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Pituitary-ovarian relationships preceding the menopause
Androstenedione metabolism in patients with endometrial cancer ANTHONY
CALANOG,
SANFORD GARY
SALL, G.
A.
LOUIS
New
York,
GORDON, SOUTHREN,
New
M.D.
M.D. M.D. M.D.
York
The plasma concentration of androstenedione and the instantaneous conversion of androstenedione to estrone was increased in patients with endometrial cancer as compared to postmenopausal control subjects. Moreover, the per cent of estrone derived from androstenedione was increased in the cancer group. (AM. J. OBSTET. GYNECOL. 129: 553, 1977.)
ESTROGENS HAVE long been implicated as playing an important role in the etiology of endometrial cancer. The fact that endometrial cancer occurs mostly in women in the postmenopausal age group has led investigators to study the source of estrogens in this age group. Longcope’ and Grodin and associates2 have shown that most, if not all, circulating estrogens in the postmenopausal woman are derived from the peripheral conversion of androgens (principally androstenedione to estrone). Hausknecht and Gusberg, using a urinary dilution technique, reported a significantly increased conversion of androstenedione to estrone in patients with endometrial cancer as compared to postmenopausal patients. In view of the importance of androstenedione metabolism, this report concerns a study of androstenedione metabolism in plasma in patients with endometrial cancer.
postmenopausal patients were admitted for benign conditions and served as controls. All 19 patients were hospitalized under basal conditions (i.e., no drug or hormonal therapy). Pertinent history and physical examinations were obtained. After an overnight fast, the 19 patients were kept in a supine position for at least an hour before the start of the constant-infusion procedure (metabolic clearance rate of androstenedione [ MCR*])was performed. A priming dose of 15 /Xi of 7 3H-androstenedione was given, followed in 30 minutes by an infusion of 30 PCi of the same steroid (in 8 per cent ethanol-saline solution) for 130 minutes at a constant rate of 0.38 ml. per minute. Blood samples of 40 ml. were collected from the opposite arm in heparinized tubes at 130, 145, and 160 minutes after the priming dose. The plasma was separated immediately and frozen at -20” C. until extracted. Analysis of the plasma extracts for MCR* and its conversions to testosterone (CR;:), estrone (CR;?), and estradiol (CRF$ was carried out with Sephadex LH 20 method previously described.4 The analyses for plasma androstenedione, estrone, and estradiol were performed with radioimmunoassay procedures? Statistical evaluation was carried out with a desk-top computer* with appropriate programs.
Material and methods Fourteen patients with postmenopausal bleeding were hospitalized at the New York Medical CollegeMetropolitan Hospital Center and, in each case, the diagnosis of endometrial carcinoma was verified by fractional curettage. A group of five normal
From the Gynecologic Oncology Section of the Departmen; of Obstetrics and Gynecology and the Department of Medicine, New York Medical College. Received for publication
Augwt
Results
5, 1976.
Instantaneous contribution of androstenedione to estrone and estradiol. (CR;2 - PC*; CR;3 - PC*)
Revised June 13, 1977. Accepted June 23, 1977. Reprint requests: Dr. Sanford Sail, New York Medical Collpge, Department of Obstetrics and Gynecology, 1249 Fifth Ave., Mew York, New York 10029.
*Programma New York. 553
101, Olivetti Underwood
Corp., New York,
Table 1. Irl\ra~~t;~neous conversion of androstenedione <‘Stradio1 cotnxrred from androstenedione) --_ Instantaneous conversion androstenedione to
(Pg. /ml.) (CR;;’ PC”)
Endonwtrlal
concw
Mean S.D.
26.6 7.4 1.9 control subjects (No. 10.3
0.3 1
Table II. Metabolic clearance androstenedione: conversion androstenedione to estradiol, endometrial cancer
G. G.
R. S. P. B. c. M. M. v. E. M. B. A. M. A.
0. C. v. C. R. s. P. R. F. F. F. R.
Weight (Pounds) 254 288 194 192 190 102 133 107 150 140 140 151 154 94
Mean &SD. *SE.
derived
Eshadiol
from
androstmedione (%) CR.m PC.4
.. ---..-
I o)w
.ndrc!::‘E
PCE’
it ,I
hiif
cR,gt’* .i,;~’, I pc”T ‘-.
