h4aturitos, 12 (1990) 99-104 Elsevier Scientific Publishers Ireland Ltd.
99
MAT 00581
Smoking
induces increased androgen levels in early post-menopausal women
A. Schlemmer,
J. Jensen,
Department of Clinical Chemirtry.
B.J.
Riis and C. Christiansen
Glostrup Hospital University of Copenhagen (Denmark)
(Receive-d31 January 1989; revision received 20 November 1989; accepted 28 February 1990)
In order to clarify the effect of smoking on androgen status in the early post-menopause we examined 267 women aged 45-54 years, of whom 146 (55%) were smokers. The cigarette smokers had a significantly higher serum concentration of androstenedione (P < 0.001) and a raised serum concentration of luteinizing hormone (P = 0.06) in comparison with the non-smokers. The number of cigarettes consumed was apparently immaterial. The concentrations of oestrone. oestradiol and follicle-stimulating hormone were similar in the two groups. This study lends support to the hypothesis that the observed decrease-drisk of endometrial and breast cancer associated with cigarette smoking may be mediated by androgenic protection. (Key words: Androstenedione, Gonadotrophins, Endogenous oestrogens, Post-menopausal smokers)
Introduction Cigarette smoking is one of the established risk factors for the development of cardiovascular disease in both men and women. Furthermore, an increased risk of osteoporotic fractures has been demonstrated in women who smoke [1,2], Nevertheless, despite the many hazards it poses to health, smoking has been claimed to afford protection against endometrial [3,4] and breast cancer in women [5-71. In this connection hormonal mechanisms, in particular an antioestrogenic effect exerted by smoking, have been proposed as mediators of the risks involved [8]. Indeed, lower urinary concentrations of oestrogen and an increased hepatic metabolism of oestrogen have been observed in pre-menopausal smokers as compared with non-smokers [9,10]. Studies in post-menopausal women have failed to detect any smoking-related differences in the serum concentrations of endogenous oestrogen [ 1l-l 31. However, among post-menopausal women receiving oestrogen replacement therapy, smokers were found to have lower serum concentraCorrespondence to: A. Schlemmer.
0378-5122/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
100
tions of oestrogen than non-smokers [ll]. This supports the theory that oestrogen metabolism is increased in smokers. In a recent study in elderly post-menopausal women, Khaw et al. 1121reported significantly higher serum concentrations of androstenedione (A) in smokers than in non-smokers, which the authors thought might explain the protective role played by smoking as regards the development of endometrial or breast cancer. These findings have not been confirmed by other investigators, nor has it been established whether or not smoking exerts a similar effect shortly after the menopause, a period of life in which the incidence of endometrial and breast cancer increases rapidly. The present study sought to clarify these points. Subjects and methods Two hundred and sixty-seven (267) post-menopausal women were selected from a normal population by questionnaire and medical screening examination to participate in a clinical trial [14]. The women were aged 45-54 years and had undergone natural menopause 6 months to 3 years prior to the study. They had oestradiol (E,) levels of below 200 pmol/l and were all free of past or present diseases or medications known to influence the variables studied. Further information regarding the selection criteria has been provided elsewhere [ 141. The present study includes data from the initial clinical examination. Blood samples were taken in the morning after an overnight fast and tobacco abstinence. All samples were stored at - 20°C until analyzed. Hormone measurements These were performed using radioimmunoassays. The E, assay was originally developed to measure the very low serum E, concentration found in post-menopausal women. The antiserum is commercially available and was supplied by CIS International (France). The specificity (cross reaction) is 1.4% in the case of oestrone (E,) and 0.3% in that of oestriol (E,). The maximum binding and non-specific binding values for the tracer were 61.1 f: 6.8% and 4.9 f 5.1070, respectively. The detection limit was 6 pmol/l in 300 ~1 serum. The intra- and interassay variations were 9% and 14%, respectively [IS]. The sensitivity and the intra- and interassay variations for the other hormones measured were as follows-E,: 44 pmol/l, 6% and 11% [15]; A: 0.2 nmol/ 1, 7% and 11% [16]; luteinizing hormone (LH): 3 munit/ml, 5% and 11%; follicle-stimulating hormone (FSH): 2 munit/ml, 3% and 13%. Body weight This was measured with the participants shoes. Smoking records The subjects’ smoking records
