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Hormone levels in healthy post-menopausal women and in women with post-menopausal bleeding with or without endometrial carcinoma
315
Maturitas, 3 (1981) 315-320
Elsevier/North-Holland
Biomedical Press
HORMONELEVELSINHEALTHYPOST-MENOPAUSALWOMENANDINWOMEN WITHPOST-MENOPAUSALBLEEDINGWITHORWITHOUT ENDOMETRIAL CARCINOMA T. VON HOLST, K. KLINGA and B. RUNNEBAUM Division of Endocrinology, Department of Obstetrics and Gynaecology, Vossstrasse 9, D-6900 Heidelberg, F.R. G.
University of Heidelberg,
(Received 27 July 1981; accepted after revision 19 October 1981)
FSH, oestrone (El), 17Poestradiol (EQ) and androstenedione (A) were determined in 250 healthy pre- and post-menopausal women, with ages ranging from 40 to 78 yr. These hormone levels were not found to have changed significantly in women of this stable, post-menopausal phase after the age of 54. The results found in this group of women (n = 107), who now range between the ages of 55 and 78, were compared with results from two groups of women who were found to have gynaecological disorders. The first group consisted of 45 women with post-menopausal bleeding without endometrial carcinoma. The second group consisted of 38 women with post-menopausal bleeding and endometrial carcinoma. FSH was determined by double-antibody radioimmunoassay. Er, Ea and A were fractionated chromatographically after extraction with ether and determined radioimmunologically. The data were analysed using the Kruskal-Wallis test and the Wilcoxon test. When comparing the measurement of hormone levels in the healthy group of women with that of women with post-menopausal bleeding without endometrial carcinoma, no differences were found. However, in the group of women with post-menopausal bleeding and endometrial carcinoma, lower levels of FSH and Ez and increases in the Er/Ea ratio were found; both changes were statistically significant. The slight increase in El and A found in these women was not significant. Any changes which occur in the hormone levels of women with endometrial carcinoma may indicate a correlation between hormones and the onset of endometrial carcinoma. (Key words: Post-menopause,
FSH, Steroids, Uterine bleeding, Endometrial carcinoma)
INTRODUCTION
Obesity, hypertension and diabetes mellitus have, for a long time, been regarded as risk factors in. the pathogenesis of endometrial carcinoma. In recent years, additional risk factors have been considered and are described as nulliparity, infertility, a later menopause and a family history of uterine cancer [l]. Epidemiological studies suggest that oestrogens may play an aetiological role in the development of endometrial carcinoma [2,3]. This study presents investigations that were made to compare various hormonal levels between healthy women of a stable, post-menopausal phase with women who have post-menopausal bleeding with or without endometrial carcinoma. 0378-5122/81/0000-0000/$02.50
0 1981 Elsevier/North-Holland
Biomedical Press
316 PATIENTS
In 250 healthy women between the ages of 40 and 78 yr, in which no gynaecological abnormalities were found, FSH, oestrone, 17/?-oestradiol and androstenedione were measured in order to determine the normal ranges of these hormones at different ages. It was found that no changes occurred in hormone levels of these women after age of 54. The results in 107 of these women over age of 54 were compared with results from two other groups of women who were found to have gynaecological disorders. The first group consisted of 45 women with post-menopausal bleeding without endometrial carcinoma and the second group consisted of 38 women with post-menopausal bleeding and endometrial carcinoma. METHODS
Those women with post-menopausal bleeding had blood samples taken between 8 and 10 a.m. one day prior to curettage. FSH was determined by using a commercially available kit (IRE, Institut National des Radioelements, Fleurus, Belgium), Specification of the standard is 1 ng = 3.26 mIU MRC 691104. The following procedure was followed to determine the values of A, Er and Es: after the addition of tritiated steroids as an internal standard to the serum samples (2-3 ml, depending on the age of each woman), the hormones were extracted with ether. The evaporated ether extracts were transferred to columns of 1 g celite (celite : propylene glycol : ethylene glycol, 4 : 1 : 1). They were then eluted with i-octane containing 5% toluene. The Ea fraction contained glycols which were separated by several washings with saline. The fractionated steroids were quantified radioimmunologically with antisera against 1 la-androstenedione (succinyl) BSA, oestroned-CMO-BSA and 17@oestradiol-6-CMO-BSA. (The antisera were supplied by Steranti, England.) There was a 70 and 80% recovery rate of the steroids after extraction and chromatography. The within-assay coefficient was below 10%. The inter-assay coefficient was 9.2, 11 .O and 14.8% for A, Er and Es, respectively, The coefficient of variation for Es determinations in serum samples with concentrations below 5 pg/ml was up to 25%. STATISTICAL ANALi’SIS
The data were analysed using the Kruskal-Wallis test for 3 and more groups [4] and the Wilcoxon test for 2 groups. RESULTS
During the peri-menopause in healthy women, a steep increase in FSH levels occurs, as does a steep decrease in oestradiol. The graphs shown in Fig. 1 indicate these changes, according to age. After the age of 54, both levels of FSH and Ez stabilize and do not change significantly thereafter. The same is true for oestrone and androstenedione. While using these results, the median and 90th percentile of the four hormone levels were calculated for 107 of the healthy women and the other 2 groups of women with gynaeco-
317
FSH
lSTRADl01
Qh1
ngllll
300 ___-____----7,
LO.0
:
200
30.0
‘\
‘1
‘\
200 IlO 60
1oc
60
6.C LO
6C
-----\
30
L.0
L_‘__--____---
20
3.c 2.(
10
1.1
_---.
