- Email: [email protected]
THE USE OF GONADOTROPIC HORMONES IN THE TREATMENT OF IMPERFECTLY MIGRATED TESTES
[DEC. 14,
1935
ADDRESSES AND ORIGINAL ARTICLES THE USE OF
GONADOTROPIC HORMONES IN THE TREATMENT OF IMPERFECTLY MIGRATED TESTES BY A. W.
SPENCE, M.D. Camb.,
M.R.C.P. Lond.
FIRST ASSISTANT, MEDICAL UNIT, ST. BARTHOLOMEW’S
HOSPITAL ;
AND
E. F. SCOWEN, M.D., M.R.C.P. Lond. SECOND ASSISTANT
IN a previous communication1 we reported results obtained in the treatment of 11 patients with
The examination of the position of the testes was made with the patients standing up to avoid any retraction of a normally situated organ. Care was also taken to note the degree of mobility of the testis and whether it could be pushed through the external ring into the neck of the scrotum. The preparation of gonadotropic hormones used was Pregnyl, usually given in doses of 600 rat units * intramuscularly into the deltoid twice weekly. The administration of smaller doses with shorter intervals between each dose-e.g., five times per week-would probably be more efficacious, but in our experience this was impracticable in the treatment of these patients, who were necessarily out-patients. A summary of the clinical findings and of the results of treatment is set out later, case by case, and summarised in Table I. In 6 of the 12 bilatera.
imperfectly migrated testes by means of the gonadotropic hormones contained in the urine of pregnant TABLE I We have now followed these patients for women. the Results Obtained in the Hormone Treatand are able to results state our a fairly long period Summarising ment of Patients with Imperfectly Migrated Testes in a total of 33 cases treated by this method. Our findings are such that we think hormone therapy deserves trial before surgical measures are undertaken. EXPERIMENTAL STUDIES
The experimental work of Evans and his associates,23 Smith and Engle,4Aschheim,5 and many others has shown that a gonad-stimulating principle is present in the anterior lobe of the pituitary, and that it controls the activity of the ovaries and testes. The evidence suggests that the hormone consists of two factors--one which brings about maturation, and one which causes luteinisation of the ovarian follicles. According to Smith, and Evans, the follicle-stimulating hormone is gametokinetic in that it stimulates both ova and the male germ cells, whereas the luteinising hormone acts principally on the connective tissue derivatives-the thecal cells of the ovaries and the interstitial cells of the testes. Large amounts of a gonadotropic principle, similar in action to that produced by the pituitary, were found by Aschheim and Zondek8 in the urine of pregnant women, and their pregnancy test depends on its presence. The effect produced by pregnancy urine extracts in the female is predominantly one of luteinisation and in the male of hypertrophy of the interstitial tissue of the testes. Collip and his collaborators9 do not consider that pregnancy urine extracts stimulate the seminiferous epithelium, but Smith and Leonard 10 and Evans and his associates7 state that they induce spermatogenesis, a finding which is supported by the results obtained by Brosius 11 in the treatment of azoospermia by pregnancy urine extracts. The researches of Engle 12 have further shown that in immature monkeys, in which the testes are normally situated at the upper end of the
inguinal canals, injections of extracts of anterior pituitary or of pregnancy urine bring about descent of the testes into the scrotum by the fourteenth day. Clinical
Findings patients with imperfectly migrated testes
Of the 33 treated with pregnancy urine extract in the present work, in 12 the maldescent was bilateral, in 4 unilateral with the other testis situated high in the neck of the scrotum, and in 15 unilateral with the other testie situated low in the scrotum, while in 2 the testes were situated high in the scrotum and were easily retracted. The ages of the patients ranged from 4 to 26 years, the maiority being 11 to 14 years old. 5859 4
to
26
CASES WITH TESTES IN UPPER SCROTUM
Descent of testis. Case 32 in 2t months. ,.
cases, both testes a
33"3
11
descended into the scrotum within
period varying from 3 weeks to 142 months. Case 3
that of a boy, aged 12, with Frohlich’s associated with bilaterally undescended testes ; descent was brought about in 3 weeks, but the injections which were continued for several months had little or no effect on his general condition. Case 1 was a bilateral cryptorchid aged 11, neither testis being palpable while he was under preliminary observation in the ward. At the end of 5 weeks’ treatment the right testis was in the scrotum, and the left testis was in the scrotum at the end of 9 weeks. The scrotum, however, which was very small and retracted, remained so for many months, and the testes varied in position in spite of continued treatment with gonadotropic
syndrome
* A Janssen-Loeser rat unit of gonadotropic hormone is the least amount which will provoke œstrus in half of the animals injected with all necessary precautions.13
A A
1336
tropic hormone, it was possible that he had entered into a refractory phase. Therapy was therefore discontinued
TABLE III.—CASES TREATED
for 3 months. At the end of this time treatment with gonadotropic hormone was resumed for 2 months, when the scrotum became quite lax and the testes remained low in the scrotum. At the present time, 2 months after cessation of treatment, the testes remain low in a normal scrotum.
in years and 45 Age initial condition.
1 11. Bilateral. Tes- After 5 wks. right testis low in scrotum ; after 9 wks. left low in scrotum. Posites not palpable. Scrotum retrac- tions later varied in spite of continued treatment. After 6 mths. menformon ted. 2500 units given in addition intramuscularly twice weekly for 2 mths. Treatment with pregnyl continued for 9 mths. No change in condition. Treat ment stopped for 3 mths.; pregnyl injections then resumed for 2! mths. At the end of this period both testes low in scrotum and scrotum lax. After 2 mths. without treatment, testes low in scrotum and scrotum normal.
