CLINICAL STUDY
Maintenance of spermatogenesis in hypogonadotropic
hypogonadal men with human chorionic gonadotropin alone
Marion Depenbusch, Sigrid von Eckardstein, Manuela Simoni and Eberhard Nieschlag
Institute of Reproductive Medicine of the University, Domagkstr. 11, D-48149 Mu¨nster, Germany
(Correspondence should be addressed to E Nieschlag; Email:
[email protected])
Abstract
Objective: It is generally accepted that both gonadotropins LH and FSH are necessary for initiation and
maintenance of spermatogenesis. We investigated the relative importance of FSH for the maintenance
of spermatogenesis in hypogonadotropic men.
Subjects and methods: 13 patients with gonadotropin deficiency due to idiopathic hypogonadotropic
hypogonadism (IHH), Kallmann syndrome or pituitary insufficiency were analyzed retrospectively.
They had been treated with gonadotropin-releasing hormone (GnRH) ðn ¼ 1Þ or human chorionic
gonadotropin/human menopausal gonadotropin (hCG/hMG) ðn ¼ 12Þ for induction of spermatogenesis.
After successful induction of spermatogenesis they were treated with hCG alone for maintenance
of secondary sex characteristics and in order to check whether sperm production could be
maintained by hCG alone. Serum LH, FSH and testosterone levels, semen parameters and testicular
volume were determined every three to six months.
Results: After spermatogenesis had been successfully induced by treatment with GnRH or hCG/hMG,
hCG treatment alone continued for 3–24 months. After 12 months under hCG alone, sperm counts
decreased gradually but remained present in all patients except one who became azoospermic.
Testicular volume decreased only slightly and reached 87% of the volume achieved with hCG/
hMG. During treatment with hCG alone, FSH and LH levels were suppressed to below the detection
limit of the assay.
Conclusion: Once spermatogenesis is induced in patients with secondary hypogonadism by GnRH or
hCG/hMG treatment, it can be maintained in most of the patients qualitatively by hCG alone, in
the absence of FSH, for extended periods. However, the decreasing sperm counts indicate that FSH
is essential for maintenance of quantitatively normal spermatogenesis.
European Journal of Endocrinology 147 617–624
Introduction
In male hypogonadotropic hypogonadism testosterone
therapy is sufficient for maturation and maintenance
of secondary sex characteristics. For stimulation of
spermatogenesis administration of gonadotropins is
necessary. If pulsatile gonadotropin-releasing hormone
(GnRH) is not indicated or desired, human chorionic
gonadotropin (hCG) is used as the source of luteinizing
hormone (LH) activity to stimulate testosterone
secretion by Leydig cells, whereas human menopausal
gonadotropin (hMG) is used as the source of folliclestimulating
hormone (FSH) (1). More recently, recombinant
gonadotropins have also been used clinically
(2–4).
Several animal studies have investigated the relative
contributions of both gonadotropins for induction and
maintenance of spermatogenesis (5–10). However,
maintenance of spermatogenesis in rats, non-human
primates and humans might be species-specifically
regulated. Earlier case reports showed that spermatogenesis
can be maintained in idiopathic hypogonadotropic
hypogonadism (IHH) patients with hCG alone
(11), and Vicari (1992) demonstrated that spermatogenesis
can even be induced with hCG alone in IHH
patients, but the addition of hMG improved the sperm
output in some patients (12). Therefore FSH and LH/
testosterone in combination and alone seem to be sufficient
to maintain spermatogenesis to a certain extent
(13).
Hypogonadotropic hypogonadism (HH) provides a
pathological situation which allows the relative contributions
of LH and FSH for human spermatogenesis to
be studied, as these patients do not produce gonadotropins,
and differential substitution of either hCG or
hMG is possible. In this study we demonstrate that
spermatogenesis in HH patients, once induced by
administration of GnRH or hCG/hMG, can in most of
European Journal of Endocrinology (2002) 147 617–624 ISSN 0804-4643
q 2002 Society of the European Journal of Endocrinology Online version via
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the patients be maintained qualitatively with hCG alone
for extended periods.
