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Received: Mar 19, 2020 Revised: Jun 10, 2020 Accepted: Jun 16, 2020 Published online Jul 14, 2020Correspondence to: Xiaming Liu https://orcid.org/0000-0002-1194-8791 Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qia-okou District, Wuhan 430030, Hubei, China. Tel: +86-27-83665308, Fax: +86-27-83665308, E-mail: Xmliu77@hust.edu.cn*These authors contributed equally to this work as co-first authors.
Copyright © 2021 Korean Society for Sexual Medicine and Andrology
Spermatogenesis of Male Patients with Congenital Hypogonadotropic Hypogonadism Receiving Pulsatile Gonadotropin-Releasing Hormone Therapy Versus Gonadotropin Therapy: A Systematic Review and Meta-Analysis
Chao Wei1,* , Gongwei Long1,* , Yucong Zhang1,2 , Tao Wang1 , Shaogang Wang1 , Jihong Liu1 , Delin Ma3 , Xiaming Liu1
Departments of 1Urology, 2Geriatric, and 3Endocrine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Purpose:Purpose: Pulsatile gonadotropin-releasing hormone (GnRH) therapy and gonadotropin therapy (GT) were widely used for male patients with congenital hypogonadotropic hypogonadism (CHH), but their efficacy was not well compared before. We conducted this meta-analysis to compare the efficacy of restoring fertility using these two therapies.Materials and Methods:Materials and Methods: PubMed, Web of Science, and Scopus were systematically searched for comparative studies evaluat-ing the efficiency of GnRH therapy and GT for male patients with CHH. For continuous outcomes, the weighted mean dif-ference (WMD) was used to measure the difference, whereas the risk ratio with 95% confidence interval was calculated for binary variables.Results:Results: Overall, eight articles from seven studies with 420 patients enrolled were included in the analysis. Patients from the two different groups were determined to be comparable in age, proportion with Kallmann syndrome, percentage of cryptor-chidism and pretreatment hormones (follicular-stimulating hormone, luteinizing hormone, and testosterone). GnRH therapy was related to a larger testicular volume (standardized mean difference=-1.43; p=0.01) and earlier spermatogenesis (WMD=-5.30 months; p=0.004) compared to GT. However, the difference in the rate of positive sperm detection (p=0.08), sperm concentration (p=0.37), and pregnancy rate (p=0.11) were not significant. Allergic reactions mostly occurred during GnRH therapy, while GT was related to a higher incidence of gynecomastia and acne.Conclusions:Conclusions: Compared to GT, GnRH was related to earlier spermatogenesis and less estradiol-related adverse reactions, al-though there were no significant differences in spermatogenesis rate, sperm concentration, and pregnancy rate. High-quality randomized controlled trials are needed for future research.
Keywords:Keywords: Chorionic gonadotropin; Gonadotropin-releasing hormone; Idiopathic hypogonadotropic hypogonadism; Kall-mann syndrome; Spermatogenesis
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Original Article
pISSN: 2287-4208 / eISSN: 2287-4690World J Mens Health 2021 Oct 39(4): 654-665https://doi.org/10.5534/wjmh.200043
Male reproductive health and infertility
Chao Wei, et al: GnRH Therapy Versus Gonadotropin Therapy for CHH
655www.wjmh.org
INTRODUCTION
Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by gonadotropin-releasing hormone (GnRH) deficiency or resistance [1]. Based on olfactory dysfunction, patients can be categorized into two subtypes, Kallmann syndrome (KalS), which is an-osmic, and idiopathic hypogonadotropic hypogonadism (IHH), which maintains normal olfactory function [2]. Because of the GnRH secretion deficiency or resistance, children with CHH display absent or arrested puberty, and their development of sex characteristics and fertil-ity are severely impeded.
Injections of testosterone can improve the devel-opment of sex organs and secondary sexual charac-teristics, but it can also inhibit spermatogenesis [3]. To restore fertility, gonadotropin therapy (GT) was developed, and the treatment of human chorionic go-nadotropin (HCG) alone or in combination with human menopausal gonadotropin (HMG) was confirmed to be effective in the induction of spermatogenesis in CHH patients [4-6]. However, the HCG/HMG therapy was conducted by intramuscular or subcutaneous injection 2–3 times weekly and the long duration of therapy and inconvenience of frequent injections result in poor compliance.
In 1978, the mechanism of pulsatile secretion of GnRH was clarified by Belchetz et al [7]. In 1982, pul-satile GnRH was first applied to six IHH patients and successfully induced spermatogenesis in three patients [8]. Through a subcutaneously placed butterfly needle, GnRH was administrated in 90- or 120-minute intervals using a portable pump, and the pulsatile administra-tion of medication more closely mimics the physiologi-cal conditions. Both pulsatile GnRH therapy and GT were recommended for the induction of male fertility [9]. However, although pulsatile GnRH therapy is closer to physiological conditions theoretically, whether it is superior to GT remains unclear. Several studies sug-gested that GnRH therapy enlarged testicular volume more efficiently [10-12], and the rate of spermatogenesis was significantly higher than GT [13]. Importantly, GnRH therapy was related to earlier spermatogenesis than GT [12-14]. However, several studies indicated that there was no difference between the two therapies [15,16]. In addition, several studies reported related side effects with highly inconsistent results [10,12,14,16].
