Growth Hormone & IGF Research 2001, Supplement A, $43-$48

Review article

G r o w t h h o r m o n e t r e a t m e n t in adults:
is t h e r e a t r u e g e n d e r d i f f e r e n c e ?
Fl~via Lucia Concei¢;~o, Sanne Fisker, Nina Vahl, Troels Krarup Hansen,
Jens Otto Lunde Jorgensen and Jens Sandahl Christiansen
Medical Department M, Aarhus University Hospital, Kommunehospitalet, DK-8000 Aarhus, Denmark

Summary The importance of growth hormone (GH) deficiency in adults became evident at the end of the 1980s,
when the first clinical studies on GH replacement therapy in adults were published. Since then, accumulated
experience has shown a great individual variability in the response to GH replacement, including a potential difference
in responsiveness between genders. The aim of this paper is to review the data regarding the effects of gender
differences on GH pharmacokinetics, pharmacodynamics, and efficacy of replacement. In addition, we start with a short
review of the possible role of GH in sexual development and sexual life. © 2001 Harcourt PublishersLtd

Key words: growth hormone, gender, pharmacokinetics, pharmacodynamics, sex life, growth hormone treatment

INTRODUCTION there is a great individual variability in the response to

Raben was the first to use growth hormone (GH) in an
adult with panhypopituitarismL In 1962, he described
the effects of its use in a 35-year-old woman who had
received replacement therapy with the exception of GH
for 8 years before GH therapy was started. After
3 months of treatment, the patient noticed increased
vigour, ambition, and sense of well-being.
The importance of GH deficiency (GHD) in adults
became evident at the end of the 1980s when the first
clinical studies on GH replacement therapy in adults
were published 2,3. It was shown that untreated GH-
deficient patients have changes in body composition,
including an increase in body fat (with a predominance
of visceral fat), a decrease in lean body mass (LBM), a
decrease in bone mineral content (BMC), an impairment
of muscle strength, a decrease in their quality of life, and
an increase in mortality, especially resulting from cardio-
vascular disease 4. It was also shown that many of these
features can be improved with the use of GH therapy.
Since then, accumulated experience has shown that
Correspondence to: Prof. J. Sandahl Christiansen, Medical Department M,
Aarhus University Hospital, Kommunehospitalet, DK-8000 Aarhus, Denmark.
Tel: +45-89-492010; Fax: +45-89-492013; E-mail: jsc@afdm.au.dk
GH replacement, including a potential difference in res-
ponsiveness between genders.
SEXUAL DEVELOPMENT, SEXUAL LIFE AND
REPRODUCTION
There are several lines of evidence showing that GH may
have a role in sexual life and reproductive function. It
has been known for many years that boys with GHD and
Laron syndrome have a small penis, reduced testicular
volume, and delayed puberty that can be improved by
the use of CH or insulin-like growth factor I (IGF-I)s-8. An
impairment of Leydig cell function in some GH-deficient
individuals has also been described 9. While some studies
have shown that GH administration improves testos-
terone production in response to stimulation with
human chorionic gonadotropin 1°-12, suggesting a permis-
sive role of GH in Leydig cell activity, this has not been a
consistent finding 13.
GH administration to men with childhood-onset GHD
resulted in normalization of androgen-dependent body
hair development, without a concomitant increase in
androgen levels TM. Laron e t al. 6 also showed that the pro-
motion of androgen effects by GH did not correlate with
serum androgen levels. In their study, GH therapy in