1.87 1.49 0.40
66 18 10
2.15 1.43 0.64
43
42
;
23 IO
J”” j
from
2I 13 :Jl
rates (MCR*), production rates (PR*), and plasma levels (PC*) of ratio (CR@), of androstenedione to estrone, conversion ratio (CR&) of and conversion ratio (CRfi,T) of androstenedione to testosterone in patients
MCRA (L. iday)
MCR%q. (L. ldaylsq.
M. M.)
PC* (Pg. 14
PRA (mg. Iday)
with
CR@ (%J
CR& (%J
CR;; ( %)
1,822 3.680 j875 ,579 786 ,431 ,828 ,171 ,828 ,620 ,411 1,672 1,542 1,049
822 1.586 2:050 969 430 987 1,143 849 1,057 840 840 1,001 924 766
930 1.120 1:140 950 900 1,000 950 950 1,090 1,000 1,050 990 950 930
0.76 1.78 2.34 0.92 0.39 0.99 1.09 0.81 1.15 0.84 0.88 0.99 0.88 0.71
1.2 2.4 8.3 1 .o 1.6 2.7 1.6 3.4 2.1 3.1 1.8 1.1 3.2 3.2
0.2 0.1 0.3 0.1 0.4 0.2 0.2 0.2 0.5 0.1 0.4 0.3 0.2 0.1
11.4 x.9 19.2 14.1 Il.2 26.4 22.4 16.1 16.2 12.7 II.0 11.9 10.3 20.1
1,806 889 237
1,019 387 104
996 75 20
1.04 0.48 0.13
2.6 1.8 0.5
0.23 0.13 0.03
15.13 .5.1X 1.39
(Table I). In patients with endometrial cancer, there is a significantly higher instantaneous conversion of androstenedione to estrone (P < 0.05) but not to estradiol (P > 0.7) as compared to that in postmenopausal control subjects. Per cent of the circulating plasma estrone and estradiol
,ilir 1
= 5)
0.69
S.E.
Subject
(per cent of estrone
(No. = I-fJ
Mean 2S.D. iS.E. Postmenopausal
and estradiol
Es&one converted
of
Estradiol (Pg. ImU (CR;p. PC”)
EStrOtle
I
to estrone
androstenedione
* 100 (Table
I). In
(CR;;’
- PC* . PCE’ patients with
endometrial cancer, 66 per cent of estrone and 21 per cent of estradiol were derived from androstenedione in the blood whereas, in the postmenopausal group, equal amounts of estrone (43 per cent) and estradiol (42 per cent) were derived from this plasma steroid.
Plasma concentration (PC*), metabolic clearance and production rates (PR*) of andros(MCR*), tenedione. (Tables II and III). The mean PC” of endometrial cancer patients was significantly elevated when compared to that of the postmenopausal control subjects (P < 0.02). While the mean MCR* and PRA were somewhat increased in patients with endometrial cancer, the values were not significantly different from those of the postmenopausal control subjects. (P > 0. I and > 0.02, respectively). The MCR*, when corrected for surface area (square meters), showed no difference between the two groups. Plasma estrone (El) and estradiol (Ez) (Tables IV and V). In comparing the postmenopausal control subjects and endometrial cancer group, there was no statistical difference in plasma levels of El and E; (P > 0.3
Volume Number
129 5
Androstenedione
metabolism
in patients
with endometrial
Table III. Metabolic clearance rates (MCR*), production rates (PR*), and plasma levels (PC*) of androstenedione: Conversion ratio (CR;: ) of androstenedione to estrone, conversion ratio (CR@) androstenedione to estradiol, and conversion ratio (CR$,T) of androstenedione to testosterone in postmenopausal control subjects Weight (pour&)
.subjtYt 1. I. v. A. s.
c. N. A. c:. I.
MCRA CL. /day)
180 194 150 154 136
Mean 2S.D. iSI:.
MCRVsq. (Lldaylsq.