wearing light indoor clothing but no
were obtained
by means of questionnaires
101
which the women completed themselves. The validity of the information was assessed in personal interviews. The rate of discrepancy between the responses given in the questionnaires and at the interviews was below 3% (expressed as the percentage variation calculated from duplicate determinations). A smoker was defined as anyone who had smoked at least 3 cigarettes per day during the preceding 6 months. Statistical analyses The t-test for unpaired data was used to assess differences between the two groups. To test interrelationships between the parameters, linear regression analysis was used where one of two parameters was exposed to variation, while Pearson’s correlation analysis was used where both parameters were exposed to variation. Results Fifty-five (55) percent (n = 146) of the women were smokers, the mean consumption being 13 cigarettes daily (range 4-30 cigarettes/day). Body weight was significantly lower among the smokers, averaging 4.3 kg less (P < 0.01) than the mean for the non-smokers (Table I), the two groups being similar with regard to chronological age and height. The smokers were on average 2.6 months older in terms of menopausal age (P < 0.05). The smokers had a 22% higher level of A than the non-smokers (Table II), which was statistically significant (P < 0.001). No significant differences were observed as regards serum E, or E,. Serum FSH concentrations were similar in the smokers and the non-smokers, but the smokers tended to have a higher mean concentration of LH, although the difference failed to reach statistical significance (P = 0.06). No dose-response effect was observed between increasing cigarette consumption and serum concentrations of A (r = 0.05, NS). The correlations between serum E, and E, and between serum A and E, were significant and similar in both the smokers and the non-smokers (r = 0.3%
TABLE I RELEVANT CLINICAL DATA ON 267 POST-MENOPAUSAL SMOKING HABITS
Smokers Non-smokers
WOMEN ACCORDING TO
n
Age (years)
Menopausal age (months)
Weight (kg)
Height (cm)
146 121
50.0 f 2.5 50.4 f 2.4
21.5* + 9.9 18.9 + 9.8
61 7** f 11.0 66.0 f 11.4
162.3 f 5.4 162.7 2 5.8
Values are expressed as mean f S.D. Significance of difference between smokers and non-smokers: *P < 0.05; **P < 0.01.
102 TABLE II MEAN LEVELS OF SEX HORMONES AND GONADOTROPHINS SMOKERS
Androstenedione (nmol/l) Oestrone @mol/l) Oestradiol (pmol/l) FSH (mtmit/ml) LH (munit/ml)
IN SMOKERS AND NON-
Smokers (n = 146)
Non-smokers (n = 121)
Significance of difference
2.95 f
2.42 f 0.99
P< 0.001
1.38
180 f 47
172 f 48
NS
21 I: 16
19 f
14
NS
15 f 50
14 f 21
NS
29 f
27 f
P = 0.06
Values are expressed as mean f mone.
13
10
S.D. FSH = follicle-stimulating
hormone, LH = luteinizing hor-
0.50; P < 0.001) (Table III), whereas no correlations serum A or serum E, and body weight in either group.
were observed between
Discussion Mean body weight in the smokers was significantly lower than that in the nonsmokers. Similar differences in body weight have been reported previously [l-3]. The explanation for this may be the lower calorie intake in smokers, although their metabolism may also be generally increased, as suggested by earlier studies [9,10]. The lower body weight in the smokers might have led to reduced serum concentrations of oestrogen as a result of decreased peripheral conversion of A to E,. However, the serum concentrations of oestrogen were found to be similar in the two groups. TABLE III CORRELATIONS BETWEEN SEX HORMONES AND BODY WEIGHT IN POST-MENOPAUSAL SMOKERS AND NON-SMOKERS Smokers (n = 146)
Non-smokers (n = 121)
E, vs. E, A vs. E,
0.40*** 0.50***
0.35*** 0.50***
E, vs. body wt. A vs. body wt.
