Metabolic side-effects of oral contraceptives

8 Metabolic Side-Effects of Oral Contraceptives J. W . H . D O A R

Combined oral contraceptives containing a synthetic oestrogen and progestogen were first introduced in 1961. Their popularity grew rapidly and by 1969 it was estimated that these drugs were being used by 18.5 million women throughout the world. The occurrence of a wide variety of clinical side-effects encouraged the development of new compounds and methods such as sequential preparations and low-dose progestogen-only administration. It was initially assumed that the contraceptive effect was due to suppression of ovulation secondary to inhibition of gonadotrophin secretion at the hypothalamo-pituitary level. It later became apparent, however, that these steroids have other anti-fertility effects including direct actions on the cervical mucus and endometrium, and their ability to impede passage of the sperm and implantation of the fertilised ovum. Indeed, ovulation occurs regularly in women receiving low-dose progestogen medication. While this review is concerned mainly with metabolic changes occurring in oral contraceptive users, a brief outline of the clinical side-effects is relevant. Symptoms of early pregnancy such as nausea, vomiting and breast enlargement and tenderness are common after starting oral contraceptives, but usually disappear after 1 to 3 cycles. Menstrual irregularity, spotting and amenorrhoea are also common, but can often be corrected by changing to a different preparation. While pre-menstrual symptoms may be relieved by oral contraceptive medication, occasional cases of marked depression can occur. ]-he incidence is difficult to assess, but may be as high as 6 to 7 per cent of users (Herzberg, Johnson and Brown, 1970), and this depression is often associated with a reduction of libido. It has been suggested that depression occurs more commonly with high-dose progestogen combinations (Grant and PryseDavies, 1968), but the evidence is not conclusive. An increased incidence of migrainous headaches in oral contraceptive users has been reported, with attacks tending to occur particularly during the period off the contraceptive (Whitty, Hockaday and Whitty, 1966). A serious complication of oral contraceptive medication is the increased incidence of venous thromboembolic disease and cerebral thrombosis. Morbidity and mortality from these conditions are increased about six-fold Clinics in Endocrinology and Metabolism--Vol. 2, No. 3, November 1973.

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in oral contraceptive users (Inman and Vessey, 1968; Vessey and Doll, 1968). The degree of risk appears to be related to the dose of oestrogen, and this has encouraged restriction of the oestrogen content of oral contraceptives in general use to 50 gg. There also appears to be an increased risk of myocardial infarction in women with hypercholesterolaemia (Oliver, 1970), and Riddoch, Jefferson and Bickerstaff (1971) have described chorea resulting from oral contraceptive medication. Other miscellaneous effects attributed to oral contraceptives include ureteral dilatation, chloasma and masculinisation of the fetus. Studies published during the past six years have shown that contraceptive steroids cause a plethora of metabolic side-effects which are unrelated to their antifertility action. The oral contraceptive user's body chemistry is changed and there is virtually no organ system that is not affected in some way. The effect of these changes on the health of the user is unknown, but clearly important to establish in view of the widespread administration of oral contraceptives to healthy women. In particular, the effects on carbohydrate and lipid metabolism cannot be viewed with equanimity when considered in relation to the known association of such abnormalities with the development of occlusive vascular disease. The metabolic effects of oral contraceptives have been previously reviewed (Salhanick et al, 1969; Corfman, 1969; Lancet, 1969). In several instances they superficially resemble changes which occur during pregnancy. It must be realised, however, that the actions of natural and synthetic steroids often differ widely. Many of the contraceptive steroids have been modified chemically, usually by 17~t-alkyl substitution to render them active by mouth. The oestrogens used have almost invariably been 17~-ethinyloestradiol or its 3-methyl ether, mestranol. The progestogens are generally derived from either 19-nortestosterone or 17a-hydroxyprogesterone (Table 1). Table 1. Classification of some synthetic progestogens Parent compound

Progestogen

19-Nortestosterone

Norethisterone Norethisterone acetate Ethynodiol diacetate

17c~-Hydroxyprogesterone

Lynoestrenol Norethynodrel Medroxyprogesteroneacetate Megestrol acetate Chlormadinoneacetate

Synthetic progestogens possess not only the biological actions of progesterone itself, but may also have other properties including oestrogenic, antioestrogenic, androgenic, anti-androgenic, glucocorticoid and anabolic effects. Early work suggested that certain progestogens, such as norethisterone, could be converted to oestrogenic substances in vivo (Brown and Blair, 1960). In vitro studies, however, have failed to demonstrate the formation of oestrogens from progestogens with a 17a-ethinyl side chain, and it appears that the increased oestrogen content of the urine after progestogen administration

METABOLIC SIDE-EFFECTS OF ORAL CONTRACEPTIVES

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may have been an artefact caused by acid extraction (Breuer, 1970). The specific metabolic effects of a given oral contraceptive preparation are difficult to predict but presumably depend on: 1. The nature of the oestrogen and/or progestogen. 2. The dose in relation to body weight. 3. The route of administration (oral or parenteral). 4. The duration of medication. 5. The health and age of the user.