‘.___,
\\
/’ 5
‘\L____----_______------
0.'
1.2 LL ‘6
L6 50
52
5L 56
58
60 62
64
66
68
YEARS
‘2
U
L6
LB 50
52
54
56
58
60
62
61
66
68
YEARS
Fig. 1. FSH and 1Ilp+estradiol in serum of 250 healthy women with normal gynaecological findings in relation to age. Median and 90th percentiles are marked by continuous and broken lines.
logical disorders; all women were between the ages of 55 and 78. The statistical calculations of the homone data in the 3 groups of women (mean +_SEM) are shown in Table I. No significant differences were found in the hormone levels of women with post-menopausal bleeding without endometrial carcinoma, when compared with the hormone levels of healthy women. The hormone levels found in the healthy group of women (normal ranges) and the -group of women with post-menopausal bleeding and endometrial carcinoma are plotted in Fig. 2. The following results were found when the hormone levels were determined in the group of healthy women and the group of women with endometrial carcinoma. FSH. In the group of women with post-menopausal bleeding and endometrial carcinoma, the FSH level was found to be significantly lower than the levels found in the healthy women and women without the carcinoma. Oestrone. The mean levels for oestrone found in all groups of women were not significantly different. Still, a slight increase did occur in the group of women with the carcinoma. Oestradiol. A significantly lower E, level was found in the group of women with endometrial carcinoma, as compared to the other groups of women.
318 TABLE I Compilation and statistical analysis (mean + SEM) of serum hormone levels found in healthy postmenopausal women compared to women with post-menopausal bleeding with or without endometrial carcinoma. Serum parameter
Diagnosis Normal (n = 107)
FSH (&ml) Oestrone (El) (pgjml) Oestradiol (Ea) (pg/mB El/E2 Androstenedione (A) (pg/mL)
Post-menopausal bleeding without endometrial carcinoma (n = 45)
Endometrium carcinoma (n = 38)
23.1 zk 0.8 37.3 * 1.4
22.5+ 1.3* 39.6 zk 3.0 *
16.8 t 44.3 f
0.9 ** 3.5 *
13.2+ 0.9 3.6 + 0.2
12.02 1.0* 4.0 _+ 0.4 *
85 + 12.3 !I
1.1 ** 3.0 ***
719
f36
700
+46*
1076
+128*
* Not significant. **P < 0.05. ***p< 0.001.
E~IRONE
FSH
m-
EllRAOlOL
: t _--___ . :
Eo-
It A&
.
.
.
.
t . 9-
?? : ?? * .
m
.
__---_?* . .
0
Fig. 2. Serum values of 38 women with endometrial oestrone, oestradiol and androstenedione.
