1085 The influence of

photoirradiation

in vivo

is unmechanism to physical and chemical carcinogens in vitro and in vivo14 15 and the role played by this process in the hereditary dynamics of the cell demand that this subject be investigated more care-

known, but the proven sensitivity of the

on s.c.E.

S.c.E.

fully. Section of Genetics, Service of Pathology. Service of Neonatology, Department of Pediatrics,

V. J. GOYANES-VILLAESCUSA M. UGARTE

Juan Canalejo Hospital, La Coruńa, Spain

A. VAZQUEZ

PROGESTAGENS, BLOOD-CLOTTING, AND BLOOD-PRESSURE

SIR,—Dr Meade and his colleagues (Nov. 5, p. 948) believe that their

seem to

the effects of progestagens in blood-clotting tests contrast with ours. They cite one of our prospective studies which showed that the acceleration of clotting during conventional combined oestrogen/progestagen oral contraception rapidly disappeared when progestagen-only contraception was substituted. Our findings were confirmed in two

findings

on

separate studies1-3 of different progestagens. Meade et al., by contrast, did random clotting studies on a small group of women, taking a variety of combined oral-contraceptive preparations, who had presented for entry into a cardiovascular study. They contend that women on 50 µg oestrogen formulations which contained 3-4 mg of norethisterone had more striking changes than did women taking preparations with 1 mg, and concluded that their results contrasted with ours. The comparison is invalid: their results are not relevant to our studies of the progestagens norethisterone and chlormadinone acetate, where no concomitant oestrogen was administered. Furthermore we are not aware of any available preparations containing 3-4 mg norethisterone; norethisterone acetate has different biological properties. Evidence is accumulating to indicate that it is principally the a:strogenic and not the progestagenic component of combined oral-contraceptive preparations which causes the acceleration of blood-clotting. While the paper of Meade et al. lends support to the effect of oestrogens, it is important to avoid confusion about the role of progestagens. Hæmatology Department, Withington Hospital,

L. POLLER J. M. THOMSON

Manchester M20 8LR

SIR,—The report on coagulation and fibrinolytic systems, plasma lipids, and blood-pressure of women taking various oral contraceptives by Dr Meade and his colleagues contains so few data on such a number of products that not one of the many comparisons attempted between different pills yielded a statistically significant difference, except for factor vn. Howwith the statistical deficiencies of at a time when the most widely in prescribed contraceptive pills the U.K. are those containing norgestrel with 30 µg ethinyloestradiol, that the paper contains two serious errors and makes no reference to other published work to put into perspective the significance or otherwise of these conclusions; the first error concerns the hypothesis which Meade et al. advance that progestagen, norgestrel, carries predisposition to cause hypertension, and the second is that it has metabolic products with oestrogenic activity. Meade et al., on the basis of apparently single blood-pressure observations in 15 women (the number of observations is equal to the number of women) and without any pretreatment readings, conclude that 30 µg oestrogen preparations "may have a blood-pressure-raising effect attributable to the particular progestagen, d-norgestrel, used". Their data are too flimsy ever,

our

main

the paper. We

concern are

is

not

disturbed,

13 Wolff, S., Rodin, B., Cleaver, J. E.Nature, 1977, 265, 347. 14. Stetka, D. G., Wolff, S.Mutation.Res. 1976, 41, 333. 15 Allen, J. W., Latt, S. A. Chromosoma, 1976, 58, 325. 1. Poller, L , Thomson, J. M., Thomas, P. W. Br. med. J. 1972, iv, 391. 2 Poller, L., Thomson, J. M., Tabiowo, A., Priest, C. M. ibid. 1969,i, 554. 3. Poller, L , Thomson, J. M., Thomas, P. W. ibid. 1971, iv, 648.

