- Email: [email protected]
HEPATOCELLULAR CARCINOMA IN A PATIENT ON ORAL CONTRACEPTION WHO HAD BEEN EXPOSED TO HEPATITIS B VIRUS
194
epithelium, are only too obvious. In terms of the incurred by the health services in treating the more
mal cervical expenses
RELATION OF MYOCARDIAL INFARCTION TO
advanced lesions, it was estimated in the U.S.A. that for every dollar spent, 9 were saved.8 LALITHA N. MENDIS Departments of Virology and Gynæcology, St Thomas’ Hospital and Medical School, London SE1 7EH
CONDITIONSt AND
PREDISPOSING
RECENT*
OC
USE,
TUBAL LIGATIONS EXCLUDED
-
I
I
I
JENNIFER M. BEST R. W. TAYLOR J. E. BANATVALA
RISK OF MYOCARDIAL INFARCTION IN ORAL-CONTRACEPTIVE USERS
SIR,-Dr Jick (June 2, p. 1187), commenting on
our
study’
of oral contraceptives (OCs) and myocardial infarction, argues that our study was seriously biased, but we find his reasons un-
persuasive.
’
Avoidance of OCs by women with predisposing conditions such as angina or diabetes-together with the rarity of these conditions--does mean that our study "cannot provide information on the hazards of OC use in such women." We agree, and so stated. By the same token, Jick’s speculation about the possibility that OC use might depend on the severity of a predisposing condition such as hypertension seems moot. We are not familiar with any study, or theory, connecting the "coronary-prone" personality type to "the decision to continue or discontinue OCs in the face of repeated warnings." For this reason, personality type, as well as many other familiar risk indicators of myocardial infarction, were not discussed as potentially confounding variables. Jick draws attention to our figure of 539controls without, predisposing conditions. This was a transcribing error which we regret. In fact, there were 539 controls with, and 1203 without, predisposing conditions. Thus the proportion of controls without predisposing conditions was 69%, a figure that accords well with those in other studies. Jick gives no reason-and we cannot think of any-why, among women not using OC’s, those protected from pregnancy by sterilisation should have been excluded (while users of intrauterine devices, diaphragms, and so on, were acceptable). He even suggests that women whose husbands had had vasectomies should have been excluded, as if a husband’s contraceptive practice could be a risk factor for myocardial infarction in the wife: we saw no reason to make allowance for vasectomy and hence we did not record data on it. However, we did record data on tubal ligation. Exclusion of women who had tubal ligations did not materially change any of the estimates of OC effect upon myocardial infarction risk. Nor did the further exclusion of predisposed women, together with women over 45 years of age, appreciably diminish the discordance between our results and those of Jick et al.:2,3 from the data in the accompanying table the rate ratio among women below the age of 45 was 6.4, whereas in Jick’s study the corresponding estimate among women below the age of 46 was 15. In attempting to explain the discordant results between our study and his, Jick concentrates on what he sees as possible biases in our study but does not respond to our reservations about possible selection bias in his own investigation. When we sought permission to interview patients we frequently found the physician and patient eager to collaborate if OCs were in use at the time of the infarction; conversely, we were often told that it was unnecessary to proceed with the interview if OCs were not in use. Such a tendency is conducive to an upward bias in the exposure-rate among the enrolled cases and, thereby, in the magnitude of the observed association. For this rea-
*Last use within the month before admission. as: ponderal index (weight /lteight [in]2) =0.04 (1 lb=454 g; 1 in=2.54 cm); treated diabetes; history of lipid abnormality; treated hypertension; treated angina pectoris; history of pre-eclamptic toxsemia.
tDefined
aimed at a 100% participation-rate within a pre-defined sampling frame. We achieved a rate of 94%, while Jick was able to interview only 15% of the potential cases considered eligible for study. We continue to be concerned that the participation of such a small subgroup might have been enhanced by knowledge, on the part of the consenting persons, of OC
son we
use.
Drug Epidemiology Unit, Boston University Medical Center, Cambridge, Massachusetts 02138, U.S.A.