Subjects and methods
Subjects
In an open uncontrolled retrospective trial we studied
13 of all patients with secondary hypogonadism who
were treated with GnRH or hCG/hMG for induction of
spermatogenesis. The selection criterion for these 13
patients was, that after spermatogenesis had been
successfully induced, they were treated with hCG
instead of testosterone preparations for the maintenance
of secondary sex characteristics. Gonadotropin
deficiency resulted from IHH ðn ¼ 3Þ; Kallmann syndrome
ðn ¼ 4Þ or pituitary insufficiency (pre-pubertal:
n ¼ 2; post-pubertal: n ¼ 4). In most cases pituitary
insufficiency was due to pituitary tumors (Table 1).
Some patients had a history of treated unilateral or
bilateral maldescended testes: all patients with IHH,
one patient with Kallmann syndrome and one with
post-pubertal pituitary insufficiency. Clinical examinations
had been performed at intervals of 3 to 6
months. Patients’ ages ranged from 19 to 38 years at
the beginning of treatment, all were azoospermic and
had serum LH and FSH levels below the normal range.
Treatment
Patients with secondary hypogonadism can be effectively
treated with pulsatile GnRH or hCG/hMG in
order to induce spermatogenesis (14). In this study
one patient received pulsatile GnRH (5 mg/120 min)
and 12 patients received hCG/hMG therapy according
to common clinical guidelines with 3 £ 150 IU hMG
subcutaneously per week and individually adapted
hCG doses ranging from 2 £ 500 to 2500 IU per week
(1). After successful induction of spermatogenesis
testosterone production was maintained with hCG
instead of substituting testosterone. Treatment was
continued as long as patients preferred hCG over
testosterone substitution. For analysis of data we
differentiated 4 different phases of treatment.
Phase 1 – testosterone treatment Patients received
either testosterone enanthate (Testoviron-Depot-250,
Schering, Berlin, Germany) 250 mg/14–28 days intramuscularly,
or transdermal testosterone (Testoderm 15,
Ferring, Kiel, Germany) 15 mg/day applied on the
scrotum.
Phase 2 – hCG alone treatment (only in those
patients subsequently treated with hCG/hMG)
Patients received 500–2500 IU hCG (Choragon 1500,
Ferring; Primogonyl, Schering; Pregnesin 5000,
Serono, Unterschleißheim, Germany; Predalon 500,
Table 1 Characteristics of the hypogonadotropic hypogonadal men included in the analysis.
Age (years)
(at start of hCG
treatment, phase 2)
Duration of treatment (months)
Sperm concentration (mill/ml)
at end of
Patient no. Diagnosis Maldescended testis hCG/hMG or GnRH
hCG alone
(phase 4) hCG/hMG or GnRH
hCG alone
(phase 4)
1 19 Kallmann syndrome No 25 20 2.4 1.1
2 32 Kallmann syndrome Yes 19 3 9.8 9.0
3 37 Kallmann syndrome No 5 4 0.1 0
4 24 Kallmann syndrome No 43 5 5.1 0.1
5 24 IHH Yes 16 15 97.5 8.3
6 21 IHH Yes 16 25 4.8 3.6
7 32 IHH Yes 9 3 5.8 7.2
8 21 Pituitary insufficiency pre-pubertal
(craniopharyngeoma surgery, radiation)
No 9 4 21.5 0.5
9 27 Pituitary insufficiency pre-pubertal
(craniopharyngeoma surgery)
No 9 24 1.2 0.4
10 38 Pituitary insufficiency post-pubertal (adenoma) No 8 10 210 74.3
11 32 Pituitary insufficiency post-pubertal No 27 6 3.3 3.1
12 33 Pituitary insufficiency post-pubertal No 57 6 0.6 0.1
13 29 Pituitary insufficiency post-pubertal
(craniopharyngeoma surgery)
No 32 11 2.5 0.1
618 M Depenbusch and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147
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Organon, Oberschleißheim, Germany), twice per week
subcutaneously.