Due to the controversial results regarding the ef-
ficacy of GnRH and GT, we performed this systematic review and meta-analysis to directly compare the effi-cacy and safety of these two therapy modalities.
MATERIALS AND METHODS
No previous protocol was published for this system-atic review and meta-analysis.
1. Literature searchA comprehensive literature search was conducted
for studies published from the inception of databases to February 10, 2020, in PubMed, Web of Science, and Scopus to identify studies comparing GnRH therapy to GT in CHH treatment.
Separate searches were carried out using diagnosis (hypothalamic hypogonadism, hypogonadotropic hypo-gonadism, CHH, IHH, Kallmann’s syndrome) and inter-vention terms (GnRH, follicular-stimulating hormone [FSH], HCG, HMG). The detailed search string was listed in Supplement Table 1.
Titles and abstracts of articles identified by the key-word search were screened against the study selection criteria. Potentially relevant articles were evaluated of the full text. An additional manual search of refer-ences from identified studies was performed. Two in-dependent reviewers screened all studies according to inclusion and exclusion criteria, and all disagreements were resolved by discussion with a third author.
2. Study selection criteriaStudies that met the following criteria were included
in this meta-analysis:1) The diagnosis of CHH was based on reliable evi-
dence including history, hormone tests, and imag-ing tests.
2) The efficacy or safety of GnRH and GT in male patients was compared.
3) The therapy protocol was documented with de-tailed regimens.
4) The articles were written in English or Chinese with English abstracts.
5) The required data should be complete with confi-dence intervals (CIs), standard deviation (SD), or standard error.
Studies that met the following criteria were exclud-ed:
1) The study was a review with no original data.
https://doi.org/10.5534/wjmh.200043
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2) The study was a case report that reported the efficacy of GnRH therapy or GT with a limited sample size (less than 5).
3. Data extraction and quality assessmentTwo reviewers independently extracted data from
every study and evaluated methodological quality. The following information was extracted from each study: number of cases; proportion of KalS; proportion of cryptorchidism; age at initial treatment; duration of therapy and follow-up; pretreatment and posttreatment FSH, luteinizing hormone (LH), estradiol, testosterone, testicular volume; rate of spermatogenesis at the end of study; time to the first sperm detection; sperm concen-tration; rate of pregnancy; and events of side effects.
The quality of each study was determined using the ROBINS-1 tool, a tool recommended by Cochrane for assessing risk of bias in non-randomised studies of in-terventions [17]. The graph for risk of bias was gener-ated with robvis tool [18].
4. Data analysisA formal meta-analysis of studies comparing the
efficacy (testosterone, testicular volume, rate of sper-matogenesis, time to first sperm detection, sperm count, and rate of pregnancy) of GnRH therapy to GT for CHH was conducted (primary outcomes). Successful spermatogenesis was defined as the appearance of at least one sperm cell in the semen. Additionally, the side
effects of the two treatments were compared (secondary outcomes). Besides, a subgroup analysis of the rate of spermatogenesis according to the presence of cryptor-chidism was performed.
For outcomes of continuous variables, the weighted mean difference (WMD) was used to measure the dif-ference, whereas the risk ratio (RR) with 95% CI was calculated for binary variables. Standardized mean dif-ference (SMD) was used if the results were measured using different scales or the reported outcomes varied greatly. For studies reporting medians and ranges, a validated mathematical model was used to convert the median (range) to mean±SD [19].
When two publications reported the same study, rel-evant parameters were only counted once for the scope of the present analysis. For example, this approach was employed for the study published by Schopohl et al [12] and Schopohl [20]. When two studies reported by the same group contained overlapping patients, we only used the relevant data of the higher-quality study.
A fixed-effects model was used to calculate the pooled estimates if no significant heterogeneity was identified (I2<50%). Otherwise, a random-effects model was used. Additionally, a sensitivity analysis was also performed by changing effect model. Due to the limited number of included studies, the publication bias was evaluated by using Egger linear regression. All statisti-cal analyses were performed by using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK), except for
Records excluded afterreview of titles and abstracts
(n=1,902)
Full-text articles excluded, withreasons (n=28):
Review, case report (n=13)Not HH (n=6)No comparison (n=9)
Additional records identifiedthrough reference list
(n=1)
Records after duplicates removed(n=1,937)
Records screened(n=35)
Full-text articles assessedfor eligibility
(n=7)
Studies included in meta-analysis
(n=8)a
Records identified throughdatabase searching
(n=2,490)
Fig. 1. PRISMA flow chart of the screen-ing of eligible studies. aOf the eight ar-ticles included, two articles reported the outcomes of the same study [12,20].
Chao Wei, et al: GnRH Therapy Versus Gonadotropin Therapy for CHH
657www.wjmh.org
Tabl
e 1.