HEPATOCELLULAR CARCINOMA IN A PATIENT ON ORAL CONTRACEPTION WHO HAD BEEN EXPOSED TO HEPATITIS B VIRUS
SiR,-Hepatic tumours in patients on oral or systemic contraceptives have been reported.’ Usually they are benign adenomas,2,3 and primary hepatocellular carcinoma (PHCC) rarer. However, in endemic regions (especially in Africa and Asia) where hepatitis B virus (HBV) is prevalent, the
is I incidenceI
of PHCC is also high,4 and over the past decade oral contra- r ception has been introduced into many developing countries,i We report here the earlier than usual development of PHCC in a patient who had evidence of previous asymptomatic HBV exposure and who was on the pill at the same time. The patient, a female Chinese, age 29, presented in January, 1979, with a 2-month history of pruritus, epigastric dis comfort, and weight loss. There was no history of hepatitis or liver disease. In 1972 she started taking ’Anovular’ (norethisterone acetate 4 mg, ethinyloestradiol 50 p.g) and she had been on ’Ovral’ (levonogesterol 0-5 mg and ethinylaestradiol 50 g since 1974. She was emaciated. There were no signs of chronic, liver disease. The right and left lobes of the liver were enlarge to 16 cm and 15 cm, respectively. Spleen was 3 cm enlarged A bruit over the right lobe was present. The results of invest)I gations were: bilirubin 1.2mg/dl, alkaline phosphatase 181 units (normal <100), SGOT 135 IU/1 (normal <40), >200 IU/1; acantitrypsin 538 mg/dl (130-320), -acid-gtyc protein 180 mg/dl (45-110); hepatoma liver antigen positive. !I
SGPTI
ot-fetoprotein
Programme analysis. Disease control programs: cancer. Washington, D.C. US Department of Health, Education and Welfare. 1966: 14-19. 1. Shapiro S, Slone D, Rosenberg L, Kaufman DW, Stolley PD, Miettinen OS. Oral-contraceptive use in relation to myocardial infarction. Lancet 1979; i: 743-47. 2.
Jick H, Dinan B, Rothman KJ. Oral contraceptives and nonfatal myocardial infarction. JAMA 1978; 239: 1403-06. 3. Jick H, Dinan B, Herman R, Rothman KJ. Myocardial Infarction and other vascular diseases in young women. JAMA 1978; 240: 2548-52.
1100
ng/ml, HBSAg negative counterimmunods
Christopherson WM, Mays ET, Burrows G. Hepatocellular carcinoma in young women on oral contraceptives. Lancet 1978;i:38. 2. Baum JK, Holtz F, Bookstein JJ, Klein EW. Possible association between benign hepatomas and oral contraceptives. Lancet 1973; ii: 926-929. 3. Anon. Liver tumours and the pill. Brit Med J 1977;ii:345. 4. Szmuness W. Hepatocellular carcinoma and the hepatitis B virus: evidence for a causal association. Progr Med Virol 1978; 24: 40-69. 5. Oon CJ, Yo SL. Presence of a hepatoma-liver antigen in the sera of patients with primary hepatocellular carcinoma. Singapore Med J1979: 20: 1.
8.
SAMUEL SHAPIRO DENNIS SLONE OLLI S. MIETTINEN
317-22.
195
trophoresis anti-HBAg positive (Abbott); colloid indium liver showed multiple definite filling defects in both lobes; selective hepatic angiography showed enlarged liver with difscan
fused vascular tumour; percutaneous liver biopsy showed
PHCC; chest X-ray, no metastases. Previous exposure of hepatitis B infection6is reflected in the presence of the antibody to core antigen which is present in 95CCof our PHCC patients compared with 30% in symptomfree HBsAg-negative blood-donors. In Singapore, PHCC in women of childbearing age (15-40 years) is rare (4 in 1968 and nil in 1970); most tumours appear in older women about 100 cases in each 10-year group being reported every year in women over the age of 40. Since an individual who carries the antibody to hepatitis B core antigen has a relative risk of more than 40 times normal of developing PHCC in this area (unpublished) it is possible that the earlier development of PHCC in this patient may have been due to either earlier neonatal infection or the concomitant administration of mstrogens and progestagens. Since oestrogen and progesterone birth-control pills have been consumed by women in HBV endemic regions in Asia and Africa, it would be important to know whether there is a true increase in hepatic tumours and an earlier appearance of such
malignancies. This work was supported by grants from the Shaw Foundation and Singapore Turf Club. S-L. Y. is in receipt of a Lee Foundation liver cancer research fellowship. We thank Prof. K. Shanmugaratnan for access to the Singapore Cancer Registry data.