0.11 0.05 ,
0.14 0.14
***p < 0.001. E, = oestradiol. E, = oestrone, A = androstenedione.
103
The smokers were 2.6 months older in terms of menopausal age, but it is unlikely that this influenced the findings in the present study. Epidemiological studies have suggested that the risk of developing endometrial or breast cancer is lower in women who smoke [3-71, although the relationship is not understood. The development of both types of cancer is, however, somehow linked to the endogenous sex steroid milieu [8] and studies have demonstrated that smoking in some way influences sex hormone metabolism t9,101. The results of the present study in fact confirm the findings published previously by our own [ll] and other groups [12,13] to the effect that smoking does not lead to reduced serum concentrations of oestrogen in post-menopausal women who are not receiving hormone replacement therapy. In post-menopausal women, the serum concentration of oestrogen is low, approaching the detection limits of many assays. In the present study the sensitivity of the E, assay was 44 pmol/l and that of the E, assay was 6 pmol/l, these values being substantially below the mean post-menopausal levels, which confirms the validity of our oestrogen results. Khaw et al. [12] reported an increased serum concentration of A in smokers as compared with non-smokers and our results confirmed their findings. The reason for this is obscure. Theoretically, it could be due to increased secretion of A in response to direct nicotine stimulation of the adrenals, the pituitary gland or the hypothalamus. Neither the literature nor our study results include any data to support the contention that nicotine has a direct stimulatory action on the adrenals. On the other hand, Suzuki et al. [17] demonstrated that nicotine stimulated the pituitary production of adrenocorticotrophic hormone (ACTH). Furthermore, both humans [18] and rats [19] exhibited a transitory rise in circulating LH levels after nicotine exposure. The results of the present study indicated a strong tendency towards increased LH levels in the smokers, although the rises did not reach statistical significance (P = 0.06). While it is not conclusive, this finding supports the theory that the elevated concentration of A is caused by direct pituitary or hypothalamic stimulation. Our results showed significant correlations between E, and E,, and between A and E,. These correlations have been demonstrated several times before (16,201 and are the result of hormonal inter-convertibility. The correlations in the smokers and the non-smokers were similar, suggesting that smoking does not interfere with the conversion processes. This is further supported, of course, by the similar E, concentrations in the two groups. A significant, but relatively weak, correlation between E, and fat mass has been demonstrated previously [16,21] and was confirmed in the present study, although our results did not reach significance. There is no doubt that fat mass is a determinant of serum E, in post-menopausal women, although it undoubtedly acts in concert with other factors. Our results demonstrate that early post-menopausal women who smoke have a lower body weight and a higher serum concentration of A than non-smokers. The latter effect may be due to direct nicotine stimulation of ACTH production in the
104
pituitary gland. This finding suggests that protection against smoking-related cancers of the reproductive organs is afforded by increased androgenic rather than oestrogenic activity as previously postulated. Further investigations are needed in this area to gain deeper insight into this question. References 1
2
3 4
5 6
10 11 12 13 14
15
16
17 18 19 20 21
Daniel1 HW. Osteoporosis of the slender smoker. Arch Intern Med 1976; 136: 298-304. Williams AR, Weiss NS, Ure CL, Ballard J, Daling JR. Effect of weight, smoking and estrogen use on the risk of hip and forearm fractures in postmenopausal women. Obstet Gynecol 1982; 60: 695-699. Lawrence C. Tessaro I, Durgerian S, Caputo T, Richart R, Jacobson M, Greenwald P. Smoking, body weight and early-stage endometrial cancer. Cancer 1987; 59: 1665-1669. Lesko SM, Rosenberg L, Kaufman DW, Helmrich SP, Miller DR, Strom B, Schottenfeld D, Rosenheim NB, Knapp RC, Lewis J, Shapiro S. Cigarette smoking and the risk of endometrial cancer. N Engl J Med 1985; 313: 593-596. Vessey M, Baron J, Doll R, McPherson K, Yeates D. Oral contraceptives and breast cancer: Final report of an epidemiological study. Br J Cancer 1983; 47: 455-462. Williams RR, Horn JW. Association of cancer sites with tobacco and alcohol consumption and socio-economics status of patients: interview study from the Third National Cancer Survey. INCI 1977; 58: 525-547. O’Connell DL, Hulka BS, Chambless LE, Wilkinson WE, Deubner DC. Cigarette smoking, alcohol consumption, and breast cancer risk. J Nat1 Cancer Inst 1987; 78: 229-234. Baron JA. Smoking and estrogen-related disease. Am J Epidemiol 1984; 119: 9-22. Michnovicz JJ, Hershcope RJ, Naganuma H, Bradlow HL, Fishman J. