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Bone loss during oestriol therapy in postmenopausal women
279
Maturitas, I (1979) 279-285 0 Elsevier/North-Holland Biomedical Press
BONE LOSS DURING OESTRIOL THERAPY IN POSTMENOPAUSAL WOMEN
R. LINDSAY ‘, D.M. HART, A. MACLEAN, J. GARWOOD, A.C. CLARK and A. KRASZEWSKI
1Departmertt of Medicine, WesternInfirmary, Glasgow GII 6MT; Departments of Obstetricsand Gynaecology, WesternInfirmary and Stobhill Hospital, GlasgowGI I 6MT, Scotland (Received 11 December 1978, accepted 7 February 1979)
In contrast to ali other oestrogens examined thus far oestriol hemisuccinate (12 mg/day) did not prevent bone loss in 28 postmenopausal women. The average bone loss, however, was somewhat less than expected from placebo studies, while the bone loss achieved by a group taking 4-6 mg/day was equal to that achieved by previous placebo groups. To be an effective agent for prevention of postmenopausal osteoporosis oestriol would have to be prescribed in daily doses considerably in excess of 12mg. (Key words: Oestriol, Bone loss, Osteoporosis,
Postmenopause)
INTRODUCTION
In previous publications we have demonstrated that oestrogen therapy prevents bone loss after oophorectomy [1,2]. We have obtained similar results in women who have undergone a natural menopause [3]. These results have been confirmed by other centres [4-61. However, it has been suggested that long-term oestrogen therapy may be associated with an increased incidence of endometrial carcinoma [7,8] and there is no doubt in our minds that oestrogen, to be effective in prevention of fracture, would have to be prescribed for a very long time [9]. In an attempt to obviate the possible risks involved in such long-term treatment, we have examined the effects of oestriol on calcium metabolism. This compound has a considerably weaker effect on the endometrium [lo] than oestradiol or oestrone, and if significant prevention of bone loss resulted from its use, then it might prove the ideal therapeutic substance for prevention of osteoporosis. PATIENTS AND METHODS
Eighty consecutive referrals to a menopausal clinic were placed in a trial of oestriol hemisuccinate (Synapause, Organon). The initial 15-wk period consisted of a doubleblind trial of oestriol hemisuccinate (2 mg BD) versus placebo, to assess the usefulness of
’ To whom requests for reprints should be addressed.
280 the compound for control of menopausal symptoms. At the end of this period the patients were all provided with active oestriol tablets and allowed to ‘increase their daily dose by 2 mg at five weekly intervals until subjective control of symptoms was achieved, or a maximum of 12 mg per day in divided doses was being prescribed. This dose was then continued and the patients followed for 2 yr. Fasting samples of blood and urine were obtained from all patients prior to the start of the trial and after 15 wk. Thereafter samples were taken from all patients just prior to the next increase in daily dose of oestriol. All patients, who did not require an increased dose had subsequent fasting blood and urine samples obtained at five weekly intervals for 25 wk, i.e., until those patients who required it had achieved 5 wk at the maximum dose of 12 mg. Of the 80 patients referred, 61 had undergone a natural menopause and 19 had had bilateral salpingooophorectomy. The age range was 43-51 yr. The mean time from the last menstrual period was 1.75 yr. Biochemical measurements on serum and urine were carried out following standard techniques. Calcium was estimated by atomic absorption spectrophotometry [ 111. Creatinine and phosphorus were measured by the Autoanalyzer techniques Nl 1 and N4, respectively. Alkaline phosphatase in serum was estimated by the method of “King and Wooton” [ 121. Bone mineral content was measured by photon-absorptiometry at the mid-point of the third right metacarpal. Measurements were obtained on all patients at their first visit and thereafter at approximately three monthly intervals until all patients had completed 2 yr at their maximum dose level. The accuracy and reproducibility of this method have been described