1096-6374/01/0A0S43+06$35.00/0 © 2001 HarcourtPublishersLtd

44 F.L. Concei~&oet al.
prepubertal GH-deficient children with low testosterone
levels resulted in an increase in penile and testicular size,
while testosterone levels remained unaffected. These
findings could suggest an interaction between GH and
sex steroids in sexual development.
Finally, studies of patients with GHD have suggested
decreased psychological well-being in these individuals.
With the use of questionnaires to assess quality of life,
disturbances in several areas such as energy, social isola-
tion, emotional distress and sex life were demonstrated
in comparison to healthy controls. Using the Nottingham
Health Profile questionnaire, which is a generic measure
of quality of life, disturbances in the patients' sex lives
were revealed, despite the fact that regular replacement
therapy with sex steroids was givenlL These findings
suggested that the prevailing routine substitution ther-
apy without GH was not sufficient to restore the sexual
function to a normal state.
Recently, Keselman et al. evaluated the social outcome
of a group of patients with childhood-onset hypopitu-
itarism 16. Seventy patients were interviewed at a mean
age of 25.6 years (range, 18-50 years). The investigators
found that 44% of the patients had no dating experience
and 52% had never had sexual intercourse. Depression
was common, especially in hypogonadic individuals. In
addition, Wiren et al. showed that with long-term GH
therapy (20-50 months), there was a significant improve-
ment in sex life, demonstrating the importance of GH ~r.
PHARMACOKINETICS
Using 24-h blood sampling for deconvolution analysis
and approximate entropy, it has been shown that women
secrete more GH in a more irregular pattern than men 18.
The mean 24-h serum GH concentration is two to three
times higher in premenopansal women than in men of
the same age, and this difference is mainly due to a
higher GH secretory burst. In contrast, the frequency of
bursts appears to be similar in men and women (Fig. 1)1L
In a recent report, Engstrom et al. showed that GH
levels are higher in young women than in young men
(age range, 21-26 years). They also showed that young
women taking oral contraceptives have even higher GH
concentrations in a morning fasting serum sample 2°.
Oral administration of oestrogen increases endoge-
nous GH levels in post-menopausal women2L An increase
in GH secretion in women during the periovulatory
phase of the menstrual cycle compared to the early follic-
ular phase has also been reported. Furthermore, the GH
secretion correlated significantly with serum oestradiol
levels = . The mechanism behind the association between
GH secretion and oestrogens is still not fully elucidated,
but it has been suggested that oestrogen has an
inhibitory effect on the production of IGF-I by the liver,
resulting in reduced negative feedback on GH secretion.
Studies on oestrogen replacement in post-menopausal
women have shown that with oral administration, an
increase in GH secretion occurs in tandem with a
decrease in IGF-I levels, which does not happen with
transdermal administration of standard doses 2~,23-25.
With regard to GH half-life, there is still some disagree-
ment about the existence of gender differences. Rosem-
baum and Gertner, after giving a constant infusion of
biosynthetic human GH, found that adult men have a
significantly higher metabolic clearance rate (MCR) than
women 2~. This difference was also evident if MCR was
corrected for body surface area.
In a more recent study, Shah et al. reported that the
mean GH half-life after bolus injection of GH tended to
be only slightly higher in men than in women2L When
corrected for body surface area, however, the differ-
ence disappeared. The absolute distribution volume was
higher in men, which was accounted for by men's greater
mean body surface area. Men and women had identical
surface area-normalized MCR. In women, comparison of
GH distribution volumes, MCR and half-life at three
phases of the menstrual cycle revealed no significant dif-
ferences between the phases, despite the expected rise in
serum oestradiol concentrations in the late follicular
phase.
Vahl et al. studied the acute effects of a single exo-
genous GH pulse in healthy adults of both sexes and
reported that the distribution halfqife of GH (calculated
from the first 10 min after peak serum GH) was higher in
males, but the elimination half-life did not differ between
genders 28. There were no gender differences in MCR and
distribution volume (Vd). Both MCR and V d were closely
related to intra-abdominal fat mass. Furthermore, posi-
tive correlations were found between GH-binding protein
(GHBP) and estimates of body fat. The same was found
by Johannsson et aI. who reported that responsiveness to
GH might be dependent on levels of GHBP and body
mass index 29. It was also shown that there are gender dif-
ferences in GHBP levels, with women having higher lev-
els than men after the age of 40 years 3°. As it seems that
the concentrations of GHBP can modulate GH half-life31,
the gender differences in GHBP could explain the differ-
ences in GH half-life found between the sexes.
PHARMACODYNAMICS
Several reports have demonstrated the influence of gen-
der on GH responsiveness, as assessed by IGF-I levels
and other parameters, with men demonstrating a greater
responsiveness to GH therapy. It has also been reported
that GH-deficient women need higher GH doses for a
longer time than men to achieve the same clinical effects
and IGF-I levels 28,32-38. Thus, Lieberman et al. employed
 GH treatment: is there a sex difference? 45

(a) Female subjects

~4 ~ 20
lo
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' 1'8 2'1 24' 3' 6' 9' 9 12 15 18 21 24 3 6 9
Time (hours) Time (hours) Time (hours)

(b) M a l e subjects

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::Z _~1.5

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9 12 15 18 21 24 3 6 9 9 12 15 18 21 24 3 6 9 9 lf2 1~5 lm8 2~1 14 3 6