Cha
ract
erist
ics o
f inc
lude
d st
udie
s in
the
met
a-an
alys
is co
mpa
ring
GnRH
and
GT
for m
ale
CHH
patie
nts
Stud
ySt
udy
desi
gnSt
udy
orig
inGn
RH
regi
men
sGT
regi
men
GnRH
/GT
Repo
rted
ou
tcom
e
Test
icul
ar
volu
me
mea
sure
men
tTo
tal
case
s (n)
Case
s of
KalS
(n)
Mea
n
age
(y)
Med
ian
FU
(mo)
Büch
ter e
t al (
1998
) [15
] RT
P, SC
Germ
any
5–20
μg
ever
y 12
0 m
inut
esHC
G 1,
000–
2,50
0 IU
twic
e a
wee
k an
d HM
G 75
–150
IU th
ree
times
a w
eek
( i.m
. or s
.c.)
6/18
2/9
30.1
/29.
1N
STV
, Rat
eS, T
imeS
, Ra
teP
Palp
atio
n or
US
Gong
et a
l (20
15) [
10]
PRP,
SCCh
ina
8–10
μg
ever
y 90
min
utes
HCG
1,00
0–2,
000
IU tw
ice
a w
eek
or e
very
ot
her d
ay (i
.m.)
12/2
28/
1513
.39/
13.8
9N
ST,
FSH,
TV,
AR
Orc
hido
met
er
Huan
g et
al (
2015
) [13
] RT
P, SC
Chin
a10
μg
ever
y 90
min
utes
HCG
3,00
0 IU
and
HM
G 75
IU tw
ice
a w
eek
(i.m
.) HC
G do
se w
as a
djus
ted
acco
rdin
g to
T le
vel.
40/5
220
/29
22.4
/20.
58.
2/9.
2T,
FSH,
TV,
Rat
eS,
Tim
eS, R
ateP
Orc
hido
met
er
Klie
sch
et a
l (19
94) [
16]
RTP,
SCGe
rman
y5–
20 μ
g ev
ery
120
min
utes
HCG
1,00
0–2,
500
IU tw
ice
a w
eek
and
HMG
75–1
50 IU
thre
e tim
es a
wee
k (i.
m. o
r s.c.
)6/
112/
730
.7/3
1.0
14.5
/15.
7FS
H, T
V, R
ateS
, Ti
meS
, SpC
, Ra
teP,
AR
Palp
atio
n or
US
Liu
et a
l (19
88) [
11]
PRP,
SCUS
A10
–20 μg
ev
ery
120
min
utes
HCG
2,00
0 IU
and
HM
G (7
5 IU
FSH
and
75
IU
LH) t
hree
tim
es a
wee
k (i.
m.)
5/10
0/0
23.1
/30.
620
.8/2
4.0
T, FS
H, T
V, R
ateS
Orc
hido
met
er
Mao
et a
l (20
17) [
14]
RTP,
SCCh
ina
10 μ
g ev
ery
90 m
inut
es
HCG
2,00
0 IU
and
HM
G 75
IU tw
ice
a w
eek
(i.m
.)HC
G do
se w
as a
djus
ted
acco
rdin
g to
T le
vel
20/1
8211
/84
27.1
/21.
515
.6/2
8.7
T, FS
H, T
V, R
ateS
, Ti
meS
, SpC
, Ra
teP,
AR
Orc
hido
met
er
Scho
pohl
et a
l (19
91)
[12]
a , Sch
opoh
l (19
93)
[20]
a
PRP,
SCGe
rman
y4–
16 μ
g ev
ery
90 o
r 120
m
inut
es
HCG
2,50
0 IU
thre
e tim
es a
wee
k in
itial
ly a
nd
then
redu
ced
acco
rdin
g to
T a
nd e
stra
diol
le
vel
HMG
150
IU tw
ice
a w
eek
was
add
ed 2
–3
mon
ths l
ater
and
dos
age
incr
ease
d
acco
rdin
g to
test
icul
ar g
row
th a
nd sp
erm
co
unt (
i.m.)
18/1
88/
921
.1/2
3.6
9.3/
14.4
T, TV
, Rat
eS,
Tim
eS, S
pC,
Rate
P, AR
Orc
hido
met
er
GnRH
: gon
adot
ropi
n-re
leas
ing
horm
one,
GT:
gon
adot
ropi
n th
erap
y, C
HH: c
onge
nita
l hyp
ogon
adot
ropi
c hy
pogo
nadi
sm, K
alS:
Kal
lman
n sy
ndro
me,
FU:
follo
w-u
p, R
TP: r
etro
spec
tive,
SC:
sin
gle
cent
er, P
RP: p
rosp
ectiv
e, H
CG: h
uman
cho
rioni
c go
nado
trop
in, H
MG:
hum
an m
enop
ausa
l gon
adot
ropi
n, i.
m.:
intr
amus
cula
r inj
ectio
n, s.
c.: su
bcut
aneo
us in
ject
ion,
NS:
not
spec
ified
, TV:
test
icul
ar
volu
me,
Rat
eS: r
ate
of p
ositi
ve sp
erm
atog
enes
is, T
imeS
: tim
e ne
eded
to in
duce
sper
mat
ogen
esis,
Rat
eP: r
ate
of p
regn
ancy
, T: p
ost-
trea
tmen
t tes
tost
eron
e, F
SH: p
ost-
trea
tmen
t fol
licul
ar-s
timul
at-
ing
horm
one,
AR:
adv
erse
reac
tion,
SpC
: spe
rm co
unt,
US: u
ltras
onog
raph
y.a Th
ese
two
artic
les r
epor
ted
the
sam
e ou
tcom
es fr
om th
e sa
me
stud
y.
https://doi.org/10.5534/wjmh.200043
658 www.wjmh.org
the calculation of Egger’s linear regression test, which was conducted in STATA ver. 12.0 (Stata Corp., College Station, TX, USA).
