Acta Obstet Gynecol Scand Suppl 54
ESTROGENIC HORMONES - GENERAL CONSIDERATIONS Mirjam Furuhjelm From the Karolinska Institute, Department of Obstetrics and Gynaecology, Sabbatsberg Hospital (Head : Prof : A . Ingelman-Sundberg), Stockholm, Sweden
The estrogen biosynthesis in the fetoplacental unit is somewhat different from the one outlined in Fig. 4. The sequence cholesterol-+ C p l steroids -+ C,, steroids -b CISsteroids can be completed in the adult in all steroidogenic organs. In the fetoplacental unit, this is not so. A complete steroid biosynthesis there unconditionally requires the involvement of the placenta. The fetal organs are not capable of converting cholesterol into Cln steroids and in the fetoplacental unit this reaction takes place in the placenta. Placenta, in turn, is lacking totally the capacity of converting CZ1steroids into Cln steroids, which process instead takes place in the fetal organs (Fig. 5). 16 IX hydroxylation, which is a necessary step BIOSYNTHESIS in the formation of estriol, takes place in the The most important estrogens are three, viz.: fetal liver. The aromatization of Ring A is perestrone (El), estradiol (E2), and estriol (E:O formed in the placenta. (Fig. 1). The biosynthesis of estriol is some- Since demethylations as well as aromatizations, what different from that of the other two, but both of which are involved in the estrogen they have like all natural steroid estrogens one biosynthesis, are comparatively common biobiosynthetic step in common, namely the splitchemical reactions, small quantities of estrogen ting off of the methyl group 19 and the arocan be produced in the human body by nonmatization of Ring A in this connection (Fig. 2). endocrine tissue. This reaction takes place in ovaries, testes, adrenal cortex, and in the fetoplacental unit. The reactions are catalyzed by iron containing enzymes, and require molecular oxygen and OH Estradiol NADPH. The process is stimulated by gonadoEstrone tropins in vivo as well as in vitro. The biosynthesis of estriol comprises besides the aromatization of Ring A also hydroxylation in 16 IX position (Fig. 3). In this process the liver plays an important part.
Placenta, ovaries, adrenal glands and testes are capable of synthesizing estrogens in man. Estrogens, with their 18 carbon atoms, represent the last link in the chain of partial decomposition and oxidation processes constituting the human steroid biosynthesis. Estrogens develop from cholesterol over Clo substances, i.e. over androgens. Already in the 1930’s, Zondek (1 1) discussed the role of the androgenic Cle steroids as precursors of the estrogens. This hypothesis has been suggested in old sources in the First Book of Moses, 2:22: ”And the rib which the Lord God had taken from Man made he a Woman and brought her unto the Man.”
& I
Fig. 4 shows a simplified scheme of the biosynthesis of the biologically active human steroids.
OH
16a - Hydroxyestrone
Estriol
Fig. I . The three most important estrogens : estrone, estradiol and estriol. Acta Obstet Gynecol Scand Suppl 54
30
Mirjam Furuhjelm
&
Eleod~.o~o~~+Ho@ 0
0
0
II
fl
Formaldehyde +H-C-ti
NnodPH,
0 Estrone
Fig. 2. Aromatization of ring A.
The transformation of estrogenic hormones. Among the three principal estrogens in man, 17 (3-estradiolis the main product of the ovary, and is transformed in the body into estrone. Estradiol and estrone can be mutually transformed into each other by the activity of a specific 17 B-hydroxysteroid dehydrogenase. Both estradiol and estrone can be transformed into estriol. The transformation essentially takes place in the liver, where there is an interconversion between estrone and estradiol. Estradiol is 1,000 times as active as estriol and 100 times as active as estrone. All three estrogens are excreted in the urine as glucuronidate and sulphate conjugates.