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1215182124 3 6 9 1215182124 3 6 9 9 1215182124 3 6 9
Time (hours) Time (hours) Time (hours)
Fig. 1 Illustrative profiles of 24-h serum GH concentrations measured by time-resolved immunofluorometric assay in 3 women (a) and 3
men (b). Blood was sampled at 10-min intervals for 24 h in 11 women and 11 men, and results are illustrated for 3 volunteers of each
gender. The upper panels depict the measured serum GH concentrations over time with their intrasample dose-dependent standard
deviations and the fitted curves predicted by deconvolution analysis. The lower panels depict the deconvolution-calculated GH-secretory
profiles consisting of almost exclusively burst-like GH-secretory episodes widely distributed over 24 h. Very low rates of basal secretion are
also shown, but constitute less than 10% of total daily GH production in these healthy middle-aged individuals. Reprinted, with permission,
from van den Berg et aL J Clin Endocdnol Metab 1996; 81 : 2460-2467. © The Endocrine Society

an IGF-I generation test to examine the changes in the older w o m e n taking oral oestrogen and those not taking
IGF-I and IGF-binding protein 3 (IGFBP-3) responses to oestrogen, indicating a predominant effect of oestrogen
GH that occur with ageing and oestrogen replacement over age in w o m e n with regard to responsiveness to GH.
therapy in healthy adults s2. The IGF-I response to GH Eden et al. studied the effects of 2 weeks of GH treat-
was significantly decreased with age in men, and with m e n t on IGF-I, insulin, testosterone, sex h o r m o n e -
oral oestrogen therapy in post-menopausal women. The binding globulin (SHBG), lipids, and markers of b o n e
response a m o n g y o u n g w o m e n in the follicular phase of turnover in healthy individuals 33. They examined three
the menstrual cycle was intermediate between that of groups of y o u n g people: men, w o m e n using oral
46 E L. Conceif#o et al.
contraceptives, and women who were not, and found
that with regard to IGF-I, the response was highest in
men and lowest in the women taking oral contraceptives.
Decreased levels of total cholesterol, low-density lipopro-
tein (LDL)-cholesterol and SHBG were seen only in the
men. Increases in insulin, triglycerides and bone markers
were found both in men and in women without oral con-
traceptives, whereas in the women taking oral contracep-
tives, changes were only noted in insulin and telopeptide
of collagen type I.
In GH-deficient patients, Span et al. showed that
women had lower basal IGF-I levels, and that during GH
replacement, after the titration phase, the daily GH dose
required to normalize IGF-I levels in women (with or
without oestrogen replacement therapy) remainedun-
changed, while in men a decreasing dosage was required
over time 34. The weight-corrected GH dose required to
achieve adequate IGF-I levels was higher in the oestro-
gen-treated women than in the women without oestro-
gen replacement. Furthermore, GH responsiveness
doubled over time in the androgen-substituted group of
men, but not in the men without androgen replacement,
reflecting an increase in GH responsiveness by exoge-
nous androgen therapy during continued GH treatment.
Likewise, Drake et al. reported a gender difference in
IGF-I responsiveness to GH in GH-deficient adults
treated for 3 months~t The daily dose was 50% higher in
women than in men, and the time to achieve the main-
tenance dose was also significantly longer in women.
Murray et al. demonstrated that the GH dose required
in an individual is mainly dependent on the serum IGF-I
SDS before therapy3Z In their study, women had lower
basal IGF-I levels and required a higher GH maintenance
dose to normalize IGF-I.
Using an individualized dose schedule of GH treat-
ment, Johannsson et al. found that women needed a
higher GH dose per kg of body weight than men to
achieve normalized IGF-I levels3L The same was found
by Janssen et al. who investigated the effect of three dif-
ferent doses of GH on IGF-I and IGFBP-3 in patients with
GHD 38. Female patients had significantly lower IGF-I
levels both at the start of the study and after 12 weeks of
treatment, although the percentage increase in serum
IGF-I during GH treatment was not different between the
sexes.
The lipolytic response to a GH exogenous pulse was
studied by Vahl et al. 28. They demonstrated a greater
response in healthy men than in healthy women.
CLINICAL PRESENTATION
There are few reports about the differences in the clinical
presentation of GHD between genders. Rosen et al.
reported that, other than the expected differences in
body composition, there was a reduced percentage of
extracellular water in women compared to men with
GHD 39. Not surprisingly, a greater amount of body fat
and a lower LBM have been reported in women com-
pared to men 29,4°.
Patients with hypopituitarism have a higher mortality
rate from cardiovascular disease when compared to the
general population 4. It has also been suggested that
women with hypopituitarism show a greater increase in
vascular mortality than men4L
E F F I C A C Y OF R E P L A C E M E N T
It is a common experience that the clinical response to
GH replacement is highly individual (as is seen in most
other hormonal replacement therapies). Some reports
point to a gender difference as one of the factors respon-
sible for this variability. Thus, with regard to body com-
position, almost all the studies undertaken have shown
a greater increase in LBM and total body water, and a
greater reduction in fat mass and waist:hip ratio, with GH
replacement in men compared to women 29,4°,a2-4~.
There are still some controversial findings concerning
the response of lipid profiles to GH replacement. The
majority of studies have shown a greater reduction in
total and LDL-cholesterol in men, and this has also been
true of apolipoprotein B concentrations. Some studies
have demonstrated an increase in high-density lipopro-
tein cholesterol in women, whereas others have shown
an increase in men only. Although not a universal find-
ing, an increase in triglyceride concentrations in women
but no effect in men has also been reported 42,44-46.
Gender differences in the effects of GH replacement
on markers of bone turnover have been described.
Johansson et aL assessed the effects of long-term treat-
ment with GH on bone metabolism and bone mineral
density (BMD) in men and women with GHD4L With the
same dose of GH, adjusted for body surface area, the
increase in serum IGF-I was greater in men. After adjust-
ments in dose during the open phase of the study, the
final dose was approximately twofold higher in women.
The serum concentrations of osteocalcin increased more
in men than in women when the same dose of GH per
unit body surface was given, but they increased to the
same extent in men and women when adjusted doses
were used. Similar results were found with the other
markers of bone formation (bone alkaline phosphatase
and procollagen type I C-peptide) and bone resorption
(telopeptide of collagen type I). Total body BMC and
femoral neck BMC and BMD increased significantly in
men, but not in women, after 33 months of GH treatment.
Many studies have focused on the role of oestrogens as
being responsible for gender differences. The fact that in
some studies there were no differences between women

