ORAL CONTRACEPTIVE AGENTS
9 percent frequency in women with a negative history."' Clezy reported a 58 percent incidence of hypertension on at least one visit in women with a positive history of hypertension during pregnancy, compared with a 23 percent incidence in women with a negative history."10 He also observed a 53 percent incidence of hypertension on one or more visits during oral contraceptive therapy in women with a parental history of hypertension compared with a 30 percent incidence in those with a negative family history. It seems likely that the estrogen-induced changes in the renin-angiotension-aldosterone system act on the background of genetic predisposition for hypertension, to produce significant hypertension in a small percentage of persons.
Liver Disease and Abnormalties of Laboratory Tests DELBERT A. FISHER, MD*
THE STEROID HORMONES in contraceptive preparations exert a number of metabolic effects on the liver. In addition to the alterations in carbohydrate and lipid metabolism already discussed, these hormones modify the rate of synthesis and secretion of a variety of plasma proteins, particularly those that bind hormones and metal ions. The protein most thoroughly studied is thyroxine binding globulin (TBG), an interalpha globulin which is the primary carrier protein for thyroid hormones in serum. The administration of estrogens to euthyroid subjects results in increased serum concentrations of TBG, with the result that serum thyroxine and triiodothyronine concentrations increase. Free hormone concentrations, however, are unchanged after equilibrium is reestablished and hormone production rates remain unchanged. 117-120 In contrast, androgenic hormones and a number of synthetic progestational agents, including norethandrolone and methandrostenolone, reduce serum TBG and thyroid hormone concentrations, also without altering free thyroxine concentrations *Chief, Pediatric Endocrinology, Harbor General Hospital; Professor of Pediatrics, UCLA School of Medicine.
40
JANUARY 1975 * 122 * 1
or thyroid hormone turnover rates.'20-'23 These changes in TBG concentration which occur with estrogen or androgen administration are associated with reciprocal changes in the plasma levels of thyroxine binding prealbumin (TBPA).123 During therapy with oral contraceptive agents combining estrogen and a progestational steroid, the effect of estrogen on TBG synthesis predominates; that is, a significant increase in serum TBG concentration occurs."9"24 However, there is no change or an actual increase in serum TBPA concentration.'24",25 It is presumed that these changes reflect changes in synthesis and secretion of these carrier proteins by the liver, since degradation rates are not altered.'23 More recently, estrogen has been shown to increase plasma concentrations of corticosteroid binding globulin, testosterone-estradiol binding globulin and ceruloplasmin (copper binding protein),126-128 and these binding protein levels as well as serum levels of transferrin (iron binding protein) and transcobalamin (vitamin B12 binding protein) are increased in women taking contraceptive steroid hormone preparations containing estrogen and a progestational agent.'25"29-'34 In this regard, administration of these drugs stimulates the changes in serum protein concentrations observed during pregnancy. The increases in these binding protein concentrations result in increased serum levels of the bound hormones, metals or vitamins, but, by analogy with the normal thyroid hormone turnover rates in patients with increased TBG levels, turnover rates and body economy of the hormones, metals, or vitamins are thought to be unchanged. Increased concentrations of a second group of plasma proteins also occurs; these act as precursors of more active compounds by serving as substrates for a series of enzyme systems. They include angiotensinogen (or renin substrate), plasminogen and fibrinogen.125"132 Plasma levels of alpha antitrypsin, beta,, globulin, hemopexin and alpha2 macroglobulin also tend to increase, whereas plasma concentrations of the acute phase reactants, orosmucoid and haptoglobulin, decrease; serum albumin concentrations increase slightly if at all.125,129"132 These changes in serum protein concentrations are summarized in Table 19. The levels of beta lipoproteins tend to increase and are discussed more fully in the section dealing with serum lipid alterations. The changes in renin substrate are discussed under hypertension. All of these effects presumably are due to the
ORAL CONTRACEPTIVE AGENTS