Hepatoma and Liver Study Group, University Department of Medicine I, Singapore General Hospital, Singapore 3,
CHONG-JIN OON
and W.H.O. Immunology and Training Centre,
Singapore
SUI-LAN YO SOH-HA CHAN
PLASMA 1,25(OH)2 VITAMIN D CONCENTRATIONS IN NUTRITIONAL OSTEOMALACIA
larger series, the report by Dr Eastwood and his colleagues (June 30, p. 1377) of normal SIR,-We can confirm, in
by giving small doses of 25-OHD (or vitamin D), which immediately raises the p!asma-l,23(OH)D to very high concentrations, or by giving 1,23(OH)D itself. Indeed, the surprise is not perhaps that the 1,25(OH)2D concentrations may be normal in osteomalacia but that they are not even higher since the plasma calcium and phosphate concentrations are low and parathyroid-hormone concentrations are high. Perhaps they are inappropriately low because the low plasma-25OHD concentrations are limiting 1,25(OH)P production. This may seem unlikely when the plasma-25-OHD level is in either
the nanomolar range, but it may be that both Eastwood et al. and ourselves in fact overestimating the plasma-25-OHD conrentrntinn M.R.C. Mineral Metabolism
General Infirmary, Leeds LS1 3EX
the plasma-l,25(OH)2D concentrations were measurable in all twelve patients, and in ten values were in the normal range. However, we do not believe that it is necessary to invoke a role for vitamin D metabolites other than 25-OHD and 1,25(OH)2D in the pathogenesis of vitamin-D-deficient osteomalacia. All our twelve patients were completely cured histologically, radiologically, and biochemically in 6-12 months and small daily doses of 1,25(OH)2D3 or 1«OHD3 which raised the fasting plasma-1,25(OH)2D concentration 24 h after the dose into or above the high-normal range. Healing occurred in the absence of measurable plasma 25-OHD and 24,25(OH)2D in most of our patients. We do not agree therefore with the conclusion that 1,25(OH)2D cannot heal osteomalacia or that 24,25(OH)2D is essential for bone mineralisation.2 A normal plasma-l,25(OH)2D concentration is not sufficient to prevent osteomalacia developing when the plasma-25OHD concentration is very low-in this situation a high 1,25(OH)2D concentration is needed. This can be achieved
MUNRO PEACOCK P. J. HEYBURN J. AARON
EFFECT ON BONE OF WITHDRAWAL OF ŒSTROGEN THERAPY
SiR,—Dr Horsman and colleagues (July 7, p. 33) have made valuable contribution towards our approach to oestrogen therapy for the prevention of postmenopausal osteoporosis, in so far as they have shown, by metacarpal morphometric measurements, that bone loss is unexpectedly rapid in the first year after oestrogen withdrawal. This confirms the findings of Lindsay et al. who showed, using single-source gamma-ray photon absorptiometry, an exceptionally rapid loss of metacarpal bone over a four year period after oestrogen withdrawal. a
Unfortunately single-source photon absorptiometric measurements vary with changes in soft tissue composition and hence the loss of bone mass found by Lindsay et al. could, in part at least, have been explained by an effect of oestrogen on the soft tissues rather than bone. However this technical lack of precision would now not appear to be significant since metacarpal morphometric measurements are unaffected by soft tissue com-
position. It
a
plasma 1,25(OH)2D concentrations in 3 patients with nutritional osteomalacia. Our data, presented in February, 1979, at the 4th International Meeting on Vitamin D’ and discussed in some detail with Dr Eastwood, derive from twelve patients with proven osteomalacia (six Asian subjects and six patients with small-bowel disease). The plasma 25-OHD concentrations were low in five and unmeasurable in seven of the patients, but
Unit,
was not
clear in the letter of Horsman et al. whether their
postmenopausal women had undergone hysterectomy and oophorectomy or were women with intact uteruses and ovaries, nor did they state which oestrogen was used and how it was administered. There is evidence that intermittent low-dose oestrogen therapy (<20 jjtg mestranol daily) has a greater osteotrophic effect than doses higher dose continuous oestrogen therapy (20-40 !Jog mestranol daily).2.3 Hence it is quite possible that intermittent low-dose oestrogen therapy may not be associated with such a rapid rate of bone-loss after oestrogen withdrawal as that seen after the continuous regimens of Lindsay et al. and (presumably) Horsman et al. Most postmenopausal women receiving oestrogen for the prevention or treatment of osteoporosis have intact uteruses and ovaries and under these circumstances intermittent oestrogen/progestagen regimens have been shown to be the safest method of giving hormone replacement therapy if uterine neoplasia is to be avoided.4 Hence we should reserve judgment on bone loss after oestrogen withdrawal until the effects of withdrawal of intermittent oestrogen therapy have been investigated. Horsman et al. also showed that there was little acceleration in bone loss after withdrawal of calcium supplements given to a similar group of women. In this way they intimated that calcium therapy was superior to oestrogen therapy. However, for 1.
