- Email: [email protected]
Testosterone and 17β-oestradiol secretion of the human ovary. I. Normal young women, and premenopausal women with endometrial hyperplasia
Maturitas, 2 (1979) l-5
o Elsevier/NorthNolland
Biomedical Press
AND17&4lESTRADIOLSECRETIONOFTHEHUMANOVARY. I.NORMALYOUNGWOMEN,ANDPREMENOPAUSALWOMENWITH ENDOMETRIALHYPERPLASIA
TESTOSTERONE
J. BOTELLA-LLUSIA ‘,* A. ORIOL-BOSCH ‘, F. SANCHEZGARRIDO J.A.F. TRESGUERRES ” 1 Department
of Obstetrics and Gynaecology and a Department
’and
of Experimental
Endocrinology,
University of Madrid School of Medicine, Madrid, Spain
(Received 19 March 1979, accepted 3 July 1979)
Testosterone
and 17P-oestradiol were determined
in blood obtained from the ovarian veins of and 10 of whom were premenopausal with uterine bleedings and endometrial hyperplasia. The concentrations of these two hormones in the cubital veins of the premenopausal women were also determined. It was found that the concentrations of the two hormones were not significantly greater in the premenopausal women than in the control group of young normally ovulating and menstruating women in the periovulatory phase of the menstrual cycle, but that the ovarian secretion rates of both hormones, particularly of testosterone, were considerably greater in the premenopausal women. In these women the concentrations of both hormones were significantly lower in the cubital veins than in the ovarian veins. The conclusion is that the augmented oestrogenic effect on the endometrium and on other target organs of premenopausal women with endometrial hyperplasia may be due not only to an increased ovarian secretion rate of estradiol, but also and more specifically to an increased ovarian secretion rate of testosterone, and to the rapid conversion of this hormone into oestradiol in the periphery. 26 women, 16 of whom were young and regularly ovulating and menstruating,
(Key words: Testosterone,
17paestradio1, Ovarian vein blood, Premenopause)
INTRODUCTION
It is often assumed that functional uterine bleeding in conjunction with endometrial hyperplasia, not an uncommon occurrence in the premenopausal years, is due to an excess of circulating oestrogens 131. This assumption is based on indirect evidence and on the determination of oestrogen levels in peripheral blood. Little appears to be known about the ovarian secretion rates of oestrogens in such women [2], despite the fact that reports have been published on methods by which to study these, both in vivo [4,7] and in vitro [ 11. The present paper gives the results of a study in which the ovarian secretion rates of testosterone and of 17&oestradiol were calculated from the levels of these hormones found in blood drawn from the ovarian veins of premenopausal women with * Address for correspondence: Prof. J. Botella-Llusii, Departamento de Obstetricia y Ginecologi’a, Hospital Clinico de la Facultad de Medicina, Universidad Complutense de Madrid, Planta 5’ Norte, Ciudad Universitaria, Madrid 3, Spain.
2
endometrial hyperplasia and functional bleedings, and, for comparative purposes, of young women with normal menstrual cycles. MATERIAL AND METHODS
The study involved 26 women. 16 were young women, aged 18-25, with normal menstrual cycles: six were in the follicular phase (days 5-12) of their cycles, six in the periovulatory phase (days 13-15) and four in the luteal phase (days 16-23). The other 10 women were premenopausal, presenting with endometrial hyperplasia and uterine bleedings. Further details of the premenopausal women are given in Table I. After laparotomy, a polyvinyl catheter was inserted into the ovarian veins on both sides. Blood was drawn for exactly 5 min, and from this the daily ovarian secretion rates of testosterone and of 17&oestradiol were computed. It may well be that the ovarian secretion rates, particularly of testosterone, differ at different times of the day; in order to reduce this complicating factor as much as possible, the blood was drawn between 9 and 10 a.m. in all instances. The levels of testosterone and of oestradiol were determined by radioimmunoassay, the testosterone by a method of Tresguerres and Oriol-Bosch [8], and the oestradiol by a method of MartinezCuarro et al. [5], RESULTS
(a) Young women with regular cycles
Fig. 1 shows the actual concentrations found. The women are grouped according to the stage of their menstrual cycle: follicular (6 women), periovulatory (6) and luteal (4). Fig. 2 shows the computed 24-h production of the two hormones.