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med 1986; 315: 1305-1309. Hart P, Farrell GC, Cooksley WGE, Powell LW. Enhanced drug metabolism in cigarette smokers. Br Med J 1976; 2: 147-149. Jensen J, Christiansen C, Rodbro P. Cigarette smoking, serum estrogens, and bone loss during hormone replacement therapy early after menopause. N Engl J Med 1985; 313: 973-975. Khaw KT, Tazuke S, Barrett-Connor E. Cigarette smoking and levels of adrenal androgensin post-menopausal women. N Engl J Med 1988; 318: 1705-1709. Friedman AJ, Ravnikar VA, Barbieri RI. Serum steroid hormone profiles in postmenopausal smokers and non-smokers. Fertil Steril 1987; 47: 398-401. Christiansen C, Christensen MS, McNair P, Hagen C, Stocklund KE, Transbol I. Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females. Eur J Clin Invest 1980; 10: 273-279. Jensen J, Riis BJ, Hummer L, Christiansen C. The effects of age and body composition on circulating serum oestrogens and androstenedione after the menopause. Br J Obstet Gynecol 1985; 92: 260-265. Hummer L, Nielsen MD, Christiansen C. An easy and reliable radioimmunoassay of serum androstenedione: age-related normal values in 252 females aged 2 to 70 years. Stand J Clin Lab Invest 1983; 43: 301-306. Suzuki T, Ikeda H, Narita S, Shibata 0, Waki S, Egashira H. Adrenal cortical secretion in response to nicotine in conscious and anaesthetized dogs. Q J Exp Physiol 1973; 58: 139-142. Winternitz WW, Quillen D. Acute hormonal response to cigarette smoking. J Clin Pharmacol 1977; 17: 389-397. Blake CA. Paradoxical effect of drugs acting on the central nervous system on the preovulatory release of pituitary luteinizing hormone in pro-oestrous rats. J Endocrinol 1978; 79: 319-326. Rozenberg S, Bosson D, Peretz A, Caufriez A, Robyn C. Serum levels of gonadotrophins and steroid hormones in the post-menopause and later life. Maturitas 1988; 10: 215-224. Poortman J, Thijssen JHH, De Waard F. Plasma oestrone, oestradiol and androstenedione levels in post-menopausal women: Relation to body weight and height. Maturitas 1981; 3: 65-71.
99
MAT 00581
Smoking
induces increased androgen levels in early post-menopausal women
A. Schlemmer,
J. Jensen,
Department of Clinical Chemirtry.
B.J.
Riis and C. Christiansen
Glostrup Hospital University of Copenhagen (Denmark)
(Receive-d31 January 1989; revision received 20 November 1989; accepted 28 February 1990)
In order to clarify the effect of smoking on androgen status in the early post-menopause we examined 267 women aged 45-54 years, of whom 146 (55%) were smokers. The cigarette smokers had a significantly higher serum concentration of androstenedione (P < 0.001) and a raised serum concentration of luteinizing hormone (P = 0.06) in comparison with the non-smokers. The number of cigarettes consumed was apparently immaterial. The concentrations of oestrone. oestradiol and follicle-stimulating hormone were similar in the two groups. This study lends support to the hypothesis that the observed decrease-drisk of endometrial and breast cancer associated with cigarette smoking may be mediated by androgenic protection. (Key words: Androstenedione, Gonadotrophins, Endogenous oestrogens, Post-menopausal smokers)
Introduction Cigarette smoking is one of the established risk factors for the development of cardiovascular disease in both men and women. Furthermore, an increased risk of osteoporotic fractures has been demonstrated in women who smoke [1,2], Nevertheless, despite the many hazards it poses to health, smoking has been claimed to afford protection against endometrial [3,4] and breast cancer in women [5-71. In this connection hormonal mechanisms, in particular an antioestrogenic effect exerted by smoking, have been proposed as mediators of the risks involved [8]. Indeed, lower urinary concentrations of oestrogen and an increased hepatic metabolism of oestrogen have been observed in pre-menopausal smokers as compared with non-smokers [9,10]. Studies in post-menopausal women have failed to detect any smoking-related differences in the serum concentrations of endogenous oestrogen [ 1l-l 31. However, among post-menopausal women receiving oestrogen replacement therapy, smokers were found to have lower serum concentraCorrespondence to: A. Schlemmer.