w i t h or w i t h o u t o e s t r o g e n r e p l a c e m e n t 3s s u g g e s t e d t h a t
t h e r e m u s t be a d d i t i o n a l factors involved. Thus, Fisker et
al. s h o w e d in a g r o u p of patients w i t h GHD t h a t female
patients h a v e lower IGF-I levels t h a n male patients, while
in t h e control g r o u p no differences were seen b e t w e e n
t h e g e n d e r s 4s. Testosterone levels were significantly
lower in t h e female patients c o m p a r e d to t h e female con-
trols, w h e r e a s n o differences were f o u n d in t h e levels of
t h e male p a t i e n t s c o m p a r e d w i t h t h o s e of t h e male con-
trols. Testosterone levels were also lower in patients
t r e a t e d w i t h h y d r o c o r t i s o n e (reflecting r e d u c e d a d r e n a l
a n d r o g e n secretion) w h e n c o m p a r e d to t h e levels of t h e
rest of t h e female patients. In t h e p a t i e n t group, oestra-
diol levels of t h e two g e n d e r s were identical, resulting
from low oestradiol levels a m o n g t h e w o m e n . The testos-
terone/SHBG ratio, w h i c h was u s e d as an estimate of free
testosterone, was lower in female patients c o m p a r e d to
female controls. F u r t h e r m o r e , oestradiol levels were n o t
c o r r e l a t e d to IGF-I, w h e r e a s a positive correlation was
f o u n d b e t w e e n t e s t o s t e r o n e a n d IGF-I in female patients.
Testosterone a d m i n i s t r a t i o n increases IGF-I levels in
h e a l t h y m e n a n d in m e n w i t h h y p o g o n a d i s m 49,5°. In addi-
tion, t h e a d m i n i s t r a t i o n of d e h y d r o e p i a n d r o s t e r o n e to
ageing m e n a n d w o m e n leads to an increase in IGF-I
t o g e t h e r with a decrease in IGFBP-1, reflecting a n
i n c r e a s e d bioavailability of IGF-151. These findings, a n d
t h e w e l l - k n o w n lipolytic a n d a n a b o l i c actions of testos-
t e r o n e on b o d y composition, p o i n t to a possible role of
a n d r o g e n s in t h e o b s e r v e d g e n d e r differences in
r e s p o n s e to GH.
CONCLUSIONS
W o m e n s h o w h i g h e r levels of e n d o g e n o u s G H secretion
t h a n men. No m a j o r c o n s i s t e n t g e n d e r differences in
t h e p h a r m a c o k i n e t i c s of e n d o g e n o u s a n d e x o g e n o u s
GH h a v e b e e n reported. The p h a r m a c o d y n a m i c s of GH
a d m i n i s t r a t i o n differ b e t w e e n m e n a n d w o m e n , w i t h
men showing the most marked hormonal and metabolic
response. GH-deficient w o m e n n e e d a h i g h e r GH dose
t h a n m e n in o r d e r to o b t a i n equal benefits from GH
r e p l a c e m e n t therapy.
ACKNOWLEDGEMENTS
Dr. Fl~via Lucia Conceiq~o is s u p p o r t e d b y a g r a n t from
CNPq-Brazil.
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