1125 while the patient was on placebo. The intervening episodes occurred during administration of two agents with opposite effects on calcium metabolism, administered in a series of investigations into the relationship of calcium metabolism and the cyclic psychoses. The second episode began while the patient was on oral dihydrotachysterol 0-6 mg daily plus calcium lactate 750 mg daily. This episode of hyperthermia was by far the most severe and lengthy observed; it lasted 4 days, prompting withdrawal of dihydrotachysterol and calcium on the second day and vigorous fluid was required on the third day. The fourth and fifth episodes were aborted within 2 h by subcutaneous injections of 140 M.R.C. units synthetic salmon calcitonin (’Calcimar’, Armour Pharmaceutical) given, respectively, at the 10th and 4th hours of the episodes. Since, in three similar patients, salmon calcitonin was associated with increased C.S.F. calcium and since there is evidence for the involvement of calcium in the posterior hypothalamic regulation of body temperature,3.S it may well be that calcitonin exerted its apparent beneficial effects via a central mechanism. Since calcitonin promotes sequestration of calcium from serum to bone and from cytoplasm to mitochondria6 a direct effect on muscle, by reducing cytoplasmic calcium, seems equally plausiblel°2and is supported by our finding that calcitonin lowered the serum-c.P.K. in five patients with raised baseline of this enzyme (unpublished). However, no significant changes in oral temperature occurred in ten normothermic psychotic patients given calcitonin and seven others given dihydrotachysterol, even in those with raised C.P.K. values-a suggested indicator of susceptibility to iatrogenic
hyperpyrexia.’ This experience adds to the data suggesting a critical role for calcium in hyperthermic crises. Furthermore calcitonin therapy in such crises seems well worth further investigation. Laboratory of Clinical Psychopharmacology, Division of Special Mental Health Research, Intramural Research Program, National Institute of Mental Health, Saint Elizabeth’s Hospital, Washington, D.C. 20032, U.S.A.
JOHN SCOTT CARMEN RICHARD JED WYATT
TREATMENT OF CRYPTORCHIDISM BY SYNTHETIC LUTEINISING-HORMONE-RELEASING HORMONE
SIR,-Dr Hamilton (Oct. 22,
p.
875) questions the patho-
physiological background for using luteinising-hormonereleasing hormone (L.H.-R.H.) in cryptorchidism. There is clinical and experimental evidence that gonadotrophin and testosterone are involved in the process of testicular descent, so that administration of L.H.-R.H. might be the logical approach in most patients with cryptorchidism. Human chorionic gonadotrophin (H.C.G.) has been used successfully since the first report by Schapiro. Systemic testosterone causes testicular descent in the macaque.8 The increased frequency of cryptorchidism in hypogonadotrophic hypogonadism and a report of impaired L.H.-R.H. response in cryptorchid babies9point to an insufficiency in the hypothalamo-pituitary-gonadal system. Functional and ultrastructural findings in oestrogen-induced cryptorchidism in mice’O-’2 and rats" and its prevention with H.c.G. suggest involvement of gonadotrophins in the process of descent. The 3. Myers, R. D., Gisolfi, C. V., Mora, F.Nature, 1977, 266, 178. 4. Myers, R. D., Simpson, C. W., Higgins, D., Nattermann, R. A., Rice, J.C., Redgrave, P., Metcalf, G.Brain Res. Bull. 1976, 1, 301. 5. Gisolfi, C. V., Wilson, N. C., Myers, R. D., Phillips, M. I. Brain Res. 1976,
101, 160. 6. Rasmussen, H. Clin. Endocr Metab. 1972, 1, 3. 7. Schapiro, B. Dt. med. Wschr. 1931, 38, 38. 8. Hamilton, J. B. Anat. Rec. 1939, 70, 533. 9. Job, J. C., Gendrel, D., Safer, A., Roger, M.,
Chaussain, J. L. Acta
1977, 85, 644. 10. Hadziselimovic, F., Herzog, G. J. pediat.Surg. 1976, 11, 1. 11. Hadziselimovic,F.Adv.Anat.Embryol. Cell Biol. 1977,p. 53. 12. Hadziselimovic, F., Girard, J.Horm.Res. 1977, 8, 76. 13. Rajfer, J., Walsh, P. Birth Defects Orig. Art. Ser. 1977, 13, no. 2,
endocr.