elsewhere [ 131. Standard statistical methods were used to analyse the results. RESULTS Of the initial 80 patients entered into the trial 72 completed the double-blind study. There was no significant difference between 4 mg oestriol hemisuccinate and placebo when control of the classical menopausal symptoms, hot flushes and sweating attacks, were considered (Lindsay and Hart, unpubl. data). When patients were allowed to increase their daily dose levels, 64 patients agreed to continue. Five patients, of whom three were originally on placebo, stated that 4 mg was an adequate dose to control symptoms. However, 46 patients required 8-12 mg/day for symptomatic relief, and 28 required 12 mg (all therapy in divided doses). Five further patients were unhappy on 12 mg and were removed from the trial. Since this part of the study was not double-blind, we can draw no conclusions on the effect of these higher doses of oestriol on symptom control. The patients who did not wish to continue after the 4 mg daily dose period were all offered other standard oestrogen compounds. Ail achieved adequate symptom control on one ofthese preparations. Serum calcium, phosphate and alkaline phosphatase No significant changes in serum calcium, phosphate or alkaline phosphatase were observed at each dose level (Table I). There was a slight reduction in calcium at 8, 10 and
281 TABLE I Biochemical data from all patients during the trial. No significant changes were recorded. For conversion to SI units divide serum Ca by 4 and serum phosphate by 3.10. Description
Daily dose of oestriol (mg)
Serum Ca (mg/lOO ml) Serum PO4 (mg/lOO ml) Alkaline phosphatase (KA units)
0
4
6
8
12
9.80 + 0.12 3.56 + 0.11
9.70 f 0.08 3.64 * 0.12
9.75 f 0.09 3.59 * 0.16
9.68 i 0.08 3.47 f 0.12
9.65 f 0.12 3.45 + 0.14
9.01 f 0.45
9.21 f 0.44
8.90 + 0.40
8.75 f 0.39
8.69 f 0.44
OESTRIOL HEMISUCCINATE Bone Mined
Content mg/mm
44-
p~o*oo1
43-
42-
41-
YEARS
Fig. 1. The ratio of calcium to creatinine in fasting urine specimens during increasing doses of oestriol hemisuccinate. The results (means i SEM) are expressed in conventional units and the conversion factor to SI units is X0.86. Only those 28 patients who reached 12 mg/day are included in the fgure and statistical differences were calculated using a paired ‘Y-test.
282
12 mg/day but this did not reach significant levels. Analysis using only the results from those 28 patients who reached 12 mg/day revealed identical results to those of the group as a whole, with no significant changes observed. These results are similar to those originally reported by Gallagher and Nordin [14] when daily dose of oestriol hemisuccinate was increased to only 8 mg/day in 10 patients. Urine calciumjcreatinine
Gradually increasing the daily dose of oestriol hemisuccinate produced a fall in calcium/creatinine (Ca/Cr) which became significant at only the 12 mg dose level (PO.01). Using the paired r-test a significant reduction in Ca/Cr was obtained for only those 28 patients who reached 12 mg/day (Fig. 1). Urinary hydroxyproline/creatine
(OH&r)
There was no consistent change in the excretion of hydroxyproline at doses of 4-8 (P 0.05) whether all patients were considered or only those who reached 12 mg/day (Fig. 2). All these measurements were obtained after 5 wk therapy at each dose level. There were no further changes with time and in those patients who were followed for 2 yr the serum and urine values remained similar throughout this period. mg/day . At 12 mg/day there was a significant fall in OH&r
Photonsbsorptiometry
results
The mean metacarpal mineral content of all patients on their first visit was 43.5 + 0.8 mg/mm and of the 28 patients requiring 12 mg/day as final dose, the initial metacarpal
Mean +fSEM
Hydr0xypmline/Creatinine dmg 0.03
pco.05
OESTRIOL HEMWJCCINATE DAILY DOSE (mgl Fig. 2. The ratio of hydroxyproline to creatinine in fasting urine specimens during incremental of oestrioi hemisuccinate. For conversion to SI units multiply by 2.8.
doses
283 Fasting C&r mgh
0.16-
o-140.12-
O.lO-
I I1
**
o.oa-
Means f SEM
pco.01
I
1X
0.06-
I
0
I
2
I
4
I 6
I 8
I 10
I
12
OESTRIOL HEMISUCCINATE DAILY DOSE (mg) Fig.