RESULTS
1. Characteristics of the included studiesOverall, eight articles with 420 patients were includ-
ed in the meta-analysis after screening (Fig. 1) [10-16,20]. Among these patients, 204 patients and 216 patients were diagnosed with KalS and IHH respectively. Of these studies, two articles reported the outcomes of the same research, and the relevant outcomes were used
only once in our analysis [12,20]. Huang et al [13] and Mao et al [14] conducted two studies with overlapping data, as well as Büchter et al [15] and Kliesch et al [16]. When two studies were included in a single analysis, we used the data of Huang et al [13] and Kliesch et al [16] because of their higher quality.
The characteristics of the included studies are pre-sented in Table 1. Most of these studies were conducted in Germany and China, and one was conducted in the USA in 1988. Four of the seven included studies were retrospective, and others were prospective. The com-bination of HCG and HMG for GT was used in most studies except for the study conducted by Gong et al
Domains:
D1: bias due to confounding
D2: bias due to selection of participants
D3: bias in classification of interventions
D4: bias due to deviations from intended interventions
D5: bias due to missing data
D6: bias in measurement of outcomes
D7: bias in selection of the reported result
SeriousModerateLowNo information
Judgement
Stu
dy
D1
D2
D3
D4
D5
D6
D7
Ove
rall
Buchter et al (1998) [15]
Gong et al (2015) [10]
Huang et al (2015) [13]
Kliesch et al (1994) [16]
Liu et al (1988) [11]
Mao et al (2017) [14]
Schopohl et al (1991) [12]
Risk of bias domains
..
Fig. 2. The risk of bias graph of included studies based on the ROBINS-1 method.
Fig. 3. Forest plots of posttreatment physiological parameters of patients after gonadotropin-releasing hormone (GnRH) or gonadotropin therapy (GT). (A) Forest plot of posttreatment testosterone of patients after GnRH or GT. The posttreatment testosterone level of the GnRH group was significantly lower than that of the GT group. (B) Forest plot of posttreatment testicular volume of patients after GnRH or GT. GnRH therapy was related to larger posttreatment testicular volume. HCG: human chorionic gonadotropin, HMG: human menopausal gonadotropin, SD: standard deviation, CI: confidence interval, df: degree of freedom.
Study or subgroupHCG/HMG GnRH Mean difference
Huang et al (2015) [13]
Kliesch et al (1994) [16]
Liu et al (1988) [11]
Schopohl et al (1991) [12]
Total (95% CI)
Heterogeneity: Tau =9.76; chi =15.36, df=3 (p=0.002); I =80%
Test for overall effect: Z=4.39 (p<0.0001)
2 2 2
14.4
26.8
21.0
22.5
8.0
2.4
2.5
8.1
Mean SD Total
52
11
11
18
92
Weight
26.7%
24.5%
28.2%
20.6%
100.0%
IV, random, 95% CI
7.00 [4.29, 9.71]
5.40 [2.04, 8.76]
12.00 [9.77, 14.23]
5.70 [1.18, 10.22]
7.75 [4.29, 11.21]
IV, random, 95% CIMean difference
20 0 10 20
Favours[GnRH]
Favours[HCG/HMG]
7.4
21.4
9.0
16.8
5.2
3.8
1.9
5.5
Mean SD Total
40
6
5
18
69
10
Study or subgroupHCG/HMG GnRH Std. mean difference
Gong et al (2015) [10]
Huang et al (2015) [13]
Kliesch et al (1994) [16]
Liu et al (1988) [11]
Schopohl et al (1991) [12]
Total (95% CI)
Heterogeneity: Tau =1.33; chi =36.00, df=4 (p<0.00001); I =89%
Test for overall effect: Z=2.53 (p=0.01)
2 2 2
6.01
7.6
14.5
8.9
8.4
1.33
4.2
5.7
0.51
3.0
Mean SD Total
22
52
11
11
18
114
Weight
20.2%
23.3%
20.1%
14.5
22.0
100.0
%
%
%
IV, random, 95% CI
2.78 [ 3.78, 1.79]
0.12 [ 0.53, 0.29]
0.42 [ 1.43, 0.58]
3.77 [ 5.61, 1.93]
0.97 [ 1.67, 0.28]
1.43 [ 2.55, 0.32]
IV, random, 95% CIStd. mean difference
4 0 2 4
Favours[GnRH]
Favours[HCG/HMG]
13.09
8.1
17.3
11.4
11.1
3.82
4.0
7.3
0.85
2.4
Mean SD Total
12
40
6
5
18
81
2
A
B
Testosterone
Testicular volume
Chao Wei, et al: GnRH Therapy Versus Gonadotropin Therapy for CHH
659www.wjmh.org
[10], in which the patients were adolescent boys treated with HCG alone. Notably, most included studies were conducted based on limited sample size (the number of the GnRH cases was less than 10 in three studies).