carcinoma plotted in the normal ranges of FSH,
319
El/E2 ratio. The E,/E, ratio in the group of women with endometrial carcinoma was significantly higher than the norm; the difference was statistically confirmed. The highest E,/E, ratio in the normal group was 13 5, while in the carcinoma group, 9 out of 35 ratios were higher than 15.9. Androstenedione. The mean level of A in the healthy group of women was within the range previously described by others [ 11 ,121. There was a higher level of A found in the group of women with endometrial carcinoma; however, this difference could not be statistically confirmed due to the scattering of the data. The results found in the hormone levels of the two groups of women - those healthy and those with endometrial carcinoma - were matched (n = 35) with regard to age and weight. The mean age in both groups was 67 yr; the difference between the matched pairs was less than 2 yr. The mean deviation in weight was 3 kg. The differences for the lower FSH level and the lower El/E, ratio was verified as was the trend to higher levels of E, and A in the carcinoma group of women. However, the lower level of Es (P < 0.05) could not be confirmed statistically. A correlation of age and body weight to the concentrations of the hormones determined could not be detected. DISCUSSION
Based on previous clinical observations [5], oestrogens have been suspected as being a factor in the pathogenesis of endometrial carcinoma. Retro- and prospective studies with oestrogen therapy support this suspicion [3]. Although the involvement with androgens in this respect is still not clear, it is known that oestrogens in the post-menopause result mainly from the aromatisation of androstenedione [6]. Apart from the steroid metabolism, changes that occur in the hypo-thalamic function may also play a role in patients with endometrial carcinoma [7]. More specific and sensitive methods have been developed over the past several years for determining the levels of gonadotrophins, oestrogens and androgens. Several investigations have been made [8-121 on post-menopausal women with regard to concentration and metabolism of various hormonal levels. The results of such studies, however, have not proved to be homogenous [ 131. On the basis of data from patients with endometrial carcinoma compared to healthy women, the lowering of FSH and Es levels, the trend of higher El and A levels, and the significantly raised El/E, ratio should lead to further investigations in order to determine whether a combination of these hormone levels can detect a risk-group in the pathogenesis of endometrial carcinoma.
REFERENCES [l] Ambrus, J.L., Gilette, M., Nolan, C., Jung, O., Regalia-Spavento, S., Spavento, P., Novick, A. and Ambrus, CM. (1980) Estrogens and endometrial cancer. In: The menopause and postmenopause. pp. 237-244. Editors: N. Pasetto, R. Paoletti and J.L. Ambrus. MTP Press Ltd., Lancaster. [ 21 Ziel, H.K. and Finkle, W.D. (1975) Increased risk of endometrial carcinoma among users of conjugated estrogens. N. Engl. J. Med. 293,1167-1170.
320 [3] Don Gambrell, R. Jr. (1980) Role of estrogens and progestogens in the etiology of breast and endometriat neoplasia. In: The menopause and postmenopause. pp. 289-304. Editors: N. Pasetto, R. Paoletti and J.L. Ambrus, MTP Press Ltd., Lancaster. [4] Kruskal, W.H. and Wallis, W.A. (1952) Use of ranks in one-criterion variance analysis. J. Am. Assoc. 47,614-617. ]5 ] Meissner, W.A., Sommers, SC. and Sherman, G. (1957) Endometrial hyperplasia, endometrial carcinoma, and endometriosis produced experimentally by estrogen. Cancer lO, SOO-509. [6‘1 Grodin, J.M., Siiteri, P.K. and MacDonald, P.C. (1973) Source of estrogen production in postmenopausal women. J. Clin. Endocrinol. Metab. 36,207-214. ]7‘1 Benjamin, F. and Deutsch, S. (1976) Plasma levels of fractionated estrogens and pituitary hormones in endometrial carcinoma. Am. J. Obstet. Gynecol. 126,638-647. [8] Judd, H.L., Lucas, W.E. and Yen, S.S.C. (1976) Serum 17pestradiol and estrone levels in postmenopausal women with and without endometrial cancer. J. Clin. Endocrinol. Metab. 43,272278. [9] Longcope, C. (1974) Steroid production in pre- and postmenopausal women. In: The menopause syndrome. pp. 6-11. Editors: R.B. Greenblatt, V.B. Makesh and P.G. McDonough. Medcorn Press, New York. [lo] Rader, M.D., Flickinger, G.L., de Villa, G.O. Jr., Mikuta, J.J. and Mikhail, G. (1973) Plasma estrogensin postmenopausal women. Am. J. Obstet. Gynecol. 116,1069-1073. [ 111 Thijssen, J.H.H. and Longcope, C. (1976) Post-menopausal estrogen production. In: Consensus on menopause research, pp. 25-28. MTP Press Ltd., Lancaster. [,12] Vermeulen, A. (1980) Sex hormone status of the postmenopausal women. Maturitas 2,81-89. [ 131 Lucas, W.E. and Yen, S.S.C. (1979) A study of endocrine and metabolic variables in postmenopausal women with endometrial carcinoma. Am. J. Obstet. Gynecol. 134,180-186.