In 4 of the bilateral cases descent of one testicle occurred after treatment for 5-9 months. In the remaining 2 bilateral cases descent has not been brought about after treatment for 7-9 months. Of the 4 unilateral cases in whom the scrotal testis was situated in the upper scrotum, in 3 both testes were low in the scrotum at the end of 2 weeks, 2 months, and 5 months respectively. In the remaining case at the end of 7 months the scrotal testis was low in the scrotum, but the position of the inguinal testis remained unchanged. In the unilateral cases with the scrotal testis low in the scrotum, 8 were successful after 2 weeks’ to 12 months’ treatment and 7 unsuccessful after treatment for 5 to 9 months. In the 2 cases in which the testis was situated in the upper scrotum and frequent retraction troubled the patient, the testis assumed a position low in the scrotum after 2! and 3 months of treatment and retraction no longer occurred. Thus in half the bilateral cases both testes descended, in one-third one descended, and in one-sixth descent has not yet taken place. Of the 19 unilateral cases a successful descent was brought about in 11 (58 per cent.). Of the total 33 cases there have been 10 failures (30 per cent.). We have been able to follow up the early cases after cessation of treatment. It is our custom to ask patients to present themselves at hospital every one, two, or three months after they have discontinued treatment. In 9 out of 11 such cases (3 bilateral and 6 unilateral) the testes are still in the scrotum 1-11 months after treatment was stopped. In 1 bilateral case one testis has retracted into the inguinal canal after 1 month without treatment, and in 1 unilateral case the position of the testis varies 10 months after treatment (Table II.). TABLE II
Summarising
the
Follow-up of 11Cases after ofTreatment
R It result.
g
Bilateral; 1 After 4 mths. right testis low in scrotum, before, right left at external ring and can be pushed orchidopexy. into scrotum. Later position of right Right testis now varied. After 10 mths., both low in at external ring; scrotum. After 11 mths., treatment left in inguinal stopped ; 1 mth. later right testis in canal and cannot mid-scrotum ; left in inguinal canal. be pushed into According to patient, position varies, scrotum. but both testes usually in scrotum.
2 10.
year
3 12. Frohlich’s syn- After 3 wks. both testes in scrotum. drome with biTreatment continued for 2 mths. laterally undes- General condition unchanged. cended testes. 4 12. Bilateral; 1 After 2 wks. right testis low in scrotum. After 5 mths. both testes low in scrotum. year before, left orchidopexy. Treatment continued for 7 mths. After Now left testis in 6 mths. without treatment both testes inguinal canal low in scrotum. and cannot be pushed into scrotum. Right in inguinal canal and easily pushed into 5
scrotum. 10. Bilateral. Both
After 2 wks. right testis in scrotum. After 4 wks. both low in scrotum. Treatment continued for 2 mths. After 4 mths. canals; right be pushed into without treatment, testes varied in neck of scrotum, position. Treatment recontinued for 2 mths. After further 4 mths. without cannot. left i treatment, testes low in scrotum. testes in
inguinal can
614.
Bilateral. Right After 5 wks. left testis low in scrotum, right in upper scrotum. After 2 mths. both low in scrotum, but position varies. After 7 mths. both low in scrotum.
testis in inguinal canal, and cannot be pushed into scrotum. Left not
palpable. 7 14. Bilateral. Left After 3 mths. left testis low in scrotum. orchidopexy pre- After 9 mths. right testis still in viously. Now left inguinal canal. testis in neck of scrotum, right in inguinal canal
Cessation
TESTES REMAINED IN SCROTUM
and
cannot
pushed into
be
scro-
tum.
8 St. Bilateral. Both After 4 mths. right testis in mid-scrotum ; in inguinal canals right inguinal hernia. After 5 mths. and cannot be left still in inguinal canal. pushed into scrotum. 9 11. Bilateral. Both After 2 mths. right testis in scrotum. testes in inguinal After 7 mths. right low in scrotum ; canals and cannot position of left unchanged. be pushed into scrotum. Left inguinal hernia. Scrotum retracted.
RETRACTION INTO INGUINAL CANAL
2
(bilateral) after cessation of treatment for 1 month (retraction of one testis). 18 (unilateral) after cessation of treatment for 10 months (position varies).
Case
COMPLICATIONS OF TREATMENT
After the first, and sometimes also after the second in a considerable number of cases there has been a local reaction consisting of pain, redness, and swelling round the site of the injection. This has the patient from even been severe enough to using his arm next day, but as a rule it has disappeared by the second or third day. Reactions were not observed after subsequent injections, provided that the same site was used. If a different site was chosen, it was not unusual to produce some local reaction. Occasionally a slight reaction was observed locally
injection,
prevent
A ’.
10 10. Bilateral. Both After 3 mths. right testis in mid-scrotum, testes in inguinal left at external ring and easily pushed canals, very small, into scrotum. After 5 mths. right low cannot be pushed in scrotum ; position of left unchanged. into scrotum. 11 13. Bilateral. Both After 7 mths. testes in inguinal
.
no
change in condition.
canals and cannot be pushed into scrotum.
12 5. Bilateral. Both After 7 mths. both testes at external testes in inguinal ring and can be brought into scrotum. canals and cannot After 9 mths. condition unchanged. be pushed into scrotum.
I.
1337 TABLE
Agein
years and initial condition.
Õ
TABLE
II1.-( continued) 6m
Result.
Left1After 2 wks. both testes 13 14. Unilateral. small and and normal in size.
low in scrotum
testis
in upper scrotum. Right testis small, in inguinal canal and cannot be pushed into
Unilateral.1After 2 mths. right testis low in scrotum, left in upper scrotum. Left inguinal After 5 mths. both low in hernia. small, upper scrotum and scrotum. easily retracted into inguinal canal. Left in inguinal canal and cannot be pushed into scrotum.
Rightintestis
15 13. Unilateral. LeftAfter 1 mth. left testis low in scrotum, testis in inguinal right in mid-scrotum. After 2 mths. canal; right in both low in scrotum. After 1 mth. without treatment both low in scrotum. upper scrotum and easily retracted.
Unilateral.JAfter
Right testis in in-
8 mths. testis
just above external
ring.
Unilateral.After 7 mths. left testis low in scrotum, testis in right in inguinal canal. inguinal canal "
26 12. Unilateral. Left J.After 6 mths. left testis still in inguinal testis in inguinal canal, but can easily be pushed into canal and cannot lower scrotum. After 9t mths. position be pushed into unchanged. Right testis increased in scrotum. Right size. testis small.
