty; T2D,
type 2 diabetes mellitus.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the en-
docrine community.
0021-972X/07/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 92(9):3560–3567
Printed in U.S.A. Copyright © 2007 by The Endocrine Society
doi: 10.1210/jc.2007-0458
3560
Information regarding the impact of long-term GH ther-
apy (i.e. ⬎2 yr) on the incidence of nonfatal cerebrovascular
and cardiovascular diseases in sufficiently large populations
of hypopituitary patients is currently lacking. Therefore, the
aim of the present study was 2-fold: 1) to make a retrospec-
tive comparison of the incidence of nonfatal stroke and car-
diac events between a large cohort of patients with confirmed
GHD on GH replacement and a control cohort from the
general population; and 2) to compare the prevalence of DM
and cardioprotective medication between the cohorts at the
time of questionnaire distribution with adjustment for pos-
sible confounders and effect modifiers.
Patients and Methods
Patient study base
Prevalent cases of adult-onset (AO) GHD were recruited from the
Department of Endocrinology at all Swedish University Hospitals and
one county hospital, with the inclusion criterion of severe GHD deter-
mined by dynamic testing (peak GH ⬍ 3
g/liter). Tests included the:
insulin tolerance test (n ⫽ 409); arginine and arginine-insulin tests (n ⫽
203 and n ⫽ 2, respectively); GHRH and GHRH-arginine tests (n ⫽ 32
and n ⫽ 29, respectively); and others (n ⫽ 66), such as glucagon,
clonidine, l-dopa, apomorphine, and a 24-h GH profile (n ⫽ 103). At
least one of the other aforementioned tests had been used among 64
patients with a 24-h GH profile, and among remaining patients (n ⫽ 39),
only five had less than two other pituitary deficiencies (19), and their
24-h GH profile showed a maximum GH ⱕ 1.7
g/liter. Of the patients,
87% had a today recommended test (20), and the test was repeated in
13%. Among those with a less accurate test, only 14% had less than two
other pituitary deficiencies. GHD diagnoses were made between 1967
and 2001. Local representatives of the study group submitted informa-
tion for each patient concerning cause of pituitary deficiency and other
patient characteristics.
A total of 750 patients (82%) responded to a questionnaire sent in
April 2003. After completion of information (n ⫽ 26), they then consti-
tuted the study base. Of the study base, 53% (n ⫽ 399) were men, and
47% (n ⫽ 351) were women. Median age at the end of study was 59
(5th-95th percentile, 31–78) in men and 58 (31–76) in women. The major
cause of pituitary deficiency was pituitary adenoma (Fig. 1), hyperfunc-
tional in 31% of the cases. Of adenomas, 4% in men and 15% in women
were ACTH secreting, and 92% of men and 84% of women were cured
upon GHD diagnosis. Four percent of adenomas in men and 8% in
women were GH secreting. Of the patients with pituitary adenomas,
82% underwent surgery, 49% had received conventional cranial radio-
therapy (CRT), and 7% stereotactic irradiation. The frequency of CRT-
treated adenomas in males and females with and without stroke (lifelong
incidence) was similar (54 vs. 50% and 57 vs. 51%, respectively), and no
patients with CRT due to reasons other than pituitary adenoma suffered
strokes. Figure 2 presents the frequencies of different pituitary substi-
tutions when GHD was confirmed and replacements at the end of study
period. Only 7% of men and 9% of women had isolated GHD, and the
remaining patients had multiple pituitary deficiencies. At the end of the
study, women underwent sex steroid replacement therapy to the same
extent, regardless of whether they were ⱖ50 or younger than 50 yr old
(50 vs. 53%, respectively). Female patients with or without a history of
stroke also underwent sex steroid replacement to the same extent (50 vs.
52%, respectively). Combination therapies (estrogens and gestagens)
were mainly administered orally (62%) or through transdermal appli-
cation (6%), followed by estradiol administered as oral (21%) or trans-
dermal (11%) therapy.