Animals belonging to the Equus family, including the horse, are remarkable estrogen producers. Pregnant mares excrete more than 100 mg a day, a record broken only by the stallion, the greatest producer of estrogen among all living things, though being of the male sex. The estrogens in the horse consist partly of equilin and equilenin. They are unsaturated in Ring B, and are excreted as conjugates of sulphuric- and glucuronic acid. Estrogenic activity is a property shared by many other substances. Many phenols are estrogenic. In many plants, for instance clover, substances with estrogen effect have been found. Clover contains plenty of a weak estro-
o&-on
I
Fig. 3 Pathways of estriol biosynthesis.
The estrogens, which are increted by the ovary, are carried by the blood to the liver, where they are temporarily inactivated, metabolized, and excreted into the bile. After the absorption from the upper part of the intestine, they are again carried to the liver through the portal vessels. Small quantities are constantly passing into the circulation and reach the target organs, i.e. uterus, vagina, and mammary glands, etc. Estrogenic effects are conveyed directly or indirectly by estrogen receptors existing in such target organs as are known to be excitable by estrogens, such as endometrium, myometrium, placenta etc. Acta Obstet Gynecol Scand Suppl 54
1
I
JXP -oLJP=,&
"0
I Fig. 4. Simplified scheme of the biosynthesis of the
biologically active human steroids. Only main stages shown.
Estrogenic hormones
31
Modifications of the natural 17 P-estradiol molecule have been made in order to prevent inactivation in the liver, thus making the preparation more suitable for peroral administration. One of the most active estrogens existing is ethinyl estradiol, in which an ethinyl group is coupled to the 17-carbon atom. Approximately 20 mcg per day are sufficient as substitution in the menopause, and 50 mcg per day inhibit ovulation. The inactivation of the preparation in the liver and other tissues takes place very slowly, and it is not exactly known how it is excreted.
Fig. 5. The steroid biosynthesis of the fetoplacental unit. Free reproduction after Diczfalusy (1967). For the sake of convenience the conjugate forms of the steroids have not been drawn. *Pathway from Czl to C19 is blocked due to C17-20 lyase deficiency.
gen, genistein, which is an isoflavone. This fact is of social importance, because sheep grazing clover abundantly may become sterile owing to the estrogens consumed may cause disturbances in the estrus cycles, leading to abortion in pregnant animals. In date-palms, natural steroid estrogens have been found, principally estrone. ORALLY ACTIVE ESTROGENS Earlier, 17 P-estradiol was not considered to be orally active, since it was destroyed in the gastrointestinal tract. If 17 P-estradiol is produced in microcrystalline form, oral administration gives a good resorption. An increase by 2,000 per cent of estrogen in the blood as compared with the initial value five hours after the administration of two mg of microcrystalline 17 P-estradiol has been reported. Estradiol valerianate is also very effective by oral administration, and so is also estradiol benzoate.
Dodds and his co-workers (3), in their endeavours to develop estrogenic preparations orally active, discovered the estrogenic activity of some stilbenes and phenanthrene derivatives, of which diethyfstifbestrol (stilbol) is an example. It is potently active when taken orally. The duration of the effect produced by a single dose is long, since it is decomposed relatively slowly in the body. It is an artificial substance. Forsberg ( 5 ) has shown that juvenile female mice whose mothers had been given diethylstilbestrol during pregnancy devdop adenocarcinoma in the vagina. This seems to be the case also in man, because cases of vaginal adenocarcinoma developed on the basis of an endometriosis have been described in girls whose mothers have been treated with stilbol during pregnancy. Estrogens are excreted already during the fetal period of life, and follicles are developing cyclically to varying degrees of maturity and atresia. When a newborn girl starts her life she has already lost 80 per cent of her oocytes. At puberty, the primordial follicles have been reduced to some 500,000, and during the fertile period of life they are constantly declining in number until the menopause, when only few follicles remain. The growing follicles have an important hormonal activity. The ovary produces estrogens by two main pathways. In the theca interna estrogens are produced mainly from dehydroepiandrosterone via the As - 3 P-hydroxy pathway while estrogens from the corpus luteum are produced mainly from progesterone via the A4-3-keto pathway. Acta Obstet Gynecol Scand S u p p l 5 4
32
Mirjam Furuhjelm