27 12. Unilateral. Left lAfter 7 mths. condition unchanged. testis not pal-
pable. Right congenital hydrocele. 28 13. Unilateral. LeftAfter 7 mths. condition testis not palpable. Small left inguinal hernia.
unchanged.
29 13. Unilateral.After 5 mths. condition unchanged. Left testis not palpable. Small left inguinal hernia.
Right
cannot be pushed into scrotum. Left in upper scrotum and occasionally in inguinal canal.
and
17
25 13.
R It Result.
cannot be pushed into scrotum.
14 12.
16 144.
in years and initial condition.
guinal canal and
scrotum.
’
Age
IIL-(contin2ced)
canal and cannot be pushed into scrotum. Right
Unilateral.After 5 wks. right testis in neck of Right testis in in- scrotum. Position then varied. After guinal canal and 3 mths. remained in upper scrotum; small right inguinal hernia now present. After 6 mths. injections discontinued; 5 mths. after cessation of treatment testis still in upper scrotum ; treatment recontinued for 1 mth. ; 3 mths. later testis still in upper scrotum.
Ig 8. Unilateral. Left After 2 wks. left testis in scrotum ; testis in inguinal position then varied. After 6 wks. left canal and easily testis remained low in scrotum ; treatpushed into scro- ment continued for 3 mths. After 10 tum. Right testis mths. without treatment neither testis in scrotum, but both can be brought in scrotum and Parent says easily pushed in- easily into scrotum. to inguinal canal. position varies. Scrotum retracted. Unilateral. After 2 wks. right testis in mid-scrotum. Treatment continued for 2!- mths. After 11 mths. without treatment right testis still in scrotum. into scrotum.
19 13#.
Right testis in inguinal canal and cannot be pushed
20 14.
2 mths. right testis in upper scrotum ; small right inguinal hernia.
Unilateral. After
Right testis in inguinal canal and cannot be pushed into scrotum. Testis small.
After 12 mths.’ treatment with interval of 1 mth., right testis still in upper scrotum. Testis small.
Unilateral. After 4 mths. right testis in mid-scrotum. After 6 mths. testis still in mid-scrotum. testis in external ring and After 1 mth. without treatment testis
21 154.
Right
can be brought through into neck
still in mid-scrotum.
of scrotum. 22 13. Unilateral. Left After 5 months left testis in midtestis in inguinal scrotum. Did not attend regularly for canal and easily treatment. pushed into scrotum. Scrotum retracted.
Unilateral. After 2 mths. right testis in mid-scrotum. Right testis in in- After 2t mths. difficult to push testis guinal canal and into inguinal canal; treatment stopped. cannot be pushed After 10 mths. without treatment right
23,18.
into scrotum.
24 54.
guinal canal and cannot be pushed into scrotum. Left easily retraeted.
31 23.
Unilateral.After 2 mths. position unchanged, but testis can be pushed into neck of scrotum. After 5 mths. condition
Right testis at external ring; lower pole can be pushed into
unchanged.
scrotum. 32 12. Both testesAfter 2t mths. treatment no further After 3 mths. without in scrotum but retraction. retract easily into treatment no retraction.
inguinal canals. 33 26.
Right testis After 1 mth. testis no longer retracts. After 3 mths. testis in mid-scrotum. in upper scrotum and easily retracted, especially when patient is lifting heavy objects.
when used.
fresh sample of gonadotropic hormone was In 2 cases, after the first injection only, there
a
general reaction, consisting of malaise, anorexia, nausea, and headache. This came on the day after the injection and incapacitated the patient for that day only. There is a frequent association of inguinal hernia with the condition of imperfect migration of the testis and we have carefully examined each patient was a
with this consideration in mind. In 4 cases a hernia was present before beginning treatment ; in 5 other cases a hernia became obvious during the course of treatment. It seems highly probable that the hernia was present from the beginning and only became noticeable as the testis descended, the hernial sac presumably descending with the testis. In several cases there has been some enlargement of the testes during treatment, and in a few slight enlargement of the penis and growth of the pubic hair-an effect ascribed to stimulation of the interstitial cells of the testes (Table III.).
testis still in scrotum.
Unilateral. .After 3 wks. right testis in upper scrotum.
Right testis in in-
Small left inguinal hernia.
inguinal hernia.
8.
cannot be pushed into scrotum.
30 13. Unilateral. LeftAfter 5 mths. left testis still in inguinal testis in inguinal canal, but can be pushed into scrotum.