Hart DM, MacLean A, Clark AC, Kraszewski A, Garwood J. Bone response to termination of œstrogen treatment. Lancet 1978; i:
Lindsay R,
1325-27. 2. Aitken
Japan Medical Research Foundation Publ. No. 6, 56. Hepatitis viruses. Tokyo, 1978. 1. Peacock M, Heyburn PJ, Aaron JE, Taylor GA, Brown WB, Speed R. Osteomalacia treated with 1 hydroxy or 1,25 dihydroxy vitamin D. In: Norman AW ed. Fourth workshop on vitamin D. Berlin, New York: Walter de
6
Gruyter, 1979 (in press). 2 Rasmussen 7-13.
H, Bordier P. Vitamin D and bone. Metab Bone Dis 1978; 1:
JM, Hart DM, Lindsay R, MacDonald EB. Oestrogen dosage in the of postmenopausal osteoporosis. Medikon Int 1974; 8: 3-5. 3. Aitken JM, Lindsay R, Hart DM. Long-term oestrogens for the prevention of post-menopausal osteoporosis. Postgrad Med J 1976; 52 (suppl 6): treatment
18-25. 4. Whitehead MI, McQueen J, Minardi J, Campbell S. Progestogen modification of estrogen-induced endometrial proliferation in climacteric women. In: Cooke ID ed. The role of estrogen/progestogen in the management of the menopause. Lancaster: MTP Press, 1978: 121-33.
epithelium, are only too obvious. In terms of the incurred by the health services in treating the more
mal cervical expenses
RELATION OF MYOCARDIAL INFARCTION TO
advanced lesions, it was estimated in the U.S.A. that for every dollar spent, 9 were saved.8 LALITHA N. MENDIS Departments of Virology and Gynæcology, St Thomas’ Hospital and Medical School, London SE1 7EH
CONDITIONSt AND
PREDISPOSING
RECENT*
OC
USE,
TUBAL LIGATIONS EXCLUDED
-
I
I
I
JENNIFER M. BEST R. W. TAYLOR J. E. BANATVALA
RISK OF MYOCARDIAL INFARCTION IN ORAL-CONTRACEPTIVE USERS
SIR,-Dr Jick (June 2, p. 1187), commenting on
our
study’
of oral contraceptives (OCs) and myocardial infarction, argues that our study was seriously biased, but we find his reasons un-
persuasive.