SERUM LIPID AND LIPOPROTEIN LEVELS Studies carried out in the decade 1950-59 before the introduction of oral contraceptives showed that oestrogens decreased serum low-density-lipoprotein (LDL) and total cholesterol and increased serum high-densitylipoprotein (biDL) cholesterol levels in postmenopausal women and men, many of whom had ischaernic heart disease (Russ, Eder and Barr, 1955; Oliver and Boyd, 1956a, b; Furman et al, 1958). Serum veryqow-densitylipoprotein (VLDL) and triglyceride levels were not measured by these workers. Reports of striking increases in fasting serum triglyceride and phospholipid and a more modest elevation of serum cholesterol levels in healthy premenopausal women receiving a wide variety of combined oral contraceptives were somewhat unexpected (Wynn, Doar and Mills 1966; Wynn et al, 1969; Larsson-Cohn, Berlin and Vikrot, 1970). Analytical ultracentrifugal studies of serum lipoproteins have also shown significant increases of Sfl00.400, Sf 20-100 and Sf0_12 serum lipoprotein levels (Wynn et al, 1969). R6ssner, Larsson-Cohn and Carlson (1971) carried out preparative ultracentrifugal lipoprotein analyses in women before and while receiving mestranol 100 lag and chlormadinone acetate 3 mg. The mean triglyceride and cholesterol content of serum VLDL, LDL and HDL fractions was increased during oral contraceptive administration, but only the former achieved statistical significance. These workers also found minor changes in the lipid composition of the lipoprotein fractions, and this may explain the reduced rate of flotation of the modal component of the Sf0.12 lipoproteins observed by Wynn, Doar and Mills (1966). No consistent effect of contraceptive steroids on fasting plasma non-esterified fatty acid (NEFA) levels has been found. It seems likely that the oestrogen rather than the progestogen is responsible for the effects on serum lipid levels. Studies with oestrogen alone have generally shown an increase in serum triglyceride levels (Robinson and Le Beau, 1965; Gershberg, Hulse and Javier, 1968; Wynn and Doar, 1969a). A relation between the serum triglyceride level and the oestrogen content of the oral contraceptive has been found by Stokes and Wynn (1971) who further noted that mestranol and ethinyloestradiol produced equivalent effects at the same dose levels. Neither progestogen nor progesterone administration appear to affect serum triglyceride or cholesterol levels (Svanborg and Vikrot, 1966; Brody et al, 1968; Adams and Wynn, 1972), although Larsson-Cohn, Berlin and Vikrot (1970) found a small rise of serum triglyceride in women

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receiving 0.4 mg of norethisterone daily. These studies, however, have used low-dose progestogen medication, and the larger doses contained in the combined oral contraceptives may affect serum lipid levels. It has been suggested that certain 19-nortestosterone-derived progestogens such as norethisterone may be metabolised to oestrogenic compounds with a secondary effect on serum lipid levels. On the other hand, Larsson-Cohn et al (1970) found that the mean rise in serum triglyceride level was greater in women receiving mestranol 100 I-tg, + chlormadinone acetate 3 mg, than in a group taking mestranol 100 I.tg, + norethisterone 2 mg. They suggested that this difference was due to the antioestrogenic effect of norethisterone reducing the action of the mestranol on serum triglyceride levels in the latter group. Contraceptive steroids have sometimes been found to have different effects in subjects with hyperlipidaemia. Norethisterone acetate caused a marked reduction of elevated serum triglyceride levels in four patients with type V hyperlipoproteinaemia (Glueck et al, 1969), and a similar action of oestrogen therapy was found by Feldman, Wang and Adlersberg (1959). On the other hand, Anovlar (ethinyloestradiol 50 pg + norethisterone acetate 4 mg) nearly doubled the serum cholesterol level in a woman with type II hyperlipoproteinaemia (Smith and Prior, 1968). Furthermore, certain steroid combinations appear to act in a synergistic rather than an additive manner on serum lipid and lipoprotein levels (Hood and Cram6r, 1959). It is therefore difficult to predict the effects of any oestrogen-progestogen combination. The mechanism by which oestrogens influence lipid metabolism is unknown. There have been several reports of diminished serum post-heparin lipoprotein lipase activity (PHLA) during oral contraceptive medication, implying a reduced rate of triglyceride removal from the circulation (Hazzard et al, 1969; R6ssner et al, 1971). Both oral (Hazzard et al, 1972) and intravenous fat tolerance (R6ssner et al, 1971) are unchanged during medication, however, and Hazzard et al (1972) have recently found that oral contraceptive administration causes a resistance to the release of lipoprotein lipase by heparin rather than a deficiency of the enzyme. Isotopic studies of triglyceride turnover have shown increased rates of both triglyceride influx and efflux, with the former predominating, and suggest that the elevated serum triglyceride levels are due to an increased rate of synthesis, presumably by the liver (Kekki and Nikkil~i, 1971). Whether these effects are primarily due to the oestrogen itself or secondary to raised circulating levels of other hormones such as thyroxine, cortisol and gr6wth hormone, or to other metabolic changes such as impaired glucose tolerance and weight gain, is unknown. The pattern of change of serum lipid and lipoprotein levels during combined oral contraceptive administration does not suggest that it is caused singly by any of the above secondary changes (Doar and Wynn, 1969). A further possibility exists. The relation between the rates of synthesis of hepatic lipid and the protein moiety of lipoprotein (apolipoprotein) is unknown. During diabetic ketosis, raised circulating plasma NEFA levels stimulate hepatic synthesis of VLDL (Havel, 1961), and presumably hepatic VLDL apolipoprotein synthesis is stimulated by the increased lipid formation. Oestrogen administration induces raised circulating levels of many proteins with a carrier function, and it is possible that increased hepatic