ESTROGENIC EFFECTS The estrogens are responsible for the changes taking place in girls in puberty and for the psychical as well as the physical changes developing the girl into a woman. They cause a growth of vagina, uterus and Fallopian tubes. By the influence of the estrogens the breasts are growing. In the first place, the estrogens stimulate the growth of the ducts, the development of the stroma, and the formation of fat. In these effects, the pituitary hormones play an important part. The estrogens, furthermore, contribute to the development of the specifically feminine body type and skeletal structure. They make the skin softer and more elastic, and close the growth centers of the long bones, thus causing the height increment to cease. The growth of labia minora, the axillary hair growth as well as the pigmentation of areolae, nipples, . and genital region are dependent on estrogenic stimulation. For the development of pubic hair growth, clitoris, and labia majora additional stimulation by androgenic hormones is needed. In addition to its influence on the reproductive organs, estrogen also exerts an important influence on other epithelial structures, such as the urethral mucosa, the mucous membrane of the trigonum, as well as mucous membranes of nose, mouth, and trachea. Estrogen has a considerable effect on woman’s psyche. Absence of estrogen gives rise to nervousness, depression, irritability, and reduces libido and lust perception. During the proliferative phase of the cycle, the woman also feels more comfortable and vigorous. In the first years after the menarche and towards the end of the fertile period the estrogen cycles dominate. When the estrogen production ceases, this leads to atrophy of the mucous membrane in the urethra, the bladder, and the vagina, a loss of skin elasticity - the skin will also be thin. The bones are growing thinner, and sclerosis develops in the blood vessels. These changes illustrate the numerous effects of estrogen on the body, a field that has only recently begun to be properly appreciated. Estrogen has a slight anabolic effect. Administration of estrogen increases thyroxin- and corticosteroid-binding globulin, an effect conActa Obstet Gynecol Scand Suppl 54
trary to that of testosterone. So far, our knowledge of the effect of estrogens on carbohydrate metabolism is poor. It is unknown whether the fact that diabetes appears or becomes aggravated at the menopause has anything to do with the reduced estrogen incretion at this age. Estrogen reduces serum cholesterol and B-lipoproteins. Fertile women have relatively more a-lipoproteins and correspondingly less B-lipoproteins than men. This difference disappears after the menopause. Estrogen has an effect on tissue water- and salt retention, especially when given in large doses. This effect is considered to be due to an increased return resorption of water by renal tubuli. A certain amount of water is retained under the influence of estrogen in the premenstrual phase. The water is stored extracellularly. Estrogens, pituitary and hypothalamus Estrogen has a specific effect on the incretion of the gonadotropic hormones owing to its influence on the hypothalamus and the incretion of the releasing hormone.
Two centers in the hypothalamus are considered to play an important part in the control of the hypophysis. One center in eminentia medialis, the tonic center, is considered to be responsible for a constant basal production of gonadotropins maintaining a basal ovarial hormone production. Another center in the preoptic area, the cyclic center, is considered responsible for the increase in gonadotropin production that leads to ovulation and corpus luteum formation. The area of the anterior hypothalamus is sensible to a positive feedback of estrogen, and the influence of an inhibiting feedback proceeds to the tonic center (Fig. 6 ) . The interaction between estrogens and FSH, and between estrogens and LH, is complex. When increasing estradiol levels by exogenous administration in the postmenopause, the primary effect of such an increase is a depression of LH, followed by an inhibition of FSH with higher dosage. With still higher doses of estradiol, FSH remains low whereas LH is stimulated. As far as FSH is concerned, there exists a negatively inhibiting feedback relationship to estradiol, whereas with regard to LH there
Estrogenic hormones 33
Fig. 6. Interaction between the gonads and the hypothalamus. Adapted from Clinical Gynecologic Endocrinology and Infertility, by L. Speroff, R.H. Glass and N.G. Kase. The Williams & Wilkins Co., Baltimore, 1974.
exists a negatively inhibiting feedback with low doses of estradiol. Thus, a depression of FSH is found in the early part of the cycle when the estrogens increase, this being due to a negative feedback effect. A simultaneous, accompanying depression of LH, however, does not take place, since the positive hypothalamic center responds to the increased quantities of estrogen by blocking the negative feedback center. The negative feedback of estrogen on the LH incretion is therefore effective with rather low doses, and probably remains on its maximum level through the entire cycle. The LH fluctuation reflects the positive feedback of the estradiol during the follicular and ovulatory phases of the cycle, and during the luteal phase the LH incretion is depressed by the negative feedback of the progesterone.