Most studies were of low and moderate bias (Fig. 2 and Supplement Table 2). The imbalanced sample sizes, follow-up durations, and baseline characteristics includ-ing initial testicular volume and age of the two arms might be the reasons for the relatively lower quality. In particularly, Büchter et al [15] and Gong et al [10] did not report their follow-up length, but the follow-up strategies were described, as every 3 to 6 months in Büchter et al’s study [15] and every 3 months in Gong
et al’s study [10] until the treatment finished.Two arms of the comparison were not significantly
different in age (p=0.19), the proportion of KalS (p=0.53), and the percentage of cryptorchidism (p=0.78). Pretreatment hormones, including FSH (p=0.26), LH (p=0.11), and testosterone (p=0.65), were also similar in the GnRH group and GT group. Notably, the pre-treatment testicular volume in the GnRH group was larger than that in the GT group (WMD=0.32 mL, 95% CI=0.08–0.57; p=0.01).
Fig. 4. Forest plots of spermatogenesis of patients after gonadotropin-releasing hormone (GnRH) compared to gonadotropin therapy (GT). (A) Forest plot of rate of spermatogenesis of patients after GnRH compared to GT. The spermatogenesis rates of the two groups were not significantly different. (B) Forest plot of time to first sperm detection of patients after GnRH compared to GT. GnRH therapy was related to earlier spermato-genesis. (C) Forest plot of sperm count of patients after GnRH compared to GT. No significant difference was detected. HCG: human chorionic gonadotropin, HMG: human menopausal gonadotropin, M–H: Mantel–Haenszel, CI: confidence interval, df: degree of freedom, SD: standard de-viation.
Study or subgroupGnRH HCG/HMG Mean difference
Huang et al (2015) [13]
Kliesch et al (1994) [16]
Schopohl et al (1991) [12]
Total (95% CI)
Heterogeneity: Tau =6.82; chi =8.47, df=2 (p=0.01); I =76%
Test for overall effect: Z=2.86 (p=0.004)
2 2 2
6.5
9.0
12.0
3.1
8.8
1.6
Mean SD Total
20
5
10
35
Weight
41.7%
13.9%
44.3%
100.0%
IV, random, 95% CI
4.30 [ 6.61, 1.99]
0.30 [ 7.97, 8.57]
8.00 [ 9.88, 6.12]
5.30 [ 8.93, 1.67]
IV, random, 95% CIMean difference
20 0 10 20
Favours[GnRH]
Favours[HCG/HMG]
10.8
8.7
20.0
3.7
4.8
2.3
Mean SD Total
15
10
8
33
10
B Time to spermatogenesis
Study or subgroupHCG/HMG GnRH Risk ratio
Huang et al (2015) [13]
Kliesch et al (1994) [16]
Liu et al (1988) [11]
Schopohl et al (1991) [12]
Total (95% CI)
Total events
Heterogeneity: chi =5.72, df=3 (p=0.13); I =48%
Test for overall effect: Z=1.77 (p=0.08)
2 2
15
10
8
8
41
Events Total
52
12
10
17
91
Weight
52.7%
15.5%
6.2%
25.6%
100.0%
M H, fixed, 95% CI
0.58 [0.34, 0.98]
1.00 [0.65, 1.55]
2.00 [0.65, 6.11]
0.66 [0.36, 1.20]
0.75 [0.55, 1.03]
M H, fixed, 95% CIRisk ratio
0.2 1 2 5
Favours[GnRH]
Favours[HCG/HMG]
20
5
2
10
37
Events Total
40
6
5
14
65
0.5
A Rate of spermatogenesis
Study or subgroupHCG/HMG GnRH Mean difference
Kliesch et al (1994) [16]
Mao et al (2017) [14]
Schopohl et al (1991) [12]
Total (95% CI)
Heterogeneity: chi =3.06, df=2 (p=0.22); I =35%
Test for overall effect: Z=0.89 (p=0.37)
2 2
4.0
12.5
8.0
3.6
3.7
7.35
Mean SD Total
10
140
8
158
Weight
28.8%
37.4%
33.8%
100.0%
IV, fixed, 95% CI
1.60 [ 7.56, 4.36]
4.60 [ 9.82, 0.62]
2.16 [ 3.34, 7.66]
1.45 [ 4.65, 1.74]
IV, fixed, 95% CIMean difference
10 0 5 10
Favours[GnRH]
Favours[HCG/HMG]
5.6
17.1
5.84
6.3
9.9
3.34
Mean SD Total
5
14
10
29
5
C Sperm count
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2. Efficacy of gonadotropin-releasing hormone and gonadotropin therapy
Although the plasma testosterone in the GT group was significantly higher than plasma testosterone in the GnRH group (WMD=7.75 nmol/L, 95% CI=4.29–11.21; p<0.0001), the testicular volumes increased con-siderably more in the GnRH group (SMD=-1.43, 95% CI=-2.55–-0.32; p=0.01; Fig. 3). There was no significant difference in the rate of positive spermatogenesis (RR=0.75, 95% CI=0.55–1.03; p=0.08), but GnRH treat-ment was related to earlier spermatogenesis (WMD=-5.30 months, 95% CI=-8.93–-1.67; p=0.004; Fig. 4). The sperm count (WMD=-1.45×106/mL, 95% CI=-4.65–1.74; p=0.37) and rate of pregnancy (RR=0.60, 95% CI=0.31–1.13; p=0.11) were not significantly different between the two groups (Fig. 4, 5).