M. M.)
13.5 14.2 13.9 14.0 13.9
1,351 194 87
814 117 52
880 104 47
0.72 0.14 0.06
1.18 0.16 0.07
0.24 0.16 0.07
13.9 0.25 0.11
Table V. Estradiol and estrone postmenopausal women (Pg. ImU 7 8 10 8 7 6 6 5 ii 32 4 4 4 a8.14 1.89
The plasma concentration of androstenedione and the instantaneous conversion of androstenedione to estrone was increased in the patients with endometrial
REFERENCES
Subject v. I. V. A. s.
(Pg. 1ml.i
c. N. A. C. I.
23 25 27 24 21
Mean SD.
24 Cl
GYNECOL.
111:
7’78, 1971.
Estradiol (Pg. 1ml.i 4 6 5 6 4 -t5 0.44
cancer as compared to that in the postmenopausal control subjects. Moreover, the per cent of estrone derived from androstenedione was increased in the cancer group. The principal estrogen in the blood of postmenopausal patients is estrone, and this is derived predominantly by peripheral conversion from androstenedione. Thus, it appears that estrone may have a significant effect on the estrogen-responsive organs such as the endometrium. These data confirm the results of Hausknecht and Gusberg using urinary methods and suggest the importance of further studies in this area, particularly the sites of conversion of androstenedione to estrone. Fat tissue5 is an important site of conversion of androgens to estrogens. It has been shown that there is significant efficiency in the method by which circulating androstenedione is converted to estrone with aging,’ obesity,‘, 8 the polycystic ovary syndrome,6 diabetes, and liver disease. The relationship of these conditions to the development of endometrial cancer remains to be established.
2. Grodin, J. M., Siiteri, J. OBSTET.
levels in
Estrone
Estradiol
Comment
AM.
CR46 (%)
0.10 0.49 0.09 0.29 0.24
28.29 L 2.29
C.:
CR;; (W
1.0 1.3 1.4 1.1 1.1
and > 0.4, respectively). The plasma levels of both El and E; are significantly lower than in our normal premenopausal subjects.” Conversion ratio of androstenedione to estrone (CR;;>), estradiol (CR;?), and testosterone (CR;;) (Tables II and III). The CR@1 , CRz$, and CRg,T were not significantly different in the two groups of patients. When the postmenopausal and endometrial cancer patients are compared to premenopausal women studied in our laboratory,4 the former showed a significantly higher conversion ratio of androstenedione to estrone.
1. Longcope,
(%)
0.90 0.59 0.59 0.82 0.69
28 18 46 40 23 27 22 35 20 23 40 23 23 28
Mean S.D.
CR;;1
930 850 710 940 970
(Pg. /ml.)
G. s. 0. C. v. C. R. s. P. R. F. F. F. R.
4)
969 690 830 874 706
Es&one
G. R. P. B. c. M. M. v. E. M. B. A. hf. A.
PR“ hg.
555
of
1,609 1,145 1,378 1,451 1,172
Table IV. Estradiol and Estrone levels in patients with endometrial cancer Subject
PC* (Pg. /ml.)
cancer
Endocrinol.
Metab.
P. K., and MacDonald, 36: 207, 1973.
P. C.: J. Clin.
556
Calanog
3. Hausknecht.
et al.
K., and Gusberg, S.: AM. J. OBSTET. 116: 981, 1973. 4. Olive. J.. Vittek, J., Southren, A. L., Gordon, G., and Rafii, F.: J. Clin. Endocrinol. Metab. 36: 153, 1973. 5. Chen, J. C., Zorn, E. M., Hellberg, M. C., and Wieland: Clin. Chem. 17: 581. 1971. 6. Siiteri, P. Ii., and MacDonald, P. C.: In Greep, R. O., and Artwood, E. B.. editors: Handbook of Physiology, ed. 2, GYNECOL.
vol. 2, Washington, D. C., 1973. American Physlologiul Society, section 7, part I, pp. 615-629. 7. Hinsell, D. L., Grodin, J. M., Brenner, P. F.. Siiteri, P. K.. and MacDonald, P. C.: J. Clin. Endocrinol. Metab. 38: 476, 1974. 8. Rizkallah, T. H.. Tovell, H. M. M., and Kelly. H’. C:.: J. Clin. Endocrinol. Metab. 40: 1045, 1975.