TABLE I Data on the 10 premenopausal women in this study. Age
41 53 39 48 45 41 43 45 39 42
Diagnosis
Myoma Bleeding Myomata Bleeding Myoma Myoma Endometriosis Endometrisosis Adenomyosis Adenomyosis
Histological findings Endometrium
Ovaries
Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia
Enlarged, polycystic Atretic follicles, hyperthecosis Enlarged, polycystic Polycystic, hyperthecosis Multiple atresia, hyperthecosis Enlarged, polycystic, hyperthecosis Polycystic Polycystic Polycystic, grossly enlarged Normal corpus luteum
pi
0
FOL
m
ov
3
mrmrm LUT: E2 Pg/ml
T ng/lCOml
320 240 160 80 T CONC.
TEST
E, CONC.
ESTRAD
Fig. 1. Testosterone (T) and 17p-oestradiol (Ea) determined by radioimmunoassay in ovarian venous blood of 16 young women with normal ovulation and menses. The cases are grouped into the follicular (FOL), periovulatory (Ov), and luteal (LUT) phases of the menstrual cycle. The concentrations shown are the mean of the two ovarian veins. Fig. 2. Computed testosterone and 17p-oestradiol secretion per 24 h, based on the actual amounts determined in a 5-min period. The calculations are based on the mean secretion of both ovaries; the total secretion, therefore, is twice that indicated in this figure. The cases, 16 young women with normal ovulation and menses, are grouped into the follicular (FOL), periovulatory (OV), and luteal (LUT) phases of the menstrual cycle.
E2 pg/ml
T rq/1
!1_ L I
N
I
H
T CONC
9
P
N
H
P
E2 CONC
Fig. 3. Testosterone (T) and 17p-oestradiol (Ea) concentrations in ovarian venous blood of normal young periovulatory women (N), in ovarian venous blood of hyperoestrogenic women (H), and in peripheral blood of hyper-oestrogenic women (P).
TN Fig. 4. Computed testosterone secretion per 24 h in normal young periovulatory women (TN) and in hyper-oestrogenic women (TH), and computed 17poestradiol secretion per 24 h in normal young periovulatory women (EaN) and in hyper-oestrogenic women (EaH). The calculations are based on the mean secretion of both ovaries; the total secretion, therefore, is twice that indicated in this figure.
(b) Premenopausal women with endometrial hyperplasia Fig. 3 shows the actual concentrations of the two hormones found in the blood of the ovarian veins of the premenopausal women, and in the blood drawn from the cubital veins of these women. To facilitate an easy comparison, the concentrations found in the ovarian veins of the young women in the periovulatory phase of the menstrual cycle are also included in this figure. Fig. 4 shows the computed 24-h secretion of the two hormones in the premenopausal women and in the young periovulatory women. DISCUSSION
The number of subjects studied was, admittedly, small, but the problems of finding suitable young women for this study will be appreciated. As far as the premenopausal women were concerned, their complaints and the need for investigation justified the operations which made it possible to take blood from the ovarian veins. For the younger women, however, one was dependent on coincidence: upon the availability of women who needed to undergo abdominal surgery which did not involve the genital tract, and for whom basal temperature charts for 3 mth and repeated vaginal smears provided evidence that their menstrual cycles were ovulatory. Figs. 1 and 2 are,it is felt, self-explanatory. One point of particular interest here is that both the actual concentration of testosterone (Fig. 1) and its computed daily secretion rate (Fig. 2) in young women with normal menstrual cycles were much higher than expected.