’
Avoidance of OCs by women with predisposing conditions such as angina or diabetes-together with the rarity of these conditions--does mean that our study "cannot provide information on the hazards of OC use in such women." We agree, and so stated. By the same token, Jick’s speculation about the possibility that OC use might depend on the severity of a predisposing condition such as hypertension seems moot. We are not familiar with any study, or theory, connecting the "coronary-prone" personality type to "the decision to continue or discontinue OCs in the face of repeated warnings." For this reason, personality type, as well as many other familiar risk indicators of myocardial infarction, were not discussed as potentially confounding variables. Jick draws attention to our figure of 539controls without, predisposing conditions. This was a transcribing error which we regret. In fact, there were 539 controls with, and 1203 without, predisposing conditions. Thus the proportion of controls without predisposing conditions was 69%, a figure that accords well with those in other studies. Jick gives no reason-and we cannot think of any-why, among women not using OC’s, those protected from pregnancy by sterilisation should have been excluded (while users of intrauterine devices, diaphragms, and so on, were acceptable). He even suggests that women whose husbands had had vasectomies should have been excluded, as if a husband’s contraceptive practice could be a risk factor for myocardial infarction in the wife: we saw no reason to make allowance for vasectomy and hence we did not record data on it. However, we did record data on tubal ligation. Exclusion of women who had tubal ligations did not materially change any of the estimates of OC effect upon myocardial infarction risk. Nor did the further exclusion of predisposed women, together with women over 45 years of age, appreciably diminish the discordance between our results and those of Jick et al.:2,3 from the data in the accompanying table the rate ratio among women below the age of 45 was 6.4, whereas in Jick’s study the corresponding estimate among women below the age of 46 was 15. In attempting to explain the discordant results between our study and his, Jick concentrates on what he sees as possible biases in our study but does not respond to our reservations about possible selection bias in his own investigation. When we sought permission to interview patients we frequently found the physician and patient eager to collaborate if OCs were in use at the time of the infarction; conversely, we were often told that it was unnecessary to proceed with the interview if OCs were not in use. Such a tendency is conducive to an upward bias in the exposure-rate among the enrolled cases and, thereby, in the magnitude of the observed association. For this rea-
*Last use within the month before admission. as: ponderal index (weight /lteight [in]2) =0.04 (1 lb=454 g; 1 in=2.54 cm); treated diabetes; history of lipid abnormality; treated hypertension; treated angina pectoris; history of pre-eclamptic toxsemia.
tDefined
aimed at a 100% participation-rate within a pre-defined sampling frame. We achieved a rate of 94%, while Jick was able to interview only 15% of the potential cases considered eligible for study. We continue to be concerned that the participation of such a small subgroup might have been enhanced by knowledge, on the part of the consenting persons, of OC
son we
use.
Drug Epidemiology Unit, Boston University Medical Center, Cambridge, Massachusetts 02138, U.S.A.
HEPATOCELLULAR CARCINOMA IN A PATIENT ON ORAL CONTRACEPTION WHO HAD BEEN EXPOSED TO HEPATITIS B VIRUS
SiR,-Hepatic tumours in patients on oral or systemic contraceptives have been reported.’ Usually they are benign adenomas,2,3 and primary hepatocellular carcinoma (PHCC) rarer. However, in endemic regions (especially in Africa and Asia) where hepatitis B virus (HBV) is prevalent, the
is I incidenceI
of PHCC is also high,4 and over the past decade oral contra- r ception has been introduced into many developing countries,i We report here the earlier than usual development of PHCC in a patient who had evidence of previous asymptomatic HBV exposure and who was on the pill at the same time. The patient, a female Chinese, age 29, presented in January, 1979, with a 2-month history of pruritus, epigastric dis comfort, and weight loss. There was no history of hepatitis or liver disease. In 1972 she started taking ’Anovular’ (norethisterone acetate 4 mg, ethinyloestradiol 50 p.g) and she had been on ’Ovral’ (levonogesterol 0-5 mg and ethinylaestradiol 50 g since 1974. She was emaciated. There were no signs of chronic, liver disease. The right and left lobes of the liver were enlarge to 16 cm and 15 cm, respectively. Spleen was 3 cm enlarged A bruit over the right lobe was present. The results of invest)I gations were: bilirubin 1.2mg/dl, alkaline phosphatase 181 units (normal <100), SGOT 135 IU/1 (normal <40), >200 IU/1; acantitrypsin 538 mg/dl (130-320), -acid-gtyc protein 180 mg/dl (45-110); hepatoma liver antigen positive. !I
SGPTI
ot-fetoprotein
Programme analysis. Disease control programs: cancer. Washington, D.C. US Department of Health, Education and Welfare. 1966: 14-19. 1. Shapiro S, Slone D, Rosenberg L, Kaufman DW, Stolley PD, Miettinen OS. Oral-contraceptive use in relation to myocardial infarction. Lancet 1979; i: 743-47. 2.
Jick H, Dinan B, Rothman KJ. Oral contraceptives and nonfatal myocardial infarction. JAMA 1978; 239: 1403-06. 3. Jick H, Dinan B, Herman R, Rothman KJ. Myocardial Infarction and other vascular diseases in young women. JAMA 1978; 240: 2548-52.