Maturitas, 3 (1981) 315-320
Elsevier/North-Holland
Biomedical Press
HORMONELEVELSINHEALTHYPOST-MENOPAUSALWOMENANDINWOMEN WITHPOST-MENOPAUSALBLEEDINGWITHORWITHOUT ENDOMETRIAL CARCINOMA T. VON HOLST, K. KLINGA and B. RUNNEBAUM Division of Endocrinology, Department of Obstetrics and Gynaecology, Vossstrasse 9, D-6900 Heidelberg, F.R. G.
University of Heidelberg,
(Received 27 July 1981; accepted after revision 19 October 1981)
FSH, oestrone (El), 17Poestradiol (EQ) and androstenedione (A) were determined in 250 healthy pre- and post-menopausal women, with ages ranging from 40 to 78 yr. These hormone levels were not found to have changed significantly in women of this stable, post-menopausal phase after the age of 54. The results found in this group of women (n = 107), who now range between the ages of 55 and 78, were compared with results from two groups of women who were found to have gynaecological disorders. The first group consisted of 45 women with post-menopausal bleeding without endometrial carcinoma. The second group consisted of 38 women with post-menopausal bleeding and endometrial carcinoma. FSH was determined by double-antibody radioimmunoassay. Er, Ea and A were fractionated chromatographically after extraction with ether and determined radioimmunologically. The data were analysed using the Kruskal-Wallis test and the Wilcoxon test. When comparing the measurement of hormone levels in the healthy group of women with that of women with post-menopausal bleeding without endometrial carcinoma, no differences were found. However, in the group of women with post-menopausal bleeding and endometrial carcinoma, lower levels of FSH and Ez and increases in the Er/Ea ratio were found; both changes were statistically significant. The slight increase in El and A found in these women was not significant. Any changes which occur in the hormone levels of women with endometrial carcinoma may indicate a correlation between hormones and the onset of endometrial carcinoma. (Key words: Post-menopause,
FSH, Steroids, Uterine bleeding, Endometrial carcinoma)
INTRODUCTION
Obesity, hypertension and diabetes mellitus have, for a long time, been regarded as risk factors in. the pathogenesis of endometrial carcinoma. In recent years, additional risk factors have been considered and are described as nulliparity, infertility, a later menopause and a family history of uterine cancer [l]. Epidemiological studies suggest that oestrogens may play an aetiological role in the development of endometrial carcinoma [2,3]. This study presents investigations that were made to compare various hormonal levels between healthy women of a stable, post-menopausal phase with women who have post-menopausal bleeding with or without endometrial carcinoma. 0378-5122/81/0000-0000/$02.50
0 1981 Elsevier/North-Holland
Biomedical Press
316 PATIENTS
In 250 healthy women between the ages of 40 and 78 yr, in which no gynaecological abnormalities were found, FSH, oestrone, 17/?-oestradiol and androstenedione were measured in order to determine the normal ranges of these hormones at different ages. It was found that no changes occurred in hormone levels of these women after age of 54. The results in 107 of these women over age of 54 were compared with results from two other groups of women who were found to have gynaecological disorders. The first group consisted of 45 women with post-menopausal bleeding without endometrial carcinoma and the second group consisted of 38 women with post-menopausal bleeding and endometrial carcinoma. METHODS
Those women with post-menopausal bleeding had blood samples taken between 8 and 10 a.m. one day prior to curettage. FSH was determined by using a commercially available kit (IRE, Institut National des Radioelements, Fleurus, Belgium), Specification of the standard is 1 ng = 3.26 mIU MRC 691104. The following procedure was followed to determine the values of A, Er and Es: after the addition of tritiated steroids as an internal standard to the serum samples (2-3 ml, depending on the age of each woman), the hormones were extracted with ether. The evaporated ether extracts were transferred to columns of 1 g celite (celite : propylene glycol : ethylene glycol, 4 : 1 : 1). They were then eluted with i-octane containing 5% toluene. The Ea fraction contained glycols which were separated by several washings with saline. The fractionated steroids were quantified radioimmunologically with antisera against 1 la-androstenedione (succinyl) BSA, oestroned-CMO-BSA and 17@oestradiol-6-CMO-BSA. (The antisera were supplied by Steranti, England.) There was a 70 and 80% recovery rate of the steroids after extraction and chromatography. The within-assay coefficient was below 10%. The inter-assay coefficient was 9.2, 11 .O and 14.8% for A, Er and Es, respectively, The coefficient of variation for Es determinations in serum samples with concentrations below 5 pg/ml was up to 25%. STATISTICAL ANALi’SIS
The data were analysed using the Kruskal-Wallis test for 3 and more groups [4] and the Wilcoxon test for 2 groups. RESULTS
During the peri-menopause in healthy women, a steep increase in FSH levels occurs, as does a steep decrease in oestradiol. The graphs shown in Fig. 1 indicate these changes, according to age. After the age of 54, both levels of FSH and Ez stabilize and do not change significantly thereafter. The same is true for oestrone and androstenedione. While using these results, the median and 90th percentile of the four hormone levels were calculated for 107 of the healthy women and the other 2 groups of women with gynaeco-
317
FSH
lSTRADl01
Qh1
ngllll
300 ___-____----7,
LO.0
:
200
30.0
‘\
‘1
‘\
200 IlO 60
1oc
60
6.C LO
6C
-----\
30
L.0
L_‘__--____---
20
3.c 2.(
10
1.1
_---.
