Testosterone metabolism in endometrial cancer ANTHONY
CALANOG,
SANFORD
SALL,
GARY
G.
JAIME
OLIVO.
A.
M.D. M.D.
GORDON,
LOUIS
M.D. M.D.
SOUTHREN,
M.D.
New York, New York
Plasma testosterone (PC’), metabolic ckaranre (MCRT), a?Ld production rates (PRT) of testosterone and conversion ratio of testosterone to androstenrdionr (CR::) were performed on I1 patients with endometrial cancer and on a control group offive postmenopausal women. The PC’, MCR’, and PRT of patients with endometrial cancer are in the normal postmenopausal range. The conversion of testosterone to androstenedione in patients with endometrial cavxer was significantly decreased.
associated with a reported 20 per cent incidence of‘ endometrial cancer.‘O-I2 This condition is associated with increased plasma levels, production and metabolic clearance of testosterone, as well as elevated gonadotropins.r3, r* steroid Sal1 and Calanogrs evaluated the urinary excretion patterns of postmenopausal women with benign and neoplastic endometrium and corroborated the findings of low androsterone and etiocholanolone excretions in women with endometrial hyperplasia and cancer. The introduction of precise methods for measuring plasma levels and production rates of the various androgens and their conversions to the eStrcJgens has provided a unique opportunitv to determint whether a distinct abnormality in androgen metabolism is indeed present in endometrial cancer. Our study in endometrial cancer patients encompassed three areas: (1) the evaluation of testosterone metabolism, (2) the evaluation of androstenedione metabolism and its conversions to estrogens, and (3) the evaluation of estrogen metabolism. This initial report concerns itself with the testosterone levels, metabolic clearance rates, production rates, and interconversions to androstenedione of patients with endometrial cancer.
EPIDEMIOLOGIC studies suggest that estrogens may play an etiologic role in the development of malignancy in women, particularly in breast and endometrial cancer.lw3 Recent studies have also indicated alterations in androgen metabolism in breast and endometrial cancer.4* 5 Bulbrook and associateFs found that a discriminant function can be derived from a study of the urinary excretion patterns of 17-ketosteroids and 17-hydroxycorticoids. Patients with a positive discrimand/or inant, i.e., those with a high etiocholanolone androsterone excretion relative to the 17-hydroxycorticoids, tended to benefit from adrenalectomy with oophorectomy or hypophysectomy, whereas those with a negative discriminant did not respond. De Waard and associates9 applied Bulbrook’s concept of a hormonal discriminant function to patients with endometrial cancer and have shown that those patients excreted less etiocholanolone relative to 17-hydroxycorticoids or estrogens (mainly estriol) than normal controls. Moreover, the polycystic ovary syndrome (PCOS), characterized by anovulation and sclerocystic ovaries, is From the Gynecologic Onmlogy Section of the Department of Obstetrics and Gynecology and the Department of Medicine, New York Medical College. Received for publication Revised January Accepted Januaq
October 8, 1974.
Materials and m&hods
8, 1975.
Eleven patients (two premenopausal and nine postmenopausal) with abnormal uterine bleeding were hospitalized at the New York Medical College and the diagnosis of endometrial cancer was made by fractional
8, 1975.
Rupint requests: Sanford Sail, M.D., Neul York Medical College, Department of Obstetrics and Gynecology, 1249 Fi)h Ave., New York, New York 10029.
60
Testosterone metabolism in endometrial cancer
Volume Number
124 1
Table
I. Clinical
Patient
it. L.C. A.W.
II.
Clinical
of endometrial
Ht. (in.)
Age 46 54 58 45 55 60 60 69 78
L.M. B.F. J.G. M.F. B.S. KS. E.J.
Table
1
summary
65 60 67 61 60 62 64 61 64 64 65
summary
cancer patients Stage of disease
180 110 230 135 88 198 190 142 230 195 125
Pre-existing
Hypertension, diabetes Hypertension Obesity, hypertension, diabetes None Hypertension, diabetes Hypertension, obesity Obesity, diabetes, hypertension Hypertension Obesity, hypertension Obesity, hypertension Hypertension
I I 1 I I II II II II II III
of postmenopausal
medical problem
Years menop.
Premenop. 5 10
Premenop. 10 11 11 19 30 5 30
Body area fM.7 I.89 1.45 2.14 1.60 1.31 1.95 1.92 1.63 2.08 1.94 1.62
controls
Control
Age
Ht. (in.)
wt. (lbs.)