1100
ng/ml, HBSAg negative counterimmunods
Christopherson WM, Mays ET, Burrows G. Hepatocellular carcinoma in young women on oral contraceptives. Lancet 1978;i:38. 2. Baum JK, Holtz F, Bookstein JJ, Klein EW. Possible association between benign hepatomas and oral contraceptives. Lancet 1973; ii: 926-929. 3. Anon. Liver tumours and the pill. Brit Med J 1977;ii:345. 4. Szmuness W. Hepatocellular carcinoma and the hepatitis B virus: evidence for a causal association. Progr Med Virol 1978; 24: 40-69. 5. Oon CJ, Yo SL. Presence of a hepatoma-liver antigen in the sera of patients with primary hepatocellular carcinoma. Singapore Med J1979: 20: 1.
8.
SAMUEL SHAPIRO DENNIS SLONE OLLI S. MIETTINEN
317-22.
195
trophoresis anti-HBAg positive (Abbott); colloid indium liver showed multiple definite filling defects in both lobes; selective hepatic angiography showed enlarged liver with difscan
fused vascular tumour; percutaneous liver biopsy showed
PHCC; chest X-ray, no metastases. Previous exposure of hepatitis B infection6is reflected in the presence of the antibody to core antigen which is present in 95CCof our PHCC patients compared with 30% in symptomfree HBsAg-negative blood-donors. In Singapore, PHCC in women of childbearing age (15-40 years) is rare (4 in 1968 and nil in 1970); most tumours appear in older women about 100 cases in each 10-year group being reported every year in women over the age of 40. Since an individual who carries the antibody to hepatitis B core antigen has a relative risk of more than 40 times normal of developing PHCC in this area (unpublished) it is possible that the earlier development of PHCC in this patient may have been due to either earlier neonatal infection or the concomitant administration of mstrogens and progestagens. Since oestrogen and progesterone birth-control pills have been consumed by women in HBV endemic regions in Asia and Africa, it would be important to know whether there is a true increase in hepatic tumours and an earlier appearance of such
malignancies. This work was supported by grants from the Shaw Foundation and Singapore Turf Club. S-L. Y. is in receipt of a Lee Foundation liver cancer research fellowship. We thank Prof. K. Shanmugaratnan for access to the Singapore Cancer Registry data.
Hepatoma and Liver Study Group, University Department of Medicine I, Singapore General Hospital, Singapore 3,
CHONG-JIN OON
and W.H.O. Immunology and Training Centre,
Singapore
SUI-LAN YO SOH-HA CHAN
PLASMA 1,25(OH)2 VITAMIN D CONCENTRATIONS IN NUTRITIONAL OSTEOMALACIA
larger series, the report by Dr Eastwood and his colleagues (June 30, p. 1377) of normal SIR,-We can confirm, in
by giving small doses of 25-OHD (or vitamin D), which immediately raises the p!asma-l,23(OH)D to very high concentrations, or by giving 1,23(OH)D itself. Indeed, the surprise is not perhaps that the 1,25(OH)2D concentrations may be normal in osteomalacia but that they are not even higher since the plasma calcium and phosphate concentrations are low and parathyroid-hormone concentrations are high. Perhaps they are inappropriately low because the low plasma-25OHD concentrations are limiting 1,25(OH)P production. This may seem unlikely when the plasma-25-OHD level is in either
the nanomolar range, but it may be that both Eastwood et al. and ourselves in fact overestimating the plasma-25-OHD conrentrntinn M.R.C. Mineral Metabolism
General Infirmary, Leeds LS1 3EX
the plasma-l,25(OH)2D concentrations were measurable in all twelve patients, and in ten values were in the normal range. However, we do not believe that it is necessary to invoke a role for vitamin D metabolites other than 25-OHD and 1,25(OH)2D in the pathogenesis of vitamin-D-deficient osteomalacia. All our twelve patients were completely cured histologically, radiologically, and biochemically in 6-12 months and small daily doses of 1,25(OH)2D3 or 1«OHD3 which raised the fasting plasma-1,25(OH)2D concentration 24 h after the dose into or above the high-normal range. Healing occurred in the absence of measurable plasma 25-OHD and 24,25(OH)2D in most of our patients. We do not agree therefore with the conclusion that 1,25(OH)2D cannot heal osteomalacia or that 24,25(OH)2D is essential for bone mineralisation.2 A normal plasma-l,25(OH)2D concentration is not sufficient to prevent osteomalacia developing when the plasma-25OHD concentration is very low-in this situation a high 1,25(OH)2D concentration is needed. This can be achieved
