CHROMOSOMES AFTER ORAL CONTRACEPTIVES

830

fully observed patient with unusual manifestations not only adds to the sum of clinical knowledge but, also, may open whole new areas for exploration. The dramatic amelioration of diabetic retinopathy in a patient who has had postpartum pituitary necrosis is a case in point; a routine description of the successful removal of a parathyroid adenoma is not, regardless of the pleasure derived by the raconteur. Perhaps, more importantly, it is anecdotal evidence rather than the anecdote that is, and should be, suspect in the minds of investigators. The crying baby with wet diapers whose tears are banished by a rattle is not necessarily suffering from H

rnttle deficiency Section of Endocrinology and Metabolism, Department of Medicine, Presbyterian-St. Luke’s Hospital, 1753 West Congress Parkway, THEODORE Chicago 60612.

B. SCHWARTZ.

CHROMOSOMES AFTER ORAL CONTRACEPTIVES SIR,-Chromosome anomalies were found in 10-38% (mean 22%) of 8 unselected series1 of spontaneous abortions; by selection incidences as low as 2% or as high as 64% have been found.2 Chromosome abnormalities were found in 6 of 8 abortuses collected from women who became pregnant after taking an oral contraceptive (see accompanying table). During the same period, 4 similar specimens failed to grow in culture. The contraceptive histories of patients 1, 2, 3, 5, and 6 were similar: all had been on oral contraceptives for 11-30 mpnths and had stopped for 2-4 months. Patient 4 had a history of menstrual irregularity and was on sequential medication for only 3 months to adjust her cycle. She became pregnant about 3 months after discontinuing medication. The specimen from patient 7 was a 4-month foetus and there were strong indications that the pregnancy had been interrupted artificially. The woman who aborted specimen 8 had not discontinued medication. She had been on combined oestrogen/progestogen therapy for about 12 months, and had then changed to sequential therapy because of side-effects. This change represented a substantial reduction in the amount of progestogen ingested. She became pregnant when she had been on sequential medication for 4 or 5 months. A therapeutic abortion was performed because she had a 8-year-old child with epidermolysis bullosa. In the abortus from patient 3 a single cell with 138 chromo1.

D. H. Am. J. Obstet. Gynec. 1967, 97, 283. Kerr, M. Rashad, M. N. ibid. 1966, 94, 322. Clendenin, T. M., Bernirschke, K. Lab. Invest. 1963, 12, 1281. Hall, B. Kallén, B. Lancet, 1964, i, 110. Boue, J. G., Boue, A. C.r. Lebd. Séanc. Acad. Sci, Paris, 1966, 263, 2054. Inhorn, S. L., Therman, E. Patau, K. Am. J. clin. Path. 1964, 42, 528. Schlegel, R. J., Neu, R. L., Leao, J. C., Farias, E., Aspillaga, M. J., Gardner, L. J., Cytogenetics, 1966, 5, 430. Waxman, S. H., Arakaki, D. T., Smith, J. B. Pediatrics, Springfield, 1967, 39, 425. 2. Thiede, H. A., Salm, S. B. Am. J. Obstet. Gynec. 1966, 94, 589. Jacobson, C. B., Barter, R. H. ibid. 1967, 97, 666. Szulman, A. E., New Engl. J. Med. 1965, 272, 811. Wingate, M. B. J. Obstet. Gynœc. Br. Commonw. 1966, 73, 296.

Carr,

CHROMOSOME ANOMALIES IN ABORTUSES FROM

*

No cell

was

adequate

for

8

somes was found which proved to be a balanced hexaploid with XXXXYY sex-chromosome complex. Such a cell could have arisen in culture from a 69, XXY, triploid line but hardly from a purely diploid abortus. This specimen is therefore regarded

diploid/hexaploid or, more probably, a diploid/triploid mosaic, since all cells in culture, whole-mounts of amnion, and