Coexisting medical disease
V.C.
56 53 51 62 55
62 64 61 61 64
186 195 128 165 148
None
I.P. M.Y. D.D. J.C.
61
curettage. A group of five postmenopausal patients served as controls. Clinical summaries of both groups are in Tables I and II. All patients were hospitalized under basal conditions. The pertinent history and physical examination were obtained. The metabolic clearance (MCR) and production (PR) rates of testosterone and conversion of testosterone to androstenedione were determined with a constant infusion procedure.13 After an overnight fast the patients were kept in a supine position for at least 1 hour before the start until the end of the constant infusion. The plasma concentration of free testosterone was measured by the protein displacement method of Mayes and Nugent.“j In the constant infusion procedure, a priming dose of either 4 or 6 &i of 1,Z3H-testosterone (sp. gr. 137 &i/pg and found to be 97 per cent pure by paper chromatography in a modified Bush B 3 System) was first administered intravenously as a single injection. Thirty minutes later, an intravenous infusion was started containing either 8 or 12 &i of 1,23H-testosterone dissolved in 50 ml. of 8 per cent ethanol in saline. The labeled steroid was given at a constant rate with the aid of a Harvard pump (Model No. 6001900). Then 40 ml. of blood were withdrawn at 105, 120, and 135 minutes after initial injection. The plasma was added to tubes containing 4-14C-tesseparated, tosterone and processed. The value of the radioactivity in each plasma sample present specifically as
None None None None
Years post-men0 7 4 4 14 IO
Body area CM.‘) 1.86 1.92 1.58 1.70 1.64
testosterone and corrected for losses during the isolation procedure was calculated. The mean of the three estimates and the value for the rate of the radioactive infusion (R) were taken to calculate the metabolic clearance rate (MCR) according to the following expression: MCR (L./day) = r (m&i/day)/ Ci(m&i/L.). The production rate (PR) of testosterone was then calculated from the expression (PR [mg./day] = MCR [L./day] x MPC [mg./L.]), where MPC is the mean plasma concentration of testosterone.
Results The kinetic parameters of testosterone metabolism in normal postmenopausal women and in patients with endometrial cancer are given in Tables III and IV, respectively. Plasma testosterone (PCT). The mean PCT (0.60 2 0.34 [SD.] &L.) in the endometrial cancer group was compared to the mean PCT (0.40 ? 0.20 [S.D.] pg/L.) of the normal postmenopausal patient group and to a group of 14 normal premenopausal women (0.54 ? 0.11 [SD.] pg/L.) previously evaluated in our laboratory .I7 There was no significant difference between the mean PCT in the endometrial cancer group and the normal premenopausal and postmenopausal groups. Metabolic clearance rates of testosterone (MCRT). The mean MCRT (735 I 180 [S.D.] L./day) in the
62
Calanog et al.
,[anuarv I, 154% Am. .J. Oh&t.
Table III. Plasma concentrations, in postmenopausal controls
metabolic
clearances,
PCT (I@.)
Pat&t
production
rates, and interconversions
of testosterone
PRT (&day)
CR2
MCRT (L. iday)
-I::.
0.76 0.38
823 698
625 558
0.042 0.040
M.Y. D.D. J.C.
0.28 0.30 0.29
714 721 695
200 216 202
0.043 0.039 0.041
730 ‘- 53
364 f 218
Mean & (S.D.)
0.402
Table IV. Plasma concentrations, in endometrial cancer patients Patient
Stage of disease
L.M. B.F. J.G. M.F. B.S. R.S. E.J. J.F. ES. L.C. A.W.
I I I I I II II II II II III
Mean t (S.D.)
” 0.20
metabolic
clearances, T
(ig) 1.04 0.62 1.21 0.54 0.52 0.55 0.35 0.99 0.75 0.22 0.65 0.60
+ 0.34
endometrial cancer group was compared to the mean MCRT (730 2 53 [SD.] L./day) of the normal postmenopausal patient group and to a group of 14 normal premenopausal women (675 ? 139 [S.D.] L./day) previously evaluated in our laboratory.” There was no significant difference between the mean MCRT in the endometrial cancer group and the normal premenopausal (P > 0.4) and postmenopausal groups (P > 0.6). Production rates of testosterone (PRT). The mean PRT (502 r+ 238 [SD.] pg/day) in the endometrial cancer group was compared to the mean PRT (364 + 218 [SD.] kg/day) of the normal postmenopausal patient group and to a group of 14 normal premenopausal women (350 t 130 [SD.] pg/day) previously evaluated in our laboratory.” There was no significant difference between the mean PRT in the endometrial cancer group and the normal premenopausal (P > 0.6) and postmenopausal groups (P > 0.1). Conversion ratios of testosterone (CR%). The mean CR:: (0.02 +- 0.01 [SD.]) in the endometrial cancer group was compared to the mean CR%$ (0.04 % 0.01 [SD.]) of the normal postmenopausal patient group and to a group of 12 PCOS patientsI (0.034 r 0.019 [S.D.]) as previously evaluated in our laboratory. The endometrial cancer group had a statistically lower
production
Gynecol.