influence of estrogenic and progestational steroids or of both, on hepatic synthesis and secretion of these several classes of serum proteins. The liver appears to be extremely sensitive to sex hormone action.'35 But whether the effects of androgens and estrogens differ in the case of the individual proteins, as in the case of TBG synthesis, or whether there are additive or potentiating effects of the estrogen and progestogen, is not clear. The mechanism of the steroid effect(s) also is unclear. It has been shown that there are specific steroid binding proteins in cell cytosol of estrogen and progesterone target tissues which are involved in the transport of the steroid to the nucleus where genome activation and stimulation of ribonucleic acid (RNA) synthesis occur, followed by enhanced protein synthesis.'30 Cytosol receptors for estradiol do not appear to be present in liver, and incubation of rat liver nuclei with estradiol in rat uterine cytosol does not increase the already high levels of RNA polymerase activity.'38 Thus, whether the alterations by steroid hormones of the levels of the several serum proteins presumed to be synthesized by the liver represent a primary or a secondary effect of the hormones remains to be defined. Both the estrogen and progestational steroid in most oral contraceptive preparations are 17-aalkyl substituted compounds, and such steroids, as well as methyl testosterone, are known to produce cholestasis and hepatic dysfunction.'22'137 Hepatic excretory function measured by the disappearance of sulfobromophthalein (BSP) from the circulation is reduced in experimental animals by a number of natural and synthetic estrogens;'38 in man, it is excretion rather than conjugation of the dye that seems to be impaired.'39 In addition, large doses of estrogen or androgen will impair BSP excretion in normal humans.122 37'140'14' Progestational steroids also have been shown to inhibit hepatic glycuronyl transferase activity in vitro."42 And all of these drugs may produce elevations in serum bilirubin, alkaline phosphatase, and transaminase activities.'22"137 During therapy with oral contraceptive preparations containing estrogen and a progestational agent, increases in serum transaminase concentrations (SGOT and SGPT) occur in 5 to 20 percent of women and increases in BSP retention in 20 to 40 percent. These alterations usually are mild and are not associated with symptoms, and serum bilirubin concentrations usually are normal.'37'143"144 There is evidence to suggest that these manifesta-
tions may be more frequent and severe in postmenopausal than in pre-menopausal women; in two small series, all of 16 women manifested BSP retention (ranging from 20 to 40 percent) and elevated serum transaminase levels.'37 It is not clear whether these effects are due to the estrogen or the progestogen; there is some evidence to suggest that both components may be required.'37"145 Rarely, and there are now some 40 reported cases,'37 malaise, nausea, pruritis, and jaundice have occurred a few weeks after the patient has begun taking oral contraceptive steroid medication. These symptoms are associated with increased serum bilirubin and transaminase levels, and liver biopsy reveals dilation of bile canaliculi. By electron microscopy one can see shortening or disappearance of the microvilli, intracytoplasmic dense bodies (referred to as mitochondria-like organelles), dilation of the smooth endoplasmic reticulum and the appearance of myelin figures within mitochondria.'37"146 Cessation of contraceptive therapy usually leads to complete remission within a few weeks or months. Impaired BSP and bilirubin excretion are commonly observed late in pregnancy'47"148 and in a few instances may be of sufficient degree to produce jaundice. In these women the jaundice usually will recur with each pregnancy. About one-third of the women in whom jaundice developed with oral contraceptive steroid therapy gave a history of having experienced recurrent jaundice of pregnancy.'37 Recurrent jaundice of pregnancy and the jaundice sometimes seen with contraceptive steroid therapy are very similar. In both instances, systemic manifestations are minimal and biopsy reveals predominantly cholestasis. And in both instances there appears to be a predisposition to jaundice with exposure to increased steroid hormone levels. Why these few women are so predisposed is unclear. In any case, women with a history of acute liver disease in the past or jaundice during pregnancy or those with evidence of acute or chronic liver disease should not be given contraceptive steroid medication. Moreover, all women in whom pruritis or jaundice develops during the first few cycles while taking these drugs should have appropriate testing for hepatic dysfunction. If the serum bilirubin levels are elevated or there is more than mild BSP retention or mild elevation of serum transaminase activities, the drugs should be discontinued. Zinc metabolism has been studied in patients taking oral contraceptive drugs and serum levels THE WESTERN JOURNAL OF MEDICINE
41
h
ORAL CONTRACEPTIVE AGENTS