as a

sections of chorion were chromatin-negative-this is common in XXY triploids, whereas one would expect3 XXXXYY hexaploid cells to be chromatin-positive. No triploid or hexaploid cells were seen in cells cultured from specimens from patients 5 and 7. Only 2 types of anomaly were found—triploidy and X-monosomy. 4 out of the 8 abortuses were triploid or diploid/triploid mosaics. In the 8 unselected series1 there were 23 triploid (or diploid/triploid mosaics) among 521 abortuses which were cultured successfully. Though the present series is small, there is a striking increase in triploidy, which is highly significant statistically, particularly since the abortion of patient 8 was probably induced. Hormonal imbalance must be considered as a cause for this seeming increase in the incidence of triploidy. The apparent absence in man of a surge of gonadotrophin excretion after cessation of cestrogen-progestogen medication4 may be due to lack of a sufficiently sensitive technique. There is a suspicion that chorionic gonadotrophin may induce chromosome anomalies when injected into rabbits.5 Triploidy most likely arises from disordered behaviour of the second polar body or the entrance of 2 sperms into one ovum. In the baboon, gonadotrophin injections cause changes in the zona pelluèida.6 This could conceivably interfere with the mechanism which normally prevents the entrance of a second sperm at the time of fertilisation. Variations in oestrogen and progesterone levels affect tubal transport of the ovum.’ A temporary hormonal imbalance could conceivably delay ovum transport and lead to delayed fertilisation. This has been shown to predispose to triploidy.58 There is no evidence of an increase in congenital anomalies or multiple births in pregnancies which result after discontinuing oral contraceptives.49 No triploid conceptus is known to have gone beyond 32 weeks’ gestation,10 though 5 diploid/triploid mosaics are known to have survived birth." It is reassuring that trisomy, which is the only common type of chromosome defect at birth, was not found in this small series of abortuses. This is particularly significant, since trisomic specimens of all types equal the combined incidence of triploid and XO abortuses. Only about 1 in 40 XO conceptuses 3. 4. 5. 6. 7. 8. 9. 10. 11.

Harnden, D. G. Lancet, 1961, ii, 488. Garcia, C.-R. Am. J. med. Sci. 1967, 253, 718. Shaver, E. L., Carr, D. H. J. Reprod. Fert. (in the press). Katzberg, A. A., Hendrickx, A. G. Science, N.Y. 1966, 151, 1225. Blandau, R. J. Comparative Aspects of Reproductive Failure; p. 194. New York, 1967. Austin, C. R. Nature, Lond. 1967, 213, 1018. Rice-Wray, E. Res. Steroids, 1966, 2, 525. Edwards, J. H., Yuncken, C., Rushton, D. I., Richards, S., Mittwoch, M. Cytogenetics, 1967, 6, 81. Book, J. A., Santesson, B. Lancet, 1960, i, 858. Ferrier, P., Ferrier, S., Stalder, G., Bühler, E., Bamatter, F., Klein, D. ibid. 1964, i, 80. Ellis, J. R., Marshall, R., Normand, I. C. S., Penrose, L. S. Nature, Lond. 1963, 198, 411. Johnston, A. W., Penrose, L. S. J. Med. Genet. 1966, 3, 77. Schmid, W., Vischer, D. Cytogenetics, 1967, 6, 145.

PATIENTS WHO HAD BEEN TAKING ORAL CONTRACEPTIVES

karyotyping. c=combined. s=sequential. L.M.P.=date

of start of last menstrual

period.

831 come to term as

female infants with Turner’s

remainder being aborted spontaneously. This study was supported by the Medical

syndrome, the

Research Council of

ranncin-

Department of Anatomy, McMaster University,

Hamilton, Ontario, Canada.

DAVID H. CARR.

REPRODUCTION AND MEIOSIS IN XYY SIR,- The XYY sex-chromosome constitution is of unusual interest, because it seems to predispose to aggressive behaviour, mental subnormality, and tall stature.l Although XYY males have been reportedno data have been presented to our knowledge on the transmission of the extra Y chromosome to their offspring or on the behaviour of their chromosomes in meiosis. We here present findings on both. We studied the 7 children of an XYY man: 6 sons and 1 daughter. The 6 sons all had normal XY sex-chromosome complements, and the daughter had a normal XX constitution. The index case in the family was the daughter’s only child. This boy, who seems chromosomally normal, has mental