0.042
rates and interconversions
MCRT (L. lday)
of testosterone
PRT (/&day)
667 594 632 857 430 800 682 703 1046 793 952
694 368 765 463 224 509 239 696 785 175 619
735 2 180
502 iz 238
mean CR:: (P < 0.05).
2 0
than
the
0.020 0.018 0.030 0.02 1 0.019 0.020 0.011 0.017 0.018 0.028 0.018 0.020
post
menopausal
2 0.005
group
Comment During the past decade, there has developed the concept that endometrial cancer is a malignancy associated with an underlying endocrinopathy. The fact that it occurs mostly in women in the postmenopausal age group, in the presence of abnormal and/or unopposed estrogen stimulation, in association with diabetes and obesity, or in women with a history of infertility and anovulation such as in polycystic ovary syndrome, suggests a relationship between the derangement in the endocrine metabolism of these women and the development of the neoplasm. When the MCRT, PCT, and PRT are compared there is no significant difference noted between the endometrial cancer and the normal postmenopausal patient. Although the mean PRT of the two groups of patients are not statistically different, there is a suggestive increase in the PRT in the endometrial cancer patient. The conversion ratio of testosterone to androstenedione, however, is significantly decreased in the endometrial cancer group, as compared to the control group. The significance of the decreased conversion of testosterone to androstenedione is not known.
Volume Number
124 1
REFERENCES 1. MacMahon, B., and Cole, P. H.: Etiology of Human Breast Cancer: A Review Prepared for the Epidemiology Subcommittee, Breast Cancer Task Force, 1972. 2. Sherman, A. I., and Woolf, R. B.: AM. J. OBSTET. GYNECOL. 77: 233, 1959. 3. Wynder, E. I., Escher, G., and Mantel, N.: Cancer 19: 469, 1966. 4. Bulbrook, R. D., Hayward, J. L., and Thomas, B. S.: Lancet 1: 945, 1964. 5. DeWaard, F.: Int. J. Cancer 4: 577, 1969. 6. Bulbrook, R. D., Greenwood, F. G., and Hayward, J. L.: Lancet 1: 1154, 1960. 7. Bulbrook, R. D., Hayward, J. L., Spicer, C. C., and Thomas, B. S.: Lancet 2: 1235, 1962. 8. Bulbrook, R. D., Hayward, J. L., Spicer, C. C., and Thomas, B. S.: Lancet 2: 1238, 1962. 9. De Waard, F., Thyssen, J. H. H., Veeman, W.. and Sander, P. C.: Cancer 22: 988, 1968.
Testosterone metabolism in endometrial cancer
10. Dockerty, OBSTET.
63
M. B., Lovelady, S. B., and Foust, G. T.: AM. J. 61: 966. 1951. H.: Surg. Obstet. Gynecol. 88: 322, 1949. S. C., Hertig, A. T., and Bengioss, H.: Cancer, 1949. A. L., Gordon, G. G., Tochimoto, S., Olivo, I., D. H., and Pinzon, G.: J. Clin. Endocrinol. 29: 1356. 1969. C. W., and Lipsett, M.: J. Clin. Invest. 46: 891, GYNECOL.
11. Speert, 12. Sommers, 2: 957, 13. Southren, Sherman, Metab. 14. Bardin, 1967. 15. Sail, S., and Calanog, A.: AM. J. 153, 1972. 16. Mayes, D., and Nugent, C. A.: J. 29: 164, 1969. 17. Southren, A. L., Gordon, G. G., G., Lane, D., and Stypulkowski, Metab. 27: 686, 1967.
OBSTET.
Clin.
GYNECOL.
Endocrinol.
Tochiomoto, W.: J. Clin.
114: Metab.