The subgroup analysis according to the presence of cryptorchidism showed that the rate of spermatogene-sis remained similar for these two therapies in patients with or without cryptorchidism (Supplement Fig. 1, 2). Additionally, the presence of cryptorchidism was a predictor of the spermatogenesis rate of CHH patients (Supplement Fig. 3).
Considering that in Gong et al’s study [10], only HCG was used for the GT group, a formal meta-analysis was also performed after excluding Gong at al’s study [10]. The final outcome was consistent with the previous outcome and suggested that GnRH therapy was re-lated to larger testicle volume.
3. Side effects of gonadotropin-releasing hormone and gonadotropin therapy
Adverse reactions reported during the therapy were allergy, breast development, and acne. The incidence of overall adverse reactions was comparable in the two groups (RR=1.55, 95% CI=0.56–4.35; p=0.40). However,
the allergy occurred mostly during GnRH therapy (RR=37.93, 95% CI=7.03–204.74; p<0.0001), and the GT was related to gynecomastia and acne (RR=0.27, 95% CI=0.09–0.83; p=0.02; Fig. 6).
4. Publication bias and sensitivity analysisAll the egger’s tests showed no significant publica-
tion bias. Sensitivity analyses were conducted by changing ef-
fect model and the effect model changing did not alter any outcomes of this analysis.
DISCUSSION
To the best of our knowledge, this review is the first meta-analysis to compare GnRH therapy to GT in male CHH patients. In this analysis, we evaluated posttreat-ment physiological conditions, fertility, and adverse reactions. In conclusion, GnRH is related to larger tes-ticular volume and earlier spermatogenesis, though the rates of spermatogenesis and pregnancy are similar in both groups.
1. Interpretation of outcomesLH and FSH play an important role in the develop-
ment of sperm and the levels of them could be nor-malized in the majority of CHH after pulsatile GnRH therapy [21]. Several hormone outcomes after pulsatile GnRH were reported in our included studies and all these results showed a greatly increased level of LH and FSH [10,13,14,16]. Compared to GT, GnRH therapy was more efficient in the normalization of LH and FSH levels [10,11]. However, due to the lack of relevant data, we were unable to conduct a quantitative analy-sis to compare the posttreatment level of LH and FSH after these two therapies.
Fig. 5. Forest plot of pregnancy rate after gonadotropin-releasing hormone (GnRH) compared to gonadotropin therapy. HCG: human chorionic gonadotropin, HMG: human menopausal gonadotropin, M–H: Mantel–Haenszel, CI: confidence interval, df: degree of freedom.
Study or subgroupHCG/HMG GnRH Risk ratio
Huang et al (2015) [13]
Kliesch et al (1994) [16]
Liu et al (1988) [11]
Schopohl et al (1991) [12]
Total (95% CI)
Total events
Heterogeneity: chi =1.99, df=3 (p=0.58); I =0%
Test for overall effect: Z=1.58 (p=0.11)
2 2
0
4
1
1
6
Events Total
15
6
11
1
33
Weight
13.0%
44.5%
27.5%
15.0%
100.0%
M H, fixed, 95% CI
0.44 [0.02, 10.05]
0.73 [0.38, 1.43]
0.23 [0.03, 1.96]
1.00 [0.32, 3.10]
0.60 [0.31, 1.13]
M H, fixed, 95% CIRisk ratio
0.01 1 10 100
Favours[GnRH]
Favours[HCG/HMG]
1
3
2
1
7
Events Total
20
3
5
1
29
0.1
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Patients in the GnRH group had a lower testosterone concentration than the GT group. In the beginning, GnRH therapy aimed to maintain testosterone within the normal range [11,16]. However, later studies sug-gested that plasma testosterone levels of 8–10 nmol/L may be sufficient to induce spermatogenesis in CHH patients [13,14]. Pulsatile GnRH therapy can maintain the pulsatile secretion of gonadotropin by the pituitary gland and therefore stabilize the testosterone level. In the GT group, the fluctuation of testosterone was significant [22]. In addition, the GnRH receptors were found in spermatogonia, spermatocytes, and mature sperm [23]. Therefore, GnRH might be directly involved
in spermatogenesis, sperm maturation, and fertilization [24]. These reasons might explain why GnRH therapy could efficiently induce spermatogenesis with a lower testosterone level. Notably, the normalization of tes-tosterone could only be achieved by supraphysiological levels of LH and FSH in a subset of patients [25], and in specific populations, the level of testosterone is not correlated with the sperm concentration [26,27]. These studies suggested that the normalization of testoster-one might be unbeneficial and unessential.
