FERTILITY AND STERILITY Vol. 56, No.

2, August 1991
Copyright <> 1991 The American Fertility Society Printed on add-free paper in U.S.A.

Pharmacodynamics and pharmacokinetics after subcutaneous and

intramuscular injection of human chorionic gonadotropin*t

Werner Saal, M.D.:j:

Heinz-Jiirgen Glowania, M.D.§
Wolfgang Hengst, M.D. II
Joachim Happ, M.D.1f

Bundeswehrzentralkrankenhaus, Koblenz, Germany

Objective: The pharmacokinetics and efficiency of human chorionic gonadotropin (hCG) after
subcutaneous (SC) injection was to clarify in comparison with the intramuscular (IM) mode of
administration.
Design: In a prospective study, the pharmacokinetics of hCG and the response of serum testos-
terone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) after an IM and SC
injection of 5,000 IU hCG were evaluated up to 144 hours in two randomized groups.
Setting: The study was carried out in a clinical dermatology department providing tertiary care.
Participants: Twenty-four healthy male volunteers with a mean age of 22.7 ± 4.3 years were
divided into two groups.
Interventions: Human chorionic gonadotropin (5,000 IU) was injected IM or SC.
Main Outcome Measure: Serum concentration of ,8-hCG, T, LH, and FSH were evaluated after
IM and SC administration of hCG. Differences between the two groups were determined by t-test.
Results: Compared with IM administration of hCG, peak serum drug concentration was signif-
icantly delayed (P = 0.01) and serum half-life was prolonged (P = 0.01) after SC injection; however,
T, LH, and FSH responses were identical.
Conclusions: Subcutaneous application of 5,000 IU hCG is as effective as IM administration in
terms of steroidogenesis. Fertil Steril 56:225, 1991

Male hypogonadotropic hypogonadism can be IM injections can be performed by the physician or

treated by gonadotropin substitution. Application is
possible by parenteral access only. Until now, go-
nadotropins were administered exclusively by intra-
muscular (IM) injection. The therapeutic schedule
most frequently used provides for administration of
the preparation three times weekly .1 •2 Because the
Received April 13, 1990; revised and accepted April 12, 1991.
* Supported by Serono Pharma GmbH, Freiburg, Germany.
t Presented in part at the 17th World Congress of Dermatology,
Berlin, Germany, May 24 to 29, 1987.
:j: Present address: Department of Dermatology, Bundeswehr-
krankenhaus, Ulm, Germany.
§ Department of Dermatology.
II Department of Nuclear Medicine.
1f Reprint requests and present address: Joachim Happ, M.D.,
Diisseldorfer Str. 1-7, D-6000 Frankfurt/M., Germany.
the medical professional staff only, the patient is
expected to visit a private practice or a hospital reg-
ularly to receive treatment. Apart from the discom-
fort caused by IM injections, the time taken by this
type of application often leads to unsatisfactory
compliance because treatment frequently extends
over several months until both pubertal maturation
and a relatively normal fertility are achieved. 1- 3 To
simplify treatment and to improve patient compli-
ance during long-term gonadotropin therapy, the
subcutaneous (SC) route of administration, allowing
self-administration by the patient, had previously
been chosen by our group in treatment of hypogo-
nadotropic males. 4
To date no detailed data are available concerning
the pharmacokinetics and pharmacodynamics of