have been found to be reduced.149 The reason for this is not clear. Serum zinc levels are reduced in patients with hepatic dysfunction, and in such patients zinc excretion in urine is increased and hepatic zinc concentrations are reduced.'150 It has been suggested that a state of conditioned zinc deficiency exists in patients with liver dysfunction, and it is possible that oral contraceptive steroids, by altering hepatic zinc metabolism, produce a similar rate of zinc deficiency. Another interesting aspect of the effect of contraceptive steroids on the liver is the tendency for these agents to increase mitochondrial deltaamino-levulinic acid synthetase (DALAS) activity.151 Increased hepatic DALAS results in greater synthesis of heme protein and porphyrins"15 and increased urinary porphyrin excretion has been observed in women taking oral contraceptive steroid
drugs."'5"152 Oral contraceptives also can have an
Complications of Systemic Oral Contraceptive Therapy: Neoplasm-Breast, Uterus, Cervix and Vagina
cating abnormalities of secretion or metabolism of sex steroids in these cancers has been extensively reviewed and criticized.'54 This present overview is confined to a consideration of the potential carcinogenic effect of oral contraceptive agents in the induction of these cancers, and of the possibility that they may be important in reducing the risk factors for these malignant lesions.
MARK A. SPERLING, MD*
ADMINISTRATION OF THE ACTIVE INGREDIENTS of oral contraceptive agents-namely, compounds with estrogen or progesterone-like actions, or ablation of their actions, has been used extensively in the treatment of cancer of the sex hormone target organs. This approach has not been entirely empirical, but is based on studies in animals which suggested that increases in the production of the sex hormones or alterations in their metabolism are important factors in the development of cancer of the sex hormone target organs. In the case of the oral contraceptive agents, these target organs include the breast, uterus, cervix and vagina, and much research has been done in an attempt to define the role of sex steroids in the production, prediction and remission of these cancers. Recently the evidence for and against the hypothesis impli*Associate Chief, Pediatric Endocrinology, Harbor General Hospital; Assistant Professor of Pediatrics, UCLA School of Medicine.
42
JANUARY 1975 * 122 * 1
ameliorative effect on acute intermittent porphyria associated with the menstrual cycle or pregnancy."' Segal and Atkinson"15 have suggested that the increased heme synthesis may also enhance hepatic synthesis of microsomal cytochrome oxidase P-450, which is localized to smooth endoplasmic reticulum and involved in the metabolism of exogenous chemicals as well as endogenous substrates. But this has not yet been investigated. Finally, there is a recent report of seven patients ranging in age from 25 to 39 years who presented with benign hepatomas after having taken oral contraceptive drugs for periods ranging from six months to five years.'53 Whether the oral contraceptive drugs played any role in the development of these tumors is unclear. Further study is necessary to clarify this problem.
Breast There is still considerable disagreement as to the endocrine status of women with carcinoma of the breast. The excretion of urinary estrogen metabolites by these patients has been reported to be high, normal or low.154"155 It had also been postulated that the ratio of excreted estriol/estrone plus estradiol, might be important in the cause of the disease.'56 In a large demographic study, Asian women, who have a low incidence of mammary cancer, had a higher estriol ratio than American women, who have a much higher incidence of breast cancer.'57 However, more recently other investigators have disputed this conclusion.'55 In a study done by these investigators, total estrogen excretion in premenopausal women whose breast carcinoma was stage I to II was significantly lower than in normal controls. Post-menopausal women with breast carcinoma stage III-IV had a significant elevation of the estrone fraction. Conse-
9 percent frequency in women with a negative history."' Clezy reported a 58 percent incidence of hypertension on at least one visit in women with a positive history of hypertension during pregnancy, compared with a 23 percent incidence in women with a negative history."10 He also observed a 53 percent incidence of hypertension on one or more visits during oral contraceptive therapy in women with a parental history of hypertension compared with a 30 percent incidence in those with a negative family history. It seems likely that the estrogen-induced changes in the renin-angiotension-aldosterone system act on the background of genetic predisposition for hypertension, to produce significant hypertension in a small percentage of persons.