Estrogens as therapeutics Estrogens are resorbed through skin and mucous membranes, besides the resorption from the gastrointestinal tract. In oil solution, they are also resorbed when injected intramuscularly. All of these ways of administration have found therapeutic use. The widest use of estrogen is as substitution in menopausal and climacteric troubles and in contraceptives. Together with the other component, the progestogen, it inhibits ovulation, and the endometrium becomes unsuitable for receiving an impregnated ovum. Contraceptive pills in the market contain either ethinyl estradiol or mestranol. Trials are in progress with a view of substituting these so-called synthetic preparations by 17 B-estradiol valerianate or 17 B-estradiol in microcrystalline form.
REFERENCES 1. Burch, J.C. & Byrd, B.F.J. Effects of long-term
administration of estrogen on the occurrence of mammary cancer in women. Am J Surg 174 :411, 1971. 2. Diczfalusy, E. : Endocrine function of the human fetoplacental unit. Fed Proc 23 :791, 1964. 3 . Dodds, E.S., Lawson, W. & Williams, P.C.: Proc R SOC, London, Ser. B 132:419, 1944. 4. Higano, N., Robinson, R.W. & Cohen, W.D.:
Estrogens and cancer The estrogens have been accused of having a carcinogenic effect. Testicular, lymphoid, and skeletal tumors can be induced by the administration of estrogen in high doses, but only in mice belonging to special cancer strains. There is no evidence of estrogen, in the doses commonly used, being able to induce cancer in man. On the contrary, investigations speak in favour of estrogens, since they prevent tissue atrophy and ensuing changes, and thus tend to reduce the frequency of malignant tumors in elderly women.
Increased incidence of cardiovascular disease on castrated women. N Engl J Med 268 :1123, 1963. 5 . Forsberg, J.G.: Estrogen, vaginal cancer and vaginal development. Am J Obstet Gynecol 113 : 83, 1972. 6. Jayle, M.J.: Hormonologie de la grossesse humaine : Monographie de la revue europeenne d'endocrinologie. Gauthiers-Villars, Paris, 1965.
7. Lebech, P.E. & Olsen, C.E. : Oral treatment with 17 (3-oestradiol. Second International Symposium, New Developments in Gynaecological Endocrinology, Sittard 1970.
8. Rupp, J.J. : Clinical Endocrinology. Hoeber Medical Division, Harper & Row, New York, Evaston and London, 1967. Acta Obstet Gynecol Scand Suppl54
34
Mirjam Furuhjelm
9. Ryan, K.J., Petro, Z. & Kaiser, J. : Steroid formation by isolated and recombined ovarian granulosa and thecal cells. J Clin Endocrinol Metab 28 :355, 1968. 10. Ryan, K.J. : Steroid Metabolism in the Human Ovary. In Advances in Obstetrics and Gynaecology (eds. S.L. Marcus & C.C. Marcus). Vol. I. Wilkins Co., Baltimore, 1967.
11. Zondek, B. : Die Hormone des Ovariums und des Hypophysen vorderlappens. J. Springer, Berlin, 1931.
Acta Obstet Gynecol Scand Suppl 54
12. Frontiers of Hormone Research. 3. Estrogens in the Post-Menopause. (eds. P.H. van Keep & C. Lauritzen). S. Karger, Basel, Miinchen, Paris, London, New York, Sydney, 1975. Submitted for publication February 1976.