Vol. 56, No. 2, August 1991 Saal et al. Pharmacodynamics of hCG 225
human chorionic gonadotropin (hCG) after SC
application and its effects on the hypothalamo-
pituitary-gonadal axis. Changes in endogenous go-
nadotropin secretion during hCG therapy could not
be studied until highly specific radioimmunological
methods using monoclonal antibodies were devel-
oped because all other test systems for the deter-
mination of luteinizing hormone (LH) had high
cross-reactivity with hCG.
Our study was designed to compare the pharma-
cokinetics and pharmacodynamics of hCG after IM
and SC injection on healthy test persons. For both
modes of administration, the efficacy regarding the
steroidogenic response was investigated by measur-
ing the increase in serum testosterone (T). The effect
of the exogenous gonadotropin on the hypothalamo-
pituitary-gonadal axis was investigated by deter-
mining the endogenous LH and follicle-stimulating
hormone (FSH) serum levels.
MATERIALS AND METHODS
Subjects
Twenty-four male volunteers, between 18 and 41
years of age, participated in the study after they had
given their informed consent. They were recruited
from the in-patients of the Department of Derma-
tology of the Federal Army Central Hospital at
Koblenz, Germany. All individuals were endocri-
nologically and andrologically inconspicuous. Pa-
tients with liver or kidney dysfunction or arterial
hypertension were excluded from the study.
Study Protocol
The population of volunteers was subdivided into
two randomized groups of 12 individuals each. Group
1 received a single injection of 5,000 IU hCG (Preg-
nesin; Serono, Freiburg, Germany) IM deep intra-
gluteally. Group 2 was given the same dose SC, in
a lifted skin pleat on the ventral side of the thigh.
The substance was always applied by the same phy-
sician at 8 A.M.
Blood samples for the determination of hCG, LH,
and T were taken from a cubital vein at the following
times: immediately before the administration ofhCG
and 1, 2, 4, 6, 8, 12, 16, 22, 26, 30, 36, 48, 72, 96, 120,
and 144 hours after the injection. The serum level
ofFSH was determined at the following times: before
the injection and after 4, 12, 22, 48, 72, 96, 120, and
144 hours. Immediately after collection, the samples
226 Saal et al. Pharmacodynamics of hCG
were centrifuged and the sera stored at -20°C until
laboratory analysis.
Assays
Human chorionic gonadotropin, LH, FSH, and T
were measured in serum by the Department of Nu-
clear Medicine of the Federal Army Central Hospital
at Koblenz, Germany, using monoclonal radioim-
munoassay kits (hCG-, LH-, and FSH-MAIAclone
and T MAlA; Serono Diagnostika, Freiburg, Ger-
many). According to the specifications given by Ser-
ono, cross-reactivity of hCG with LH-MAIAclone
is 0.004%.
RESULTS
Serum IJ-bCG
Before the injection, fJ-hCG serum concentration
was at the lower detection limit in all volunteers.
After IM injection, 406.97 ± 60.19 mU/mL was
found after 6 hours; thereafter, serum hCG declined
slowly with a half-life of 31 ± 3 hours (Fig. 1). After
SC injection, the highest value of 187.47 ± 55.9
mU/mL was reached after 16 hours, and the half-
life was extended to 38 ± 3 hours (Fig. 1). The area
under the curve (AUC) was 19,777 mU/mL X hours
in group 1 and 12,586 mU/mL X hours in group 2.
Serum T
Before hCG injection, the T values were similar
in both groups. The highest serum concentration
was reached 72 hours after IM injection as well as
after SC injection. Serum T peak value showed no
significant difference after the two modes of admin-
istration (Fig. 1). The stimulation index (T maxi-
mum/basal T) was 1.89 in group 1 and 1.83 in group
2. The AUC was 1,896 ng/mL X hours in group 1
and 1,848 ng/mL X hours in group 2.
Serum LH and FSH
There was also no significant difference between
the two groups regarding the absolute values of LH
and FSH before hCG injection or during the whole
period of investigation. Serum LH dropped rapidly
during the 1st 24 hours after hCG injection. During
the following 120 hours, the serum level decreased
only slightly, and the lowest value was determined
after 144 hours, i.e., at the end of the controlled
period (Fig. 1). Serum FSH declined more slowly till
Fertility and Sterility
 T
(ng/mU
15
.......... sc
o---oiM

100 10

.......... sc
o----o IM
10

24 48 7 1l.4h
24 48 7 96 10 144 h

LH FSH
(mU/mLl, T
(mUfmU 5: :
5 - .-.-sc ....-sc
',,'•• o---o IM
o---o I M 4 ' I T

4
'•
::,, --~,:
•: 3 \i_ __ i T

................... : ,.
T
I
', ' '
2

.............
. . .:--------"<?
' '
'
' :'
48 4h 24 48
24 7

Figure 1 Serum concentration (mean ± SD) of hCG, T, LH, and FSH before and after IM and SC injection
of 5,000 IU hCG.