Liver Disease and Abnormalties of Laboratory Tests DELBERT A. FISHER, MD*
THE STEROID HORMONES in contraceptive preparations exert a number of metabolic effects on the liver. In addition to the alterations in carbohydrate and lipid metabolism already discussed, these hormones modify the rate of synthesis and secretion of a variety of plasma proteins, particularly those that bind hormones and metal ions. The protein most thoroughly studied is thyroxine binding globulin (TBG), an interalpha globulin which is the primary carrier protein for thyroid hormones in serum. The administration of estrogens to euthyroid subjects results in increased serum concentrations of TBG, with the result that serum thyroxine and triiodothyronine concentrations increase. Free hormone concentrations, however, are unchanged after equilibrium is reestablished and hormone production rates remain unchanged. 117-120 In contrast, androgenic hormones and a number of synthetic progestational agents, including norethandrolone and methandrostenolone, reduce serum TBG and thyroid hormone concentrations, also without altering free thyroxine concentrations *Chief, Pediatric Endocrinology, Harbor General Hospital; Professor of Pediatrics, UCLA School of Medicine.
40
JANUARY 1975 * 122 * 1
or thyroid hormone turnover rates.'20-'23 These changes in TBG concentration which occur with estrogen or androgen administration are associated with reciprocal changes in the plasma levels of thyroxine binding prealbumin (TBPA).123 During therapy with oral contraceptive agents combining estrogen and a progestational steroid, the effect of estrogen on TBG synthesis predominates; that is, a significant increase in serum TBG concentration occurs."9"24 However, there is no change or an actual increase in serum TBPA concentration.'24",25 It is presumed that these changes reflect changes in synthesis and secretion of these carrier proteins by the liver, since degradation rates are not altered.'23 More recently, estrogen has been shown to increase plasma concentrations of corticosteroid binding globulin, testosterone-estradiol binding globulin and ceruloplasmin (copper binding protein),126-128 and these binding protein levels as well as serum levels of transferrin (iron binding protein) and transcobalamin (vitamin B12 binding protein) are increased in women taking contraceptive steroid hormone preparations containing estrogen and a progestational agent.'25"29-'34 In this regard, administration of these drugs stimulates the changes in serum protein concentrations observed during pregnancy. The increases in these binding protein concentrations result in increased serum levels of the bound hormones, metals or vitamins, but, by analogy with the normal thyroid hormone turnover rates in patients with increased TBG levels, turnover rates and body economy of the hormones, metals, or vitamins are thought to be unchanged. Increased concentrations of a second group of plasma proteins also occurs; these act as precursors of more active compounds by serving as substrates for a series of enzyme systems. They include angiotensinogen (or renin substrate), plasminogen and fibrinogen.125"132 Plasma levels of alpha antitrypsin, beta,, globulin, hemopexin and alpha2 macroglobulin also tend to increase, whereas plasma concentrations of the acute phase reactants, orosmucoid and haptoglobulin, decrease; serum albumin concentrations increase slightly if at all.125,129"132 These changes in serum protein concentrations are summarized in Table 19. The levels of beta lipoproteins tend to increase and are discussed more fully in the section dealing with serum lipid alterations. The changes in renin substrate are discussed under hypertension. All of these effects presumably are due to the
ORAL CONTRACEPTIVE AGENTS