Mirjam Furuhjelm, M.D. Department of Obstetrics and Gynaecology Sabbatsberg Hospital S-113 82 Stockholm. Sweden
ESTROGENIC HORMONES - GENERAL CONSIDERATIONS Mirjam Furuhjelm From the Karolinska Institute, Department of Obstetrics and Gynaecology, Sabbatsberg Hospital (Head : Prof : A . Ingelman-Sundberg), Stockholm, Sweden
The estrogen biosynthesis in the fetoplacental unit is somewhat different from the one outlined in Fig. 4. The sequence cholesterol-+ C p l steroids -+ C,, steroids -b CISsteroids can be completed in the adult in all steroidogenic organs. In the fetoplacental unit, this is not so. A complete steroid biosynthesis there unconditionally requires the involvement of the placenta. The fetal organs are not capable of converting cholesterol into Cln steroids and in the fetoplacental unit this reaction takes place in the placenta. Placenta, in turn, is lacking totally the capacity of converting CZ1steroids into Cln steroids, which process instead takes place in the fetal organs (Fig. 5). 16 IX hydroxylation, which is a necessary step BIOSYNTHESIS in the formation of estriol, takes place in the The most important estrogens are three, viz.: fetal liver. The aromatization of Ring A is perestrone (El), estradiol (E2), and estriol (E:O formed in the placenta. (Fig. 1). The biosynthesis of estriol is some- Since demethylations as well as aromatizations, what different from that of the other two, but both of which are involved in the estrogen they have like all natural steroid estrogens one biosynthesis, are comparatively common biobiosynthetic step in common, namely the splitchemical reactions, small quantities of estrogen ting off of the methyl group 19 and the arocan be produced in the human body by nonmatization of Ring A in this connection (Fig. 2). endocrine tissue. This reaction takes place in ovaries, testes, adrenal cortex, and in the fetoplacental unit. The reactions are catalyzed by iron containing enzymes, and require molecular oxygen and OH Estradiol NADPH. The process is stimulated by gonadoEstrone tropins in vivo as well as in vitro. The biosynthesis of estriol comprises besides the aromatization of Ring A also hydroxylation in 16 IX position (Fig. 3). In this process the liver plays an important part.
Placenta, ovaries, adrenal glands and testes are capable of synthesizing estrogens in man. Estrogens, with their 18 carbon atoms, represent the last link in the chain of partial decomposition and oxidation processes constituting the human steroid biosynthesis. Estrogens develop from cholesterol over Clo substances, i.e. over androgens. Already in the 1930’s, Zondek (1 1) discussed the role of the androgenic Cle steroids as precursors of the estrogens. This hypothesis has been suggested in old sources in the First Book of Moses, 2:22: ”And the rib which the Lord God had taken from Man made he a Woman and brought her unto the Man.”
& I
Fig. 4 shows a simplified scheme of the biosynthesis of the biologically active human steroids.
OH
16a - Hydroxyestrone
Estriol
Fig. I . The three most important estrogens : estrone, estradiol and estriol. Acta Obstet Gynecol Scand Suppl 54
30
Mirjam Furuhjelm
&
Eleod~.o~o~~+Ho@ 0
0
0
II
fl
Formaldehyde +H-C-ti
NnodPH,
0 Estrone
Fig. 2. Aromatization of ring A.
The transformation of estrogenic hormones. Among the three principal estrogens in man, 17 (3-estradiolis the main product of the ovary, and is transformed in the body into estrone. Estradiol and estrone can be mutually transformed into each other by the activity of a specific 17 B-hydroxysteroid dehydrogenase. Both estradiol and estrone can be transformed into estriol. The transformation essentially takes place in the liver, where there is an interconversion between estrone and estradiol. Estradiol is 1,000 times as active as estriol and 100 times as active as estrone. All three estrogens are excreted in the urine as glucuronidate and sulphate conjugates.