discontinued for 3 mths. patient’s absence from England. On return scrotum empty, both testes in inguinal canals, left easily pushed into scrotum. After 6 wks. in scrotum, right in neck of scrotum. Treatment owing to
left
Discussion
Gonadotropic extract of pregnancy urine has now been used by several investigators in the treatment of imperfectly migrated testes. The first was Schapiro 16 who in 1930 treated 13 cryptorchids, in all of whom the testes descended into the scrotum
1338 more or less completely. Since then successful results have been by Goldman and Stern,17 Kunstadter and Sexton,19 Rubinstein,2O Aberle and Jenkins,21 Brosius," and Webster.22 The criticism which may be levelled at the results claimed is that the testes sometimes descend spontaneously by the time of puberty. For instance, Drake 23 has reported that 24 of 38 undescended testes came down while under observation for several years at ages ranging from 10 years to 16 in one case, amounting to 37 per cent. in whom spontaneous descent failed to take place, compared with 30 per cent. of failures in our treated cases. This, however, is the highest incidence of spontaneous descent which we have been able to find recorded and it is significant that the percentage of failures in our treated cases is smaller. We feel that it is more than a coincidence that so many of our cases responded during treatment, and that arguments in favour of the specific action of gonadotropic hormones in this respect are : (1) in 4 cases (Nos. 2, 5, 18, and 24), in which the testes descended into the scrotum during treatment, retraction of the testes into the inguinal canal occurred after treatment was discontinued ; (2) in 2 bilateral cases (Nos. 2 and 4), in which an orchido. pexy on one side had previously been performed, the testis subsequently retracted into the inguinal canal but descended into the scrotum again during hormone treatment; (3) a successful result was obtained in 2tmonths in a patient aged 18 (Case 24), in whom spontaneous descent is highly improbable. The mode of action of the gonadotropic hormones in bringing about testicular descent is unknown. It has been suggested by Engle IL2 that they may be involved in the intra-uterine descent of the testes, as they are present in the maternal circulation throughout the period of gestation. It is postulated that maldescent may be due to inability of the testes at that time to respond to the stimulus. In the hormone treatment of undescended testes there appears to be no hard-and-fast rule as to which type of case will be successful. Descent of both testes into the scrotum has been obtained in cryptorchids in whom the testes were situated in the abdominal cavity, and also in cases of inguinal testes which could not be brought into the scrotum on manipulation. We have observed however that in the few cases in which the testis could be pushed into the scrotum an early response was obtained. The treatment is also of advantage in those cases in whom the testes are situated high up in the scrotum and give rise to pain or discomfort due to retraction into the inguinal canal on exertion. Failure is obvious in cases of ectopic testis, and descent will not take place in cases of abdominal testes which do not engage at the internal ring, or of inguinal testes which are held up by adhesions. In cases which do not respond to treatment and require operation subsequently, the administration of gonadotropic hormones before and for some time after operation may be of advantage in ensuring against any likelihood of postoperative retraction into the inguinal canal. In ,the treatment of refractory cases it should be borne in mind that after prolonged administration of gonadotropic hormone there ensues a phase in which there is loss of sensitivity to the stimulus, as evidenced by the experimental work of Selye, Collip, and Thomson quoted above. For this reason it is advisable to discontinue treatment after 6-9 months and to resume it after an interval of 3 months,
reported Robins,lg
when it is probable that sensitivity has returned. In this manner the possible occurrence of atrophy of the gonads, which these authors found in some of their experimental animals treated for a long time, is prevented.
Summary
Thirty-three patients, aged 4 to 26 years, with imperfectly migrated testes have been treated with the gonadotropic hormones of pregnancy urine (pregnyl), given in doses of 500 rat units intra. muscularly twice a week. Both testes descended into the scrotum in 6 of the bilateral cases and one testis in 4, while in 2 cases descent has not occurred. In 11 out of 19 unilateral cases the testis descended, and in 2 cases with the testis high in the neck of the scrotum it assumed a position low in the scrotum. Successful results were obtained within periods ranging from 2 weeks to 14t months. The testes have remained in the scrotum in 9 out of 11 cases followed for 1-11 months after cessation of treatment. We wish to thank the physicians and surgeons of St. Bartholomew’s Hospital and elsewhere who have kindly referred these cases to us. One of us (A. W. S.) acknowledges with thanks personal and expenses grants from the Medical Research Council. We are indebted to Dr. A.N. Macbeth, of the Organon Laboratories, for generous supplies of pregnyl. REFERENCES
1. Spence, A. W., and Scowen, E. F.: Proc. Roy. Soc. Med., 1935, xxviii., 427. 2. Evans, H. M., and Long, J. A.: Proc. Nat. Acad. Sci., 1922, viii., 38. 3. Evans, H. M., Meyer, K., and Simpson, M. E.: The Growth and Gonad-stimulating Hormones of the Anterior Hypophysis. Memoirs of the University of California, 1933, vol. xi. 4. Smith, P. E., and Engle, E. T.: Amer. Jour. Anat., 1927,
xl., 159. 5. Aschheim, S.: Zeits. f. Geburtsh. u. Gynäk., 1926. xc., 387. 6. Smith, P. E.: Jour. Amer. Med. Assoc., 1935, civ., 553. 7. Evans, H. M., Pencharz, R. I., and Simpson, M. E.: Endocrinology, 1934, xviii., 607. 8. Aschheim, S., and Zondek, B.: Klin. Woch., 1928, vii., 1404. 9. Collip, J. B., Selye, H., and Thomson, D. L.: Nature, 1933, cxxxi., 56. 10. Smith, P. E., and Leonard, S. L.: Proc. Soc. Exper. Biol. Med., 1933, xxx., 1246. 11. Brosius, W. L.: Endocrinology, 1935, six., 69. 12. Engle, E. T.: Ibid., 1932, xvi., 513. 13. Janssen, S., and Loeser, A.: Naunyn-Schmiedebergs Arch.,
1930, cli., 188. 14. Burrows, H. : Brit. Jour. Surg., 1934, xxi., 507. 15. Selye, H., Collip, J. B., and Thomson, D. L.: Proc. Soc. Exper. Biol. Med., 1934, xxxi., 566. 16. Schapiro, B.: Deut. med. Woch., 1930, lvi., 1605. 17. Goldman, A., and Stern, A.: New York State Jour. Med., 1933, xxxiii., 1095. 18. Kunstadter, R. H., and Robins, L. S.: Jour. of Pediat., 1934, iv., 774. 19. Sexton, D. L.: Endocrinology, 1934, xviii., 47. 20. Rubinstein, H. S.: Ibid., 1934, xviii., 475. 21. Aberle, S. B. D., and Jenkins, R. H.: Jour. Amer. Med. Assoc., 1934, ciii., 314. 22. Webster, B.: Ibid., 1935, civ., 2157. 23. Drake, C. B.: Ibid., 1934, cii., 759.
CONFERENCE
ON
ATMOSPHERIC
POLLUTION.—
Thirty-eight representatives of local authorities and other organisations met on Nov. 25th in half-yearly conference at the offices of the Department of Scientific and Industrial Research to receive a report from Dr. G. M. B. Dobson, F.R.S., chairman of the Atmospheric Pollution Research Committee, on the progress of recent researches. A number of offers to undertake additional investigations and observations were received. Mr. J. W. Beaumont, of Halifax, reported upon the analysis of atmospheric dust samples collected in Leeds, Halifax, and Huddersfield. Representatives of the London County Council mooted the desirability of reviewing measures to obviate the emission of soot, ash, grit, and gritty particles from chimneys such as those of electric power stations. Other local authorities emphasised the need of wider remedial for combating pollution. measures The conference appointed a small committee to put forward concrete proposals for the application of such measures by industry and to devise a scheme of financial coöperation.