influence of estrogenic and progestational steroids or of both, on hepatic synthesis and secretion of these several classes of serum proteins. The liver appears to be extremely sensitive to sex hormone action.'35 But whether the effects of androgens and estrogens differ in the case of the individual proteins, as in the case of TBG synthesis, or whether there are additive or potentiating effects of the estrogen and progestogen, is not clear. The mechanism of the steroid effect(s) also is unclear. It has been shown that there are specific steroid binding proteins in cell cytosol of estrogen and progesterone target tissues which are involved in the transport of the steroid to the nucleus where genome activation and stimulation of ribonucleic acid (RNA) synthesis occur, followed by enhanced protein synthesis.'30 Cytosol receptors for estradiol do not appear to be present in liver, and incubation of rat liver nuclei with estradiol in rat uterine cytosol does not increase the already high levels of RNA polymerase activity.'38 Thus, whether the alterations by steroid hormones of the levels of the several serum proteins presumed to be synthesized by the liver represent a primary or a secondary effect of the hormones remains to be defined. Both the estrogen and progestational steroid in most oral contraceptive preparations are 17-aalkyl substituted compounds, and such steroids, as well as methyl testosterone, are known to produce cholestasis and hepatic dysfunction.'22'137 Hepatic excretory function measured by the disappearance of sulfobromophthalein (BSP) from the circulation is reduced in experimental animals by a number of natural and synthetic estrogens;'38 in man, it is excretion rather than conjugation of the dye that seems to be impaired.'39 In addition, large doses of estrogen or androgen will impair BSP excretion in normal humans.122 37'140'14' Progestational steroids also have been shown to inhibit hepatic glycuronyl transferase activity in vitro."42 And all of these drugs may produce elevations in serum bilirubin, alkaline phosphatase, and transaminase activities.'22"137 During therapy with oral contraceptive preparations containing estrogen and a progestational agent, increases in serum transaminase concentrations (SGOT and SGPT) occur in 5 to 20 percent of women and increases in BSP retention in 20 to 40 percent. These alterations usually are mild and are not associated with symptoms, and serum bilirubin concentrations usually are normal.'37'143"144 There is evidence to suggest that these manifesta-
tions may be more frequent and severe in postmenopausal than in pre-menopausal women; in two small series, all of 16 women manifested BSP retention (ranging from 20 to 40 percent) and elevated serum transaminase levels.'37 It is not clear whether these effects are due to the estrogen or the progestogen; there is some evidence to suggest that both components may be required.'37"145 Rarely, and there are now some 40 reported cases,'37 malaise, nausea, pruritis, and jaundice have occurred a few weeks after the patient has begun taking oral contraceptive steroid medication. These symptoms are associated with increased serum bilirubin and transaminase levels, and liver biopsy reveals dilation of bile canaliculi. By electron microscopy one can see shortening or disappearance of the microvilli, intracytoplasmic dense bodies (referred to as mitochondria-like organelles), dilation of the smooth endoplasmic reticulum and the appearance of myelin figures within mitochondria.'37"146 Cessation of contraceptive therapy usually leads to complete remission within a few weeks or months. Impaired BSP and bilirubin excretion are commonly observed late in pregnancy'47"148 and in a few instances may be of sufficient degree to produce jaundice. In these women the jaundice usually will recur with each pregnancy. About one-third of the women in whom jaundice developed with oral contraceptive steroid therapy gave a history of having experienced recurrent jaundice of pregnancy.'37 Recurrent jaundice of pregnancy and the jaundice sometimes seen with contraceptive steroid therapy are very similar. In both instances, systemic manifestations are minimal and biopsy reveals predominantly cholestasis. And in both instances there appears to be a predisposition to jaundice with exposure to increased steroid hormone levels. Why these few women are so predisposed is unclear. In any case, women with a history of acute liver disease in the past or jaundice during pregnancy or those with evidence of acute or chronic liver disease should not be given contraceptive steroid medication. Moreover, all women in whom pruritis or jaundice develops during the first few cycles while taking these drugs should have appropriate testing for hepatic dysfunction. If the serum bilirubin levels are elevated or there is more than mild BSP retention or mild elevation of serum transaminase activities, the drugs should be discontinued. Zinc metabolism has been studied in patients taking oral contraceptive drugs and serum levels THE WESTERN JOURNAL OF MEDICINE