3. Bone mineral content during 2 yr of treatment with oestriol hemisuccinate (n = 28). Measurement was by Photon absorptiometry and results are means f SEM.
12 mg/day
mineral content was 43.7 f 0.95 mg/mm. During the 2 yr of follow-up 24 of the 28 patients taking 12 mg/day lost bone and the mean metacarpal mineral content fell significantly to 41.9 f 1 .Omg/mm (Fig. 3). Thus the mean rate of bone loss was about 1.9% per annum. This figure is somewhat less than the amount of bone (3.6%) lost by a previous group of placebo-treated postmenopausal patients [3] and to the rate of bone loss incurred by our placebo-treated oophorectomised patients [2,9]. However, it is a significant downward trend and is unlike the effect of mestranol(~*25 mg/day) where virtually no bone is lost during treatment and under certain circumstances an actual gain of bone mass may be achieved [2,9] . The mean rate of bone loss of the 14 patients taking 4-6 mg/day was 2.7% per annum of a figure much closer to that found in our previous and ongoing placebo studies. This suggests that 8-12 mg oestriol hemisuccinate does have some retarding effect on bone loss, but is clearly not so effective as currently prescribed doses of other oestrogens. DISCUSSION It has been shown by several groups that oestrogen therapy prevents postmenopausal bone loss [2,4,5]. The oestrogens used have mostly been the synthetic compound mestranol or conjugated equine oestrogens, but it seems likely that both oestradiol and
284
oestrone themselves will possess this property. However, all these compounds also stimulate endometrial growth and if given continuously for long periods this can result in endometrial hyperplasia, the appearance of atypical histology, and perhaps may result in neoplastic change. Two retrospective reports first suggested that prescription of long-term oestrogen resulted in a clinically evident increased risk of endometrial carcinoma [7,8]. These reports have been heavily criticised, but there is no doubt in recent prospective studies that a significant proportion of patients, given continuous or intermittent oestrogen treatment, have atypical hyperplasia which need not present with postmenopausal bleeding [ 151. Our recent study of patients who have been treated successfully with mestranol, revealed a dramatic loss of bone following cessation of therapy [9]. We concluded that to protect patients from osteoporosis, prolonged treatment, for perhaps lo-20 yr or more would be required. To avoid any risk of endometrial carcinoma in patients with an intact uterus would require a progestogen be added to the therapy. Recent studies have suggested that if the progestogen is to be effective in this respect it must be prescribed for a 10day period or in a continuous fashion rather like the combined contraceptive pill, with a tablet free week to allow endometrial shedding. Progestogen, in a preliminary trial, was also an effective agent in preventing postmenopausal bone loss [3], and had significant beneficial effects on bone mass in a younger premenopausal group of women [16]. Therefore, the addition of a progestogen to oestrogen therapy may not weaken the basic effect on bone. However, it would be much more satisfactory if there was a single agent available which would effectively control symptoms and prevent bone loss, without stimulating endometrial growth. Oestriol has been advocated as the ideal candidate [ 171. Unfortunately, our study does not support this. Four mg/day of oestriol hemisuccinate was ineffective in controlling symptoms, 28 patients (35%) required 12 mg, and five (from 64) were dissatisfied at 12 mg/day. More importantly, in our view, was the fact that 12 mg/day did not prevent loss of bone, which continued at a rate not far short of that maintained by placebo-treated patients of similar age, in our previous studies [2,9]. It is likely that a higher daily dose level would be more successful. We think this is unlikely to be acceptable to patients, their physicians or the licensing authorities. It is notable that at this dose level (12 mg/day) abnormal values for clotting factors VII and X begin to become evident [18] and it is likely that at these higher oral doses the adverse effects recorded by other oestrogens would become evident. REFERENCES
[ 1 ] Aitken, J.M., Hart, D.M. and Lindsay, R., (1973) Oestrogen replacement therapy for the prevention of osteoporosis after oophorectomy. Br. Med. J. ii, 5 15-518. [2] Lindsay, R., Aitken, J.M., Anderson, J.B., Hart, D.M., MacDonald, E.B. and Clark, A.C. (1976) Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet i, 1038-1041. [3 ] Lindsay, R., Hart, D.M., Purdie, D., Ferguson, M.M., Clark, A.C. and Kraszewski, A. (1978) Comparative effects of oestrogen and a progestogen on bone loss in postmenopausal women. Clin. Sci. Mol. Med. 54.193-195. 14] Dequeker, J. and Ferin, J. (1976) Effect of long-term oestrogen therapy on bone remodelhng in women with a natural menopause: cross-sectional and longitudinal study. In: Consensus on menopause research, pp. 124-l 31. Editor: P. van Keep. MTP Press, Lancaster.