507

METABOLIC SIDE-EFFECTS OF ORAL CONTRACEPTIVES

apolipoprotein synthesis may be the primary event, causing a secondary stimulation of hepatic lipid formation. The serum triglyceride level rises quickly during combined oral contraceptive administration. Hazzard et al (1969) found a 47 per cent mean increase in serum triglyceride after only 2 weeks' medication. In a study of 19 premenopausal women tested before and at 2 weekly intervals for 32 weeks while receiving Ovulen, mean serum triglyceride and phospholipid levels rose steadily to a plateau at 6 to 8 weeks, with little change thereafter (Sachs, Wolfman and Herzig, 1969). After 3 months there appears to be no relation between duration of medication and serum triglyceride or cholesterol levels (Doar and Wynn, 1969), and serum lipid and lipoprotein levels return towards normal 3 to 6 months after medication is discontinued (Wynn et al, 1969). A rise in serum triglyceride is a remarkably common feature of combined oral contraceptive administration and was found in 95 per cent of 128 women studied longitudinally by Doar and Wynn (1969; Figure 1). The serum lipid profile during oral contraceptive medication differs from that of pregnancy in which there are marked rises of both serum triglyceride and cholesterol. 2OO •7

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Figure l. Fasting serum triglyceride levels before and during combined oral contraceptive (O.C.) administration in 128 women. A 45° line is shown. Reproduced with permission, from Doar, J. W. H. & Wynn, V. (1969)Journal of Clinical Pathology, 23, Supplement 3, 55--61. CARBOHYDRATE AND INTERMEDIARY M E T A B O L I S M The first indication that oral contraceptive administration might be associated with deterioration of glucose tolerance appeared in a report by Waine et al (1963). Since then many further studies have been published and these have been reviewed by Spellacy (1969). Most, but not all, workers have found some impairment of oral glucose tolerance with a variety of combined oral contraceptive preparations. The fasting plasma glucose level, however, has generally been unchanged. The proportion of premenopausal women with abnormal tests while receiving oral contraceptive medication has varied from 0 (Danowski et al, 1968) to 77 per cent (Spellacy et al, 1968). It has been

508

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suggested that the incidence of abnormal results increases with duration of medication (Javier, Gershberg and Hulse, 1968) but others have failed to find such an association (Wynn and Doar 1969b). The effect of combined oral contraceptives on intravenous glucose tolerance has been the subject of conflicting reports. Posner et al (1967a, b) found intravenous tolerance to be impaired in women receiving Enovid, tested at 2 and 4 to 6 months after starting medication. Spellacy and his co-workers, however, using the same drug, observed impaired glucose tolerance during the first and twelfth cycles but not during the sixth cycle of treatment. It is difficult to compare the results of different studies because of the variety of oestrogen-progestogen combinations used, case mix, duration of medication and test procedures. The interpretation of the intravenous glucose tolerance test (IVGTT) curve is also controversial. There are practical and theoretical objections to the use of the K value as an index of the curve, which are illustrated by a study of IVGTT curves in 81 women tested before and during oral contraceptive administration (Wynn and Doar, 1969b). Although the mean K value did not change significantly, the mean IVGTT area was increased during medication (P < 0-001). Similar findings were reported by Clinch, Turnbull and Khosla (1969). In general, the impairment of glucose tolerance during oral contraceptive medication is relatively mild (Figure 2), and there have been no definite reports of subjects developing clinical diabetes mellitus as a result of oral contraceptive usage. The known association of mild chemical diabetes Plasma NEFA 800[N 31

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Figure 2. Plasma glucose, N E F A , insulin and blood pyruvate levels b e f o r e and during oral contraceptive (O.C.) medication. N = the number of subjects studied. Reproduced, with permission, from W y n n , V. & D o a r , J. W . H. (1969) Journal of Clinical Pathology, 23, Supplement 3, 19--36.