41
h
ORAL CONTRACEPTIVE AGENTS
have been found to be reduced.149 The reason for this is not clear. Serum zinc levels are reduced in patients with hepatic dysfunction, and in such patients zinc excretion in urine is increased and hepatic zinc concentrations are reduced.'150 It has been suggested that a state of conditioned zinc deficiency exists in patients with liver dysfunction, and it is possible that oral contraceptive steroids, by altering hepatic zinc metabolism, produce a similar rate of zinc deficiency. Another interesting aspect of the effect of contraceptive steroids on the liver is the tendency for these agents to increase mitochondrial deltaamino-levulinic acid synthetase (DALAS) activity.151 Increased hepatic DALAS results in greater synthesis of heme protein and porphyrins"15 and increased urinary porphyrin excretion has been observed in women taking oral contraceptive steroid
drugs."'5"152 Oral contraceptives also can have an
Complications of Systemic Oral Contraceptive Therapy: Neoplasm-Breast, Uterus, Cervix and Vagina
cating abnormalities of secretion or metabolism of sex steroids in these cancers has been extensively reviewed and criticized.'54 This present overview is confined to a consideration of the potential carcinogenic effect of oral contraceptive agents in the induction of these cancers, and of the possibility that they may be important in reducing the risk factors for these malignant lesions.
MARK A. SPERLING, MD*
ADMINISTRATION OF THE ACTIVE INGREDIENTS of oral contraceptive agents-namely, compounds with estrogen or progesterone-like actions, or ablation of their actions, has been used extensively in the treatment of cancer of the sex hormone target organs. This approach has not been entirely empirical, but is based on studies in animals which suggested that increases in the production of the sex hormones or alterations in their metabolism are important factors in the development of cancer of the sex hormone target organs. In the case of the oral contraceptive agents, these target organs include the breast, uterus, cervix and vagina, and much research has been done in an attempt to define the role of sex steroids in the production, prediction and remission of these cancers. Recently the evidence for and against the hypothesis impli*Associate Chief, Pediatric Endocrinology, Harbor General Hospital; Assistant Professor of Pediatrics, UCLA School of Medicine.
42
JANUARY 1975 * 122 * 1
ameliorative effect on acute intermittent porphyria associated with the menstrual cycle or pregnancy."' Segal and Atkinson"15 have suggested that the increased heme synthesis may also enhance hepatic synthesis of microsomal cytochrome oxidase P-450, which is localized to smooth endoplasmic reticulum and involved in the metabolism of exogenous chemicals as well as endogenous substrates. But this has not yet been investigated. Finally, there is a recent report of seven patients ranging in age from 25 to 39 years who presented with benign hepatomas after having taken oral contraceptive drugs for periods ranging from six months to five years.'53 Whether the oral contraceptive drugs played any role in the development of these tumors is unclear. Further study is necessary to clarify this problem.
Breast There is still considerable disagreement as to the endocrine status of women with carcinoma of the breast. The excretion of urinary estrogen metabolites by these patients has been reported to be high, normal or low.154"155 It had also been postulated that the ratio of excreted estriol/estrone plus estradiol, might be important in the cause of the disease.'56 In a large demographic study, Asian women, who have a low incidence of mammary cancer, had a higher estriol ratio than American women, who have a much higher incidence of breast cancer.'57 However, more recently other investigators have disputed this conclusion.'55 In a study done by these investigators, total estrogen excretion in premenopausal women whose breast carcinoma was stage I to II was significantly lower than in normal controls. Post-menopausal women with breast carcinoma stage III-IV had a significant elevation of the estrone fraction. Conse-