S., Pinzon, Endocrinol.
CALANOG,
SANFORD
SALL,
GARY
G.
JAIME
OLIVO.
A.
M.D. M.D.
GORDON,
LOUIS
M.D. M.D.
SOUTHREN,
M.D.
New York, New York
Plasma testosterone (PC’), metabolic ckaranre (MCRT), a?Ld production rates (PRT) of testosterone and conversion ratio of testosterone to androstenrdionr (CR::) were performed on I1 patients with endometrial cancer and on a control group offive postmenopausal women. The PC’, MCR’, and PRT of patients with endometrial cancer are in the normal postmenopausal range. The conversion of testosterone to androstenedione in patients with endometrial cavxer was significantly decreased.
associated with a reported 20 per cent incidence of‘ endometrial cancer.‘O-I2 This condition is associated with increased plasma levels, production and metabolic clearance of testosterone, as well as elevated gonadotropins.r3, r* steroid Sal1 and Calanogrs evaluated the urinary excretion patterns of postmenopausal women with benign and neoplastic endometrium and corroborated the findings of low androsterone and etiocholanolone excretions in women with endometrial hyperplasia and cancer. The introduction of precise methods for measuring plasma levels and production rates of the various androgens and their conversions to the eStrcJgens has provided a unique opportunitv to determint whether a distinct abnormality in androgen metabolism is indeed present in endometrial cancer. Our study in endometrial cancer patients encompassed three areas: (1) the evaluation of testosterone metabolism, (2) the evaluation of androstenedione metabolism and its conversions to estrogens, and (3) the evaluation of estrogen metabolism. This initial report concerns itself with the testosterone levels, metabolic clearance rates, production rates, and interconversions to androstenedione of patients with endometrial cancer.
EPIDEMIOLOGIC studies suggest that estrogens may play an etiologic role in the development of malignancy in women, particularly in breast and endometrial cancer.lw3 Recent studies have also indicated alterations in androgen metabolism in breast and endometrial cancer.4* 5 Bulbrook and associateFs found that a discriminant function can be derived from a study of the urinary excretion patterns of 17-ketosteroids and 17-hydroxycorticoids. Patients with a positive discrimand/or inant, i.e., those with a high etiocholanolone androsterone excretion relative to the 17-hydroxycorticoids, tended to benefit from adrenalectomy with oophorectomy or hypophysectomy, whereas those with a negative discriminant did not respond. De Waard and associates9 applied Bulbrook’s concept of a hormonal discriminant function to patients with endometrial cancer and have shown that those patients excreted less etiocholanolone relative to 17-hydroxycorticoids or estrogens (mainly estriol) than normal controls. Moreover, the polycystic ovary syndrome (PCOS), characterized by anovulation and sclerocystic ovaries, is From the Gynecologic Onmlogy Section of the Department of Obstetrics and Gynecology and the Department of Medicine, New York Medical College. Received for publication Revised January Accepted Januaq
October 8, 1974.
Materials and m&hods
8, 1975.
Eleven patients (two premenopausal and nine postmenopausal) with abnormal uterine bleeding were hospitalized at the New York Medical College and the diagnosis of endometrial cancer was made by fractional
8, 1975.
Rupint requests: Sanford Sail, M.D., Neul York Medical College, Department of Obstetrics and Gynecology, 1249 Fi)h Ave., New York, New York 10029.
60
Testosterone metabolism in endometrial cancer
Volume Number
124 1
Table
I. Clinical
Patient
it. L.C. A.W.
II.
Clinical
of endometrial
Ht. (in.)
Age 46 54 58 45 55 60 60 69 78
L.M. B.F. J.G. M.F. B.S. KS. E.J.
Table
1
summary
65 60 67 61 60 62 64 61 64 64 65
summary
cancer patients Stage of disease
180 110 230 135 88 198 190 142 230 195 125
Pre-existing
Hypertension, diabetes Hypertension Obesity, hypertension, diabetes None Hypertension, diabetes Hypertension, obesity Obesity, diabetes, hypertension Hypertension Obesity, hypertension Obesity, hypertension Hypertension
I I 1 I I II II II II II III
of postmenopausal
medical problem
Years menop.
Premenop. 5 10
Premenop. 10 11 11 19 30 5 30
Body area fM.7 I.89 1.45 2.14 1.60 1.31 1.95 1.92 1.63 2.08 1.94 1.62
controls
Control
Age
Ht. (in.)
wt. (lbs.)