MUNRO PEACOCK P. J. HEYBURN J. AARON
EFFECT ON BONE OF WITHDRAWAL OF ŒSTROGEN THERAPY
SiR,—Dr Horsman and colleagues (July 7, p. 33) have made valuable contribution towards our approach to oestrogen therapy for the prevention of postmenopausal osteoporosis, in so far as they have shown, by metacarpal morphometric measurements, that bone loss is unexpectedly rapid in the first year after oestrogen withdrawal. This confirms the findings of Lindsay et al. who showed, using single-source gamma-ray photon absorptiometry, an exceptionally rapid loss of metacarpal bone over a four year period after oestrogen withdrawal. a
Unfortunately single-source photon absorptiometric measurements vary with changes in soft tissue composition and hence the loss of bone mass found by Lindsay et al. could, in part at least, have been explained by an effect of oestrogen on the soft tissues rather than bone. However this technical lack of precision would now not appear to be significant since metacarpal morphometric measurements are unaffected by soft tissue com-
position. It
a
plasma 1,25(OH)2D concentrations in 3 patients with nutritional osteomalacia. Our data, presented in February, 1979, at the 4th International Meeting on Vitamin D’ and discussed in some detail with Dr Eastwood, derive from twelve patients with proven osteomalacia (six Asian subjects and six patients with small-bowel disease). The plasma 25-OHD concentrations were low in five and unmeasurable in seven of the patients, but
Unit,
was not
clear in the letter of Horsman et al. whether their
postmenopausal women had undergone hysterectomy and oophorectomy or were women with intact uteruses and ovaries, nor did they state which oestrogen was used and how it was administered. There is evidence that intermittent low-dose oestrogen therapy (<20 jjtg mestranol daily) has a greater osteotrophic effect than doses higher dose continuous oestrogen therapy (20-40 !Jog mestranol daily).2.3 Hence it is quite possible that intermittent low-dose oestrogen therapy may not be associated with such a rapid rate of bone-loss after oestrogen withdrawal as that seen after the continuous regimens of Lindsay et al. and (presumably) Horsman et al. Most postmenopausal women receiving oestrogen for the prevention or treatment of osteoporosis have intact uteruses and ovaries and under these circumstances intermittent oestrogen/progestagen regimens have been shown to be the safest method of giving hormone replacement therapy if uterine neoplasia is to be avoided.4 Hence we should reserve judgment on bone loss after oestrogen withdrawal until the effects of withdrawal of intermittent oestrogen therapy have been investigated. Horsman et al. also showed that there was little acceleration in bone loss after withdrawal of calcium supplements given to a similar group of women. In this way they intimated that calcium therapy was superior to oestrogen therapy. However, for 1.
Hart DM, MacLean A, Clark AC, Kraszewski A, Garwood J. Bone response to termination of œstrogen treatment. Lancet 1978; i:
Lindsay R,
1325-27. 2. Aitken
Japan Medical Research Foundation Publ. No. 6, 56. Hepatitis viruses. Tokyo, 1978. 1. Peacock M, Heyburn PJ, Aaron JE, Taylor GA, Brown WB, Speed R. Osteomalacia treated with 1 hydroxy or 1,25 dihydroxy vitamin D. In: Norman AW ed. Fourth workshop on vitamin D. Berlin, New York: Walter de
6
Gruyter, 1979 (in press). 2 Rasmussen 7-13.
H, Bordier P. Vitamin D and bone. Metab Bone Dis 1978; 1:
JM, Hart DM, Lindsay R, MacDonald EB. Oestrogen dosage in the of postmenopausal osteoporosis. Medikon Int 1974; 8: 3-5. 3. Aitken JM, Lindsay R, Hart DM. Long-term oestrogens for the prevention of post-menopausal osteoporosis. Postgrad Med J 1976; 52 (suppl 6): treatment
18-25. 4. Whitehead MI, McQueen J, Minardi J, Campbell S. Progestogen modification of estrogen-induced endometrial proliferation in climacteric women. In: Cooke ID ed. The role of estrogen/progestogen in the management of the menopause. Lancaster: MTP Press, 1978: 121-33.