1935
ADDRESSES AND ORIGINAL ARTICLES THE USE OF
GONADOTROPIC HORMONES IN THE TREATMENT OF IMPERFECTLY MIGRATED TESTES BY A. W.
SPENCE, M.D. Camb.,
M.R.C.P. Lond.
FIRST ASSISTANT, MEDICAL UNIT, ST. BARTHOLOMEW’S
HOSPITAL ;
AND
E. F. SCOWEN, M.D., M.R.C.P. Lond. SECOND ASSISTANT
IN a previous communication1 we reported results obtained in the treatment of 11 patients with
The examination of the position of the testes was made with the patients standing up to avoid any retraction of a normally situated organ. Care was also taken to note the degree of mobility of the testis and whether it could be pushed through the external ring into the neck of the scrotum. The preparation of gonadotropic hormones used was Pregnyl, usually given in doses of 600 rat units * intramuscularly into the deltoid twice weekly. The administration of smaller doses with shorter intervals between each dose-e.g., five times per week-would probably be more efficacious, but in our experience this was impracticable in the treatment of these patients, who were necessarily out-patients. A summary of the clinical findings and of the results of treatment is set out later, case by case, and summarised in Table I. In 6 of the 12 bilatera.
imperfectly migrated testes by means of the gonadotropic hormones contained in the urine of pregnant TABLE I We have now followed these patients for women. the Results Obtained in the Hormone Treatand are able to results state our a fairly long period Summarising ment of Patients with Imperfectly Migrated Testes in a total of 33 cases treated by this method. Our findings are such that we think hormone therapy deserves trial before surgical measures are undertaken. EXPERIMENTAL STUDIES
The experimental work of Evans and his associates,23 Smith and Engle,4Aschheim,5 and many others has shown that a gonad-stimulating principle is present in the anterior lobe of the pituitary, and that it controls the activity of the ovaries and testes. The evidence suggests that the hormone consists of two factors--one which brings about maturation, and one which causes luteinisation of the ovarian follicles. According to Smith, and Evans, the follicle-stimulating hormone is gametokinetic in that it stimulates both ova and the male germ cells, whereas the luteinising hormone acts principally on the connective tissue derivatives-the thecal cells of the ovaries and the interstitial cells of the testes. Large amounts of a gonadotropic principle, similar in action to that produced by the pituitary, were found by Aschheim and Zondek8 in the urine of pregnant women, and their pregnancy test depends on its presence. The effect produced by pregnancy urine extracts in the female is predominantly one of luteinisation and in the male of hypertrophy of the interstitial tissue of the testes. Collip and his collaborators9 do not consider that pregnancy urine extracts stimulate the seminiferous epithelium, but Smith and Leonard 10 and Evans and his associates7 state that they induce spermatogenesis, a finding which is supported by the results obtained by Brosius 11 in the treatment of azoospermia by pregnancy urine extracts. The researches of Engle 12 have further shown that in immature monkeys, in which the testes are normally situated at the upper end of the
inguinal canals, injections of extracts of anterior pituitary or of pregnancy urine bring about descent of the testes into the scrotum by the fourteenth day. Clinical
Findings patients with imperfectly migrated testes
Of the 33 treated with pregnancy urine extract in the present work, in 12 the maldescent was bilateral, in 4 unilateral with the other testis situated high in the neck of the scrotum, and in 15 unilateral with the other testie situated low in the scrotum, while in 2 the testes were situated high in the scrotum and were easily retracted. The ages of the patients ranged from 4 to 26 years, the maiority being 11 to 14 years old. 5859 4
to
26
CASES WITH TESTES IN UPPER SCROTUM
Descent of testis. Case 32 in 2t months. ,.
cases, both testes a
33"3
11
descended into the scrotum within
period varying from 3 weeks to 142 months. Case 3
that of a boy, aged 12, with Frohlich’s associated with bilaterally undescended testes ; descent was brought about in 3 weeks, but the injections which were continued for several months had little or no effect on his general condition. Case 1 was a bilateral cryptorchid aged 11, neither testis being palpable while he was under preliminary observation in the ward. At the end of 5 weeks’ treatment the right testis was in the scrotum, and the left testis was in the scrotum at the end of 9 weeks. The scrotum, however, which was very small and retracted, remained so for many months, and the testes varied in position in spite of continued treatment with gonadotropic
syndrome
* A Janssen-Loeser rat unit of gonadotropic hormone is the least amount which will provoke œstrus in half of the animals injected with all necessary precautions.13
A A
1336
tropic hormone, it was possible that he had entered into a refractory phase. Therapy was therefore discontinued
TABLE III.—CASES TREATED
for 3 months. At the end of this time treatment with gonadotropic hormone was resumed for 2 months, when the scrotum became quite lax and the testes remained low in the scrotum. At the present time, 2 months after cessation of treatment, the testes remain low in a normal scrotum.
in years and 45 Age initial condition.
1 11. Bilateral. Tes- After 5 wks. right testis low in scrotum ; after 9 wks. left low in scrotum. Posites not palpable. Scrotum retrac- tions later varied in spite of continued treatment. After 6 mths. menformon ted. 2500 units given in addition intramuscularly twice weekly for 2 mths. Treatment with pregnyl continued for 9 mths. No change in condition. Treat ment stopped for 3 mths.; pregnyl injections then resumed for 2! mths. At the end of this period both testes low in scrotum and scrotum lax. After 2 mths. without treatment, testes low in scrotum and scrotum normal.