285 [S ] Reeker, R.R., Saville, P.D. and Heaney, R.P. (1977) Effect of oestrogens and calcium carbonate on bone loss in postmenopausal women. Annals Intern. Med. 87,649-655. [6] Horsman, A., Gallagher, J.C., Simpson, M. and Nordin, B.E.C. (1977) Prospective trial of oestrogen and calcium in postmenopausal women. Br. Med. J. ii, 789-792. [7] Smith, D.C., Prentice, R., Thompson, D.J. and Hermann, W.L. (1975) Association of exogenous oestrogen and endometrial carcinoma. New Engl. J. Med. 293,1164-l 167. [8] Zeil, H.K. and Finkle, W.D. (1975) Increased rise of endometrial carcinoma among users of conjugated oestrogens. New Engl. J. Med., 293,1167-l 170. [9] Lindsay, R., Hart, D.M., Maclean, A., Clark, A.C., Kraszewski, A. and Garwood, J. (1978) Bone response to termination of oestrogen.treatment. Lancet i, 1325-l 327. [lo] Tzmgounis, V.A., Aksu, M.F. and Greenblatt, R.B. (1978) Estriol in the management of the menopause. J. Am. Med. Assoc. 239,1638-1641. [ll] Trudeau, D.L. and Freier, E.F. (1967) Determination of calcium in urine and serum by atomic absorption spectrophotometry. Clin. Chem. 13,101-l 14. [ 121 King, E.J. and Wooton, I.D.P. (1956) Procedures for plasma microanalysis in medical biochemistry, 3rd ed. Churchill, London. [ 13 ] Shimmins, J., Smith, D.A., Aitken, J.M., Anderson, J.B. and Gillespie, F.C. (1972) The accuracy and reproducibility of bone mineral measurements “in viva” (b) Methods using sealed isotope sources. Clin. Radiol. 23,47-51. [ 141 Gallagher, J.C. and Nordln, B.E.C. (1975) Effects of oestrogen and progestogen therapy on calcium metabolism in postmenopausal women. Front. Horm. Res.. 3, 150-176. [ 15 ] Myhre, E. (1978) Endometrial response to different estrogens. In: Estrogen therapy: the benefits and risks. Frontiers of hormone research, Vol. 5, pp. 126-144. Editors: C. Lauritzen and P. van Keep. Karger, Basel. [ 161 Dequeker, J., Muylder, E. de and Ferin, J. (1977) The effect of long-term Lynestrenol treatment on bone mass in cyclic women. Contraception 15,717-723. [ 171 Follingsted, A.H. (1978) Estriol: the forgotten estrogen. J. Am. Med. Assoc. 239, 29. [18] Hart, D.M., Lindsay, R. and Purdie, D. (1978) Vascular complications of long-term oestrogen therapy. Front. Horm. Res. 5,174-191.