0378-5122/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
100
tions of oestrogen than non-smokers [ll]. This supports the theory that oestrogen metabolism is increased in smokers. In a recent study in elderly post-menopausal women, Khaw et al. 1121reported significantly higher serum concentrations of androstenedione (A) in smokers than in non-smokers, which the authors thought might explain the protective role played by smoking as regards the development of endometrial or breast cancer. These findings have not been confirmed by other investigators, nor has it been established whether or not smoking exerts a similar effect shortly after the menopause, a period of life in which the incidence of endometrial and breast cancer increases rapidly. The present study sought to clarify these points. Subjects and methods Two hundred and sixty-seven (267) post-menopausal women were selected from a normal population by questionnaire and medical screening examination to participate in a clinical trial [14]. The women were aged 45-54 years and had undergone natural menopause 6 months to 3 years prior to the study. They had oestradiol (E,) levels of below 200 pmol/l and were all free of past or present diseases or medications known to influence the variables studied. Further information regarding the selection criteria has been provided elsewhere [ 141. The present study includes data from the initial clinical examination. Blood samples were taken in the morning after an overnight fast and tobacco abstinence. All samples were stored at - 20°C until analyzed. Hormone measurements These were performed using radioimmunoassays. The E, assay was originally developed to measure the very low serum E, concentration found in post-menopausal women. The antiserum is commercially available and was supplied by CIS International (France). The specificity (cross reaction) is 1.4% in the case of oestrone (E,) and 0.3% in that of oestriol (E,). The maximum binding and non-specific binding values for the tracer were 61.1 f: 6.8% and 4.9 f 5.1070, respectively. The detection limit was 6 pmol/l in 300 ~1 serum. The intra- and interassay variations were 9% and 14%, respectively [IS]. The sensitivity and the intra- and interassay variations for the other hormones measured were as follows-E,: 44 pmol/l, 6% and 11% [15]; A: 0.2 nmol/ 1, 7% and 11% [16]; luteinizing hormone (LH): 3 munit/ml, 5% and 11%; follicle-stimulating hormone (FSH): 2 munit/ml, 3% and 13%. Body weight This was measured with the participants shoes. Smoking records The subjects’ smoking records
wearing light indoor clothing but no
were obtained
by means of questionnaires
101
which the women completed themselves. The validity of the information was assessed in personal interviews. The rate of discrepancy between the responses given in the questionnaires and at the interviews was below 3% (expressed as the percentage variation calculated from duplicate determinations). A smoker was defined as anyone who had smoked at least 3 cigarettes per day during the preceding 6 months. Statistical analyses The t-test for unpaired data was used to assess differences between the two groups. To test interrelationships between the parameters, linear regression analysis was used where one of two parameters was exposed to variation, while Pearson’s correlation analysis was used where both parameters were exposed to variation. Results Fifty-five (55) percent (n = 146) of the women were smokers, the mean consumption being 13 cigarettes daily (range 4-30 cigarettes/day). Body weight was significantly lower among the smokers, averaging 4.3 kg less (P < 0.01) than the mean for the non-smokers (Table I), the two groups being similar with regard to chronological age and height. The smokers were on average 2.6 months older in terms of menopausal age (P < 0.05). The smokers had a 22% higher level of A than the non-smokers (Table II), which was statistically significant (P < 0.001). No significant differences were observed as regards serum E, or E,. Serum FSH concentrations were similar in the smokers and the non-smokers, but the smokers tended to have a higher mean concentration of LH, although the difference failed to reach statistical significance (P = 0.06). No dose-response effect was observed between increasing cigarette consumption and serum concentrations of A (r = 0.05, NS). The correlations between serum E, and E, and between serum A and E, were significant and similar in both the smokers and the non-smokers (r = 0.3%
TABLE I RELEVANT CLINICAL DATA ON 267 POST-MENOPAUSAL SMOKING HABITS
Smokers Non-smokers
WOMEN ACCORDING TO
n
Age (years)
Menopausal age (months)
Weight (kg)
Height (cm)
146 121
50.0 f 2.5 50.4 f 2.4
21.5* + 9.9 18.9 + 9.8
61 7** f 11.0 66.0 f 11.4
162.3 f 5.4 162.7 2 5.8
Values are expressed as mean f S.D. Significance of difference between smokers and non-smokers: *P < 0.05; **P < 0.01.