retardation, multiple anomalies, and tyrosinuria due to a newly delineated inborn error, tyrosine-transaminase deficiency.a The finding of XYY sex-chromosome constitution in his grandfather, whose leucocyte cultures do not show mosaicism, was therefore entirely unexpected. The fact that all 6 sons of the XYY man were XY is notable. Four classes of gametes are possible if secondary nondisj unction occurs in the first meiotic division in such males: X, YY, XY, and Y. Union of these gametes with X-bearing ova would produce XX, XYY, XXY, and XY zygotes. Thus, female offspring might all be expected to be normal, whereas 2 of the 3 types of males might be expected to be chromosomally abnormal. Neither XXY nor XYY was observed in the 6 sons, suggesting that selection may occur toward euploidy at either meiotic, gametic, and/or zygotic levels. Meiotic studies were refused by this man, but were subsequently carried out on another XYY male with no known offspring. Two leucocyte cultures and a testicular fibroblast culture showed XYY sex-chromosome constitution with no suggestion of mosaicism. A testicular biopsy-specimen was processed for meiotic studies by a modification of the technique described by Evans et al.4 Spermatogonial metaphases were scarce, but all twenty-two examined seemed to have only one Y chromosome. Seventeen of the twenty-two contained 46 chromosomes; eleven of these were karyotyped and showed a normal XY pattern. Of the non-modal cells, four had 45 chromosomes, which upon karyotyping showed scattered losses, and one had 47 chromosomes but contained only a single Y chromosome. Diakinesis and first-meiotic-metaphase figures were plentiful. Of a hundred and fifty-five cells examined none was clearly found to contain two Y chromosomes. Representative cells shown in the accompanying figure demonstrate several typical configurations of the XY bivalent and the X and Y univalents. Although some of these were initially felt to contain two Y chromosomes, comparison with meiotic figures of four chromosomally normal men showed no discernible differences in the various configurations of the sex chromosomes or in the relative frequencies of each type of configuration. Karyotypes of secondary spermatocytes were difficult to interpret, but thirty-four of thirty-nine figures examined contained 23 chromosomes; the other five contained 24-karyotypes of these did not show conclusive evidence as to the presence or absence of two Y chromosomes. 1.

Jacobs, P. A., Brunton, M., Melville, M. M., Brittain, R. P. Nature, Lond. 1965, 208, 1351. 2. Hauschka, T. S., Hasson, J. E., Goldstein, M. N., Koept, G. F., Sandberg, A. Am. J. hum. Genet. 1962, 14, 22. Tzoneva-Maneva, M. T., Bosajieva, E., Petrov, B. Lancet, 1966, i, 1000. 3. Campbell, R. A., Buist, N. R. M., Jacinto, E. Y., Koler, R. D., Hecht, F., Jones, R. T., Society for Pediatric Research (abstract). Atlantic 4.

City, 1967. Evans, E. P., Breckon, G., Ford, C. E. Cytogenetics, 1964. 3,

289.

Meiotic preparations from

an

XYY male.

Representative diplotene-diakinesis figures showing: (A) XY bivalent with commonly observed J-shaped configuration of the Y chromosome; (B) XY bivalent with folding of the Y chromosome as in (A), but giving the appearance of two separate parallel strands; (C) X and Y univalents separated; (D) examples of X and Y chromofrom other cells. All these configurations from normal XY males. somes

were

also observed in meiotic

preparations

These findings, although preliminary, suggest that selection toward chromosomally normal spermatocytes occurs before meiosis in XYY males. The mechanism responsible for this selection is unknown, but may be related to a similar one known to occur normally in the male creeping vole (Microtus oregoni), in which the somatic cells have an XY sex-chromosome constitution and the germ cells a YO constitution.5 This study was supported in part by grants HD 01343 and CA 07941, and from the Children’s Bureau. Department of Pediatrics, University of Oregon Medical School, Portland, Oregon 97201, and Fairview Hospital and Training Center, Salem, Oregon. Metabolic Division, Children’s Hospital of Los Angeles and Department of Pediatrics, University of Southern California, Los Angeles, California 90027. Department of Pediatrics (Crippled Children’s Division) and Division of Experimental Medicine, University of Oregon Medical School, Portland, Oregon 97201.

U.S. Public Health Service genetics programme grants

HAVELOCK THOMPSON.

JOHN

MELNYK.

FREDERICK HECHT.

TRISOMY 21 OR 22 IN DOWN’S SYNDROME? SIR,-The letter of Dr. Back and his colleagues 6 prompts us to report here a possible method of identifying the G-group chromosome involved in Down’s syndrome. We are specially interested’in the possibility of classifying the meiotic chromosomes in man in the same sequence as the standardised Denver karyotype pattern for mitotic 5. 6.

Ohno, S., Jainchill, J., Stenius, C. ibid. 1963, 2, 232. Back, F., Dormer, P., Baumann, P., Olbrich, E. Lancet, 1967, i, 1228.