The study protocol was approved by the Ethics Committees at each
participating university.
Population controls
Statistics Sweden selected four controls each from the Swedish pop-
ulation register, and successfully matched these for age, gender, county
of residence, and country of birth. They were otherwise randomly se-
lected. A total of 2314 (77% of those alive and living in Sweden) subjects
responded to the questionnaire in November 2003. The participation rate
was 79% in women (n ⫽ 1104) and 76% in men (n ⫽ 1210). Median age
was 60 yr (5th-95th percentile 31–78) for men and 58 (30 –75) for women.
Statistics Sweden completed questionnaire information through inter-
view in 6% of the respondents.
Statistics Sweden provided information on age, country of birth,
marital status, income, and urban/rural residence for the responding
and nonresponding population controls. Despite the fact that partici-
pating men were somewhat younger and the participants of both gen-
ders were more often married compared with nonparticipants, no other
socioeconomic characteristics differed (data not shown). Women un-
derwent sex steroid replacement more frequently at ⱖ50 than younger
than 50 yr of age (26 vs. 7%, respectively), but there was no difference
in sex steroid use between population controls with or without a history
of stroke (21% in both groups). Combination therapies were adminis-
tered mainly through oral (53%) or transdermal application (5%), fol-
lowed by estradiol administered as oral (31%) or transdermal therapy
(10%).
Questionnaire and outcome measures
The same questionnaire was used for both patient and control co-
horts. The questions addressed background information, including cur-
rent alcohol consumption, smoking history, country of birth, educational
level and residency, body weight, and height. Physical activity during
work/leisure time was classified on a four-grade scale (21). A composite
measure of physical activity was then constructed from these variables,
and dichotomized into “low” and “high.”
Information pertaining to present DM, antidiabetic therapy (diet,
oral, or insulin medication), and use of antihypertensive, lipid-lowering,
or antithrombotic drugs was requested. Participants were asked
whether they had had a stroke (ischemic or hemorrhagic) or cardiac
event defined as MI, percutaneous transluminal coronary angioplasty
(PTCA), or bypass surgery, and during what calendar year. Two out-
come measures were used for incidence calculations: 1) nonfatal stroke,
and 2) nonfatal cardiac event.
Distributions of matching criterion, potential confounders,
and effect modifiers
Table 1 shows successful age matching along with distribution of
potential confounders and effect modifiers.
0 1020304050607080
Traum a
Cranial
radiotherapy²
Idiopathic
Craniopharyngioma
Other¹
Pituitary adenoma
%
Women
Men
FIG. 1. Causes of pituitary deficiencies in 399 AO GHD men and 351
AO GHD women.
1
Examples include Sheehan’s syndrome, empty
sella syndrome, meningioma, pituitary cyst, and hypophysitis.
2
For
reasons other than pituitary adenoma or craniopharyngioma.
Holmer et al. • Cardiovascular Disease with GH Therapy J Clin Endocrinol Metab, September 2007, 92(9):3560–3567 3561
Follow-up periods and GH therapy
Three follow-up periods were defined for the incidence studies. Start of
follow-up for the three periods was defined respectively as: 1) from birth
(lifelong period), 2) from calendar year of first confirmed pituitary hormone
deficiency (FHD) period, and 3) from calendar year of confirmed GHD
period. All periods were followed until the calendar year of first stroke or
December 31, 2002, whichever occurred first (Fig. 3). The corresponding end
of follow-up was defined for cardiac event. The same follow-up periods
were applied for the matched population control cohort.
The cumulative incidence of current or previous GH during the GHD
period was 92% for women and 94% for men. At the end of follow-up,
women and men had been on GH therapy for a median period of 6 yr
each (1–12 yr in women and 1–13 yr in men).
Information on GH dose at the end of study was available in 96% of
patients. GH doses were 0.4 mg/d in women (range 0.15– 0.9) and 0.3
mg/d in men (range 0.13– 0.6) at the time of collection of questionnaires.