When comparing the premenopausal women with the younger ones, the young women in the periovulatory phase of the menstrual cycle [6] have been taken as the norm. As far as the premenopausal women were concerned, the concentrations of testosterone and of oestradiol were both somewhat higher than in the normal periovulatory young women (Fig. 3), but what is really significant are the considerably higher daily secretion rates of these substances (Fig. 4). The oestradiol secretion rate of the premenopausal women was significantly higher (P
[l] Baird, D.T. (1974) Blood production and ovarian secretion rates of estradiol-17-P and estrone through the menstrual cycle. J. Clin. Endocrinol. 38,1009-1017. [ 21 Baird, D.T. (I 976) Ovarian secretion and metabolism in women. In: The endocrine function of the human ovary, pp. 125-133. Editors: V.H.T. James, M. Serion and G. Giusti. Academic Press, New York. [3] BotelJa-Llusii, J. (1973) Endocrinology of woman, p. 860. W.B. Saunders, Philadelphia. [4] Botella-Llusii, J., Guadalix, F.J., Martin-Santos, J. and Tresguerres, de testosterona en vena o&rica izquierda y en venas suprarrenales, radiologico. Acta Ginecol. 27, 13-18. [S] MartinezGuarro, M., Tresguerres, J.A.F., Diaz-Garcia, am&is de1 estradiol plasmatico. Actas de1 1 congreso
J.A.F. (1975) Concentration determinada por cateterismo
F. and Tejero, A. (1975) Radioimmunonational de ciencias fisiologicas, Zaragoza,
June, 1975, pp. 11.5. [6] Nimrod, A. and Ryan, K.J. (1975) Aromatization of androgens by human abdominal and breast tissues. J. Clin. Endocrinol. 40, 367-372. [7] Stahl, N.L., Teelsnik, C.R. and Greenblatt, R.B. (1973) Ovarian and adrenal peripheral testosterone levels in polycystic ovarian disease. J. Obstet. Gynecol. 117, 194-200. [8] Tresguerres, J.A.F., Fernindez, M.D., Fernandez, M.C. and Oriol-Bosch, A. (1975) Determination de la testosterona plasmitica por radioimmunoanilisis. Rev. Iber. Endocrinol. 127, 23-39.
o Elsevier/NorthNolland
Biomedical Press
AND17&4lESTRADIOLSECRETIONOFTHEHUMANOVARY. I.NORMALYOUNGWOMEN,ANDPREMENOPAUSALWOMENWITH ENDOMETRIALHYPERPLASIA
TESTOSTERONE
J. BOTELLA-LLUSIA ‘,* A. ORIOL-BOSCH ‘, F. SANCHEZGARRIDO J.A.F. TRESGUERRES ” 1 Department
of Obstetrics and Gynaecology and a Department
’and
of Experimental
Endocrinology,
University of Madrid School of Medicine, Madrid, Spain
(Received 19 March 1979, accepted 3 July 1979)
Testosterone
and 17P-oestradiol were determined
in blood obtained from the ovarian veins of and 10 of whom were premenopausal with uterine bleedings and endometrial hyperplasia. The concentrations of these two hormones in the cubital veins of the premenopausal women were also determined. It was found that the concentrations of the two hormones were not significantly greater in the premenopausal women than in the control group of young normally ovulating and menstruating women in the periovulatory phase of the menstrual cycle, but that the ovarian secretion rates of both hormones, particularly of testosterone, were considerably greater in the premenopausal women. In these women the concentrations of both hormones were significantly lower in the cubital veins than in the ovarian veins. The conclusion is that the augmented oestrogenic effect on the endometrium and on other target organs of premenopausal women with endometrial hyperplasia may be due not only to an increased ovarian secretion rate of estradiol, but also and more specifically to an increased ovarian secretion rate of testosterone, and to the rapid conversion of this hormone into oestradiol in the periphery. 26 women, 16 of whom were young and regularly ovulating and menstruating,
(Key words: Testosterone,
17paestradio1, Ovarian vein blood, Premenopause)
INTRODUCTION
It is often assumed that functional uterine bleeding in conjunction with endometrial hyperplasia, not an uncommon occurrence in the premenopausal years, is due to an excess of circulating oestrogens 131. This assumption is based on indirect evidence and on the determination of oestrogen levels in peripheral blood. Little appears to be known about the ovarian secretion rates of oestrogens in such women [2], despite the fact that reports have been published on methods by which to study these, both in vivo [4,7] and in vitro [ 11. The present paper gives the results of a study in which the ovarian secretion rates of testosterone and of 17&oestradiol were calculated from the levels of these hormones found in blood drawn from the ovarian veins of premenopausal women with * Address for correspondence: Prof. J. Botella-Llusii, Departamento de Obstetricia y Ginecologi’a, Hospital Clinico de la Facultad de Medicina, Universidad Complutense de Madrid, Planta 5’ Norte, Ciudad Universitaria, Madrid 3, Spain.
