Beruflich Dokumente
Kultur Dokumente
(Received 5 August 1985; rerurned for revision I8 November 198S;finall.v revised 6 January 1986,
accepted 3 February 1986)
SUMMARY
539
540 J . M . Wit et al.
absence of indications for primary surgical intervention (associated inguinal hernia,
testicular ectopia, puberty, previous inguinal surgery), hormonal therapy is usually
advocated.
Treatment with human chorionic gonadotrophin (hCG) has led to a wide variety of
results, but most large studies claim a positive result in 50% of the patients (Bierich, 198 I).
However, the success rate seems to be lower in children under 4 years of age (Garagorri et
al., 1982), and unpleasant side-effects include frequent erections, aggressive behaviour,
development of pubic hair, and pain at the injection site.
Intranasal therapy with synthetic luteinizing hormone releasing hormone (LHRH),
first described in 1975 (Happ et al., 1975), has led to success rates of 22-68% in most
studies. However, only five double-blind studies (Illig et af., 1977; Spona et al., 1979;
Bertelsen et al., 1981; Hagberg & Westphal, 1982; Karpe et al., 1983) have been reported
and the one with long-term follow-up (Karpe et al., 1983) showed hardly any effect in
unilateral cryptorchidism. In addition, conflicting data have been reported about the
occurrence of side-effects and about the hormonal responses.
In this study we describe the short-term effect of LHRH on testicular descent and
hormonal responses in a double-blind placebo-controlled study, and the results of I2
months of open follow-up.
RESULTS
Testiculur descenr ujtrr L H R H or plucrho
Table I shows the effect after 4 and 8 weeks. After 8 weeks, improvement of the testicular
location was found in 13 testes after LHRH and in six testes after placebo (37% vs 187;,,
P <0.05). In six of the 13 testes in which some improvement was observed after LHRH,
this improvement was considered sufficient. In the other seven a second LHRH course
was given, followed by surgery in six of them. In the placebo group there was one child
with bilateral cryptorchidism, in whom testes were felt in the scrotum after 4 weeks of
placebo. He was not treated with LHRH.
4 weeks 8 weeks
Supine Squatting
2 4 8 2 4 8 2 4 8 r,
Positive valuesdenote descenl; negative values denote ascent. Valuesare expressed in cm as means+ S D (numbers of testes in
brackets).
* Change significantly greater than 0 (two-tailed Student's r-test, P c 0.05).
t Change with LHRH significantly greater than with placebo ( P<0.05).
LHRH treatment and cryptorchidism 543
Bilateral cryptorchidism
6 II 17 1 3
Fig. I . Bilateral cryptorchidism. Changes of testicular localization after LHRH therapy and at
follow-up. Vertical downward arrows indicate descent after LHRH. Horizontal arrows indicate
that the descent is conserved at follow-up. Vertical upward arrows indicate testicular ascent at
follow-up. At the bottom-line therapeutical management is shown. Numbers in circles indicate
the number of testes.
Table 2 shows the mean change in testicular position, expressed in centimetres. Placebo
resulted in a slight descent, which was never significant after 8 weeks of treatment. After
LHRH the mean descent was somewhat greater, and significant both for unilateral and
bilateral cryptorchid testes after 8 weeks of treatment. However, it should be noted that
the average magnitude of descent was very small. The difference between placebo and
LHRH treatment was only significant in the squatting position after 2 and 8 weeks.
Side-effects
Aggressive behaviour was reported in 23% of the children treated with LHRH. and in
none of the children treated with placebo. No changes were observed in the appearance of
the scrotum, penile length or testicular volume.
Follow-up results
After the first 8 weeks the code was broken, and all but one patients who had received
placebo, were then given LHRH. Therefore, from then on the study was open and
concerned 48 patients. The results after one or two LHRH courses on testicular descent 8
weeks and 1 year after the start of the last course are shown in Figures 1 and 2. A second
LHRH course did not result in significant improvement in any of the patients.
In 19 patients with bilateral cryptorchidism (Fig. I), 21 testes did not descend, and 17
showed s m descent, of which seven re-ascended. Of 14 testes, 1 1 in the responder and
544 J . M . Wit et al.
Inp~lpmle
Inpinol.
barell
mobile
Inguinal.