The ability to restore fertility in CHH patients is the critical efficacy of these two therapies, and whether GnRH therapy is related to a higher rate of sper-
Study or subgroupGnRH HCG/HMG Risk ratio
Gong et al (2015) [10]
Kliesch et al (1994) [16]
Mao et al (2017) [14]
Schopohl et al (1991) [12]
Total (95% CI)
Total events
Heterogeneity: Tau =0.61; chi =7.42, df=3 (p=0.06); I =60%
Test for overall effect: Z=0.84 (p=0.40)
2 2 2
3
3
8
0
14
Events Total
12
6
20
18
56
Weight
24.0%
27.1%
38.6%
10.3%
100.0%
M H, fixed, 95% CI
1.83 [0.44, 7.72]
1.83 [0.52, 6.42]
2.70 [1.42, 5.11]
0.09 [0.01, 1.45]
1.55 [0.56, 4.35]
M H, fixed, 95% CIRisk ratio
0.005 1 10 200
Favours[GnRH]
Favours[HCG/HMG]
3
3
27
5
38
Events Total
22
11
182
17
232
0.1
A Total adverse reaction
Study or subgroupGnRH HCG/HMG Risk ratio
Kliesch et al (1994) [16]
Mao et al (2017) [14]
Total (95% CI)
Total events
Heterogeneity: chi =1.38, df=1 (p=0.24); I =27%
Test for overall effect: Z=4.23 (p<0.0001)
2 2
3
7
10
Events Total
6
20
26
Weight
78.2%
21.8%
100.0%
M H, fixed, 95% CI
12.00 [0.72, 199.87]
130.71 [7.74, 2208.09]
37.93 [7.03, 204.74]
M H, fixed, 95% CIRisk ratio
0.001 1 10 1,000
Favours[GnRH]
Favours[HCG/HMG]
0
0
0
Events Total
11
182
193
0.1
B Allergy
Study or subgroupGnRH HCG/HMG Risk ratio
Gong et al (2015) [10]
Kliesch et al (1994) [16]
Mao et al (2017) [14]
Schopohl et al (1991) [12]
Total (95% CI)
Total events
Heterogeneity: chi =1.24, df=3 (p=0.74); I =0%
Test for overall effect: Z=2.29 (p=0.02)
2 2
1
0
1
0
2
Events Total
12
6
20
18
56
Weight
13.5%
16.4%
34.1%
36.0%
100.0%
M H, fixed, 95% CI
0.61 [0.07, 5.25]
0.24 [0.01, 4.08]
0.34 [0.05, 2.35]
0.09 [0.01, 1.45]
0.27 [0.09, 0.83]
M H, fixed, 95% CIRisk ratio
0.002 1 10 500
Favours[GnRH]
Favours[HCG/HMG]
3
3
27
5
38
Events Total
2
11
182
17
232
0.1
C Gynecomastia and acne
Fig. 6. Forest plots of adverse reaction events after gonadotropin-releasing hormone (GnRH) or gonadotropin therapy (GT). (A) Forest plot of total adverse reaction events after GnRH or GT. The incidences of adverse reactions were similar in two groups. (B) Forest plot of allergy events after GnRH or GT. Allergies occurred only in the GnRH group, and the difference was significant. (C) Forest plot of incidence of gynecomastia and acne after GnRH or GT. GnRH therapy resulted in more estradiol-related adverse reactions, including gynecomastia and acne. HCG: human chorionic gonadotropin, HMG: human menopausal gonadotropin, M–H: Mantel–Haenszel, CI: confidence interval, df: degree of freedom.
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matogenesis has not been determined. In our analysis, the testes were enlarged in both treatment groups, but GnRH therapy was related to a larger volume. Although the testicular volume may be related to fertility [5,28,29], the rate of spermatogenesis was not significantly different between the two groups. An analysis of 48 studies of HCG/HMG therapy and 16 studies of pulsatile GnRH therapy showed that the rate of spermatogenesis was 68% (95% CI=58%–77%) in HCG/HMG treatment, which is lower than that of 77% (95% CI=63%–87%) in GnRH therapy for patients with prepuberty-onset hypogonadotropic hypogonadism [30]. This analysis was mostly based on single-arm studies. Combined with our analysis, we are optimistic about pulsatile GnRH therapy. Moreover, it was suggested that GnRH therapy is related to earlier spermatogen-esis, and GnRH therapy is associated with a shorter time to achieve sperm concentrations at various pre-determined thresholds [14]. With the aid of assisted re-production techniques such as intracytoplasmic sperm injection, shorter time to achieve pregnancy might also be practical for patients receiving GnRH therapy. Additionally, for these patients who failed to induce spermatogenesis after HCG/HMG therapy, GnRH still might be effective [31]. Therefore, patients who desire fertility may benefit more from GnRH therapy.
The sperm concentrations were compared in our analysis, and the sperm count in the GnRH group was slightly higher, though without statistical significance. In the included studies, the study conducted by Scho-pohl et al [12] was the only one that favored GT. In fact, in their research, one patient in the GT group had a sperm concentration of 26×106/mL, which was 2 to 12 fold higher than that of other patients. However, as the GnRH group was associated with a shorter time to achieve sperm concentrations at various predetermined thresholds [14], whether the final concentrations differ in the long-term treatment has not been determined. Several studies also compared sperm motility and mor-phology and obtained an insignificant difference [12,16].