Animals belonging to the Equus family, including the horse, are remarkable estrogen producers. Pregnant mares excrete more than 100 mg a day, a record broken only by the stallion, the greatest producer of estrogen among all living things, though being of the male sex. The estrogens in the horse consist partly of equilin and equilenin. They are unsaturated in Ring B, and are excreted as conjugates of sulphuric- and glucuronic acid. Estrogenic activity is a property shared by many other substances. Many phenols are estrogenic. In many plants, for instance clover, substances with estrogen effect have been found. Clover contains plenty of a weak estro-
o&-on
I
Fig. 3 Pathways of estriol biosynthesis.
The estrogens, which are increted by the ovary, are carried by the blood to the liver, where they are temporarily inactivated, metabolized, and excreted into the bile. After the absorption from the upper part of the intestine, they are again carried to the liver through the portal vessels. Small quantities are constantly passing into the circulation and reach the target organs, i.e. uterus, vagina, and mammary glands, etc. Estrogenic effects are conveyed directly or indirectly by estrogen receptors existing in such target organs as are known to be excitable by estrogens, such as endometrium, myometrium, placenta etc. Acta Obstet Gynecol Scand Suppl 54
1
I
JXP -oLJP=,&
"0
I Fig. 4. Simplified scheme of the biosynthesis of the
biologically active human steroids. Only main stages shown.
Estrogenic hormones
31
Modifications of the natural 17 P-estradiol molecule have been made in order to prevent inactivation in the liver, thus making the preparation more suitable for peroral administration. One of the most active estrogens existing is ethinyl estradiol, in which an ethinyl group is coupled to the 17-carbon atom. Approximately 20 mcg per day are sufficient as substitution in the menopause, and 50 mcg per day inhibit ovulation. The inactivation of the preparation in the liver and other tissues takes place very slowly, and it is not exactly known how it is excreted.
Fig. 5. The steroid biosynthesis of the fetoplacental unit. Free reproduction after Diczfalusy (1967). For the sake of convenience the conjugate forms of the steroids have not been drawn. *Pathway from Czl to C19 is blocked due to C17-20 lyase deficiency.
gen, genistein, which is an isoflavone. This fact is of social importance, because sheep grazing clover abundantly may become sterile owing to the estrogens consumed may cause disturbances in the estrus cycles, leading to abortion in pregnant animals. In date-palms, natural steroid estrogens have been found, principally estrone. ORALLY ACTIVE ESTROGENS Earlier, 17 P-estradiol was not considered to be orally active, since it was destroyed in the gastrointestinal tract. If 17 P-estradiol is produced in microcrystalline form, oral administration gives a good resorption. An increase by 2,000 per cent of estrogen in the blood as compared with the initial value five hours after the administration of two mg of microcrystalline 17 P-estradiol has been reported. Estradiol valerianate is also very effective by oral administration, and so is also estradiol benzoate.
Dodds and his co-workers (3), in their endeavours to develop estrogenic preparations orally active, discovered the estrogenic activity of some stilbenes and phenanthrene derivatives, of which diethyfstifbestrol (stilbol) is an example. It is potently active when taken orally. The duration of the effect produced by a single dose is long, since it is decomposed relatively slowly in the body. It is an artificial substance. Forsberg ( 5 ) has shown that juvenile female mice whose mothers had been given diethylstilbestrol during pregnancy devdop adenocarcinoma in the vagina. This seems to be the case also in man, because cases of vaginal adenocarcinoma developed on the basis of an endometriosis have been described in girls whose mothers have been treated with stilbol during pregnancy. Estrogens are excreted already during the fetal period of life, and follicles are developing cyclically to varying degrees of maturity and atresia. When a newborn girl starts her life she has already lost 80 per cent of her oocytes. At puberty, the primordial follicles have been reduced to some 500,000, and during the fertile period of life they are constantly declining in number until the menopause, when only few follicles remain. The growing follicles have an important hormonal activity. The ovary produces estrogens by two main pathways. In the theca interna estrogens are produced mainly from dehydroepiandrosterone via the As - 3 P-hydroxy pathway while estrogens from the corpus luteum are produced mainly from progesterone via the A4-3-keto pathway. Acta Obstet Gynecol Scand S u p p l 5 4
32
Mirjam Furuhjelm