Maturitas, I (1979) 279-285 0 Elsevier/North-Holland Biomedical Press
BONE LOSS DURING OESTRIOL THERAPY IN POSTMENOPAUSAL WOMEN
R. LINDSAY ‘, D.M. HART, A. MACLEAN, J. GARWOOD, A.C. CLARK and A. KRASZEWSKI
1Departmertt of Medicine, WesternInfirmary, Glasgow GII 6MT; Departments of Obstetricsand Gynaecology, WesternInfirmary and Stobhill Hospital, GlasgowGI I 6MT, Scotland (Received 11 December 1978, accepted 7 February 1979)
In contrast to ali other oestrogens examined thus far oestriol hemisuccinate (12 mg/day) did not prevent bone loss in 28 postmenopausal women. The average bone loss, however, was somewhat less than expected from placebo studies, while the bone loss achieved by a group taking 4-6 mg/day was equal to that achieved by previous placebo groups. To be an effective agent for prevention of postmenopausal osteoporosis oestriol would have to be prescribed in daily doses considerably in excess of 12mg. (Key words: Oestriol, Bone loss, Osteoporosis,
Postmenopause)
INTRODUCTION
In previous publications we have demonstrated that oestrogen therapy prevents bone loss after oophorectomy [1,2]. We have obtained similar results in women who have undergone a natural menopause [3]. These results have been confirmed by other centres [4-61. However, it has been suggested that long-term oestrogen therapy may be associated with an increased incidence of endometrial carcinoma [7,8] and there is no doubt in our minds that oestrogen, to be effective in prevention of fracture, would have to be prescribed for a very long time [9]. In an attempt to obviate the possible risks involved in such long-term treatment, we have examined the effects of oestriol on calcium metabolism. This compound has a considerably weaker effect on the endometrium [lo] than oestradiol or oestrone, and if significant prevention of bone loss resulted from its use, then it might prove the ideal therapeutic substance for prevention of osteoporosis. PATIENTS AND METHODS
Eighty consecutive referrals to a menopausal clinic were placed in a trial of oestriol hemisuccinate (Synapause, Organon). The initial 15-wk period consisted of a doubleblind trial of oestriol hemisuccinate (2 mg BD) versus placebo, to assess the usefulness of
’ To whom requests for reprints should be addressed.
280 the compound for control of menopausal symptoms. At the end of this period the patients were all provided with active oestriol tablets and allowed to ‘increase their daily dose by 2 mg at five weekly intervals until subjective control of symptoms was achieved, or a maximum of 12 mg per day in divided doses was being prescribed. This dose was then continued and the patients followed for 2 yr. Fasting samples of blood and urine were obtained from all patients prior to the start of the trial and after 15 wk. Thereafter samples were taken from all patients just prior to the next increase in daily dose of oestriol. All patients, who did not require an increased dose had subsequent fasting blood and urine samples obtained at five weekly intervals for 25 wk, i.e., until those patients who required it had achieved 5 wk at the maximum dose of 12 mg. Of the 80 patients referred, 61 had undergone a natural menopause and 19 had had bilateral salpingooophorectomy. The age range was 43-51 yr. The mean time from the last menstrual period was 1.75 yr. Biochemical measurements on serum and urine were carried out following standard techniques. Calcium was estimated by atomic absorption spectrophotometry [ 111. Creatinine and phosphorus were measured by the Autoanalyzer techniques Nl 1 and N4, respectively. Alkaline phosphatase in serum was estimated by the method of “King and Wooton” [ 121. Bone mineral content was measured by photon-absorptiometry at the mid-point of the third right metacarpal. Measurements were obtained on all patients at their first visit and thereafter at approximately three monthly intervals until all patients had completed 2 yr at their maximum dose level. The accuracy and reproducibility of this method have been described elsewhere [ 131. Standard statistical methods were used to analyse the results. RESULTS Of the initial 80 patients entered into the trial 