‘.___,
\\
/’ 5
‘\L____----_______------
0.'
1.2 LL ‘6
L6 50
52
5L 56
58
60 62
64
66
68
YEARS
‘2
U
L6
LB 50
52
54
56
58
60
62
61
66
68
YEARS
Fig. 1. FSH and 1Ilp+estradiol in serum of 250 healthy women with normal gynaecological findings in relation to age. Median and 90th percentiles are marked by continuous and broken lines.
logical disorders; all women were between the ages of 55 and 78. The statistical calculations of the homone data in the 3 groups of women (mean +_SEM) are shown in Table I. No significant differences were found in the hormone levels of women with post-menopausal bleeding without endometrial carcinoma, when compared with the hormone levels of healthy women. The hormone levels found in the healthy group of women (normal ranges) and the -group of women with post-menopausal bleeding and endometrial carcinoma are plotted in Fig. 2. The following results were found when the hormone levels were determined in the group of healthy women and the group of women with endometrial carcinoma. FSH. In the group of women with post-menopausal bleeding and endometrial carcinoma, the FSH level was found to be significantly lower than the levels found in the healthy women and women without the carcinoma. Oestrone. The mean levels for oestrone found in all groups of women were not significantly different. Still, a slight increase did occur in the group of women with the carcinoma. Oestradiol. A significantly lower E, level was found in the group of women with endometrial carcinoma, as compared to the other groups of women.
318 TABLE I Compilation and statistical analysis (mean + SEM) of serum hormone levels found in healthy postmenopausal women compared to women with post-menopausal bleeding with or without endometrial carcinoma. Serum parameter
Diagnosis Normal (n = 107)
FSH (&ml) Oestrone (El) (pgjml) Oestradiol (Ea) (pg/mB El/E2 Androstenedione (A) (pg/mL)
Post-menopausal bleeding without endometrial carcinoma (n = 45)
Endometrium carcinoma (n = 38)
23.1 zk 0.8 37.3 * 1.4
22.5+ 1.3* 39.6 zk 3.0 *
16.8 t 44.3 f
0.9 ** 3.5 *
13.2+ 0.9 3.6 + 0.2
12.02 1.0* 4.0 _+ 0.4 *
85 + 12.3 !I
1.1 ** 3.0 ***
719
f36
700
+46*
1076
+128*
* Not significant. **P < 0.05. ***p< 0.001.
E~IRONE
FSH
m-
EllRAOlOL
: t _--___ . :
Eo-
It A&
.
.
.
.
t . 9-
?? : ?? * .
m
.
__---_?* . .
0
Fig. 2. Serum values of 38 women with endometrial oestrone, oestradiol and androstenedione.