At the end of study, median serum IGF-I levels were available among
86% of the patients groups. Expressed as sd values, the IGF-I level in AO
GHD women was 0.0 (⫺2.0–2.3) and in men 0.5 (⫺2.5–3.4).
Time since FHD to start of GH treatment was 4 and 2 yr for GHD women
and men (0–27 and 0 –21, respectively). Time since confirmed GHD to start
of GH therapy was 1 yr for both GHD women and men (0– 4) (Fig 3).
Statistical analyses
Medians with 5th and 95th percentiles were applied for descriptive
statistics. For comparisons between the GHD patients and the population
controls (cohort affiliation), incidence rate ratio (IRR) and 95% confidence
intervals (CIs) for first stroke or first cardiac event (MI/PTCA/bypass
surgery) were calculated with Poisson regression models using EGRET
software (Statistics and Epidemiology Research Corp., Seattle, WA). A
lower limit of the 95% CI more than 1.00 is interpreted as a significantly
increased incidence. Likewise, an upper limit of the 95% CI less than 1.00
is interpreted as a significantly decreased incidence. Separate analyses were
performed for men and women to account for possible effect modification.
The absolute number of cases, especially among the GHD patients, was
generally very low, so models did not include potential confounders.
The prevalence of DM and use of antihypertensive, lipid-lowering, or
antithrombotic drugs was compared between the patient and control
cohorts, calculating prevalence odds ratios (PORs). Smoking habits (ev-
er/never), body mass index (BMI) (⬍20, 20 –30, and ⬎30 kg/m
2
), and
physical activity (low and high) were considered potential confounders
and included in the model, one at a time, together with cohort affiliation,
and retained if they changed the crude effect estimate by more than 15%.
If adjusted effect estimates differed less than 15% from the crude esti-
mates, we presented only the crude estimates. In a second estimation of
the aforementioned incidence and prevalence calculations, acromegaly
and Cushing’s disease patients were excluded.
Results
Incidence of nonfatal stroke and nonfatal cardiac event
Analyzed retrospectively, the lifelong incidence of nonfa-
tal stroke was three times as high among the female patients,
FIG. 2. Substitution therapies at con-
firmed GHD (A), and pituitary hormone
deficiencies and substitution therapies
at end of study (B) in 399 AO GHD men
and 351 AO GHD women. ADH, Anti-
diuretic hormone.
3562 J Clin Endocrinol Metab, September 2007, 92(9):3560–3567 Holmer et al. • Cardiovascular Disease with GH Therapy
whereas it was twice as high among the male patients, when
compared with controls (Table 2). For the FHD period, IRRs
nearly double in numerical terms were observed for nonfatal
stroke between both genders but did not reach significance.
For the GHD period, a nonsignificant 58% increase of non-
fatal stroke was observed for the male patients, whereas not
even a numerical risk increase was observed for the female
patients. However, the latter analysis was hampered by the
low number of cases.
The IRR for the lifelong incidence of nonfatal cardiac event
was slightly, but not significantly, lower for both male and
female patients (Table 2). Restricting the analyses to the FHD
period, incidence among male patients was significantly re-
duced to about half the incidence among the controls,
Birth
40 45 50 55
FHD
start
GHD
start
GH therapy
start
GHD-period 7 yr (2-14)
FHD-period 9 yr (3-32)
Birth
40
45
50 55
FHD
start
GHD
start
GH therapy
start
GHD- period 7 yr (2-17)
FHD-period 11 yr (2-37)
MEN
:
Lifelong period 58 yr (30-77)
WOMEN
:
Lifelong period 57 yr (30-75)
Definitions of the follow-up periods:
Lifelong period: From birth to 1
st
stroke/31
st
Dec 2002
FHD- period: From year of first confirmed pituitary deficiency to 1
st
stroke/31
st
Dec 2002
GHD-period: From year of confirmed GH deficiency to 1
st
stroke/31
st
Dec 2002
1
st
stroke/
31
st
Dec 2002
1
st
stroke/
31
st
Dec 2002
years
years
FIG. 3. Timetable illustrating the length (yr) of the follow-up periods for stroke (lifelong, FHD, and GHD) for median man and median woman.