CALANOG,
SANFORD GARY
SALL, G.
A.
LOUIS
New
York,
GORDON, SOUTHREN,
New
M.D.
M.D. M.D. M.D.
York
The plasma concentration of androstenedione and the instantaneous conversion of androstenedione to estrone was increased in patients with endometrial cancer as compared to postmenopausal control subjects. Moreover, the per cent of estrone derived from androstenedione was increased in the cancer group. (AM. J. OBSTET. GYNECOL. 129: 553, 1977.)
ESTROGENS HAVE long been implicated as playing an important role in the etiology of endometrial cancer. The fact that endometrial cancer occurs mostly in women in the postmenopausal age group has led investigators to study the source of estrogens in this age group. Longcope’ and Grodin and associates2 have shown that most, if not all, circulating estrogens in the postmenopausal woman are derived from the peripheral conversion of androgens (principally androstenedione to estrone). Hausknecht and Gusberg, using a urinary dilution technique, reported a significantly increased conversion of androstenedione to estrone in patients with endometrial cancer as compared to postmenopausal patients. In view of the importance of androstenedione metabolism, this report concerns a study of androstenedione metabolism in plasma in patients with endometrial cancer.
postmenopausal patients were admitted for benign conditions and served as controls. All 19 patients were hospitalized under basal conditions (i.e., no drug or hormonal therapy). Pertinent history and physical examinations were obtained. After an overnight fast, the 19 patients were kept in a supine position for at least an hour before the start of the constant-infusion procedure (metabolic clearance rate of androstenedione [ MCR*])was performed. A priming dose of 15 /Xi of 7 3H-androstenedione was given, followed in 30 minutes by an infusion of 30 PCi of the same steroid (in 8 per cent ethanol-saline solution) for 130 minutes at a constant rate of 0.38 ml. per minute. Blood samples of 40 ml. were collected from the opposite arm in heparinized tubes at 130, 145, and 160 minutes after the priming dose. The plasma was separated immediately and frozen at -20” C. until extracted. Analysis of the plasma extracts for MCR* and its conversions to testosterone (CR;:), estrone (CR;?), and estradiol (CRF$ was carried out with Sephadex LH 20 method previously described.4 The analyses for plasma androstenedione, estrone, and estradiol were performed with radioimmunoassay procedures? Statistical evaluation was carried out with a desk-top computer* with appropriate programs.
Material and methods Fourteen patients with postmenopausal bleeding were hospitalized at the New York Medical CollegeMetropolitan Hospital Center and, in each case, the diagnosis of endometrial carcinoma was verified by fractional curettage. A group of five normal
From the Gynecologic Oncology Section of the Departmen; of Obstetrics and Gynecology and the Department of Medicine, New York Medical College. Received for publication
Augwt
Results
5, 1976.
Instantaneous contribution of androstenedione to estrone and estradiol. (CR;2 - PC*; CR;3 - PC*)
Revised June 13, 1977. Accepted June 23, 1977. Reprint requests: Dr. Sanford Sail, New York Medical Collpge, Department of Obstetrics and Gynecology, 1249 Fifth Ave., Mew York, New York 10029.
*Programma New York. 553
101, Olivetti Underwood
Corp., New York,
Table 1. Irl\ra~~t;~neous conversion of androstenedione <‘Stradio1 cotnxrred from androstenedione) --_ Instantaneous conversion androstenedione to
(Pg. /ml.) (CR;;’ PC”)
Endonwtrlal
concw
Mean S.D.
26.6 7.4 1.9 control subjects (No. 10.3
0.3 1
Table II. Metabolic clearance androstenedione: conversion androstenedione to estradiol, endometrial cancer
G. G.
R. S. P. B. c. M. M. v. E. M. B. A. M. A.
0. C. v. C. R. s. P. R. F. F. F. R.
Weight (Pounds) 254 288 194 192 190 102 133 107 150 140 140 151 154 94
Mean &SD. *SE.
derived
Eshadiol
from
androstmedione (%) CR.m PC.4
.. ---..-
I o)w
.ndrc!::‘E
PCE’
it ,I
hiif
cR,gt’* .i,;~’, I pc”T ‘-.