mobile tGwatds
scrota1 neck l?O+I
mobile into
scrotum
Scrotul c
berap] Surqery No 'urrrer trwtrnent Surqery
2 4 23
Table 3. LHRH test results (median. range) before and after 4 weeks of therapy
LH (IU/l) 0 1.3 ( < 14-1.8) 1.2 ( < 14-1.8) 1.3' (1.0-3.4) 4.7' (14-11.7)
3 0 6.3 (1.8-18'2) 5.1 (1'8-16'6) 5.3' (1.0-20.0) 7.5' (4'2-15.3)
6 0 4.2 (1.6-1 1.5) 3.0 (1.8-11'4) 4.05 (24-16.0) 4.8 (?.6-11.I)
FSH (IUjl) 0 1.0 ( < 0.9-2'2) 0.9 ( < 0'9-2.5) < 0.9' ( < 0.9-2' I ) 1.2' ( < 0.9-3.4)
3 0 3.3 (2.0-8.5) 2.8 (<0.9-6.7) 4.0' (0.9-5.6) 2.4' ( 1 0 . 9 4 9 )
60' 3.5 (I4 9 . 7 ) 3.3 ( < 0.9-7.7) 4.0' (142-7.1) 2.0' (i 0.9-4.9)
three in the non-responder group, the location was considered sufficiently low at one or
more examinations, to make the diagnosis of retractile testes, and no further therapy was
advised. One testis responded well to hCG, and the remaining 23 were operated upon.
The results of the 29 patients with unilateral cryptorchidism are shown in Fig. 2. In only
four cases descent to a retractile position occurred. In one of these a scrotal position was
acquired at follow-up coinciding with pubertal development.
LHRH treatment and cryptorchidism 545
Table 4. Plasma testosterone and sex-hormone binding globulins before
and after 4 weeks of therapy
Testosterone (nmol/l)
Mean 0.17 0-16 0.36 0.20 0.39
Median 0.17 0.13 0.30 0.17 0.2I
Range c 0.05-0.40 c 0.05-0.65 0.05-1.20' 0.0845Ot 0.07-2. I O t
SHBG (nmol/l)
Mean 80 77 75 79 76
SD 21 26 27 20 24
Median 84 80 75 80 76
Range 23-123 31-115 49-109 46134 3%141
Significantly higher than before and after placebo (rank test, P < 0.01).
t No significant difference (rank test, P >0.1).
Biochemical responses
The LH and FSH response to an intravenous bolus of 25 pg LHRH per m2body surface is
shown in Table 3. Basal LH was elevated after LHRH therapy and the FSH response
diminished. Table 4 shows the plasma testosterone and SHBG before and after therapy.
In most children plasma testosterone did not increase, but in 15 of the 48 children who
received LHRH therapy, testosterone levels rose above 0.4 nmol/l, the upper normal limit
for prepubertal children (Von Schnakenburg et al., 1980).Such a level was reached by one
child after placebo, and by one other before LHRH therapy. Sex hormone binding
globulin did not change significantly. None of the biochemical responses was related to
age.
DISCUSSION
The reports on the effect of intranasal application of LHRH have yielded conflicting data.
A number of factors can be expected to influence percentage success, such as the selection
of patients (unilateral or bilateral cryptorchidism, impalpable o r inguinal testes, age, etc.),
the definition of retractile testes, the design of the study (open or placebo-controlled) and
definition of success.
Our results illustrate that various definitions of success can lead to different
interpretations. When the percentage in which any testicular descent is observed is used as
parameter, LHRH has a greater effect than placebo (37% vs 18%). When sufficient
descent is used as parameter, this was obtained in six out of 35 testes after LHRH therapy,
and two out of 34 testes after placebo. When the percentage in which full descent was
obtained either after 4 or 8 weeks is used, there is hardly any difference (9% vs 6%).When
the distance in centimetres used as a parameter of descent, there is no significant difference
between LHRH and placebo, except in squatting position. However, this difference (1 cm)
is in the same order of magnitude as the intra-observer variation of the measurement
546 J . M. Wit et al.
(J. M. Wit, submitted for publication). When the follow-up results are considered, surgery
was thought unnecessary in 40% of the bilateral cryptorchid testes, and in 14% of the
unilateral cryptorchid testes. All of these testes were not spontaneously in the scrotum,
but had been manipulated into the lower scrotum on one or more occasions during
therapy, After 1 year follow-up only in one patient was the testis spontaneously in the
scrotum in supine position. This patient had reached puberty at that time.
In agreement with Karpe et al. (1983), our data suggest that LHRH has some effect on
the relaxation of the cremasteric reflex, and makes the testis somewhat more mobile. In
this way LHRH might be used for diagnostic purposes to help to decide between retractile
testes or another form of cryptorchidism. However, there can be no absolute certainty
that testes which have partially descended by LHRH, are normal testes which will descend
spontaneously in puberty (Hadziselimovicet al., 1984).
In our study, approximately 25% of the patients presented with aggressive behaviour
during therapy. This is in concordance with two other studies (Hagberg & Westphal,
1982; Weisbach & Struth, 1983), but contrary to many others. For some parents it was a
reason to reject a second LHRH course.