The figures within brackets are the 5th and 95th percentiles for the whole groups. Corresponding analyses were performed for cardiac events.
Dec, December.
TABLE 1. Median values (5th-95th percentiles) for characteristics of 399 men and 351 women with confirmed GHD and population
controls (1174 men and 1103 women)
Men Women
Patients Controls Patients Controls
Matching criterion
Median age at study (range) 59 yr (31–78) 60 yr (31–78) 58 yr (31–76) 58 yr (30–75)
Potential confounders
BMI (kg/m²) 27 (22–34) 26 (21–32) 26 (20–38) 25 (20–33)
No history of smoking (%) 50 42 55 51
Physical activity at work (%)
a
1 42334432
2 30333235
3 23242331
451012
Winter physical activity, leisure time (%)
a
1 23182613
2 55544643
3 21252642
4 1322
Summer physical activity, leisure time (%)
a
1 7764
2 62595949
3 29313445
4 2392
Potential effect modifiers
High educational level (%)
b
42 39 43 39
Living alone (%) 24 19 35 26
Alcohol abstainers (%) 15 11 21 17
a
Four-grade-scale: 1, lowest grade of activity; 4, highest grade of activity.
b
Secondary school (UK)/high school (US) or university level.
Holmer et al. • Cardiovascular Disease with GH Therapy J Clin Endocrinol Metab, September 2007, 92(9):3560–3567 3563
whereas the IRR among females did not reach significance.
The same pattern applied to the GHD period as the start of
the observation period. However, analyses for females were
hampered by the low number of observed and expected
cases. Results did not change when excluding acromegaly
and Cushing’s disease patients.
Prevalence of DM and cardioprotective drugs
Even after confounder (BMI, smoking, and physical ac-
tivity) adjustment, the prevalence for DM among GHD
women was twice that of the population controls, whereas no
enhanced prevalence was noted among the GHD men (Table
3). GHD women and controls had diet (25 vs. 27%), oral
medication (21 vs. 19%), combination of oral medication and
insulin (18 vs. 16%), or insulin treatment (36 vs. 38%) for their
DM to the same extent, and this was also true for GHD men.
When excluding acromegaly and Cushing’s disease patients,
the prevalence for DM among female patients was higher
than in controls [POR 2.02 (1.17–3.49); P ⫽ 0.01], but after
confounder adjustment, the POR for DM was no longer sta-
tistically significant [POR 1.57 (0.87–2.84); P ⫽ 0.13].
GHD women were twice as likely to be taking lipid-
lowering drugs as the population controls, whereas no such
difference was observed for the GHD men. On the other
hand, 28% increased prevalence was observed for use of
antihypertensive drugs exclusively among males. When
smoking was included in the model, the increase was sta-
tistically significant (POR 1.33; 95% CI 1.01–1.75; P ⫽ 0.04).
The use of antithrombotic drugs was not increased among
female patients, whereas a 35% increase of the prevalence
with borderline significance of the POR was seen among
male patients. Excluding acromegaly and Cushing’s disease
patients produced only minor changes in the prevalence.