carcinoma plotted in the normal ranges of FSH,
319
El/E2 ratio. The E,/E, ratio in the group of women with endometrial carcinoma was significantly higher than the norm; the difference was statistically confirmed. The highest E,/E, ratio in the normal group was 13 5, while in the carcinoma group, 9 out of 35 ratios were higher than 15.9. Androstenedione. The mean level of A in the healthy group of women was within the range previously described by others [ 11 ,121. There was a higher level of A found in the group of women with endometrial carcinoma; however, this difference could not be statistically confirmed due to the scattering of the data. The results found in the hormone levels of the two groups of women - those healthy and those with endometrial carcinoma - were matched (n = 35) with regard to age and weight. The mean age in both groups was 67 yr; the difference between the matched pairs was less than 2 yr. The mean deviation in weight was 3 kg. The differences for the lower FSH level and the lower El/E, ratio was verified as was the trend to higher levels of E, and A in the carcinoma group of women. However, the lower level of Es (P < 0.05) could not be confirmed statistically. A correlation of age and body weight to the concentrations of the hormones determined could not be detected. DISCUSSION
Based on previous clinical observations [5], oestrogens have been suspected as being a factor in the pathogenesis of endometrial carcinoma. Retro- and prospective studies with oestrogen therapy support this suspicion [3]. Although the involvement with androgens in this respect is still not clear, it is known that oestrogens in the post-menopause result mainly from the aromatisation of androstenedione [6]. Apart from the steroid metabolism, changes that occur in the hypo-thalamic function may also play a role in patients with endometrial carcinoma [7]. More specific and sensitive methods have been developed over the past several years for determining the levels of gonadotrophins, oestrogens and androgens. Several investigations have been made [8-121 on post-menopausal women with regard to concentration and metabolism of various hormonal levels. The results of such studies, however, have not proved to be homogenous [ 131. On the basis of data from patients with endometrial carcinoma compared to healthy women, the lowering of FSH and Es levels, the trend of higher El and A levels, and the significantly raised El/E, ratio should lead to further investigations in order to determine whether a combination of these hormone levels can detect a risk-group in the pathogenesis of endometrial carcinoma.
REFERENCES [l] Ambrus, J.L., Gilette, M., Nolan, C., Jung, O., Regalia-Spavento, S., Spavento, P., Novick, A. and Ambrus, CM. (1980) Estrogens and endometrial cancer. In: The menopause and postmenopause. pp. 237-244. Editors: N. Pasetto, R. Paoletti and J.L. Ambrus. MTP Press Ltd., Lancaster. [ 21 Ziel, H.K. and Finkle, W.D. (1975) Increased risk of endometrial carcinoma among users of conjugated estrogens. N. Engl. J. Med. 293,1167-1170.
320 [3] Don Gambrell, R. Jr. (1980) Role of estrogens and progestogens in the etiology of breast and endometriat neoplasia. In: The menopause and postmenopause. pp. 289-304. Editors: N. Pasetto, R. Paoletti and J.L. Ambrus, MTP Press Ltd., Lancaster. [4] Kruskal, W.H. and Wallis, W.A. (1952) Use of ranks in one-criterion variance analysis. J. Am. Assoc. 47,614-617. ]5 ] Meissner, W.A., Sommers, SC. and Sherman, G. (1957) Endometrial hyperplasia, endometrial carcinoma, and endometriosis produced experimentally by estrogen. Cancer lO, SOO-509. [6‘1 Grodin, J.M., Siiteri, P.K. and MacDonald, P.C. (1973) Source of estrogen production in postmenopausal women. J. Clin. Endocrinol. Metab. 36,207-214. ]7‘1 Benjamin, F. and Deutsch, S. (1976) Plasma levels of fractionated estrogens and pituitary hormones in endometrial carcinoma. Am. J. Obstet. Gynecol. 126,638-647. [8] Judd, H.L., Lucas, W.E. and Yen, S.S.C. (1976) Serum 17pestradiol and estrone levels in postmenopausal women with and without endometrial cancer. J. Clin. Endocrinol. Metab. 43,272278. [9] Longcope, C. (1974) Steroid production in pre- and postmenopausal women. In: The menopause syndrome. pp. 6-11. Editors: R.B. Greenblatt, V.B. Makesh and P.G. McDonough. Medcorn Press, New York. [lo] Rader, M.D., Flickinger, G.L., de Villa, G.O. Jr., Mikuta, J.J. and Mikhail, G. (1973) Plasma estrogensin postmenopausal women. Am. J. Obstet. Gynecol. 116,1069-1073. [ 111 Thijssen, J.H.H. and Longcope, C. (1976) Post-menopausal estrogen production. In: Consensus on menopause research, pp. 25-28. MTP Press Ltd., Lancaster. [,12] Vermeulen, A. (1980) Sex hormone status of the postmenopausal women. Maturitas 2,81-89. [ 131 Lucas, W.E. and Yen, S.S.C. (1979) A study of endocrine and metabolic variables in postmenopausal women with endometrial carcinoma. Am. J. Obstet. Gynecol. 134,180-186.