to

support this conclusion, and other clinical evidence in much

larger studies indicates that their statement is untrue. Thus, for instance, Bergstein included in his clinical trial of 150 ug levonorgestrel (D-norgestrel) plus 30 ug ethinyloestradiol 30 women who had exhibited hypertension while receiving combined pills containing 50 µg oestrogen. In 24 of these 30 women, the blood-pressure fell to not more than 120/80 mm Hg after the change of pill.’ In a U.K. trial of D,L-norgestrel 500 µg plus ethinyloestradiol 30 ug, detailed analysis of blood-pressure in terms of increments and decrements of 10 mm Hg showed no significant difference in 623 women studied for an average of more than eight cycles.2 In another study in the U.S.A., with a formulation containing 300 µg D,L-norgestrel and 30 µg ethinyloestradiol, paired t-tests showed highly significant falls in both systolic (P=0.003) and diastolic (P=0.011) pressures in 638 women after one year.3 The fall in systolic blood-pressure was still significant after two years, and even after three years both the mean systolic and mean diastolic pressure were lower than the pre-treatment means in the 136 women who completed 3 years, as the following results demonstrate. Blood-pressures, given as the mean and S.D. of 3-monthly readings for each patient (in mm Hg) were, for the duration shown: Bloodpressure

Pretreatment

(638)

Systolic

112.8

+11.2

+_10.1

+_10.7

End

Diastolic

End year 2

End year 3

(638)

(288)

(136)

111.6

111.8

112.3 +11-2

year 1

70.5

69.7

69.5

69.2

+7.5

+7.3

±7.4

+7-9

Of the drop-outs, only 4 were withdrawn because of a raised blood-pressure. Norgestrel-containing pills may occasionally be associated with raised blood-pressure, but the above data do not indicate that there is in general a blood-pressure-raising effect.

is alleged by Meade et al. to be partly metabooestrogen. Fotherby et al. reported that 0.2% of an administered dose of D,L-norgestrel appeared in the urine as 18-homo-ethinyloestradiol.4 They considered that, since 18-homo-ethinyloestradiol was a very weak oestrogen it would not be expected to exert any significant oestrogenic effect when produced as a metabolite in the amount that they had estimated. This accords with biological tests, since in no biological system that is universally acknowledged to test cestrogenicity has norgestrel been found to have any oestrogenic activity. Later, Sisenwine et al. found that 18-homo-ethinyloestradiol was at least partially produced in vitro when acidic or mildly alkaline conditions existed during extraction of the urine for analytical purposes.5 By devising a method whereby production of this oestrogenic substance as an artefact was prevented, they showed that the amount of 18-homo-ethinyloestradiol and of its 16&bgr;-hydroxy derivative occurring as true metabolites in the urine was not 02%, but less than 001% of the dose ofD,L-

Norgestrel

lised

to

norgestrel.6 Sisenwine

et

al. have since shown that the conversion of

norgestrel to oestrogenic metabolites shows strong stereospecificity, possibly being confined entirely to the inactive isomer, which was never present in ’Microgynon 30’, ’Ovranette’ or ’Ovran 30’, and has now been eliminated from ’Eugynon 30’.7 As for the suggestion that norgestrel may be many times more potent in its action of the hypothalamo-pituitary-ovarian axis than is norethisterone, Edgren has shown (by the inhibition of compensatory ovarian hypertrophy in hemicastrated rats) that norgestrel has only 63% of the pituitary-inhibitory potency of norethisterone.8 1. Bergstein, N. A. M. Clin. Ther. 1977, 1, 26. 2. Bye, P. G. T., Elstein, M. Br. med. J. 1973, i, 389. 3. Korba, V. Personal communication. 4. Fotherby, K., and others J. Endocr. 1972, 52, 1. 5. Sisenwine, S. F., and others Acta endocr. 1973, 73, 91. 7. Sisenwine, S. F., and others Drug Metab. Dapos. 1975, 3, 180. 8. Edgren, R. A. in The Chemical Control of Fertility (edited by D. Lednicer); p. 23. New York, 1969.