Coexisting medical disease
V.C.
56 53 51 62 55
62 64 61 61 64
186 195 128 165 148
None
I.P. M.Y. D.D. J.C.
61
curettage. A group of five postmenopausal patients served as controls. Clinical summaries of both groups are in Tables I and II. All patients were hospitalized under basal conditions. The pertinent history and physical examination were obtained. The metabolic clearance (MCR) and production (PR) rates of testosterone and conversion of testosterone to androstenedione were determined with a constant infusion procedure.13 After an overnight fast the patients were kept in a supine position for at least 1 hour before the start until the end of the constant infusion. The plasma concentration of free testosterone was measured by the protein displacement method of Mayes and Nugent.“j In the constant infusion procedure, a priming dose of either 4 or 6 &i of 1,Z3H-testosterone (sp. gr. 137 &i/pg and found to be 97 per cent pure by paper chromatography in a modified Bush B 3 System) was first administered intravenously as a single injection. Thirty minutes later, an intravenous infusion was started containing either 8 or 12 &i of 1,23H-testosterone dissolved in 50 ml. of 8 per cent ethanol in saline. The labeled steroid was given at a constant rate with the aid of a Harvard pump (Model No. 6001900). Then 40 ml. of blood were withdrawn at 105, 120, and 135 minutes after initial injection. The plasma was added to tubes containing 4-14C-tesseparated, tosterone and processed. The value of the radioactivity in each plasma sample present specifically as
None None None None
Years post-men0 7 4 4 14 IO
Body area CM.‘) 1.86 1.92 1.58 1.70 1.64
testosterone and corrected for losses during the isolation procedure was calculated. The mean of the three estimates and the value for the rate of the radioactive infusion (R) were taken to calculate the metabolic clearance rate (MCR) according to the following expression: MCR (L./day) = r (m&i/day)/ Ci(m&i/L.). The production rate (PR) of testosterone was then calculated from the expression (PR [mg./day] = MCR [L./day] x MPC [mg./L.]), where MPC is the mean plasma concentration of testosterone.
Results The kinetic parameters of testosterone metabolism in normal postmenopausal women and in patients with endometrial cancer are given in Tables III and IV, respectively. Plasma testosterone (PCT). The mean PCT (0.60 2 0.34 [SD.] &L.) in the endometrial cancer group was compared to the mean PCT (0.40 ? 0.20 [S.D.] pg/L.) of the normal postmenopausal patient group and to a group of 14 normal premenopausal women (0.54 ? 0.11 [SD.] pg/L.) previously evaluated in our laboratory .I7 There was no significant difference between the mean PCT in the endometrial cancer group and the normal premenopausal and postmenopausal groups. Metabolic clearance rates of testosterone (MCRT). The mean MCRT (735 I 180 [S.D.] L./day) in the
62
Calanog et al.
,[anuarv I, 154% Am. .J. Oh&t.
Table III. Plasma concentrations, in postmenopausal controls
metabolic
clearances,
PCT (I@.)
Pat&t
production
rates, and interconversions
of testosterone
PRT (&day)
CR2
MCRT (L. iday)
-I::.
0.76 0.38
823 698
625 558
0.042 0.040
M.Y. D.D. J.C.
0.28 0.30 0.29
714 721 695
200 216 202
0.043 0.039 0.041
730 ‘- 53
364 f 218
Mean & (S.D.)
0.402
Table IV. Plasma concentrations, in endometrial cancer patients Patient
Stage of disease
L.M. B.F. J.G. M.F. B.S. R.S. E.J. J.F. ES. L.C. A.W.
I I I I I II II II II II III
Mean t (S.D.)
” 0.20
metabolic
clearances, T
(ig) 1.04 0.62 1.21 0.54 0.52 0.55 0.35 0.99 0.75 0.22 0.65 0.60
+ 0.34
endometrial cancer group was compared to the mean MCRT (730 2 53 [SD.] L./day) of the normal postmenopausal patient group and to a group of 14 normal premenopausal women (675 ? 139 [S.D.] L./day) previously evaluated in our laboratory.” There was no significant difference between the mean MCRT in the endometrial cancer group and the normal premenopausal (P > 0.4) and postmenopausal groups (P > 0.6). Production rates of testosterone (PRT). The mean PRT (502 r+ 238 [SD.] pg/day) in the endometrial cancer group was compared to the mean PRT (364 + 218 [SD.] kg/day) of the normal postmenopausal patient group and to a group of 14 normal premenopausal women (350 t 130 [SD.] pg/day) previously evaluated in our laboratory.” There was no significant difference between the mean PRT in the endometrial cancer group and the normal premenopausal (P > 0.6) and postmenopausal groups (P > 0.1). Conversion ratios of testosterone (CR%). The mean CR:: (0.02 +- 0.01 [SD.]) in the endometrial cancer group was compared to the mean CR%$ (0.04 % 0.01 [SD.]) of the normal postmenopausal patient group and to a group of 12 PCOS patientsI (0.034 r 0.019 [S.D.]) as previously evaluated in our laboratory. The endometrial cancer group had a statistically lower
production
Gynecol.