There was no difference in the rate of pregnancy between the two groups (p=0.11). Büchter et al [15] and Kliesch et al [16] suggested that most pregnancies oc-curred with counts far below the normal range, and the sperm concentrations at pregnancy were similar. This might explain the similarity of pregnancy rate with different sperm concentrations because the low concentration of sperm is sufficient for pregnancy.
Büchter et al [15] showed that GnRH therapy tended to be related to a shorter duration before pregnancy, but the difference was not significant because of the limited study size. A study with a larger size is still warranted to ascertain the effect of different therapies on the duration until pregnancy.
Although the overall incidence of adverse reactions was comparable in the two therapies, the specific ad-verse responses were different. GT was related to gyne-comastia and acne, and the increased level of estradiol induced by HCG might be a reasonable explanation [32]. Allergy occurred mostly in GnRH therapy, and most of them were mild to moderate dermatological allergic re-actions. Before the decision of treatment, these related adverse reactions should be considered, and the ad-verse responses during GnRH therapy seem to be more acceptable for patients.
The cost of treatment is an essential factor in clini-cal practice. The pulsatile GnRH therapy is much more expensive than the HCG/HMG therapy and the burden of drug and device cost could limit the use of GnRH therapy. Besides, the constant carrying of the pump, the refilling of medication, and frequent chang-ing of injection sites also result in inconvenience for patients. However, with the decreasing of medication and device, more patients can afford the cost of treat-ment and the improved devices with smaller size and more volume could also reduce the inconvenience in the future. In addition, HCG/HMG therapy requires frequent hospital visits, twice to three times a week, which is also inconvenience for patients living in the place where the community doctors and family doctors are not available. Patients and doctors can choose the optimal treatment method by considering the efficacy and the patterns of these treatment.
2. Effect of cryptorchidism statusCryptorchidism was reported to be a predictor for
spermatogenesis in CHH patients [21,29]. Our analysis confirmed that cryptorchidism was related to a lower rate of spermatogenesis (Supplement Fig. 3). Mao et al [14] suggested that cryptorchidism was also related to a longer time to first sperm detection and a lower sperm concentration. Büchter et al [15] also reported a delayed duration until spermatogenesis, but the difference was not significant in their study. In particular, Büchter et al [15] noted that the two patients who failed sper-matogenesis had bilateral cryptorchidism until 22 and
Chao Wei, et al: GnRH Therapy Versus Gonadotropin Therapy for CHH
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17 years of age, respectively. This finding suggests that early intervention is essential for patients with crypt-orchidism.
According to the subgroup analysis (Supplement Fig. 1, 2), the rates of spermatogenesis did not differ between GnRH therapy and GT, regardless of the cryptorchidism status. The cryptorchidism status was unlikely to affect the clinical decision on therapy selec-tion.
3. Strengths and limitationsOur study is the first meta-analysis that compared
the effect and adverse reactions of GnRH therapy to GT based on comparative studies. We comprehensively evaluated the effect of these two therapies using vari-ous parameters. Subgroup analyses were also per-formed to assess the effect of cryptorchidism status.
There are several limitations to our study. First, some biases were inevitable because of their nonrandomized and retrospective nature. For example, in the retro-spective study, testicular volumes were not assessed in a standardized manner or by the same clinician, leading to variation in determining testicular volumes. Also, the orchidometer was used in the majority of the included studies and the reliability could be com-promised. Second, the follow-up time of some included studies was not long enough, and in some studies, the follow-up durations and sample sizes of two arms were not comparable. Third, the sample size of most included studies was small, and the two studies from the same group had the majority of included cases which could be a potential source of bias. Additionally, as an es-sential parameter, the time to pregnancy was not well-documented in most studies, and in future research, this parameter should be analyzed to compare the efficacy of different therapies. Fourth, the baseline features, such as age, of the patient population differed vastly among the included studies and the dosages of regimens were also different among the included re-searches. Finally, our conclusions were based on studies investigating HMG and should be cautiously applied to recombinant human FSH, which is widely used in CHH treatment.
CONCLUSIONS
Our study suggested that although the two therapies exhibited no significant difference in spermatogenesis
rate, sperm count, and pregnancy rate, GnRH therapy was related to larger testicular size, shorter time to sperm detection, and less estradiol-related adverse reac-tions. More prospective, randomized studies with larger sample sizes are warranted to ascertain the advantages of pulsatile GnRH therapy.
ACKNOWLEDGEMENTS
This research was supported by National Natural Science Foundation of China (Grant Number: 81702518, 81500636) and Innovation Foundation of Huazhong University of Science and Technology (Grant Number 2019kfyXKJC06).
Conflict of Interest
The authors have nothing to disclose.
Author Contribution
Conceptualization: XL, DM. Data curation: CW, YZ, TW. For-mal analysis: GL, YZ, SW. Funding acquisition: XL. Project ad-ministration: XL. Supervision: JL. Writing – original draft: CW, GL. Writing – review & editing: TW, SW.
Supplementary Materials
Supplementary materials can be found via https://doi.org/10.5534/wjmh.200043.
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