1086 The above evidence shows that, in their allegations about the pharmacological properties of norgestrel and about the predisposition of low-oestrogen pills and of norgestrel-containing pills to cause hypertension, Meade et al. are in all respects wrong. Our data strongly suggest that the low-oestrogen norgestrelcontaining pills are less likely to cause hypertension than their

greater than with oral contraceptives containing progestagens other than norgestrel. Research Laboratories, Department of Obstretics and Gynæcology, University College Hospital Medical School,

London WC1E 6HX

G. I. M. SWYER

predecessors. P. G. T. BYE R. A. WISEMAN

Schering Chemicals Limited, Burgess Hill, Sussex RH15 9NE Wyeth Laboratories, John Wyeth & Brother Ltd, Taplow, Berkshire SL6 0PH

SIR,-Your editorial (Oct. 15, p. 808) raises several interestE.

SIR,—Dr Meade and his colleagues reported pressures to be

higher

LIPOPROTEINS AND ATHEROMA

in

women

taking

oral

J. B. MAKIN

mean

blood-

contraceptives

30 ug oestrogen than in those on 50 µg prepareffect they considered to be attributable to the ations, D-norgestrel present in 30 µg but not in the 50 µg preparations. There were only 15 women on the 30 µg preparations, and the mean blood-pressure differences (+S.E.) (125.3±1.94/75.2+1.40 for the- 50 µg and 1297±36/81.9±2.9 for the 30 µg preparations) were small and not statistically significant. Nevertheless, the news media, always attracted by possibilities of danger and uninterested in evidence of safety, seized on the opportunity presented by this paper for raising further doubts in the minds of oral-contraceptive users and, perhaps, of their medical advisers. In the B.B.C. Tonight programme of Nov. 4 Mr John Timpson interviewed Dr Meade and announced that the 30 µg pills, though generally believed to be safer than the 50 µg ones, might present further hazards because of the higher content of progestagen. Dr Meade explained his findings with regard to blood-pressure in wholly unexceptionable terms, emphasising that the difference found was not conclusive, that the numbers studied were small, and that the dialogue about this particular aspect of the pill at the moment was entirely within the medical profession and between the medical profession and the pharmaceutical industry-in effect, that it was an inappropriate matter for the mass media. My reasons for commenting at all are first, that once again, unnecessary anxiety may have been engendered by thoughtless probing of inappropriate medical matters by news media; and second, to draw attention to published data on blood-pressure changes in women taking norgestrel, data which were mentioned neither by Meade et al. in their paper nor during the television interview. There are at least twelve published reports on the blood-pressure findings in women taking norgestrel-containing oral contraceptives,1-12 apart from data collected by the manufacturers but not so far published. They involve substantially more than 10 000 women and although for some the duration of treatment was only a few months, for others it extended to 9 years. The conclusions to be drawn from these reports are that an occasional patient develops hypertension, as happens sporadically with other oestrogencontaining regimens; that most women show no meaningful variation in either systolic or diastolic pressure; and that approximately equal numbers show minor degrees of rise and fall in both systolic and diastolic pressure, the effects being no