Phase 3 – hCG/hMG treatmentWhile continuing the
same dosage of hCG, each patient simultaneously
received 150 IU hMG (Menogon, Ferring; Fertinorm
HP 150, Serono; Gonal-F 150, Serono), three times
weekly subcutaneously. Pulsatile GnRH treatment: the
patient received 5 mg GnRH/120 min subcutaneously
using a Zyklomat pulse set (Lutrelef, Ferring).
Phase 4 – hCG alone treatment Immediately after
successful induction of spermatogenesis with GnRH or
hCG/hMG or achievement of pregnancy, patients
continued to receive individual doses of hCG
(500–2500 IU twice weekly) subcutaneously, adjusted
to trough serum testosterone levels to be maintained
in the normal range.
Methods
During the course of treatment, physical and clinical
control examinations such as semen analysis, determination
of testicular volume and hormone analysis were
performed every three to six months. Blood samples
were drawn for hormone measurements as well as
hematology and clinical chemistry (data not shown).
Hormone analysis LH and FSH were analyzed by
immunofluorometric assays (Delfia, Wallac, Freiburg,
Germany). The lower detection limits were 0.12 IU/l
for LH and 0.25 IU/l for FSH. The normal range is
2–10 IU/l for LH and 1–7 IU/l for FSH. Interassay
variance of all assays did not exceed 6.5% for LH and
4.5% for FSH. Serum testosterone was determined
using a commercial fluoroimmunoassay (Delfia,
Wallac). The lower detection limit was 0.5nmol/l.
The normal range for testosterone is above 12 nmol/l.
Interassay variance of all assays did not exceed 12.9%.
Semen analysis Semen parameters were analyzed
according to WHO guidelines (15) and subjected to
internal (16) and external (17) quality control.
Testicular volume Determination of testicular volume
was performed by palpation and sonography using a
7.5 Mhz sector scan until 1999 (Sonoline Versa Pro,
Siemens, Erlangen, Germany), thereafter using a high
Figure 1 Individual sperm concentrations and testicular volumes. (A) Individual sperm concentrations in men with IHH (n ¼ 3; open
symbols) or Kallmann syndrome (n ¼ 4; solid symbols) under hCG/hMG or hCG alone. (B) Individual testicular volumes in men with
IHH (n ¼ 2; open symbols) or Kallmann syndrome (n ¼ 2; solid symbols) under hCG/hMG or hCG alone. (C) Individual sperm
concentrations in men with pre-pubertal (n ¼ 2; open symbols) or post-pubertal (n ¼ 4; solid symbols) pituitary insufficiency under
hCG/hMG or hCG alone. (D) Individual testicular volumes in men with pre-pubertal (n ¼ 1; open symbols) or post-pubertal (n ¼ 3; solid
symbols) pituitary insufficiency under hCG/hMG or hCG alone. T, testosterone.
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 FSH maintenance of spermatogenesis in hypogonadotropic men 619
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frequency 7.5Mhz convex scanner (Ultrasound
Scanner Type 2002 ADI, B&K Medical, Gentofte,
Denmark). The procedure for calculation of testicular
volume has been described previously (18, 19).
Statistical analysis
Statistical analysis was performed using GraphPad
Prism software (version 2.01). Results are given as
means^S.D. Differences between groups were tested
by Mann–Whitney rank sum test.