In our patients intranasal LHRH led to increased mean basal and peak LH values
during an i.v. LHRH test. These results are in line with those of some of the previous
studies (Happ et af.,1978; Illig et al., 1980;Hagberg & Westphal, 1982; Karpe et al., 1983),
but contrary to others which found no changes (Pirazzoli et al., 1978; Spona et al., 1979;
Hadziselirnovicet al., 1980; De Muinck Keizer-Schrama et af., 1984).The decreased FSH
response to LHRH, found in our study, confirms the findings of most previous studies.
The high testosterone values in 15 of the 48 children after 4 weeks of LHRH therapy
support the results of some studies (Spona et al., 1979; Karpe et af., 1983),but most other
studies found no differences (Happ et al., 1978; Pirazzoli et a/., 1978; Illig er al., 1980;
Frick etal., 1980; De Muinck Keizer-Schrama et al., 1984).Possibly, the timing of the i.v.
LHRH test, 1 h after intranasal administration accounts for the relatively high LH and
testosterone values in our study (Dahlen et al., 1974).
In conclusion, contrary to some other studies, our results indicate that intranasal
LHRH application has a limited value for the treatment of cryptorchidism, especially in
unilateral cryptorchidism. As the mobility of the testis seems to be enhanced by LHRH,
an LHRH course might be suitable as a diagnostic tool to differentiate between retractile
testes and other disorders of testicular descent. As hCG therapy seems to have an equally
limited effect at a young age (Garagorri et al., 1982), and the generally accepted opinion is
that therapy should be carried out between 2 and 3 years of age, there appears to be no
good alternatives for surgical therapy. The rising frequency of orchidopexies, as observed
in the United Kingdom (Chilvers et al., 1984) and the Netherlands can probably only be
countered by meticulous examination and notation of testicular descent after birth,
thorough and repeated physical examination in supine and squatting position, and
LHRH therapy in case of suspicion of retractile testes.
ACKNOWLEDGEMENTS
Thanks are due to Drs A. Vos, M. Jansen, A. Burger-de Geus, M. H. Rijvekamp, S.
Ekkelkamp, M. W. van Maarschalkerweerd and R. Chadha for assistance in the study
protocol; to Drs R. H. J. Odink, W. Oostdijk, J. L. M. Strengers, H. A. A. Brouwers, A.
Jans and W. Hack for clinical assistance; to Professor J. H. H.Thyssen and Dr H. van
LHRH treatmenr and cryptorchidism 547
Kessel for biochemical determinations; and to Mrs E. Ram, L. van Dijk and Mr T.
Schipper for administrative support.
REFERENCES
BERTELSEN, A., SKAKKEBAEK, N.. MAIJRITZEN, K., PRE~SS.P.. PEDERSEN. P.V. & THORUP. J. (1981) Intranasalt
gonadotropinfrigorende hormon (LHRH) som behaved retentio testis. Ugeskrifr for Laeger. 143, 1595-
1597.
BIERICH,J.R. (198 I ) Gonadotropin therapy for the undescended tests. In Pediatric Andrology (eds S.J. Kogan &
E.S. Hafez), pp. 163-171. M. Nijhoff Publish, The Hague.
BIJLSMA. J.W.J., DUURSMA, S.A., THUSSEN, J.H.H. & HUBER, 0.(1982) Influence of nondrolondecanoate on the
pituitary-gonadal axis in males. Acta Endocrinologica. 101, 108-1 12.
CHILVERS. C., PIKE, M.C., FORMAN. D..FOGELMAN. K. & WADSWORTH, M.E.J. (1984) Apparent doubling of
frequency of undescended testis in England and Wales in 1962-8 I . Lancet. ii, 330-332.
COUR-PALAIS. I.J. (1966) Spontaneous descent of the testicle. Lancet. i. 4 0 3 4 0 5 .
DAHLEN.H.G., KELLER.E. & SCHNEIDER. H.P.G. Linear dose dependent LH release following intranasally
sprayed LRH. Hormone Metabolism Research. 6 . 5 10-5 13.
DEMUINCKKEIZER-SCHRAMA.S.M.P.E.. HAZEBROEK, F.W.J.. DROP.S.L.S..VISSER, H.K.A.&MoLENAAR. J.C.
( 1984)Behandeling van niet-ingedaalde testis met gonadoreline (LH-RH) per neusspray: eerste ervaringen
en resultaten. Nederlanh Tijdschriyt Voor Geneesk unde, 128,208 1-2084.