In 4 of the bilateral cases descent of one testicle occurred after treatment for 5-9 months. In the remaining 2 bilateral cases descent has not been brought about after treatment for 7-9 months. Of the 4 unilateral cases in whom the scrotal testis was situated in the upper scrotum, in 3 both testes were low in the scrotum at the end of 2 weeks, 2 months, and 5 months respectively. In the remaining case at the end of 7 months the scrotal testis was low in the scrotum, but the position of the inguinal testis remained unchanged. In the unilateral cases with the scrotal testis low in the scrotum, 8 were successful after 2 weeks’ to 12 months’ treatment and 7 unsuccessful after treatment for 5 to 9 months. In the 2 cases in which the testis was situated in the upper scrotum and frequent retraction troubled the patient, the testis assumed a position low in the scrotum after 2! and 3 months of treatment and retraction no longer occurred. Thus in half the bilateral cases both testes descended, in one-third one descended, and in one-sixth descent has not yet taken place. Of the 19 unilateral cases a successful descent was brought about in 11 (58 per cent.). Of the total 33 cases there have been 10 failures (30 per cent.). We have been able to follow up the early cases after cessation of treatment. It is our custom to ask patients to present themselves at hospital every one, two, or three months after they have discontinued treatment. In 9 out of 11 such cases (3 bilateral and 6 unilateral) the testes are still in the scrotum 1-11 months after treatment was stopped. In 1 bilateral case one testis has retracted into the inguinal canal after 1 month without treatment, and in 1 unilateral case the position of the testis varies 10 months after treatment (Table II.). TABLE II
Summarising
the
Follow-up of 11Cases after ofTreatment
R It result.
g
Bilateral; 1 After 4 mths. right testis low in scrotum, before, right left at external ring and can be pushed orchidopexy. into scrotum. Later position of right Right testis now varied. After 10 mths., both low in at external ring; scrotum. After 11 mths., treatment left in inguinal stopped ; 1 mth. later right testis in canal and cannot mid-scrotum ; left in inguinal canal. be pushed into According to patient, position varies, scrotum. but both testes usually in scrotum.
2 10.
year
3 12. Frohlich’s syn- After 3 wks. both testes in scrotum. drome with biTreatment continued for 2 mths. laterally undes- General condition unchanged. cended testes. 4 12. Bilateral; 1 After 2 wks. right testis low in scrotum. After 5 mths. both testes low in scrotum. year before, left orchidopexy. Treatment continued for 7 mths. After Now left testis in 6 mths. without treatment both testes inguinal canal low in scrotum. and cannot be pushed into scrotum. Right in inguinal canal and easily pushed into 5
scrotum. 10. Bilateral. Both
After 2 wks. right testis in scrotum. After 4 wks. both low in scrotum. Treatment continued for 2 mths. After 4 mths. canals; right be pushed into without treatment, testes varied in neck of scrotum, position. Treatment recontinued for 2 mths. After further 4 mths. without cannot. left i treatment, testes low in scrotum. testes in
inguinal can
614.
Bilateral. Right After 5 wks. left testis low in scrotum, right in upper scrotum. After 2 mths. both low in scrotum, but position varies. After 7 mths. both low in scrotum.
testis in inguinal canal, and cannot be pushed into scrotum. Left not
palpable. 7 14. Bilateral. Left After 3 mths. left testis low in scrotum. orchidopexy pre- After 9 mths. right testis still in viously. Now left inguinal canal. testis in neck of scrotum, right in inguinal canal
Cessation
TESTES REMAINED IN SCROTUM
and
cannot
pushed into
be
scro-
tum.
8 St. Bilateral. Both After 4 mths. right testis in mid-scrotum ; in inguinal canals right inguinal hernia. After 5 mths. and cannot be left still in inguinal canal. pushed into scrotum. 9 11. Bilateral. Both After 2 mths. right testis in scrotum. testes in inguinal After 7 mths. right low in scrotum ; canals and cannot position of left unchanged. be pushed into scrotum. Left inguinal hernia. Scrotum retracted.
RETRACTION INTO INGUINAL CANAL
2
(bilateral) after cessation of treatment for 1 month (retraction of one testis). 18 (unilateral) after cessation of treatment for 10 months (position varies).
Case
COMPLICATIONS OF TREATMENT
After the first, and sometimes also after the second in a considerable number of cases there has been a local reaction consisting of pain, redness, and swelling round the site of the injection. This has the patient from even been severe enough to using his arm next day, but as a rule it has disappeared by the second or third day. Reactions were not observed after subsequent injections, provided that the same site was used. If a different site was chosen, it was not unusual to produce some local reaction. Occasionally a slight reaction was observed locally
injection,
prevent
A ’.
10 10. Bilateral. Both After 3 mths. right testis in mid-scrotum, testes in inguinal left at external ring and easily pushed canals, very small, into scrotum. After 5 mths. right low cannot be pushed in scrotum ; position of left unchanged. into scrotum. 11 13. Bilateral. Both After 7 mths. testes in inguinal
.
no
change in condition.
canals and cannot be pushed into scrotum.
12 5. Bilateral. Both After 7 mths. both testes at external testes in inguinal ring and can be brought into scrotum. canals and cannot After 9 mths. condition unchanged. be pushed into scrotum.
I.
1337 TABLE
Agein
years and initial condition.
Õ
TABLE
II1.-( continued) 6m
Result.
Left1After 2 wks. both testes 13 14. Unilateral. small and and normal in size.
low in scrotum
testis
in upper scrotum. Right testis small, in inguinal canal and cannot be pushed into
Unilateral.1After 2 mths. right testis low in scrotum, left in upper scrotum. Left inguinal After 5 mths. both low in hernia. small, upper scrotum and scrotum. easily retracted into inguinal canal. Left in inguinal canal and cannot be pushed into scrotum.
Rightintestis
15 13. Unilateral. LeftAfter 1 mth. left testis low in scrotum, testis in inguinal right in mid-scrotum. After 2 mths. canal; right in both low in scrotum. After 1 mth. without treatment both low in scrotum. upper scrotum and easily retracted.
Unilateral.JAfter
Right testis in in-
8 mths. testis
just above external
ring.
Unilateral.After 7 mths. left testis low in scrotum, testis in right in inguinal canal. inguinal canal "
26 12. Unilateral. Left J.After 6 mths. left testis still in inguinal testis in inguinal canal, but can easily be pushed into canal and cannot lower scrotum. After 9t mths. position be pushed into unchanged. Right testis increased in scrotum. Right size. testis small.