There was no difference in the effect modifier “educational
level” between patients and controls, but both GHD men and
women were likely to live alone, and GHD men abstained
TABLE 2. IRRs calculated from Poisson regression models for nonfatal stroke and cardiac events among AO GHD patients as compared
with age- and gender-matched control cohort subjects
Disease, follow-up period, gender
AO GHD patients Control cohort AO GHD vs. control cohort
Cases PY
a
Cases PY
a
IRR 95% CI P value
Stroke
Lifelong incidence
Men 29 21,949 51 69,918 1.81 1.15–2.86 0.01
Women 22 19,036 24 61,116 2.94 1.65–5.25 ⬍0.001
FHD period
b
Men 18 4,727 33 14,693 1.70 0.95–3.01 0.07
Women 11 5,001 18 16,185 1.98 0.93–4.19 0.07
GHD period
c
Men 13 2,857 26 9,034 1.58 0.81–3.08 0.18
Women 4 2,630 13 8,331 0.97 0.32–2.99 0.96
Cardiac events
d
Lifelong incidence
Men 25 21,931 96 68,171 0.81 0.52–1.26 0.35
Women 7 19,323 24 60,722 0.92 0.39–2.13 0.84
FHD period
b
Men 11 4,826 69 14,366 0.47 0.25–0.90 0.02
Women 6 5,063 19 16,132 1.01 0.40–2.52 0.99
GHD period
c
Men 9 2,873 59 8,771 0.47 0.23–0.94 0.03
Women 4 2,638 15 8,274 0.83 0.28–2.52 0.75
a
Person-years (PY) under observation.
b
From year of FHD to first stroke/cardiac disease or December 31, 2002.
c
From year of diagnosis of GHD to first stroke/cardiac disease or December 31, 2002.
d
Comprises MI, bypass surgery, and PTCA.
TABLE 3. Crude and confounder-adjusted PORs for DM, the use of antihypertensive drugs, lipid-lowering drugs, and antithrombotic
drugs among men and women with AO GHD as compared with the control cohort
Prevalence Crude analyses Confounder-adjusted analyses
AO GHD
(yes/no)
Control cohort
(yes/no)
POR (95% CI) P value POR 95% CI P value
Confounders
a
included in the model
Women
DM 30/319 39/1048 2.53 (1.54– 4.13) ⬍0.001 1.95 1.15–3.32 0.01 BMI, physical activity, smoking
Antihypertensive drugs 80/267 217/882 1.22 (0.91–1.63) 0.18 1.05 0.77–1.42 ⬎0.5 BMI
Lipid-lowering drugs 49/296 79/1005 2.11 (1.44–3.08) ⬍0.001
Antithrombotic drugs 24/327 71/1033 1.07 (0.66–1.72) ⬎0.5
Men
DM 27/366 77/1115 1.07 (0.68–1.68) ⬎0.5
Antihypertensive drugs 98/300 243/954 1.28 (0.98–1.68) 0.07
Lipid-lowering drugs 51/334 166/1021 0.94 (0.67–1.32) ⬎0.5
Antithrombotic drugs 64/335 150/1060 1.35 (0.98–1.85) 0.06
a
The confounder was kept in the model and presented in the table only if it changed the crude estimate more than 15%.
3564 J Clin Endocrinol Metab, September 2007, 92(9):3560–3567 Holmer et al. • Cardiovascular Disease with GH Therapy
from alcohol to a greater extent than controls (Table 1). When
living alone was included in the model, the prevalence for
DM or cardioprotective drugs did not change (data not
shown).
Discussion
This is the first comprehensive study on cerebrovascular
and cardiovascular morbidity in hypopituitary patients with
confirmed AO GHD on long-term GH therapy. Both women
and men with GHD had significantly increased risk for non-
fatal stroke during the lifelong follow-up, and again women
were at higher risk than men. However, among the GHD
women, no risk increase for nonfatal stroke was recorded
during the FHD (IRR 1.98) or GHD periods (IRR 0.97), during
which most patients had GH replacement. However, the
latter period was hampered by a minute number of obser-
vations. The same pattern was seen among the GHD men,
but risk for nonfatal stroke did not seem to level off quite as
much during the FHD (IRR 1.70) and GHD periods (IRR
1.58). We excluded patients with acromegaly and Cushing’s
disease, well known to have an increased cardiovascular risk
(22, 23), but the estimates did not change.
The incidence of nonfatal stroke was high before the FHD
and GHD periods in the present study. The cause is not
known, but the patients may have been pituitary deficient
before the date of diagnosed pituitary tumor (2). It is also
relevant that women with longer duration of hypopituitar-
ism symptoms before pituitary tumor diagnosis later suf-
fered fatal strokes (24).
