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28 Berry CM, Thompson JD, Hatcher R. The radio receptor assay for hCG in ectopic pregnancy. Obstet Gynecol 1979;54:43-6. 29 Schwartz RO, De Pietro DL. Beta-hCG as a diagnostic aid for suspected ectopic pregnancy. Obstet Gynecol 1980;56:197-9. 30 Phipps JJ, Naftalin NJ. Ectopic pregnancy diagnosed by measurement of hCG but not laparotomy. Lancet 1986;i:552. 31 Pittaway DE, Reish RL, Wentz AD. Doubling times of hCG increase in early viable pregnancies. AmJ Obstet Gynecol 1985;152:299-303. 32 Kadar N, De Vore G, Romero R. Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy. Obstet Gynecol 1981;58:156-61. 33 Stenman UH, Alfthan H, Myllyness L, Seppala M. Ultrarapid and sensitive time resolved fluoroimmunometric assay for hCG. Lancet 1983;ii:647-9. 34 Milwidsky A, Segar S, Menasbe M, Adori A, Palti A. Corpus luteum in ectopic pregnancy. Ints7 Fertil 1984;29:244-7. 35 Radwanska E, Frankenberg J, Allen El. Plasma progesterone levels in normal and abnormal early human pregnancy. Fertil Steril 1978;30:398-402. 36 Mathews CP, Goulson PB, Wild RA. Serum progesterone levels as an aid to the diagnosis of ectopic pregnancy. Obstet Gynecol 1986;68:390-4. 37 Romero R, Copel NA, Kadar N, Jeauty P, Decherney A, Hobbins JC. Value of culdocentesis in the diagnosis of ectopic pregnancy. Obstet Gynecol 1985;65:519-22. 38 Weckstein LN, Boucher AR, Tucker H, Gibson D, Rettenmaier MA. Accurate diagnosis of early ectopic pregnancy. Obstet Gynecol 1985;65:393-7. 39 Reece EA, Petrie RH, Sirmans MF, Finster M, Todd WD. Combined intrauterine and extrauterine gestations: review. Am 7 Obstet Gynecol 1983;146:323-30. 40 Spirt BA, O'Hara KR, Gordon L. Pseudo-gestational sac in ectopic pregnancy: sonographic and pathologic correlation. 7ournal of Clinical Ultrasound 1981;9:338-43. 41 Robinson HP, de Crespigny LC. Ectopic pregnancy. Clin Obstet Gynecol 1983;1O:407-12. 42 Webster HD Jr, Barclay DL, Fischer CK. Ectopic pregnancy: a seventeen year review. AmJ7 Obstet Gynecol 1965;92:23-34. 43 Mahony BS, Filly RA, Nyberg DA, Callen PW. Sonographic evaluation of ectopic pregnancy. J Ultrasound Med 1985;4:221-9. 44 Gleicher N, Giglia RV, Deppe G, Elrad H, Friberg J. Direct diagnosis of unruptured ectopic pregnancy by real-time ultrasonography. Obstet Gynecol 1983;61:425-8. 45 Kim DS, Chung SR, Park MI, Yim YP. Comparative review of diagnostic accuracy in tubal pregnancy: a 14 year survey of 1040 cases. Obstet Gynecol 1987;70:547-54. 46 Gonzalez FA, Waxman M. Ectopic pregnancy. Diagnostic Gynecology and Obstetrics 1981;3:101-9. Genes on the X and Y chromosomes controlling sex Genetic sex is a matter of quantity The way in which differentiated tissues arise from pluripotent cells in the embryo remains mysterious. Gene regulation is the key, of course, and much is being learnt about, for example, the control of transcription by DNA binding proteins.' The sex difference is an example of differentiation that might be expected to yield answers if only because many species, including man, have heteromorphic sex chromosomes that segregate to offspring in a predictable fashion. But the segregation is not quite predictable: in our own species there are exceptions to the X-Y sex determining system, and these interesting exceptions are now providing answers to questions about the initiation of mammalian sex differentiation. To understand the importance of these findings we must go back to the late 1950s, when it was confirmed that males had a 46, XY and females a 46, XX karyotype. In both mouse and man XO was found to be female and XXY to be male, indicating the dominant role of the Y chromosome in the differentiation of the testis.23 This was a surprise to some because in Drosophila melanogaster and some other invertebrates sex was known to be determined by the ratio of X chromosomes to autosomes-thus XOs were male and XXYs female.4 Study of correlations between karyotypes and phenotypes in chromosomal variants of Klinefelter's and Turner's syndromes soon showed that the testis determining factors, as they were called, were located in the short arm of the Y chromosome5; those without this segment in at least some cells were invariably female. Somatic cell mosaics with XX/XXY and XO/XY sex chromosome complements and XX/XY chimaeras were sometimes intersexes, with both testes and ovaries showing varying degrees of dysgenesis. The most extreme examples of sex reversal were males with Klinefelter's syndrome and an apparently XX female karyotype6 and females with gonadal dysgenesis and an apparently XY male karyotype.7 The "XX males" and "XY females" were predicted to have gained or lost the testis determining segment as a result of accidental recombination between the differential segments ofthe X and Y chromosomes during male meiosis.8 The first clue in favour of such abnormal X-Y interchange was the observation that several XX males had lost the father's Xg blood group allele in the process.8 Later it was shown that one X chromosome was a little longer than the other9 and that the tip of the short arm of the Y could sometimes be seen at the end of one of the X chromosomes.'0 Conclusive proof came from DNA probing, which showed that many XX males not only had specific sequences from the short arm of the Y" in BMJ VOLUME 297 10 SEPTEMBER 1988 the distal end of the short arm of the X'2 but also had lost X sequences.'3 Conversely, a smaller proportion of XY females could be shown to have lost short arm sequences of the Y chromosome. 