27 12. Unilateral. Left lAfter 7 mths. condition unchanged. testis not pal-
pable. Right congenital hydrocele. 28 13. Unilateral. LeftAfter 7 mths. condition testis not palpable. Small left inguinal hernia.
unchanged.
29 13. Unilateral.After 5 mths. condition unchanged. Left testis not palpable. Small left inguinal hernia.
Right
cannot be pushed into scrotum. Left in upper scrotum and occasionally in inguinal canal.
and
17
25 13.
R It Result.
cannot be pushed into scrotum.
14 12.
16 144.
in years and initial condition.
guinal canal and
scrotum.
’
Age
IIL-(contin2ced)
canal and cannot be pushed into scrotum. Right
Unilateral.After 5 wks. right testis in neck of Right testis in in- scrotum. Position then varied. After guinal canal and 3 mths. remained in upper scrotum; small right inguinal hernia now present. After 6 mths. injections discontinued; 5 mths. after cessation of treatment testis still in upper scrotum ; treatment recontinued for 1 mth. ; 3 mths. later testis still in upper scrotum.
Ig 8. Unilateral. Left After 2 wks. left testis in scrotum ; testis in inguinal position then varied. After 6 wks. left canal and easily testis remained low in scrotum ; treatpushed into scro- ment continued for 3 mths. After 10 tum. Right testis mths. without treatment neither testis in scrotum, but both can be brought in scrotum and Parent says easily pushed in- easily into scrotum. to inguinal canal. position varies. Scrotum retracted. Unilateral. After 2 wks. right testis in mid-scrotum. Treatment continued for 2!- mths. After 11 mths. without treatment right testis still in scrotum. into scrotum.
19 13#.
Right testis in inguinal canal and cannot be pushed
20 14.
2 mths. right testis in upper scrotum ; small right inguinal hernia.
Unilateral. After
Right testis in inguinal canal and cannot be pushed into scrotum. Testis small.
After 12 mths.’ treatment with interval of 1 mth., right testis still in upper scrotum. Testis small.
Unilateral. After 4 mths. right testis in mid-scrotum. After 6 mths. testis still in mid-scrotum. testis in external ring and After 1 mth. without treatment testis
21 154.
Right
can be brought through into neck
still in mid-scrotum.
of scrotum. 22 13. Unilateral. Left After 5 months left testis in midtestis in inguinal scrotum. Did not attend regularly for canal and easily treatment. pushed into scrotum. Scrotum retracted.
Unilateral. After 2 mths. right testis in mid-scrotum. Right testis in in- After 2t mths. difficult to push testis guinal canal and into inguinal canal; treatment stopped. cannot be pushed After 10 mths. without treatment right
23,18.
into scrotum.
24 54.
guinal canal and cannot be pushed into scrotum. Left easily retraeted.
31 23.
Unilateral.After 2 mths. position unchanged, but testis can be pushed into neck of scrotum. After 5 mths. condition
Right testis at external ring; lower pole can be pushed into
unchanged.
scrotum. 32 12. Both testesAfter 2t mths. treatment no further After 3 mths. without in scrotum but retraction. retract easily into treatment no retraction.
inguinal canals. 33 26.
Right testis After 1 mth. testis no longer retracts. After 3 mths. testis in mid-scrotum. in upper scrotum and easily retracted, especially when patient is lifting heavy objects.
when used.
fresh sample of gonadotropic hormone was In 2 cases, after the first injection only, there
a
general reaction, consisting of malaise, anorexia, nausea, and headache. This came on the day after the injection and incapacitated the patient for that day only. There is a frequent association of inguinal hernia with the condition of imperfect migration of the testis and we have carefully examined each patient was a
with this consideration in mind. In 4 cases a hernia was present before beginning treatment ; in 5 other cases a hernia became obvious during the course of treatment. It seems highly probable that the hernia was present from the beginning and only became noticeable as the testis descended, the hernial sac presumably descending with the testis. In several cases there has been some enlargement of the testes during treatment, and in a few slight enlargement of the penis and growth of the pubic hair-an effect ascribed to stimulation of the interstitial cells of the testes (Table III.).
testis still in scrotum.
Unilateral. .After 3 wks. right testis in upper scrotum.
Right testis in in-
Small left inguinal hernia.
inguinal hernia.
8.
cannot be pushed into scrotum.
30 13. Unilateral. LeftAfter 5 mths. left testis still in inguinal testis in inguinal canal, but can be pushed into scrotum.