the end of the investigation, 144 hours after hCG
injection (Fig. 1). No side effects were observed at
the injection site after SC or IM injection of hCG.
DISCUSSION
The pharmacokinetics of hCG and the testicular
steroidogenic response after IM and intravenous in-
jection in normal men are well known from the in-
vestigations of other authors. For the IM mode of
administration, our results are similar to those re-
ported previously.5-7 In our study, the peak of hCG
serum level was reached 6 hours after IM injection
of 5,000 IU hCG, and the serum half-life was 31 ± 3
hours. Other investigators found the peak of hCG
in serum (or plasma) after 5,000 to 10,000 IU hCG
between 65 and 86 •7 hours, and the half-life was de-
termined to range from 246 to 325 •7 hours. The phar-
macokinetics of hCG after SC injection is described
for the first time in the present study. Compared
with IM administration, the peak hCG serum level
was delayed after SC administration, and the mag-
nitude was reduced. The half-life was extended,
which indicates a slower diffusion of the SC-admin-
istered hCG into circulation.
The testicular steroidogenic response, however,
was similar after IM and SC injection of 5,000 IU
hCG. The peak of serum Twas reached after 72
hours, and the stimulation index was 1.89 and 1.83,
respectively after IM and SC administration. In ac-
cordance with our results, other authors described
a broad peak of plasma T at 48 to 96 hours6- 11 after
a single IM injection of 1,500 to 10,000 IU hCG.
Sometimes an additional smaller peak at 2 to 4 hours
was found. The maximum plasma T levels in normal
men after a single injection of 5,000 IU hCG or more
were 1. 7 to 2.4-fold higher than the basal value.S-9 •12
By 5,000 to 6,000 IU hCG, maximum stimulation of
testicular steroidogenesis seems to be achieved be-
cause higher doses and multiple injections did not
lead to a further increase. 7•9 •13-15 A second injection
of hCG within 24,7 48, 16 and 72 17 hours after the first

Vol. 56, No.2, August 1991 Saal et al. Pharmacodynamics of hCG 227
injection does not lead to a further increase of
plasma T. This desensitization is regarded to be most
likely because of an estradiol-induced inhibition of
enzyme activity11 •18·19 and a receptor down regulation
in the testis. 20·21 In spite of the markedly lower hCG
plasma concentration during the 1st 48 hours after
SC injection, we found a similar stimulation of tes-
ticular steroidogenesis after IM and after SC ad-
ministration. Under both conditions, maximum T
levels were found when plasma hCG was relatively
low again (48 to 120 hours after injection of hCG).
In accordance with the results of other investiga-
tors,6·7·18 these data demonstrate that there is nodi-
rect correlation between the actual serum levels of
hCG and T. This is in keeping with the concept that
the late response represents restimulation of Leydig
cells by residual hCG as they emerge from the re-
fractoriness induced by the initial stimulus. 7·9·10·22
So there is evidence that the initial hCG level is less
important and that the amount of hCG, necessary
to achieve maximum steroidogenic response is
smaller than assumed. It was demonstrated that
multiple low-dose hCG administration, in contrast
to a single high dose, does not desensitize but rather
enhances Leydig cell steroidogenesis. 18 The slower
release of the SC-injected hCG has no negative effect
on testicular steroidogenesis in the doses used in
our study. The delayed resorption and the prolonged
half-life might help to prevent Leydig cell desensi-
tization after hCG administration.
The effect of the applied hCG on the hypothal-
amo-pituitary-gonadal axis was also investigated in
the present study. Because of the pulsatile nature
of LH and, to a lesser extent, FSH secretion, our
results are only an approximate value of exact mul-
tiple sample assayed integrated hormone concen-
trations. 23 In spite of this reservation, our data pro-
vide some interesting findings. Serum LH and FSH
showed a continuous decline throughout the whole
period of observation (i.e., 144 hours) after hCG ad-
ministration, which to the present knowledge is me-
diated by T. A direct negative feedback of hCG on
gonadotropin secretion is unlikely because the in-
creased hCG levels 6 hours after IM and 16 hours
after SC injection did not cause an immediate drop
of the endogenous gonadotropin levels. The LH
value did not decrease to a plateau until 26 hours
later. A negative correlation with the T level seemed
to be more apparent than with serum hCG.
The results of this study are of great clinical sig-
nificance. In spite of the different pharmacokinetic
results after IM and SC application of a single bolus
228 Saal et al. Pharmacodynamics of hCG
injection of 5,000 IU hCG, both routes of application
showed equal effectiveness in terms of steroidogen-
esis. Thus, long-term treatment can be carried out
easily because the SC injection can be done by the
patient himself.
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