L.H.-R.H. TESTS IN CRYPTORCHIDISM
ultrastructural studies of the Leydig cells of cryptorchid male newborns shows that the interstitial cells are atrophic.’"’" The testosterone content of testes from treated mice was significantly lower than that of newborn controls.12 H.c.G. injected together with oestrogen prevents atrophic changes of Leydig cells. 10. 11 Adult male mice, which have been treated in utero with oestrogens, also show atrophy of Leydig celfs.12 The mean testosterone content of testes from adult mice treated during intrauterine development was 19 ng, significantly lower than that of controls (72.5 ng) as estimated by direct radioimmunoassay.11,12 The ultrastructural alterations of interstitial cells produced in the animal experiments closely resemble those found at biopsy in cryptorchid infants. 11I In our clinical investigations 69 boys (bone age 2-10 years, puberty rating I [Tanner]) with unilateral or bilateral cryptorchidism, admitted for orchidopexy, underwent a L.H.-R.H. test (see table). The mean basal L.H. was 2.75 mi.u./ml and the mean peak response of 6.6 mi.u./ml did not differ from data for normal boys of the same age.14 However, the very wide range allowed three groups to be distinguished. The mean follicle-stimulating hormone (F.S.H.) value in cryptorchid boys studied (1.48 mi.u./ml) and the maximum (4-43 mi.u./ml) accord with normal F.S.H. values.14 We always saw an F.S.H. response but it was low in group I and normal or slightly above normal in the other two groups. Electronmicroscopy of biopsy material from boys with no response to L.H.-R.H. (group I) show that the Leydig cells are scarce and poorly developed. The interstitium is collagenised and there is no correlation between the stage of collagenisation of peritubular connective tissue and L.H. increase. The biopsy findings for 23 cryptorchid boys aged 2-5 years were related to their L.H. increase in response to L.H.-R.H. The number of spermatogonia per tubular cross-section was positively correlated with the L.H. increase
(r=0.57). We conclude that there is experimental evidence that testicular descent in man requires an intact hypothalamo-pituitary gonadal system. It might be reasonable therefore to continue treatment after correction of the abnormal position. Further studies will show whether such a prolonged substitution can increase the fertility-rate. F. HADZISELIMOVIC J. GIRARD University Children’s Hospital, CH-4005
B. HERZOG
Basle, Switzerland
ZINC, PLASMA ANDROGENS AND MALE STERILITY SIR,-Dr Antoniou and her colleagues (Oct. 29, p. 895) draw attention to the role of zinc in testicular function. We have investigated the relationship between oligospermia, serum-zinc, and serum testosterone and dihydrotestosterone (D.H.T.) in ten infertile men before and after oral administration of zinc sulphate 220 mg three times daily for 4-8 weeks. Zinc was measured by atomic-absorption spectrophotometry and testosterone and D.H.T. by radioimmunoassay.1 The serum-zinc was below normal in six men. Zinc and D.H.T. concentration were correlated (p
p. 107.
Pediat. 1974, 84, 371. J. M., Thorneycroft,I.
1. Barberia
H. Steroids,
1974, 23, 757.
1126 EFFECT OF ZINC ADMINSTRATION ON SERUM-ZINC, PLASMA-TESTOSTERONE AND SPERM-COUNT: MEAN ± S.E.M.
These findings seem to be confirmed by fifteen more cases but the data are incomplete. The wife of one patient became pregnant after her husband had taken zinc sulphate for 6 weeks. Serum-zinc concentrations depend upon nutritional factors 2-1 geological environment,6 and, probably, other factors Plasma-testosterone is related to serum-zinc only in men over 36 years of age.7 Zinc plays an important role in prostatic, epididymal, and testicular function,2,4.8-11but the relationship between oligospermia and zinc has not yet been studied. Our findings seem to open a new prospect for the treatment of some cases of oligospermia of unknown origin.
Oulu, Finland
T. RIITA HARTOMA
Foundation de Recherche
K. NAHOUL A. NETTER
Hormonologie,
94260 - Fresnes, France
FERTILISATION IN WOMEN WITH INTRAUTERINE DEVICES
SIR,-Landesman et al.12 and Beling et al.," using a radioiman antiserum specific to the [3-subunit of gonadotrophin (H.C.G.), have detected circulating H.C.G. during the luteal phase in women fitted with an intrauterine device (L U .D.). They regard this as a sign of fertilisation, implying that l.U.D.s act by interfering with implantation rather than by inhibiting fertilisation. Landesman et al. detected H.C.G. in 12-19% of LU.D. users as early as 5-7 days after the predicted ovulatory luteinising-hormone (L.H.) surge. Beling et al. found H.C.G. in 3 out of 30 I.U.D. users (10%) but not until 10-13 days after the postulated ovulation. Beling et al. also reported a rise of H.C.G. in two cycles during which fertilisation occurred and normal pregnancies ensued; this rise did not occur until 10 days after a registered ovulatory L.H. surge. In an i.u.D. user the same rise occurred 12 days after a detected ovulatory L.H.-peak. We have studied 55 I.U.D. users (’CuT-200’) and found only 1 with detectable H.C.G. concentrations. Blood-samples were taken 10-15 days after the predicted ovulatory L.H. surge from women with a history of regular menstrual cycles of between 24 and 32 days. 2 unprotected patients who became pregnant were also monitored by determination of L.H. and H.C.G. from plasma samples obtained three times weekly. In both pregnancies the H.C.G. did not rise until the 12th day after the detected
munoassay with human chorionic
ovulatory L.H. surge. We feel that a radioimmunoassay specific
for the
p-subunit
2. 3. 4. 5.