2
endometrial hyperplasia and functional bleedings, and, for comparative purposes, of young women with normal menstrual cycles. MATERIAL AND METHODS
The study involved 26 women. 16 were young women, aged 18-25, with normal menstrual cycles: six were in the follicular phase (days 5-12) of their cycles, six in the periovulatory phase (days 13-15) and four in the luteal phase (days 16-23). The other 10 women were premenopausal, presenting with endometrial hyperplasia and uterine bleedings. Further details of the premenopausal women are given in Table I. After laparotomy, a polyvinyl catheter was inserted into the ovarian veins on both sides. Blood was drawn for exactly 5 min, and from this the daily ovarian secretion rates of testosterone and of 17&oestradiol were computed. It may well be that the ovarian secretion rates, particularly of testosterone, differ at different times of the day; in order to reduce this complicating factor as much as possible, the blood was drawn between 9 and 10 a.m. in all instances. The levels of testosterone and of oestradiol were determined by radioimmunoassay, the testosterone by a method of Tresguerres and Oriol-Bosch [8], and the oestradiol by a method of MartinezCuarro et al. [5], RESULTS
(a) Young women with regular cycles
Fig. 1 shows the actual concentrations found. The women are grouped according to the stage of their menstrual cycle: follicular (6 women), periovulatory (6) and luteal (4). Fig. 2 shows the computed 24-h production of the two hormones.
TABLE I Data on the 10 premenopausal women in this study. Age
41 53 39 48 45 41 43 45 39 42
Diagnosis
Myoma Bleeding Myomata Bleeding Myoma Myoma Endometriosis Endometrisosis Adenomyosis Adenomyosis
Histological findings Endometrium
Ovaries
Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia Hyperplasia
Enlarged, polycystic Atretic follicles, hyperthecosis Enlarged, polycystic Polycystic, hyperthecosis Multiple atresia, hyperthecosis Enlarged, polycystic, hyperthecosis Polycystic Polycystic Polycystic, grossly enlarged Normal corpus luteum
pi
0
FOL
m
ov
3
mrmrm LUT: E2 Pg/ml
T ng/lCOml
320 240 160 80 T CONC.
TEST
E, CONC.
ESTRAD
Fig. 1. Testosterone (T) and 17p-oestradiol (Ea) determined by radioimmunoassay in ovarian venous blood of 16 young women with normal ovulation and menses. The cases are grouped into the follicular (FOL), periovulatory (Ov), and luteal (LUT) phases of the menstrual cycle. The concentrations shown are the mean of the two ovarian veins. Fig. 2. Computed testosterone and 17p-oestradiol secretion per 24 h, based on the actual amounts determined in a 5-min period. The calculations are based on the mean secretion of both ovaries; the total secretion, therefore, is twice that indicated in this figure. The cases, 16 young women with normal ovulation and menses, are grouped into the follicular (FOL), periovulatory (OV), and luteal (LUT) phases of the menstrual cycle.
E2 pg/ml
T rq/1
!1_ L I
N
I
H
T CONC
9
P
N
H
P
E2 CONC
Fig. 3. Testosterone (T) and 17p-oestradiol (Ea) concentrations in ovarian venous blood of normal young periovulatory women (N), in ovarian venous blood of hyperoestrogenic women (H), and in peripheral blood of hyper-oestrogenic women (P).