14 It became clear that XX males and XY females held the key to sex differentiation. The goal was to clone the gene for testis determination from the DNA of XX males with X-Y interchange. It is now almost certain that this goal has been achieved. Page et al reported last December the details of a likely candidate for the testis determining gene.'5 This was cloned from an XX male and was found to be missing from a female who had a reciprocal translocation between the short arm of the Y chromosome and chromosome 22 that was associated with the loss of a tiny segment (160 kilobases) of the short arm of the Y chromosome. The gene codes for a protein that contains a series of zinc fingers, a motif characteristic of proteins that bind DNA, which are thought to participate in regulating transcription. Its action on the pathway to differentiation of the testis is unknown, but it might well be the primary sex determining signal. A key observation in the important paper by Page et al is that in addition to the Y linked gene there is apparently a copy of the testis determining gene carried by the short arm of the X chromosome. This copy is distinguishable by restriction mapping and is located more proximally, where it might be expected to be subject to X inactivation. Given that the X homologue codes for the same protein as the Y homologue, female somatic cells (whether XX, XO, or XXX, and so on) have only one active copy of the gene compared with male cells (whether XY, XXY, XXXY, or XYY), which have at least two. XX males usually have two doses because the Y homologue is transferred to part of the X chromosome that escapes inactivation. The implication of these findings is that our species now falls into line with other species, including Drosophila melanogaster, in which the primary sex determining system depends on active gene dosage. In fact all mammalian species tested are consistent with the dosage system, and even in birds (which have nothing comparable with X inactivation) it seems likely that the ZZ male has a double dose of the testis determining gene compared with the ZW female. It follows that the description testis determining gene is misleading as the same gene leads to ovarian differentiation if present in a single dose. As suggested by German, it would be better to refer to the X and Y homologues as gonad differentiating genes and the loci as GDX and GDY, respectively.'6 Several groups of patients remain in whom unusual gonadal 635 differentiation requires a more complex explanation. Failure of testis differentiation in XY females may result not only from deletion of the GDY locus because of X-Y interchange. Deletion of the GDX locus would have the same effect and may even be responsible for familial cases inherited in an X linked recessive manner, provided that XX carriers of GDX deletions were fertile. Alternatively, other gene mutations affecting later stages in the pathway to testis differentiation may be involved. The defect in XX true hermaphroditism and in XX males without the GDY locus is even more intriguing. XX true hermaphrodites have both ovarian and testicular tissue (usually ovotestes) associated with ambiguity of the external and internal genitalia.' The phenotype is identical to spontaneous human XX/XY chimaeras and to artificial XX/XY aggregation chimaeras in mice, but neither the GDY locus nor any other Y specific sequence can be detected.'" Similarly, in XX males without the GDY locus other Y specific sequences are almost invariably absent. These patients are phenotypically rather different from X-Y interchange males-principally because they often have hypospadias-and they probably belong to the same range of abnormal gonadal differentiation as XX hermaphrodites. It might be that in both these XX cases the dosage of gonad differentiating factors is disturbed by an inversion or other mutation on the short arm of one X chromosome such that one GDX locus escapes from X inactivation. Random X inactivation of the two X chromosomes will then lead to somatic cell mosaicism for cells with two active doses of GDX and cells with only one active dose. This is identical to XX/XY chimaerism, in which some cells are testis determining and others are ovary determining. Again familial cases with siblings affected either by XX true herniaphroditism or XX Klinefelter's syndrome (or both)'7 may all be explained by the X chromosome with the activated GDX locus sometimes being transmitted as an X linked dominant trait (with variable penetrance) by unaffected fertile XX mothers or XY fathers. The techniques of molecular genetics are powerful, and we may confidently expect tests of these hypotheses in experimental animals. For example, the sex reversal of female embryos by adding additional copies of the GDX gene during early development would provide confirmation. But the important message at the moment is that a DNA binding protein will probably shortly be characterised whose primary function is to determine quantitatively the direction a group of cells will take along the pathway to tissue differentiation. M A FERGUSON-SMITH Professor of Pathology, University of Cambridge, Cambridge CB2 IQP 1 Evans RM, Hollenberg SM. Zinc fingers: gilt by association. Cell 1988;52: 1-3. 