Results
Treatment
Patients had been pretreated with testosterone (phase
1) for a median duration of 20 months with a minimum
of 5 months and a maximum of 14 years. Treatment
with hCG alone (phase 2) lasted for a median time
of 3.5 months with a minimum of 1 month and a maximum
of 6 months. Induction of spermatogenesis with
pulsatile GnRH or hCG/hMG (phase 3) lasted for a
median time of 16 months with a minimum of five
months and a maximum of 57 months (individual
treatment periods are given in Table 1). As previously
reported (14), the testicular volume at the beginning
of therapy was a significant predictor ðP ¼ 0:017Þ for
the necessary length of hCG/hMG or GnRH treatment
until spermatogenesis was induced. At the end of
GnRH or hCG/hMG treatment patients had a median
sperm concentration of 3.3 millions/ml (mill/ml) with
a minimum of 0.1 mill/ml and a maximum of
210 mill/ml. Bitesticular volumes had increased
initially from a mean volume of 6.5ml (minimum:
2.4 ml, maximum: 40 ml) to a mean of 24.0ml (minimum:
10.2 ml, maximum: 57.2 ml). In four patients
not desiring pregnancy, induction of spermatogenesis
was terminated after sperm had appeared in the ejaculate.
Five of nine patients successfully induced pregnancies.
These results are comparable to those published
previously on a larger cohort (14).
After GnRH or hCG/hMG treatment, testosterone
production was maintained with administration of
hCG alone (phase 4). The median treatment duration
was 10 months with a minimum of three and a maximum
of 25 months (individual treatment periods are
given in Table 1). hCG alone maintained spermatogenesis
at a lower concentration in all patients, with
the exception of one who became azoospermic after
four months. This patient only achieved a sperm concentration
of 0.1 mill/ml after five months treatment
with hCG/hMG. After six months semen parameters
of 10 patients were analyzed. The median sperm
concentration was 0.5 mill/ml with a minimum of
0.1 mill/ml and a maximum of 94 mill/ml (Fig. 1A
and 1C). When considering the maximum response to
GnRH or hCG/hMG treatment as 100%, after six
months treatment with hCG alone sperm concentration
was 31% of the concentration achieved with GnRH or
hCG/hMG (Fig. 2). Testicular volume achieved at the
end of GnRH or hCG/hMG treatment was also considered
to be equal to 100% in each individual. After
six months with hCG alone the testicular volume of
seven patients was determined and reached 80% of
maximum (Fig. 3).
After 12 months with hCG alone, semen parameters
and testicular volume of four patients were available for
analysis. The median sperm count was 1.55 mill/ml
with a minimum of 0.1 mill/ml and a maximum of
74.3 mill/ml (Fig. 1A and 1B). Expressed as a percentage
of the maximum response to GnRH or hCG/hMG,
the mean sperm concentration was 43% (Fig. 2) and
the mean testicular volume was 87% (Fig. 3).
Figure 2 Sperm concentration under hCG alone expressed as a
percentage of the last sample under hCG/hMG. T, testosterone.
Figure 3 Bitesticular volume under hCG alone expressed as a
percentage of the last value under hCG/hMG. T, testosterone.
620 M Depenbusch and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147
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After 15 months with hCG alone semen parameters
of four patients and testicular volume of five patients
were available for analysis. The median sperm count
was 1.25 mill/ml with a minimum of 0.1 mill/ml and
a maximum of 8.3 mill/ml (Fig. 1A and 1B). Expressed
as a percentage of the maximum response under GnRH
or hCG/hMG, the mean sperm concentration was still
25.6% (Fig. 2) and the mean testicular volume was
86% (Fig. 3).
After 24 months with hCG alone, semen parameters
and testicular volume of three patients were available
for analysis. The median sperm count was 1.7 mill/ml
with a minimum of 0.4 mill/ml and a maximum of
3.6 mill/ml (Fig. 1A and 1B). Expressed as a percentage
of the maximum response to GnRH or hCG/hMG, the
mean sperm concentration was 51.9% (Fig. 2) and
the mean testicular volume was 90% (Fig. 3).
Four of the thirteen patients included are currently
still under hCG treatment. The others stopped hCG
treatment because they had no current wish for a
child and wanted to use testosterone treatment to
avoid any other method of contraception or because
they preferred the application intervals of testosterone
injections. One patient wished to achieve paternity
and therefore added hMG again.
Comparing the different patient groups there was no
obvious difference in the ability to maintain sperm production
during treatment with hCG alone. The patients
with Kallmann syndrome tended to have lower sperm
concentrations and testicular volumes, but this was
Figure 4 Serum hormone levels in individual
patients (the bar shows the mean value).