102 TABLE II MEAN LEVELS OF SEX HORMONES AND GONADOTROPHINS SMOKERS
Androstenedione (nmol/l) Oestrone @mol/l) Oestradiol (pmol/l) FSH (mtmit/ml) LH (munit/ml)
IN SMOKERS AND NON-
Smokers (n = 146)
Non-smokers (n = 121)
Significance of difference
2.95 f
2.42 f 0.99
P< 0.001
1.38
180 f 47
172 f 48
NS
21 I: 16
19 f
14
NS
15 f 50
14 f 21
NS
29 f
27 f
P = 0.06
Values are expressed as mean f mone.
13
10
S.D. FSH = follicle-stimulating
hormone, LH = luteinizing hor-
0.50; P < 0.001) (Table III), whereas no correlations serum A or serum E, and body weight in either group.
were observed between
Discussion Mean body weight in the smokers was significantly lower than that in the nonsmokers. Similar differences in body weight have been reported previously [l-3]. The explanation for this may be the lower calorie intake in smokers, although their metabolism may also be generally increased, as suggested by earlier studies [9,10]. The lower body weight in the smokers might have led to reduced serum concentrations of oestrogen as a result of decreased peripheral conversion of A to E,. However, the serum concentrations of oestrogen were found to be similar in the two groups. TABLE III CORRELATIONS BETWEEN SEX HORMONES AND BODY WEIGHT IN POST-MENOPAUSAL SMOKERS AND NON-SMOKERS Smokers (n = 146)
Non-smokers (n = 121)
E, vs. E, A vs. E,
0.40*** 0.50***
0.35*** 0.50***
E, vs. body wt. A vs. body wt.
0.11 0.05 ,
0.14 0.14
***p < 0.001. E, = oestradiol. E, = oestrone, A = androstenedione.
103
The smokers were 2.6 months older in terms of menopausal age, but it is unlikely that this influenced the findings in the present study. Epidemiological studies have suggested that the risk of developing endometrial or breast cancer is lower in women who smoke [3-71, although the relationship is not understood. The development of both types of cancer is, however, somehow linked to the endogenous sex steroid milieu [8] and studies have demonstrated that smoking in some way influences sex hormone metabolism t9,101. The results of the present study in fact confirm the findings published previously by our own [ll] and other groups [12,13] to the effect that smoking does not lead to reduced serum concentrations of oestrogen in post-menopausal women who are not receiving hormone replacement therapy. In post-menopausal women, the serum concentration of oestrogen is low, approaching the detection limits of many assays. In the present study the sensitivity of the E, assay was 44 pmol/l and that of the E, assay was 6 pmol/l, these values being substantially below the mean post-menopausal levels, which confirms the validity of our oestrogen results. Khaw et al. [12] reported an increased serum concentration of A in smokers as compared with non-smokers and our results confirmed their findings. The reason for this is obscure. Theoretically, it could be due to increased secretion of A in response to direct nicotine stimulation of the adrenals, the pituitary gland or the hypothalamus. Neither the literature nor our study results include any data to support the contention that nicotine has a direct stimulatory action on the adrenals. On the other hand, Suzuki et al. [17] demonstrated that nicotine stimulated the pituitary production of adrenocorticotrophic hormone (ACTH). Furthermore, both humans [18] and rats [19] exhibited a transitory rise in circulating LH levels after nicotine exposure. The results of the present study indicated a strong tendency towards increased LH levels in the smokers, although the rises did not reach statistical significance (P = 0.06). While it is not conclusive, this finding supports the theory that the elevated concentration of A is caused by direct pituitary or hypothalamic stimulation. Our results showed significant correlations between E, and E,, and between A and E,. These correlations have been demonstrated several times before (16,201 and are the result of hormonal inter-convertibility. The correlations in the smokers and the non-smokers were similar, suggesting that smoking does not interfere with the conversion processes. This is further supported, of course, by the similar E, concentrations in the two groups. A significant, but relatively weak, correlation between E, and fat mass has been demonstrated previously [16,21] and was confirmed in the present study, although our results did not reach significance. There is no doubt that fat mass is a determinant of serum E, in post-menopausal women, although it undoubtedly acts in concert with other factors. Our results demonstrate that early post-menopausal women who smoke have a lower body weight and a higher serum concentration of A than non-smokers. The latter effect may be due to direct nicotine stimulation of ACTH production in the