72 completed the double-blind study. There was no significant difference between 4 mg oestriol hemisuccinate and placebo when control of the classical menopausal symptoms, hot flushes and sweating attacks, were considered (Lindsay and Hart, unpubl. data). When patients were allowed to increase their daily dose levels, 64 patients agreed to continue. Five patients, of whom three were originally on placebo, stated that 4 mg was an adequate dose to control symptoms. However, 46 patients required 8-12 mg/day for symptomatic relief, and 28 required 12 mg (all therapy in divided doses). Five further patients were unhappy on 12 mg and were removed from the trial. Since this part of the study was not double-blind, we can draw no conclusions on the effect of these higher doses of oestriol on symptom control. The patients who did not wish to continue after the 4 mg daily dose period were all offered other standard oestrogen compounds. Ail achieved adequate symptom control on one ofthese preparations. Serum calcium, phosphate and alkaline phosphatase No significant changes in serum calcium, phosphate or alkaline phosphatase were observed at each dose level (Table I). There was a slight reduction in calcium at 8, 10 and
281 TABLE I Biochemical data from all patients during the trial. No significant changes were recorded. For conversion to SI units divide serum Ca by 4 and serum phosphate by 3.10. Description
Daily dose of oestriol (mg)
Serum Ca (mg/lOO ml) Serum PO4 (mg/lOO ml) Alkaline phosphatase (KA units)
0
4
6
8
12
9.80 + 0.12 3.56 + 0.11
9.70 f 0.08 3.64 * 0.12
9.75 f 0.09 3.59 * 0.16
9.68 i 0.08 3.47 f 0.12
9.65 f 0.12 3.45 + 0.14
9.01 f 0.45
9.21 f 0.44
8.90 + 0.40
8.75 f 0.39
8.69 f 0.44
OESTRIOL HEMISUCCINATE Bone Mined
Content mg/mm
44-
p~o*oo1
43-
42-
41-
YEARS
Fig. 1. The ratio of calcium to creatinine in fasting urine specimens during increasing doses of oestriol hemisuccinate. The results (means i SEM) are expressed in conventional units and the conversion factor to SI units is X0.86. Only those 28 patients who reached 12 mg/day are included in the fgure and statistical differences were calculated using a paired ‘Y-test.
282
12 mg/day but this did not reach significant levels. Analysis using only the results from those 28 patients who reached 12 mg/day revealed identical results to those of the group as a whole, with no significant changes observed. These results are similar to those originally reported by Gallagher and Nordin [14] when daily dose of oestriol hemisuccinate was increased to only 8 mg/day in 10 patients. Urine calciumjcreatinine
Gradually increasing the daily dose of oestriol hemisuccinate produced a fall in calcium/creatinine (Ca/Cr) which became significant at only the 12 mg dose level (PO.01). Using the paired r-test a significant reduction in Ca/Cr was obtained for only those 28 patients who reached 12 mg/day (Fig. 1). Urinary hydroxyproline/creatine
(OH&r)
There was no consistent change in the excretion of hydroxyproline at doses of 4-8 (P 0.05) whether all patients were considered or only those who reached 12 mg/day (Fig. 2). All these measurements were obtained after 5 wk therapy at each dose level. There were no further changes with time and in those patients who were followed for 2 yr the serum and urine values remained similar throughout this period. mg/day . At 12 mg/day there was a significant fall in OH&r
Photonsbsorptiometry
results
The mean metacarpal mineral content of all patients on their first visit was 43.5 + 0.8 mg/mm and of the 28 patients requiring 12 mg/day as final dose, the initial metacarpal
Mean +fSEM
Hydr0xypmline/Creatinine dmg 0.03
pco.05
OESTRIOL HEMWJCCINATE DAILY DOSE (mgl Fig. 2. The ratio of hydroxyproline to creatinine in fasting urine specimens during incremental of oestrioi hemisuccinate. For conversion to SI units multiply by 2.8.
doses
283 Fasting C&r mgh
0.16-
o-140.12-
O.lO-
I I1
**
o.oa-
Means f SEM
pco.01
I
1X
0.06-
I
0
I
2
I
4
I 6
I 8
I 10
I
12
OESTRIOL HEMISUCCINATE DAILY DOSE (mg) Fig.
3. Bone mineral content during 2 yr of treatment with oestriol hemisuccinate (n = 28). Measurement was by Photon absorptiometry and results are means f SEM.