One reason for the reduced risk for nonfatal stroke among
the GHD women may be increased prescription of lipid-
lowering drugs, possibly explained by the increased preva-
lence of DM, shown in our GHD women because guidelines
recommend lipid-lowering drugs at low levels of total cho-
lesterol (25). Furthermore, women with DM have greater
lipoprotein abnormalities than men with the same cardio-
vascular risk (26). Most likely, lipid-lowering drugs and GH
therapy contributed to the reduction in nonfatal strokes in
GHD women in the present study.
Although GHD is the first deficiency occurring (27), it was
previously seldom detected, probably because GH therapy
was not available. Unsubstituted GHD has been advocated
as a strong candidate for the increased cardiovascular risk in
these patients. However, even if the incidence of nonfatal
stroke was no longer increased during the GHD period, we
cannot conclude that GH therapy per se protected against
stroke because patients with fatal stroke were not included
in this study. However, a recent prospective population-
based study showed that low-serum IGF-I levels increase the
risk for ischemic stroke (28). The type of stroke was not
defined in the present study, but a near significant increase
in antithrombotic medication in AO GHD men (35%) favors
ischemic stroke.
In population-based studies, sex steroid therapy for post-
menopausal women was related to increased cardiovascular
risk (29, 30). In comparison to population controls, GHD
women in the present study used sex steroid replacement
more frequently before age 50 yr. However, it is not known
whether this early replacement contributed to an increased
incidence of lifelong nonfatal stroke. In comparison to pop-
ulation controls, there was no difference in the use of the
different estrogen and gestagen compounds, or evidence that
GHD women who suffered a nonfatal stroke used sex steroid
replacement more often than those who did not.
Subclinical hypothyroidism causes increased cardiovas-
cular risk (31). However, in a previous study, hypopituitary
patients had slightly higher circulating free thyroxine levels
(5), not shown to increase cardiovascular risk. Furthermore,
thyroxine doses and the percentage on replacement were
similar in GHD men and women with or without lifelong
stroke in the present study.
Glucocorticoid overdose has also been advanced as a po-
tential inducer of cardiovascular risk (32). In the present
study, there was no significant difference in glucocorticoid
dosage or percentage on replacement between GHD men
and women with or without lifelong stroke (data not shown).
An important issue is whether CRT of a pituitary tumor
increases the risk for subsequent stroke, which has been
suggested (33, 34). No difference in the incidence of nonfatal
stroke was recorded in GHD patients with or without CRT
in the present study. This concurs with studies revealing no
association between the biological equivalent dose of radio-
therapy and risk for subsequent stroke (24, 35).
A decreased incidence of nonfatal cardiac events was seen
among GHD men, but not in women, during both the FHD
and GHD periods. A decline in MI has been reported after
5-yr GH therapy, if both fatal and nonfatal events were
included (4). However, when excluding fatal events, no dif-
ference remained, suggesting that GH provides protection
against serious MI with a rapid time course. This is consistent
with findings that low-serum IGF-I may be involved in the
pathogenesis of ischemic heart disease (36). Another expla-
nation is the significant increase in antihypertensive drug
prescription recorded in GHD men, who were also more
likely than controls to have no smoking history. As for all
other cardioprotective drugs in the present study, an obser-
vational bias is possible not only because patients on GH
therapy visit their doctor more often and have investigations
on blood pressure, lipid levels, and glycosylated hemoglo-
bin, but also because endocrinologists are now aware of the
increased cardiovascular risk among GHD. However, this
cannot explain the difference between men and women. On
the contrary, because target blood pressure levels in diabetics
are narrower (⬍130/80 mm Hg) (25), a higher prescription
of antihypertensive drugs would be expected among GHD
women. Medical health care is also very uniform in Sweden,
meaning that all patients in the present study received equal
attention from endocrinologists.