FARRINGTON, G.H. (1968) The position and retractibility of the normal testis in childhood with reference to the
diagnosis and treatment of cryptorchidism. Journul of Pediatric Surgery. 3, 53-59.
FRICK.J., DONNER, CH.. KUNIT, G., GALVAN. G. & BERNROIDER.G. ( 1980)The effect ofchronic administration
of a synthetic LH-RH analogue intranasally in cryptorchid boys. lnfernationol Journal of Andrology, 3,
469478.
GARAGORRI. J.M., JOB, J.C.. CANLORBE. P. & CHAUSSAIN. J.S. (1982) Results of early treatment of
cryptorchidism with human chorionic gonadotropin. Journal of Pediutrics, 101, 923-927.
HADZISELIMOVIC, F., GIRARD. J.. H~CHT. B., V A N DER OHE.M. & STALDER, G. ( 1980) Effect of LH-RH treatment
on hypothalamo-pituitary-gonadalaxis and Leydig cell ultrastructure in cryptorchid boys. Hormone
Research. 13, 358-366.
HADZISELIMOVIC, F., GIRARD. J. & HERZOG,B. (1984) Jahre Erfahrung mit der hormonellen kombinierten
Behandlung des Kryptorchismus. Zeitschrgf fur Kinderchirurgie. 39, 326327.
HAGBERG, S. & WESTPHAL, 0. (1982) Treatment of undescended testes with intranasal application of synthetic
LH-RH. European Journal of Pediatrics. 139, 285-288.
HAPP. J., KOLLMAN, F.. KRAWEHL, C.. NEUBAUER. M. & BEYER. J. (1975) lntranasal GnRH therapy of
maldescended testes. Hormone and Metabolic Research, 7,440441.
HAPP. J., KOLLMANN, F.. KRAWEHL. C., NEUBAUER. M.. KRAUSE.U., DEMISCH.K., SANDOW. J., V O N
RECHENBERG, W. & BEYER,I. (1978) Treatment of cryptorchidism with pernasal gonadotropin-releasing
hormone therapy. Fertility and Sterility, 29, 546-55 I .
HEDINCER, C. (1979) Histological data in cryptorchidism. In Cryptorchidism: Diagnosis and Treatment, (ed J.C.
Job), pp. 2-13. S. Karger, Basel.
ILLIG. R., EXNER,G.U.,KOLLMANN. F.. KELLERER. K., BORKENSTEIN, M.. LUNGLMAYR. L., KIJBER. W. &
PRADER. A. (1977) Treatment of cryptorchidism by intranasal synthetic luteinising-hormone releasing
hormone. Lancet, ii, 5 18-520.
ILLIG, R.,TORRESANI. T., BUCHER. H., ZACHMANN. M. & PRADER. A. (1980) Effect of intranasal LH-RH therapy
on plasma LH. FSH and testosterone, and relation to clinical results in prepubertal boys with
cryptorchidism. Clinical Endocrinology. 12, 9 1-97,
KARPE,B, ENEROTH,P. & RITZEN,E.M. (1983) LHRH treatment in unilateral cryptorchidism: Effect on
testicular descent and hormonal response. Journal of Pediatrics, 106, 892-897.
PIRAZZOLI, P., ZAPPULLA. F.. BERNARDI.F., VILLA.M.P.. ALEKSANDROWICZ, D., SCANDOLA, A., STANCARI. P.,
CICOGNANI, A. & CACCIARI. E. (1978) Luteinising hormone-releasing hormone nasal spray as therapy for
undescended testicle. Archives of Diseases in Childhood. 53, 235-238.
SCORER, C.G.(1964) The descent of the testis. Archives of Diseases in Childhood, 39, 685-609.
SPONA.J., GLEISPACH, H.. HAPP.J.. KOLLMAN. F.. TORRESANI, T. & VON DER OHE.M. ( 1979)Changes of serum
testosterone and of LHRH test after treatment of cryptorchidism by intranasal LH-RH. Endocrinologica
Experimentalis. 13, 201-207.
548 J . M. Wit et al.
VAN KAMMEN,E.. THLISSEN,J.H.H., RADEMAKER, B. & SCHWARZ, F. (1975) The influence of hormonal
contraceptives on sex hormone binding globulin (SHBG) capacity. Contrucepion. 11.53-59.
VONSCHNAKENBURG. K.,BIDLINGMAIER. F. & KNORR.D. (1980) 17-Hydroxyprogesterone,androstencdione
and testosterone in normal children and in prepubertal patients with congenital adrenal hyperplasia.
European JOWMI of Pediarrics, 133,259-267.
WEBEACH.L.L.. STRUTH,B. (1983) Die Behandlung des Maldescensus testis rnit LH-RH-nasalspray. Urologe,
22, 176179.