1.87 1.49 0.40
66 18 10
2.15 1.43 0.64
43
42
;
23 IO
J”” j
from
2I 13 :Jl
rates (MCR*), production rates (PR*), and plasma levels (PC*) of ratio (CR@), of androstenedione to estrone, conversion ratio (CR&) of and conversion ratio (CRfi,T) of androstenedione to testosterone in patients
MCRA (L. iday)
MCR%q. (L. ldaylsq.
M. M.)
PC* (Pg. 14
PRA (mg. Iday)
with
CR@ (%J
CR& (%J
CR;; ( %)
1,822 3.680 j875 ,579 786 ,431 ,828 ,171 ,828 ,620 ,411 1,672 1,542 1,049
822 1.586 2:050 969 430 987 1,143 849 1,057 840 840 1,001 924 766
930 1.120 1:140 950 900 1,000 950 950 1,090 1,000 1,050 990 950 930
0.76 1.78 2.34 0.92 0.39 0.99 1.09 0.81 1.15 0.84 0.88 0.99 0.88 0.71
1.2 2.4 8.3 1 .o 1.6 2.7 1.6 3.4 2.1 3.1 1.8 1.1 3.2 3.2
0.2 0.1 0.3 0.1 0.4 0.2 0.2 0.2 0.5 0.1 0.4 0.3 0.2 0.1
11.4 x.9 19.2 14.1 Il.2 26.4 22.4 16.1 16.2 12.7 II.0 11.9 10.3 20.1
1,806 889 237
1,019 387 104
996 75 20
1.04 0.48 0.13
2.6 1.8 0.5
0.23 0.13 0.03
15.13 .5.1X 1.39
(Table I). In patients with endometrial cancer, there is a significantly higher instantaneous conversion of androstenedione to estrone (P < 0.05) but not to estradiol (P > 0.7) as compared to that in postmenopausal control subjects. Per cent of the circulating plasma estrone and estradiol
,ilir 1
= 5)
0.69
S.E.
Subject
(per cent of estrone
(No. = I-fJ
Mean 2S.D. iS.E. Postmenopausal
and estradiol
Es&one converted
of
Estradiol (Pg. ImU (CR;p. PC”)
EStrOtle
I
to estrone
androstenedione
* 100 (Table
I). In
(CR;;’
- PC* . PCE’ patients with
endometrial cancer, 66 per cent of estrone and 21 per cent of estradiol were derived from androstenedione in the blood whereas, in the postmenopausal group, equal amounts of estrone (43 per cent) and estradiol (42 per cent) were derived from this plasma steroid.
Plasma concentration (PC*), metabolic clearance and production rates (PR*) of andros(MCR*), tenedione. (Tables II and III). The mean PC” of endometrial cancer patients was significantly elevated when compared to that of the postmenopausal control subjects (P < 0.02). While the mean MCR* and PRA were somewhat increased in patients with endometrial cancer, the values were not significantly different from those of the postmenopausal control subjects. (P > 0. I and > 0.02, respectively). The MCR*, when corrected for surface area (square meters), showed no difference between the two groups. Plasma estrone (El) and estradiol (Ez) (Tables IV and V). In comparing the postmenopausal control subjects and endometrial cancer group, there was no statistical difference in plasma levels of El and E; (P > 0.3
Volume Number
129 5
Androstenedione
metabolism
in patients
with endometrial
Table III. Metabolic clearance rates (MCR*), production rates (PR*), and plasma levels (PC*) of androstenedione: Conversion ratio (CR;: ) of androstenedione to estrone, conversion ratio (CR@) androstenedione to estradiol, and conversion ratio (CR$,T) of androstenedione to testosterone in postmenopausal control subjects Weight (pour&)
.subjtYt 1. I. v. A. s.
c. N. A. c:. I.
MCRA CL. /day)
180 194 150 154 136
Mean 2S.D. iSI:.
MCRVsq. (Lldaylsq.