Vallee, B. L. Physiol. Rev. 1959, 39, 443. Halsted, J. A., Smith, J. C. Lancet, 1970, i, 322. Prasad, A. S., Halsted, J. A., Nadimi, M. Am. J. Med. 1961, 31, 532. Hartoma, T. R., Sotaniemi, E. A., Pelkonen, O., Ahlqvist, J. Eur. J. clin. Pharmac. 1977, 12, 1. 6. Hartoma, T. R. Unpublished. 7. Hartoma, T. R. Acta physiol. scand. 1977, 100, 1. 8. Bertrand, G. C. r. Acad. Sci. 1920,171, 176. 9. Mawson, C. A., Fischer, M. I. Can. J. med. Sci. 1952, 30, 336. 10. Eliasson, R., Lindholmer, C. Andrologie, 1971, 3, 146. 11. Wallace, A. M., Grant, J. K. Biochem. Soc. Trans. 1975, 3, 540. 12. Landesman, R., Coutinho, E. M., Saxena, B. B. Fertil. Steril. 1976, 27, 13.
1062. C. 855.
Beling,
will not detect significantly increased amounts of in plasma until 9-10 days after the midcycle L.H. peak, and thus presumably not until implantation has already happened. The finding of Landesman et al. of H.C.G. in plasma as early as 5 days after a predicted ovulation seems to be uncertain, due to the unknown temporal relation between sampling and ovulation and subsequent menstruation. The late luteal phase peaking of L.H. cannot be ruled out in a H.C.G. radioreceptor assay. Landesman et al. do not give any reference values for their H.c.G. radioimmunoassay, and in no instance was the rise in plasma-H.c.G. more than threefold. In our single positive H.c.G. sample, recorded in a woman who was monitored by measurements done three times weekly, we found a 10-fold rise from the basal values of the assay used. Furthermore Groom has reportedI4 measurable amounts of the p-subunit of H.C.G. in 11% of random home-collected bloodsamples. Thus a small rise in H.c.G., measured with a specific radioimmunoassay for the 3-subunit in a single sample obtained during a luteal phase, is not a sure sign of conception. More careful monitoring of larger series of l.u.D. users must be done before we can decide if the I.V.D. is abortifacient. The frequency of "early abortions" should also be studied in cycles of H.C.G.
H.c.G.
unprotected women. Steroid Research Laboratory, Department of Medical Chemistry,
Department of Physiology, University of Oulu,
en
of
University of Helsinki, SF-00170 Helsinki 17, Finland
C. G. NILSSON P. LÄHTEENMÄKI
FLOPPY-INFANT SYNDROME: IS OXAZEPAM THE ANSWER?
SIR,-Dr Gillberg (July 30, p. 244) has suggested that oxazepam in pre-eclampsia might be safer for the newborn infant than is diazepam. Oxazepam has been used in this way at Redhill General Hospital since March, and so far all infants have been born in good condition. A double-blind trial with diazepam did not seem justified, since diazepam has affected our babies in the past and similar findings have been recorded by others. 1-5 one of the metabolites of diazepam. Because it short half-life6-8 and no known biologically active metabolites, it might be expected to be the safer drug. We have investigated the value of oxazepam in pre-eclampsia by clinical findings and measurement of plasma and urine drug concentrations. Small divided doses of 30-45 mg daily were prescribed without any adverse effects on the babies. Subsequently 75 mg daily has been used successfully in six pregnancies. Maternal and cord blood samples were taken and the Apgar scores were recorded. In the infants urinary excretions of free and conjugated oxazepam were measured within the first 24 h and the plasma concentrations of oxazepam were determined at 24 and 48 h. Oxazepam crossed the placenta and at the time of delivery concentrations were usually higher in cord blood than maternal blood. No case of "floppy infant" syndrome has been encountered in thirty pregnancies managed in this way. Oxazepam is of limited use in pre-eclampsia because no parenteral formulation is available. However, patients tolerate the drug well and are not unduly drowsy. Urinary oestrogen con-
Oxazepam is
has
a
14. Groom, G. V. J. Reprod. Fertil. 1977, 51, 273. 1. Shannon, R. W., Fraser, G. P., Aitken, R. G., Harper, J. R. Br. J. clin. Pract. 1972, 26, 271. 2. Scher, J., Hailey, D. M., Beard, R. W. J. Obstet. Gynœc. Br. Commonw.
1972, 79, 635. Kanto, J., Errkola, R. Ann. Chir. Gynœc. fenn. 1974, 63, 489. Cree, J. E., Meyer, J., Hailey, D. M. Br. med. J. 1973, iv, 251. Gamble, J. A. S., Moore, J., Lamki, H., Howard, P. J. Br. J. Obstet. Gynœc. 1977, 84, 588. 6. Vessman, J., Alexanderson, B., Sjöqvist, F., Strindberg, B., Sundwall, A. in The Benzodiazepines (edited by S. Garattini, E. Mussini, and L. O. Randall); p. 165. New York, 1973. 7. Wretlind, M., Pilbrant, A., Sundwall, A., Vessman, J. Acta pharmac. toxi3. 4. 5.
G., Cederquist, L. L., Fuchs, F. Am. J. Obstet. Gynec. 1976, 125,
col., 1977, 40, suppl. 1, p. 28. 8.
Alvan, G., Siwers, B., Vessman, J. ibid. p. 40.