discontinued for 3 mths. patient’s absence from England. On return scrotum empty, both testes in inguinal canals, left easily pushed into scrotum. After 6 wks. in scrotum, right in neck of scrotum. Treatment owing to
left
Discussion
Gonadotropic extract of pregnancy urine has now been used by several investigators in the treatment of imperfectly migrated testes. The first was Schapiro 16 who in 1930 treated 13 cryptorchids, in all of whom the testes descended into the scrotum
1338 more or less completely. Since then successful results have been by Goldman and Stern,17 Kunstadter and Sexton,19 Rubinstein,2O Aberle and Jenkins,21 Brosius," and Webster.22 The criticism which may be levelled at the results claimed is that the testes sometimes descend spontaneously by the time of puberty. For instance, Drake 23 has reported that 24 of 38 undescended testes came down while under observation for several years at ages ranging from 10 years to 16 in one case, amounting to 37 per cent. in whom spontaneous descent failed to take place, compared with 30 per cent. of failures in our treated cases. This, however, is the highest incidence of spontaneous descent which we have been able to find recorded and it is significant that the percentage of failures in our treated cases is smaller. We feel that it is more than a coincidence that so many of our cases responded during treatment, and that arguments in favour of the specific action of gonadotropic hormones in this respect are : (1) in 4 cases (Nos. 2, 5, 18, and 24), in which the testes descended into the scrotum during treatment, retraction of the testes into the inguinal canal occurred after treatment was discontinued ; (2) in 2 bilateral cases (Nos. 2 and 4), in which an orchido. pexy on one side had previously been performed, the testis subsequently retracted into the inguinal canal but descended into the scrotum again during hormone treatment; (3) a successful result was obtained in 2tmonths in a patient aged 18 (Case 24), in whom spontaneous descent is highly improbable. The mode of action of the gonadotropic hormones in bringing about testicular descent is unknown. It has been suggested by Engle IL2 that they may be involved in the intra-uterine descent of the testes, as they are present in the maternal circulation throughout the period of gestation. It is postulated that maldescent may be due to inability of the testes at that time to respond to the stimulus. In the hormone treatment of undescended testes there appears to be no hard-and-fast rule as to which type of case will be successful. Descent of both testes into the scrotum has been obtained in cryptorchids in whom the testes were situated in the abdominal cavity, and also in cases of inguinal testes which could not be brought into the scrotum on manipulation. We have observed however that in the few cases in which the testis could be pushed into the scrotum an early response was obtained. The treatment is also of advantage in those cases in whom the testes are situated high up in the scrotum and give rise to pain or discomfort due to retraction into the inguinal canal on exertion. Failure is obvious in cases of ectopic testis, and descent will not take place in cases of abdominal testes which do not engage at the internal ring, or of inguinal testes which are held up by adhesions. In cases which do not respond to treatment and require operation subsequently, the administration of gonadotropic hormones before and for some time after operation may be of advantage in ensuring against any likelihood of postoperative retraction into the inguinal canal. In ,the treatment of refractory cases it should be borne in mind that after prolonged administration of gonadotropic hormone there ensues a phase in which there is loss of sensitivity to the stimulus, as evidenced by the experimental work of Selye, Collip, and Thomson quoted above. For this reason it is advisable to discontinue treatment after 6-9 months and to resume it after an interval of 3 months,
reported Robins,lg
when it is probable that sensitivity has returned. In this manner the possible occurrence of atrophy of the gonads, which these authors found in some of their experimental animals treated for a long time, is prevented.
Summary
Thirty-three patients, aged 4 to 26 years, with imperfectly migrated testes have been treated with the gonadotropic hormones of pregnancy urine (pregnyl), given in doses of 500 rat units intra. muscularly twice a week. Both testes descended into the scrotum in 6 of the bilateral cases and one testis in 4, while in 2 cases descent has not occurred. In 11 out of 19 unilateral cases the testis descended, and in 2 cases with the testis high in the neck of the scrotum it assumed a position low in the scrotum. Successful results were obtained within periods ranging from 2 weeks to 14t months. The testes have remained in the scrotum in 9 out of 11 cases followed for 1-11 months after cessation of treatment. We wish to thank the physicians and surgeons of St. Bartholomew’s Hospital and elsewhere who have kindly referred these cases to us. One of us (A. W. S.) acknowledges with thanks personal and expenses grants from the Medical Research Council. We are indebted to Dr. A.N. Macbeth, of the Organon Laboratories, for generous supplies of pregnyl. REFERENCES
1. Spence, A. W., and Scowen, E. F.: Proc. Roy. Soc. Med., 1935, xxviii., 427. 2. Evans, H. M., and Long, J. A.: Proc. Nat. Acad. Sci., 1922, viii., 38. 3. Evans, H. M., Meyer, K., and Simpson, M. E.: The Growth and Gonad-stimulating Hormones of the Anterior Hypophysis. Memoirs of the University of California, 1933, vol. xi. 4. Smith, P. E., and Engle, E. T.: Amer. Jour. Anat., 1927,
xl., 159. 5. Aschheim, S.: Zeits. f. Geburtsh. u. Gynäk., 1926. xc., 387. 6. Smith, P. E.: Jour. Amer. Med. Assoc., 1935, civ., 553. 7. Evans, H. M., Pencharz, R. I., and Simpson, M. E.: Endocrinology, 1934, xviii., 607. 8. Aschheim, S., and Zondek, B.: Klin. Woch., 1928, vii., 1404. 9. Collip, J. B., Selye, H., and Thomson, D. L.: Nature, 1933, cxxxi., 56. 10. Smith, P. E., and Leonard, S. L.: Proc. Soc. Exper. Biol. Med., 1933, xxx., 1246. 11. Brosius, W. L.: Endocrinology, 1935, six., 69. 12. Engle, E. T.: Ibid., 1932, xvi., 513. 13. Janssen, S., and Loeser, A.: Naunyn-Schmiedebergs Arch.,
1930, cli., 188. 14. Burrows, H. : Brit. Jour. Surg., 1934, xxi., 507. 15. Selye, H., Collip, J. B., and Thomson, D. L.: Proc. Soc. Exper. Biol. Med., 1934, xxxi., 566. 16. Schapiro, B.: Deut. med. Woch., 1930, lvi., 1605. 17. Goldman, A., and Stern, A.: New York State Jour. Med., 1933, xxxiii., 1095. 18. Kunstadter, R. H., and Robins, L. S.: Jour. of Pediat., 1934, iv., 774. 19. Sexton, D. L.: Endocrinology, 1934, xviii., 47. 20. Rubinstein, H. S.: Ibid., 1934, xviii., 475. 21. Aberle, S. B. D., and Jenkins, R. H.: Jour. Amer. Med. Assoc., 1934, ciii., 314. 22. Webster, B.: Ibid., 1935, civ., 2157. 23. Drake, C. B.: Ibid., 1934, cii., 759.
CONFERENCE
ON
ATMOSPHERIC
POLLUTION.—
Thirty-eight representatives of local authorities and other organisations met on Nov. 25th in half-yearly conference at the offices of the Department of Scientific and Industrial Research to receive a report from Dr. G. M. B. Dobson, F.R.S., chairman of the Atmospheric Pollution Research Committee, on the progress of recent researches. A number of offers to undertake additional investigations and observations were received. Mr. J. W. Beaumont, of Halifax, reported upon the analysis of atmospheric dust samples collected in Leeds, Halifax, and Huddersfield. Representatives of the London County Council mooted the desirability of reviewing measures to obviate the emission of soot, ash, grit, and gritty particles from chimneys such as those of electric power stations. Other local authorities emphasised the need of wider remedial for combating pollution. measures The conference appointed a small committee to put forward concrete proposals for the application of such measures by industry and to devise a scheme of financial coöperation.