This is the largest study investigating nonfatal cardiovas-
cular disease in GH-treated GHD patients to date, allowing
us sufficient capacity to significantly detect risk estimates
observed in previous studies (2, 3), whereas for specific sub-
group analyses with fewer cases, this capacity was naturally
lower. Because of wide CIs, relatively large effects could not
be excluded. To detect a significant risk increase of about
three with 80% power (e.g. upper confidence limit for stroke
among men for the GHD period), a study size of about half
the present is required. Conversely, to detect a significant
risk increase of about 1.6 (as in the present study), a study size
Holmer et al. • Cardiovascular Disease with GH Therapy J Clin Endocrinol Metab, September 2007, 92(9):3560–3567 3565
of about four times the present is required. The present
patient cohort was based on a cross-section of survivors, and
our results may be hampered by fatal cerebrovascular and
cardiovascular events before this study. However, because
survival within 28 d after both stroke and MI has improved
markedly in Sweden (37), the incidence of nonfatal events
has become a major issue.
There is no evidence for selection of patients alive at in-
clusion in the study because the causes of GHD were dis-
tributed as expected (38). GHD was confirmed after adequate
testing in most patients, and GH doses seemed adequate with
higher doses in women than men (39), and with sd IGF-I
levels at the mid ranges.
Population controls matched for potential confounders,
age, gender, county of residence, and country of birth were
used in the present study. The participation rate among
controls was uniquely high (77%) and very close to that
among the patients (82%). The same questionnaire was sent
in the same manner to both patients and control cohorts.
This study is the first to show the prevalence of DM and
cardioprotective medication after 6-yr GH therapy. The
cause was not overtreatment of GH because the sd IGF-I level
was exactly in the mid range. Based on a majority of non-
insulin treatments, the GHD women had an increased prev-
alence of T2D. This increase was seen even after exclusion of
acromegaly and Cushing’s disease patients, but when in-
cluding confounders in the model, POR for T2D was no
longer significant, indicating that the increased prevalence of
DM was partly attributed to higher BMI and lower physical
activity. When including the effect modifier “living alone” in
the model, no change was seen in these estimates. Thus, it
seems that T2D can only be avoided if BMI and physical
activity are carefully observed. Previously, shorter GH treat-
ment periods have shown an increase in blood glucose levels
(14), more deleterious in GHD women (14), but provided that
fat mass was reduced and lean mass increased during longer
GH therapy unchanged insulin sensitivity has been recorded
(40). Unfortunately, given the lack of information on the
incidence of DM in this study, we cannot state whether there
was a decline or an increase in DM after 6-yr GH therapy.
In conclusion, in a cohort of 750 patients with AO GHD,
prescription of cardioprotective drugs and 6-yr GH therapy
may have resulted in a reduced risk for nonfatal stroke,
particularly noted in women, and in a decline in nonfatal
cardiac events in GHD men. GHD women had an increased
prevalence of T2D, partly attributed to higher BMI and lower
physical activity. Continuous surveillance of cardiovascular
risk, and especially of DM, is recommended in this patient
population.
Acknowledgments
Received March 1, 2007. Accepted June 28, 2007.
Address all correspondence and requests for reprints to: Eva-Marie
Erfurth, Department of Endocrinology, Lund University Hospital, SE-
221 85 Lund, Sweden. E-mail: Eva-Marie.Erfurth@med.lu.se.
This work was supported by the Swedish Research Council (Grant K
2002-72X-14257-01), the Swedish Children’s Cancer Foundation, and the
Medical Faculty, Lund University, Sweden. Generous grants were pro-
vided by Pfizer AB, Eli Lilly Sweden AB, and Ipsen Scandinavia A/S.
This study is retrospectively registered at www.clinicaltrials.gov
(March 2007).
Disclosure Statement: E.-M.E. received grant support from Pfizer AB,
Eli Lilly Sweden AB, and Ipsen Scandinavia A/S.
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