(A) Serum LH in men with secondary
hypogonadism treated with hCG/hMG or hCG
alone (patient treated with pulsatile GnRH
excluded). Normal range: 2–10 IU/l.
(B) Serum FSH in men with secondary
hypogonadism treated with hCG/hMG or hCG
alone (patient treated with pulsatile GnRH
excluded). Normal range: 1–7 IU/l.
(C) Serum testosterone in men with
secondary hypogonadism treated with
hCG/hMG or pulsatile GnRH and then with
hCG alone. Normal range: .12 nmol/l. T,
testosterone.
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 FSH maintenance of spermatogenesis in hypogonadotropic men 621
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not statistically significant. There was also no correlation
of the testicular volume or the gonadotropin
levels at the beginning of therapy or the treatment
duration (neither phase 3 nor phase 4) with the maintained
sperm concentrations. However, this might be
due to the small patient number in the groups.
Hormones
Prior to treatment with GnRH or hCG/hMG all patients
had serum FSH and LH levels around the detection
limit (FSH: 0:4^0:5 IU=l; LH: 0:2^0:1 IU=l); testosterone
levels were in the normal range ð19:9^
21:6 nmol=lÞ: One patient had detectable serum LH
and FSH levels during treatment with hCG alone
(phase 2) indicating a partial gonadotropin secretion
in this patient. With hCG/hMG treatment testosterone
levels remained in the normal range ð19:4^
10:7 nmol=lÞ; FSH levels rose to the normal range
ð4:9^2:7 IU=lÞ; LH levels were around the detection
limit ð0:4^0:6 IU=lÞ except in one patient who had
detectable LH, again probably due to partial gonadotropin
secretion. The patient treated with pulsatile
GnRH had a serum FSH value of 6.8 IU/l and a
serum LH value of 10.7 IU/l and was excluded from
the gonadotropin analysis in Fig. 4A and 4B. FSH
levels decreased after patients discontinued GnRH or
hMG and continued with hCG alone and fell back to
below the detection limit (FSH , 0:25 IU=l; Fig. 4B).
LH levels were also below the detection limit
(LH , 0:12 IU=l; Fig. 4A). Testosterone levels were
generally in the normal range ðtestosterone
. 12 nmol=lÞ: If they were below the normal range,
this was mostly due to the period of time since the
last application of testosterone or hCG. In one patient
an insufficient compliance was possible, and in another
one the dosage of hCG had to be adjusted (Fig. 4C).
Discussion
Male hypogonadotropic hypogonadism (HH), characterized
by the absence of endogenous gonadotropin
secretion, is a convenient model to assess the effects
of LH and FSH on human spermatogenesis. In this
retrospective analysis of 13 HH patients we demonstrate
that spermatogenesis can, in most of the patients,
be maintained qualitatively but not quantitatively for
extended periods by treatment with hCG alone in the
absence of FSH, once it had been induced by GnRH
or hCG/hMG therapy, as case reports had shown
previously (11).
Studies in rodents, non-human primates and
humans have shown that LH/testosterone is essential
for spermatogenesis (7, 8, 10, 20–24), while the role
of FSH in the maintenance of spermatogenesis remains
controversial. In monkeys treated with a GnRH antagonist
to suppress pituitary gonadotropin production,
the administration of FSH alone was sufficient to
maintain spermatogenesis, at least in part (25). Other
studies are quoted supporting the hypothesis that
spermatogenesis can be completed in the absence of
FSH. The FSH b subunit knockout mouse has a qualitatively
normal production of sperm in the absence of
FSH (26), and mice with a disruption of the FSH
receptor also produce qualitatively normal sperm
(27). Active immunization against FSH (5) and the
FSH receptor in monkeys (28) decreased but did not
completely deplete spermatogenesis. However, nonspecific
effects of the immunoneutralization procedure
are possible (29). It has also previously been described
that there are certain differences in spermatogenetic
pathways in rodents and primates (29). Recently, two
men with a mutation in the FSH b subunit gene and
azoospermia have been reported (30, 31). These cases
demonstrate the essential role of FSH for the initiation
of spermatogenesis but add little information about the
role of FSH in the maintenance of spermatogenesis. In
an experimental study carried out with normal men,
Matsumoto et al. (32) demonstrated that normal
levels of FSH are not required for the maintenance of
qualitatively normal spermatogenesis but are required
for the maintenance of quantitatively normal spermatogenesis.