2 Welshons WJ, Russell LB. The Y chromosome as the bearer of male determining factors in the mouse. Proc Natl Acad Sci U,SA 1959;45:560-6. 3 Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex determining mechanism. Nature 1959;183:302-3. 4 Baker BS, Belote JM. Sex determination and dosage compensation in Drosophila melanogaster. Ann Rev Genet 1983;17:345-93. 5 Jacobs PA, Ross A. Structural abnormalities of the Y chromosome in man. Nature 1966;210:352-4. 6 de la Chapelle A, Hortling H, Niemi M, Wennstrom J. XX sex chromosomes in a human male: first case. Acta Med Scand [Suppl] 1964;412:25-38. 7 Ferguson-Smith MA. Karyotype-phenotype correlations in gonadal dysgenesis and their bearing on the pathogenesis of malformations. J Med Genet 1965;2:93-156. 8 Ferguson-Smith MA. X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter's syndrome. Lancet 1966;ii:475-6. 9 Madan K. Chromosome measurements on an XXp+ male. Hum Genet 1976;32:141-2. 10 Magenis RE, Webb MJ, McKean RS, et al. Translocation (X; Y) (p22.23:pl 1.2) in XX males: etiology of male phenotype. Hum Genet 1982;62:271-6. 11 Guellaen G, Casanova M, Bishop C, Geldwerth D, Andre E, Fellous M, Weissenbach J. Human XX males with Y single-copy DNA fragments. Nature 1984;307:172-3. 12 Magenis RE, Casanova M, Fellous M, Olson S, Sheehy R. Further cytologic evidence for Xp-Yp translocation in XX males using in situ hybridisation with Y-derived probe. Hum Genet 1987;75:228-33. 13 Petit C, de la Chapelle A, Levilliers J, Castillo S, Noel B, Weissenbach J. An abnormal terminal X-Y interchange accounts for most but not all cases of human XX maleness. Cell 1987;49:595602. 14 Disteche CM, Casanova M, Saal H, et al. Small deletions of the short arm of the Y chromosome in 46XY females. Proc Natl Acad Sci USA 1986;83:7841-4. 15 Page DC, Mosher R, Simpson EM, et al. The sex determining region of the human Y chromosome encodes a finger protein. Cell 1987;51: 1091-104. 16 German J. Gonadal dimorphism explained as a dosage effect of a locus on the sex chromosomes, the gonad-differentiation locus (GDL). AmJ3 Hum Genet 1988;42:414-21. 17 Skordis NA, Stetka DG, MacGillivray MH, Greenfield SP. Familial 46, XX males coexisting with familial 46, XX true hermaphrodites in same pedigree. J7 Pediatr 1987;110:244-8. Sickness absence: the doctor's role Mostly concerned with serious illness Sickness absence, or more accurately absence from work attributed to incapacity, is expensive for the country and for employers. Its cost must be measured not only in social security payments but also in the loss of productivity and the inefficiencies of employing extra staff or organising overtime to cover for missing staff. Government statistics do not record sickness absence as such, but in the United Kingdom before 1983 some 375 million days of sickness and invalidity benefit were paid annually because of certified incapacity for work.' This figure includes payments to the unemployed sick who would not necessarily be in work if they were fit and excludes married women who opt out of the state insurance scheme, special occupational groups such as non-industrial civil servants, and absences lasting less than four days (which did not qualify for benefit). More recent data also exclude payments under the statutory sick pay scheme and are therefore less relevant. The epidemiology of sickness absence is complicated by the variety of indices used to measure it. Two important features do, however, emerge clearly. Firstly, the demographic pattern of short term absences differs from that of longer absences. As might be expected, long term absence tends to 636 be a problem of older employees; short absences occur more often in the young, especially in women.2 Thus any analysis should examine not only the total time lost from work but also the numbers and lengths of spells which make up the total. Secondly, ill health is only one of many factors that determine whether an employee takes sick leave. Other influences include working conditions, the size and structure of the employing organisation, the arrangements for sick pay, and personal characteristics such as age, sex, personality, and family responsibilities.3 There are appreciable regional differences in the rates of sickness absence, with the highest frequencies in the north and west. This variation is apparent even within geographically homogeneous industries such as the Post Office3 and may result from cultural differences as well as from differences in morbidity. One implication of these observations is that the control of short term sickness is primarily a problem for the manager. Employees who go off sick do not divide neatly into the genuinely ill who are deserving of sympathy and the malingerers who can be uncovered by careful medical examination. When patients suffer from chronic disorders such as asthma or colitis they may be expected to need more BMJ VOLUME 297 10 SEPTEMBER 1988