0.042
rates and interconversions
MCRT (L. lday)
of testosterone
PRT (/&day)
667 594 632 857 430 800 682 703 1046 793 952
694 368 765 463 224 509 239 696 785 175 619
735 2 180
502 iz 238
mean CR:: (P < 0.05).
2 0
than
the
0.020 0.018 0.030 0.02 1 0.019 0.020 0.011 0.017 0.018 0.028 0.018 0.020
post
menopausal
2 0.005
group
Comment During the past decade, there has developed the concept that endometrial cancer is a malignancy associated with an underlying endocrinopathy. The fact that it occurs mostly in women in the postmenopausal age group, in the presence of abnormal and/or unopposed estrogen stimulation, in association with diabetes and obesity, or in women with a history of infertility and anovulation such as in polycystic ovary syndrome, suggests a relationship between the derangement in the endocrine metabolism of these women and the development of the neoplasm. When the MCRT, PCT, and PRT are compared there is no significant difference noted between the endometrial cancer and the normal postmenopausal patient. Although the mean PRT of the two groups of patients are not statistically different, there is a suggestive increase in the PRT in the endometrial cancer patient. The conversion ratio of testosterone to androstenedione, however, is significantly decreased in the endometrial cancer group, as compared to the control group. The significance of the decreased conversion of testosterone to androstenedione is not known.
Volume Number
124 1
REFERENCES 1. MacMahon, B., and Cole, P. H.: Etiology of Human Breast Cancer: A Review Prepared for the Epidemiology Subcommittee, Breast Cancer Task Force, 1972. 2. Sherman, A. I., and Woolf, R. B.: AM. J. OBSTET. GYNECOL. 77: 233, 1959. 3. Wynder, E. I., Escher, G., and Mantel, N.: Cancer 19: 469, 1966. 4. Bulbrook, R. D., Hayward, J. L., and Thomas, B. S.: Lancet 1: 945, 1964. 5. DeWaard, F.: Int. J. Cancer 4: 577, 1969. 6. Bulbrook, R. D., Greenwood, F. G., and Hayward, J. L.: Lancet 1: 1154, 1960. 7. Bulbrook, R. D., Hayward, J. L., Spicer, C. C., and Thomas, B. S.: Lancet 2: 1235, 1962. 8. Bulbrook, R. D., Hayward, J. L., Spicer, C. C., and Thomas, B. S.: Lancet 2: 1238, 1962. 9. De Waard, F., Thyssen, J. H. H., Veeman, W.. and Sander, P. C.: Cancer 22: 988, 1968.
Testosterone metabolism in endometrial cancer
10. Dockerty, OBSTET.
63
M. B., Lovelady, S. B., and Foust, G. T.: AM. J. 61: 966. 1951. H.: Surg. Obstet. Gynecol. 88: 322, 1949. S. C., Hertig, A. T., and Bengioss, H.: Cancer, 1949. A. L., Gordon, G. G., Tochimoto, S., Olivo, I., D. H., and Pinzon, G.: J. Clin. Endocrinol. 29: 1356. 1969. C. W., and Lipsett, M.: J. Clin. Invest. 46: 891, GYNECOL.
11. Speert, 12. Sommers, 2: 957, 13. Southren, Sherman, Metab. 14. Bardin, 1967. 15. Sail, S., and Calanog, A.: AM. J. 153, 1972. 16. Mayes, D., and Nugent, C. A.: J. 29: 164, 1969. 17. Southren, A. L., Gordon, G. G., G., Lane, D., and Stypulkowski, Metab. 27: 686, 1967.
OBSTET.
Clin.
GYNECOL.
Endocrinol.
Tochiomoto, W.: J. Clin.
114: Metab.
S., Pinzon, Endocrinol.