12 mg/day
mineral content was 43.7 f 0.95 mg/mm. During the 2 yr of follow-up 24 of the 28 patients taking 12 mg/day lost bone and the mean metacarpal mineral content fell significantly to 41.9 f 1 .Omg/mm (Fig. 3). Thus the mean rate of bone loss was about 1.9% per annum. This figure is somewhat less than the amount of bone (3.6%) lost by a previous group of placebo-treated postmenopausal patients [3] and to the rate of bone loss incurred by our placebo-treated oophorectomised patients [2,9]. However, it is a significant downward trend and is unlike the effect of mestranol(~*25 mg/day) where virtually no bone is lost during treatment and under certain circumstances an actual gain of bone mass may be achieved [2,9] . The mean rate of bone loss of the 14 patients taking 4-6 mg/day was 2.7% per annum of a figure much closer to that found in our previous and ongoing placebo studies. This suggests that 8-12 mg oestriol hemisuccinate does have some retarding effect on bone loss, but is clearly not so effective as currently prescribed doses of other oestrogens. DISCUSSION It has been shown by several groups that oestrogen therapy prevents postmenopausal bone loss [2,4,5]. The oestrogens used have mostly been the synthetic compound mestranol or conjugated equine oestrogens, but it seems likely that both oestradiol and
284
oestrone themselves will possess this property. However, all these compounds also stimulate endometrial growth and if given continuously for long periods this can result in endometrial hyperplasia, the appearance of atypical histology, and perhaps may result in neoplastic change. Two retrospective reports first suggested that prescription of long-term oestrogen resulted in a clinically evident increased risk of endometrial carcinoma [7,8]. These reports have been heavily criticised, but there is no doubt in recent prospective studies that a significant proportion of patients, given continuous or intermittent oestrogen treatment, have atypical hyperplasia which need not present with postmenopausal bleeding [ 151. Our recent study of patients who have been treated successfully with mestranol, revealed a dramatic loss of bone following cessation of therapy [9]. We concluded that to protect patients from osteoporosis, prolonged treatment, for perhaps lo-20 yr or more would be required. To avoid any risk of endometrial carcinoma in patients with an intact uterus would require a progestogen be added to the therapy. Recent studies have suggested that if the progestogen is to be effective in this respect it must be prescribed for a 10day period or in a continuous fashion rather like the combined contraceptive pill, with a tablet free week to allow endometrial shedding. Progestogen, in a preliminary trial, was also an effective agent in preventing postmenopausal bone loss [3], and had significant beneficial effects on bone mass in a younger premenopausal group of women [16]. Therefore, the addition of a progestogen to oestrogen therapy may not weaken the basic effect on bone. However, it would be much more satisfactory if there was a single agent available which would effectively control symptoms and prevent bone loss, without stimulating endometrial growth. Oestriol has been advocated as the ideal candidate [ 171. Unfortunately, our study does not support this. Four mg/day of oestriol hemisuccinate was ineffective in controlling symptoms, 28 patients (35%) required 12 mg, and five (from 64) were dissatisfied at 12 mg/day. More importantly, in our view, was the fact that 12 mg/day did not prevent loss of bone, which continued at a rate not far short of that maintained by placebo-treated patients of similar age, in our previous studies [2,9]. It is likely that a higher daily dose level would be more successful. We think this is unlikely to be acceptable to patients, their physicians or the licensing authorities. It is notable that at this dose level (12 mg/day) abnormal values for clotting factors VII and X begin to become evident [18] and it is likely that at these higher oral doses the adverse effects recorded by other oestrogens would become evident. REFERENCES
[ 1 ] Aitken, J.M., Hart, D.M. and Lindsay, R., (1973) Oestrogen replacement therapy for the prevention of osteoporosis after oophorectomy. Br. Med. J. ii, 5 15-518. [2] Lindsay, R., Aitken, J.M., Anderson, J.B., Hart, D.M., MacDonald, E.B. and Clark, A.C. (1976) Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet i, 1038-1041. [3 ] Lindsay, R., Hart, D.M., Purdie, D., Ferguson, M.M., Clark, A.C. and Kraszewski, A. (1978) Comparative effects of oestrogen and a progestogen on bone loss in postmenopausal women. Clin. Sci. Mol. Med. 54.193-195. 14] Dequeker, J. and Ferin, J. (1976) Effect of long-term oestrogen therapy on bone remodelhng in women with a natural menopause: cross-sectional and longitudinal study. In: Consensus on menopause research, pp. 124-l 31. Editor: P. van Keep. MTP Press, Lancaster.
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