ESTROGENIC EFFECTS The estrogens are responsible for the changes taking place in girls in puberty and for the psychical as well as the physical changes developing the girl into a woman. They cause a growth of vagina, uterus and Fallopian tubes. By the influence of the estrogens the breasts are growing. In the first place, the estrogens stimulate the growth of the ducts, the development of the stroma, and the formation of fat. In these effects, the pituitary hormones play an important part. The estrogens, furthermore, contribute to the development of the specifically feminine body type and skeletal structure. They make the skin softer and more elastic, and close the growth centers of the long bones, thus causing the height increment to cease. The growth of labia minora, the axillary hair growth as well as the pigmentation of areolae, nipples, . and genital region are dependent on estrogenic stimulation. For the development of pubic hair growth, clitoris, and labia majora additional stimulation by androgenic hormones is needed. In addition to its influence on the reproductive organs, estrogen also exerts an important influence on other epithelial structures, such as the urethral mucosa, the mucous membrane of the trigonum, as well as mucous membranes of nose, mouth, and trachea. Estrogen has a considerable effect on woman’s psyche. Absence of estrogen gives rise to nervousness, depression, irritability, and reduces libido and lust perception. During the proliferative phase of the cycle, the woman also feels more comfortable and vigorous. In the first years after the menarche and towards the end of the fertile period the estrogen cycles dominate. When the estrogen production ceases, this leads to atrophy of the mucous membrane in the urethra, the bladder, and the vagina, a loss of skin elasticity - the skin will also be thin. The bones are growing thinner, and sclerosis develops in the blood vessels. These changes illustrate the numerous effects of estrogen on the body, a field that has only recently begun to be properly appreciated. Estrogen has a slight anabolic effect. Administration of estrogen increases thyroxin- and corticosteroid-binding globulin, an effect conActa Obstet Gynecol Scand Suppl 54
trary to that of testosterone. So far, our knowledge of the effect of estrogens on carbohydrate metabolism is poor. It is unknown whether the fact that diabetes appears or becomes aggravated at the menopause has anything to do with the reduced estrogen incretion at this age. Estrogen reduces serum cholesterol and B-lipoproteins. Fertile women have relatively more a-lipoproteins and correspondingly less B-lipoproteins than men. This difference disappears after the menopause. Estrogen has an effect on tissue water- and salt retention, especially when given in large doses. This effect is considered to be due to an increased return resorption of water by renal tubuli. A certain amount of water is retained under the influence of estrogen in the premenstrual phase. The water is stored extracellularly. Estrogens, pituitary and hypothalamus Estrogen has a specific effect on the incretion of the gonadotropic hormones owing to its influence on the hypothalamus and the incretion of the releasing hormone.
Two centers in the hypothalamus are considered to play an important part in the control of the hypophysis. One center in eminentia medialis, the tonic center, is considered to be responsible for a constant basal production of gonadotropins maintaining a basal ovarial hormone production. Another center in the preoptic area, the cyclic center, is considered responsible for the increase in gonadotropin production that leads to ovulation and corpus luteum formation. The area of the anterior hypothalamus is sensible to a positive feedback of estrogen, and the influence of an inhibiting feedback proceeds to the tonic center (Fig. 6 ) . The interaction between estrogens and FSH, and between estrogens and LH, is complex. When increasing estradiol levels by exogenous administration in the postmenopause, the primary effect of such an increase is a depression of LH, followed by an inhibition of FSH with higher dosage. With still higher doses of estradiol, FSH remains low whereas LH is stimulated. As far as FSH is concerned, there exists a negatively inhibiting feedback relationship to estradiol, whereas with regard to LH there
Estrogenic hormones 33
Fig. 6. Interaction between the gonads and the hypothalamus. Adapted from Clinical Gynecologic Endocrinology and Infertility, by L. Speroff, R.H. Glass and N.G. Kase. The Williams & Wilkins Co., Baltimore, 1974.
exists a negatively inhibiting feedback with low doses of estradiol. Thus, a depression of FSH is found in the early part of the cycle when the estrogens increase, this being due to a negative feedback effect. A simultaneous, accompanying depression of LH, however, does not take place, since the positive hypothalamic center responds to the increased quantities of estrogen by blocking the negative feedback center. The negative feedback of estrogen on the LH incretion is therefore effective with rather low doses, and probably remains on its maximum level through the entire cycle. The LH fluctuation reflects the positive feedback of the estradiol during the follicular and ovulatory phases of the cycle, and during the luteal phase the LH incretion is depressed by the negative feedback of the progesterone.