104
pituitary gland. This finding suggests that protection against smoking-related cancers of the reproductive organs is afforded by increased androgenic rather than oestrogenic activity as previously postulated. Further investigations are needed in this area to gain deeper insight into this question. References 1
2
3 4
5 6
10 11 12 13 14
15
16
17 18 19 20 21
Daniel1 HW. Osteoporosis of the slender smoker. Arch Intern Med 1976; 136: 298-304. Williams AR, Weiss NS, Ure CL, Ballard J, Daling JR. Effect of weight, smoking and estrogen use on the risk of hip and forearm fractures in postmenopausal women. Obstet Gynecol 1982; 60: 695-699. Lawrence C. Tessaro I, Durgerian S, Caputo T, Richart R, Jacobson M, Greenwald P. Smoking, body weight and early-stage endometrial cancer. Cancer 1987; 59: 1665-1669. Lesko SM, Rosenberg L, Kaufman DW, Helmrich SP, Miller DR, Strom B, Schottenfeld D, Rosenheim NB, Knapp RC, Lewis J, Shapiro S. Cigarette smoking and the risk of endometrial cancer. N Engl J Med 1985; 313: 593-596. Vessey M, Baron J, Doll R, McPherson K, Yeates D. Oral contraceptives and breast cancer: Final report of an epidemiological study. Br J Cancer 1983; 47: 455-462. Williams RR, Horn JW. Association of cancer sites with tobacco and alcohol consumption and socio-economics status of patients: interview study from the Third National Cancer Survey. INCI 1977; 58: 525-547. O’Connell DL, Hulka BS, Chambless LE, Wilkinson WE, Deubner DC. Cigarette smoking, alcohol consumption, and breast cancer risk. J Nat1 Cancer Inst 1987; 78: 229-234. Baron JA. Smoking and estrogen-related disease. Am J Epidemiol 1984; 119: 9-22. Michnovicz JJ, Hershcope RJ, Naganuma H, Bradlow HL, Fishman J. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med 1986; 315: 1305-1309. Hart P, Farrell GC, Cooksley WGE, Powell LW. Enhanced drug metabolism in cigarette smokers. Br Med J 1976; 2: 147-149. Jensen J, Christiansen C, Rodbro P. Cigarette smoking, serum estrogens, and bone loss during hormone replacement therapy early after menopause. N Engl J Med 1985; 313: 973-975. Khaw KT, Tazuke S, Barrett-Connor E. Cigarette smoking and levels of adrenal androgensin post-menopausal women. N Engl J Med 1988; 318: 1705-1709. Friedman AJ, Ravnikar VA, Barbieri RI. Serum steroid hormone profiles in postmenopausal smokers and non-smokers. Fertil Steril 1987; 47: 398-401. Christiansen C, Christensen MS, McNair P, Hagen C, Stocklund KE, Transbol I. Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females. Eur J Clin Invest 1980; 10: 273-279. Jensen J, Riis BJ, Hummer L, Christiansen C. The effects of age and body composition on circulating serum oestrogens and androstenedione after the menopause. Br J Obstet Gynecol 1985; 92: 260-265. Hummer L, Nielsen MD, Christiansen C. An easy and reliable radioimmunoassay of serum androstenedione: age-related normal values in 252 females aged 2 to 70 years. Stand J Clin Lab Invest 1983; 43: 301-306. Suzuki T, Ikeda H, Narita S, Shibata 0, Waki S, Egashira H. Adrenal cortical secretion in response to nicotine in conscious and anaesthetized dogs. Q J Exp Physiol 1973; 58: 139-142. Winternitz WW, Quillen D. Acute hormonal response to cigarette smoking. J Clin Pharmacol 1977; 17: 389-397. Blake CA. Paradoxical effect of drugs acting on the central nervous system on the preovulatory release of pituitary luteinizing hormone in pro-oestrous rats. J Endocrinol 1978; 79: 319-326. Rozenberg S, Bosson D, Peretz A, Caufriez A, Robyn C. Serum levels of gonadotrophins and steroid hormones in the post-menopause and later life. Maturitas 1988; 10: 215-224. Poortman J, Thijssen JHH, De Waard F. Plasma oestrone, oestradiol and androstenedione levels in post-menopausal women: Relation to body weight and height. Maturitas 1981; 3: 65-71.