TN Fig. 4. Computed testosterone secretion per 24 h in normal young periovulatory women (TN) and in hyper-oestrogenic women (TH), and computed 17poestradiol secretion per 24 h in normal young periovulatory women (EaN) and in hyper-oestrogenic women (EaH). The calculations are based on the mean secretion of both ovaries; the total secretion, therefore, is twice that indicated in this figure.
(b) Premenopausal women with endometrial hyperplasia Fig. 3 shows the actual concentrations of the two hormones found in the blood of the ovarian veins of the premenopausal women, and in the blood drawn from the cubital veins of these women. To facilitate an easy comparison, the concentrations found in the ovarian veins of the young women in the periovulatory phase of the menstrual cycle are also included in this figure. Fig. 4 shows the computed 24-h secretion of the two hormones in the premenopausal women and in the young periovulatory women. DISCUSSION
The number of subjects studied was, admittedly, small, but the problems of finding suitable young women for this study will be appreciated. As far as the premenopausal women were concerned, their complaints and the need for investigation justified the operations which made it possible to take blood from the ovarian veins. For the younger women, however, one was dependent on coincidence: upon the availability of women who needed to undergo abdominal surgery which did not involve the genital tract, and for whom basal temperature charts for 3 mth and repeated vaginal smears provided evidence that their menstrual cycles were ovulatory. Figs. 1 and 2 are,it is felt, self-explanatory. One point of particular interest here is that both the actual concentration of testosterone (Fig. 1) and its computed daily secretion rate (Fig. 2) in young women with normal menstrual cycles were much higher than expected.
When comparing the premenopausal women with the younger ones, the young women in the periovulatory phase of the menstrual cycle [6] have been taken as the norm. As far as the premenopausal women were concerned, the concentrations of testosterone and of oestradiol were both somewhat higher than in the normal periovulatory young women (Fig. 3), but what is really significant are the considerably higher daily secretion rates of these substances (Fig. 4). The oestradiol secretion rate of the premenopausal women was significantly higher (P
[l] Baird, D.T. (1974) Blood production and ovarian secretion rates of estradiol-17-P and estrone through the menstrual cycle. J. Clin. Endocrinol. 38,1009-1017. [ 21 Baird, D.T. (I 976) Ovarian secretion and metabolism in women. In: The endocrine function of the human ovary, pp. 125-133. Editors: V.H.T. James, M. Serion and G. Giusti. Academic Press, New York. [3] BotelJa-Llusii, J. (1973) Endocrinology of woman, p. 860. W.B. Saunders, Philadelphia. [4] Botella-Llusii, J., Guadalix, F.J., Martin-Santos, J. and Tresguerres, de testosterona en vena o&rica izquierda y en venas suprarrenales, radiologico. Acta Ginecol. 27, 13-18. [S] MartinezGuarro, M., Tresguerres, J.A.F., Diaz-Garcia, am&is de1 estradiol plasmatico. Actas de1 1 congreso
J.A.F. (1975) Concentration determinada por cateterismo
F. and Tejero, A. (1975) Radioimmunonational de ciencias fisiologicas, Zaragoza,
June, 1975, pp. 11.5. [6] Nimrod, A. and Ryan, K.J. (1975) Aromatization of androgens by human abdominal and breast tissues. J. Clin. Endocrinol. 40, 367-372. [7] Stahl, N.L., Teelsnik, C.R. and Greenblatt, R.B. (1973) Ovarian and adrenal peripheral testosterone levels in polycystic ovarian disease. J. Obstet. Gynecol. 117, 194-200. [8] Tresguerres, J.A.F., Fernindez, M.D., Fernandez, M.C. and Oriol-Bosch, A. (1975) Determination de la testosterona plasmitica por radioimmunoanilisis. Rev. Iber. Endocrinol. 127, 23-39.