Estrogens as therapeutics Estrogens are resorbed through skin and mucous membranes, besides the resorption from the gastrointestinal tract. In oil solution, they are also resorbed when injected intramuscularly. All of these ways of administration have found therapeutic use. The widest use of estrogen is as substitution in menopausal and climacteric troubles and in contraceptives. Together with the other component, the progestogen, it inhibits ovulation, and the endometrium becomes unsuitable for receiving an impregnated ovum. Contraceptive pills in the market contain either ethinyl estradiol or mestranol. Trials are in progress with a view of substituting these so-called synthetic preparations by 17 B-estradiol valerianate or 17 B-estradiol in microcrystalline form.
REFERENCES 1. Burch, J.C. & Byrd, B.F.J. Effects of long-term
administration of estrogen on the occurrence of mammary cancer in women. Am J Surg 174 :411, 1971. 2. Diczfalusy, E. : Endocrine function of the human fetoplacental unit. Fed Proc 23 :791, 1964. 3 . Dodds, E.S., Lawson, W. & Williams, P.C.: Proc R SOC, London, Ser. B 132:419, 1944. 4. Higano, N., Robinson, R.W. & Cohen, W.D.:
Estrogens and cancer The estrogens have been accused of having a carcinogenic effect. Testicular, lymphoid, and skeletal tumors can be induced by the administration of estrogen in high doses, but only in mice belonging to special cancer strains. There is no evidence of estrogen, in the doses commonly used, being able to induce cancer in man. On the contrary, investigations speak in favour of estrogens, since they prevent tissue atrophy and ensuing changes, and thus tend to reduce the frequency of malignant tumors in elderly women.
Increased incidence of cardiovascular disease on castrated women. N Engl J Med 268 :1123, 1963. 5 . Forsberg, J.G.: Estrogen, vaginal cancer and vaginal development. Am J Obstet Gynecol 113 : 83, 1972. 6. Jayle, M.J.: Hormonologie de la grossesse humaine : Monographie de la revue europeenne d'endocrinologie. Gauthiers-Villars, Paris, 1965.
7. Lebech, P.E. & Olsen, C.E. : Oral treatment with 17 (3-oestradiol. Second International Symposium, New Developments in Gynaecological Endocrinology, Sittard 1970.
8. Rupp, J.J. : Clinical Endocrinology. Hoeber Medical Division, Harper & Row, New York, Evaston and London, 1967. Acta Obstet Gynecol Scand Suppl54
34
Mirjam Furuhjelm
9. Ryan, K.J., Petro, Z. & Kaiser, J. : Steroid formation by isolated and recombined ovarian granulosa and thecal cells. J Clin Endocrinol Metab 28 :355, 1968. 10. Ryan, K.J. : Steroid Metabolism in the Human Ovary. In Advances in Obstetrics and Gynaecology (eds. S.L. Marcus & C.C. Marcus). Vol. I. Wilkins Co., Baltimore, 1967.
11. Zondek, B. : Die Hormone des Ovariums und des Hypophysen vorderlappens. J. Springer, Berlin, 1931.
Acta Obstet Gynecol Scand Suppl 54
12. Frontiers of Hormone Research. 3. Estrogens in the Post-Menopause. (eds. P.H. van Keep & C. Lauritzen). S. Karger, Basel, Miinchen, Paris, London, New York, Sydney, 1975. Submitted for publication February 1976.
Mirjam Furuhjelm, M.D. Department of Obstetrics and Gynaecology Sabbatsberg Hospital S-113 82 Stockholm. Sweden