However, it has been suggested that FSH
could still be present in this experimental setting as
suppression of gonadotropins was achieved with
testosterone. Evidence from the non-human primate
indicates that even during testosterone application for
several months small amounts of biologically active
FSH remain present (33). In normal men participating
in contraceptive studies it is similarly very difficult to
suppress FSH secretion completely (34). This has
recently been confirmed using a more sensitive FSH
assay (35).
In the testis, LH acts primarily on Leydig cell testosterone
production. In the hypogonadal (hpg ) mouse,
which is completely deprived of gonadotropins due to
major deletions in the GnRH gene, it could be shown
that application of testosterone is sufficient to induce
spermatogenesis and that the threshold of testosterone
for maintenance is comparably low (36). In monkeys it
has been shown that after surgical hypophysectomy
complete but quantitatively reduced spermatogenesis
could be maintained with testosterone therapy alone
(37). In the human, administration of testosterone
after induction of azoospermia with GnRH antagonists
resulted in a rebound of sperm production. However,
this rebound was only observed after the GnRH
antagonist had been withdrawn, leaving the possibility
of a short-term increase in LH and/or FSH (38). Earlier
case reports on two patients with hypogonadotropic
hypogonadism showed that spermatogenesis induced
by hCG/hMG could be maintained by hCG alone (11).
Long-term treatment with hCG alone in HH patients
also effectively induced and maintained spermatogenesis
(12). However, the completeness of absence of
622 M Depenbusch and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147
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gonadotropins in these cases (sporadic pulses?)
remained unclear and the addition of hMG improved
sperm function and output in some patients (12).
There might be a residual FSH secretion in patients
with HH. Notwithstanding, during treatment with
hCG alone our patients all had FSH levels below the
detection limit of our assay (,0.25 IU/l, Fig. 4B).
Concerning the wide range in sperm concentration
observed in this retrospective analysis, the following
aspects have to be considered: there are different
causes of HH (anatomical lesions, genetic/idiopathic
causes). Therefore the age of onset (pre- versus postpubertal)
and the extent of pituitary failure (complete/
partial) may lead to differences in the response
to treatment. In cases of acquired HH, a more rapid
improvement in spermatogenesis in response to
gonadotropin therapy is expected compared with the
idiopathic/genetic variants, presumably because testicular
development had been normal before the onset
of disease (39). In our retrospective analysis there is
no obvious difference in sperm concentrations achieved
by men with different causes of HH, consistent with
findings from our larger series of HH patients (14).
Another explanation for the wide range of sperm
concentration might be pre-existing (i.e. independent
of gonadotropins) fertility problems, a history of
maldescended testes and the duration of treatment
with hCG/hMG.
In summary, FSH and LH/testosterone in combination
and alone are able to maintain spermatogenesis
to a certain extent. For quantitatively normal
spermatogenesis both gonadotropins are required
(13). Consistent with these findings, our current
study demonstrates that, in patients with HH, once
spermatogenesis has been induced by gonadotropin
therapy, it can in most of the patients be maintained
qualitatively, although quantitatively reduced, with
hCG alone at least for some time in the absence of
FSH. This has implications for the cost/effectiveness of
this treatment since obviously expensive FSH preparations
can be eliminated for longer periods once
spermatogenesis has been induced.
Acknowledgements
We thank PD Dr Maria Byrne and Susan Nieschlag, MA
for language editing of the manuscript.
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Received 25 March 2002
Accepted 8 July 2002
624 M Depenbusch and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147
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