M. M.)
13.5 14.2 13.9 14.0 13.9
1,351 194 87
814 117 52
880 104 47
0.72 0.14 0.06
1.18 0.16 0.07
0.24 0.16 0.07
13.9 0.25 0.11
Table V. Estradiol and estrone postmenopausal women (Pg. ImU 7 8 10 8 7 6 6 5 ii 32 4 4 4 a8.14 1.89
The plasma concentration of androstenedione and the instantaneous conversion of androstenedione to estrone was increased in the patients with endometrial
REFERENCES
Subject v. I. V. A. s.
(Pg. 1ml.i
c. N. A. C. I.
23 25 27 24 21
Mean SD.
24 Cl
GYNECOL.
111:
7’78, 1971.
Estradiol (Pg. 1ml.i 4 6 5 6 4 -t5 0.44
cancer as compared to that in the postmenopausal control subjects. Moreover, the per cent of estrone derived from androstenedione was increased in the cancer group. The principal estrogen in the blood of postmenopausal patients is estrone, and this is derived predominantly by peripheral conversion from androstenedione. Thus, it appears that estrone may have a significant effect on the estrogen-responsive organs such as the endometrium. These data confirm the results of Hausknecht and Gusberg using urinary methods and suggest the importance of further studies in this area, particularly the sites of conversion of androstenedione to estrone. Fat tissue5 is an important site of conversion of androgens to estrogens. It has been shown that there is significant efficiency in the method by which circulating androstenedione is converted to estrone with aging,’ obesity,‘, 8 the polycystic ovary syndrome,6 diabetes, and liver disease. The relationship of these conditions to the development of endometrial cancer remains to be established.
2. Grodin, J. M., Siiteri, J. OBSTET.
levels in
Estrone
Estradiol
Comment
AM.
CR46 (%)
0.10 0.49 0.09 0.29 0.24
28.29 L 2.29
C.:
CR;; (W
1.0 1.3 1.4 1.1 1.1
and > 0.4, respectively). The plasma levels of both El and E; are significantly lower than in our normal premenopausal subjects.” Conversion ratio of androstenedione to estrone (CR;;>), estradiol (CR;?), and testosterone (CR;;) (Tables II and III). The CR@1 , CRz$, and CRg,T were not significantly different in the two groups of patients. When the postmenopausal and endometrial cancer patients are compared to premenopausal women studied in our laboratory,4 the former showed a significantly higher conversion ratio of androstenedione to estrone.
1. Longcope,
(%)
0.90 0.59 0.59 0.82 0.69
28 18 46 40 23 27 22 35 20 23 40 23 23 28
Mean S.D.
CR;;1
930 850 710 940 970
(Pg. /ml.)
G. s. 0. C. v. C. R. s. P. R. F. F. F. R.
4)
969 690 830 874 706
Es&one
G. R. P. B. c. M. M. v. E. M. B. A. hf. A.
PR“ hg.
555
of
1,609 1,145 1,378 1,451 1,172
Table IV. Estradiol and Estrone levels in patients with endometrial cancer Subject
PC* (Pg. /ml.)
cancer
Endocrinol.
Metab.
P. K., and MacDonald, 36: 207, 1973.
P. C.: J. Clin.
556
Calanog
3. Hausknecht.
et al.
K., and Gusberg, S.: AM. J. OBSTET. 116: 981, 1973. 4. Olive. J.. Vittek, J., Southren, A. L., Gordon, G., and Rafii, F.: J. Clin. Endocrinol. Metab. 36: 153, 1973. 5. Chen, J. C., Zorn, E. M., Hellberg, M. C., and Wieland: Clin. Chem. 17: 581. 1971. 6. Siiteri, P. Ii., and MacDonald, P. C.: In Greep, R. O., and Artwood, E. B.. editors: Handbook of Physiology, ed. 2, GYNECOL.
vol. 2, Washington, D. C., 1973. American Physlologiul Society, section 7, part I, pp. 615-629. 7. Hinsell, D. L., Grodin, J. M., Brenner, P. F.. Siiteri, P. K.. and MacDonald, P. C.: J. Clin. Endocrinol. Metab. 38: 476, 1974. 8. Rizkallah, T. H.. Tovell, H. M. M., and Kelly. H’. C:.: J. Clin. Endocrinol. Metab. 40: 1045, 1975.