containing an

ing points. Perhaps the most important is the precise relationship between plasma high-density lipoprotein (H.D.L.) and verylow-density liproprotein (V.L.D.L.) concentrations and their possible relation to atheroma. It does seem that an erroneous inference is being drawn in assuming that low H.D.L. concentrations may be causative in the atherogenic process, that high H.D.L. concentrations are protective, and that a search for agents to raise H.D.L. concentrations will lead to significant clinical benefits. H.D.L. is formed in the liver and, perhaps, gut. In the circulation H.D.L. acquires cholesterol esters, while the proportion of free cholesterol decreases.’ H.D.L. is involved in the activation of lecithin/cholesterol acyl transferase (L.C.A.T.).2 The nature of this activation is unclear, though in vitro H.D.L. acts as a substrate but triglyceride-rich particles enhance the activity.3 It is possible, therefore, that the triglyceride-rich lipoproteins are the biological substrates—H.D.L. being essential as a co-factor or as a cholesterol-ester acceptor. Apart from this biological activity of H.D.L. (with its possible secondary effects on lipoprotein-lipase activity4) H.D.L. has been reported to associate with cell membranes.5 The most outstanding of these features would seem to be L.C.A.T. activation, so suggestions that H.D.L. is primarily a means for the carriage of tissue cholesterol back to the liver6 or that H.D.L. "competes" with low-density lipoprotein’ seem unnecessarily complex. Any model of H.D.L. metabolism not integrating the known properties of H.D.L. is inadequate, and the concept that H.D.L. prevents atheroma through a primary biological action seems even more bizarre. Has Nature foreseen the development of a disorder of modern civilisation and overcome the process by providing a transport service from the liver to collect material from the arterial intima and return it to the liver? The primary role of H.D.L. lies in the plasma-lipoprotein metabolic pathway, and changes of H.D.L. concentration could reflect changes of input or output-i.e., turnover within the pathway. A model such as that previously proposed4 shows how decreased H.D.L. concentration caused through increased turnover could be secondary to high triglyceride turnover, and recent’ observations support this.8 Carlson and Bottiger9 and Dolder and Oliverio have implicated high serum-triglyceride as a risk factor in coronary heart-disease. LOW H.D.L. may be a byproduct of the atherogenic process rather than its cause. Department of Chemical Pathology, Royal Free Hospital, London NW3 2QG Department of Chemical

Whittington Hospital, London N19 5NF

1. El-Tawil, N. Z., and others, Fertil. Steril. 1969, 20, 405. 2. Bergstenin, N. A. M. Clin. Ther. 1971, 1, 26. 3. Bye, P. G. T., Elstein, M. Br. med. J 1973, 2, 389. 4. Wynn, V., and others, Excerpta med. int. Congr. Ser. 1974, no. 334, p. 47. 5. Brat, T. H. Curr. med. Res. Opin. 1974, 2, 465. 6. Muller, P., and others, Sem. Hôp. Paris (Ther.) 1975, 51, 91. 7. Apelo, R., Veloso, I. Fertil. Steril. 1975, 26, 283. 8. Foss, G. L., Fotherby, K. Curr. med. Res. Opom. 1975, 3, 72. 9. Korba, V. D., and others, Fertil Steril. 1975 26, 973. 10. Ingermansow, C. A., and others, Acta obstet. gynec. scand. 1976, suppl. 54, 11.

p. 71. Briggs, M. A. Paper presented

at a

symposium on Advances

trol, held in Moscow on Nov. 16-19th 1976. 12 Woutersz, T. B. J. reprod. Med 1976, 6, 338.

in

Fertility Con-

D. G. CRAMP

Pathology, T. R. TICKNER

1. Lewis, B. Biochem. Soc. Trans. 1977, 5, 589. 2. Kostner, G. Scand. J. clin. Lab. Invest. 1974, 33, suppl. no. 137, p. 19. 3. Marcel, Y. L., Vezina, C. ibid. p. 45. 4. Cramp, D. G., Tickner, T. R., Wills, M. R. Lancet, 1976, ii, 176. 5. Tall, A. R., Small, D. M. Nature, 1977, 265, 163. 6. Glomset, J. A. J. Lipid Res. 1968, 9, 155. 7. Carew, T. E., Koschinsky, T., Hayes, S. B., Steinberg, D. Lancet, 1976, i, 1315. 8. Blum, C. B., Levy, R. I., Eisenberg, S., Hall, M., Goebel, R. H., Berman, M. J. clin. Invest. 1977, 60, 795. 9. Carlson, L. A., Böttiger, L. E. Lancet, 1972, i, 865. 10. Dolder, M. A., Oliver, M. F. Br. Heart J. 1975, 37, 493.

Progestagens, blood-clotting, and blood-pressure.

1085 The influence of photoirradiation in vivo is unmechanism to physical and chemical carcinogens in vitro and in vivo14 15 and the role played by...
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