509

METABOLIC SIDE-EFFECTS OF ORAL CONTRACEPTIVES

mellitus with occlusive vascular disease (Keen et al, 1965; Epstein, 1967), however, emphasises the importance of even minor deteriorations of glucose tolerance. Longitudinal studies using a wide variety of combined oral contraceptives showed that oral and intravenous glucose tolerance deteriorated in 78 per cent and 70 per cent of women respectively, when the results were analysed in terms of the area between the individual curves and the abscissa (Wynn and Doar, 1969b; Figure 3). This study also demonstrated the reversibility of these changes. Oral and intravenous glucose tolerance

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Figure 3. OGTT glucose area before and during combined oral contraceptive (O.C.) medication in 91 women. A 45° line is shown. N = the number of subjects studied. Reproduced, with permission, from Wynn, V. & Doar, J. W. H. (1969) Journal of Clinical Pathology, 23, Supplement 3, 19--36. improved in 90 per cent and 85 per cent respectively of subjects studied on average four months after oral contraceptives were discontinued. The majority of workers have found no relation between the change of glucose tolerance during medication and the subject's age, degree of obesity, change of weight during therapy, or parity. Opinion is divided, however, about the importance of a family history of diabetes mellitus. While the incidence of abnormal glucose folerance tests appears to be higher in subjects with such a family history (Gershberg, Javier and Hulse, 1964; Wynn and Doar, 1966), the mean deterioration of glucose tolerance is similar in subjects with and without this characteristic (Wynn and Doar, 1969b). A striking finding is the elevation of both fasting and postglucose blood pyruvate and lactate levels during oral and intravenous glucose tolerance tests in women receiving combined oral contraceptives (Doar, Wynn and Cramp, 1969; Wynn and Doar, 1969b). Studies of pyruvate metabolism using a primed sodium L ( + ) lactate infusion technique have suggested that the high bl6od pyruvate and lactate levels are due to increased formation rather than impaired pyruvate and lactate degradation (Doar, Wynn and Cramp, 1969; Doar, 1969). Levels of these metabolites return to normal after

510

J.w.H.

DOAR

medication is discontinued. The elevated fasting blood pyruvate level during oral contraceptive medication may in part be due to increased formation of pyruvate from alanine, secondary to increased activity of alanine aminotransferase (Braidman and Rose, 1971). This, however, would not explain the greater rise of blood pyruvate levels above the fasting level following glucose administration (Wynn and Doar, 1969c), a finding which suggests increased activity of the glycolytic pathway. Most workers have found the tasting plasma insulin to be unchanged by combined oral contraceptives (Spellacy et al, 1968; Wynn and Doar, 1969b). Following oral/intravenous glucose administration, plasma insulin levels are generally higher in treated subjects (Spellacy et al, 1968; Wynn and Doar, 19690; Javier, Gershberg and Flulse, 1968). Again, postglucose plasma insulin levels fall after medication is discontinued (Wynn and Doar, 1969b). A major and still incompletely answered point of discussion is the role played by the oestrogen and progestogen in these changes. Goldman and Ovadia (1969) found impaired intravenous glucose tolerance during oestrogen therapy with diethylstilboestrol or premarin. Similar findings were noted by Pyor~tlii, Pyoriilii and Lampinen (1967) after two weeks' treatment with ethinyloestradiol, and Javier, Gershberg and Flulse (1968) found some determration of oral glucose tolerance during mestranol therapy. A recent extensive study by Spellacy, Buhi and Birk (1972a), however, showed no deterioration of oral glucose tolerance, blood glucose or plasma insulin levels in subjects receiving premarin, mestranol or ethinyloestradiol. Longitudinal studies of the effects of synthetic progestogens on oral and intravenous glucose tolerance in women have been carried out using chlormadinone acetate (Larsson-Cohn, Tengstr6m and Wide, 1969; Vermeulen, Daneels and Thiery, 1970), norethisterone (Larsson-Cohn et al, 1969), ethynodiol diacetate (Goldman and Eckerling, 1970; Spellacy et al, 1972b), medroxyprogesterone acetate (Goldman, Ovadia and Eckerling, 1968; Spellacy et al, 1970), and megestrol acetate (Adams and Wynn, 1972). The majority of these studies have shown no effect on glucose tolerance, but plasma insulin responses have sometimes been increased, suggesting increased resistance of peripheral tissues to the action of this hormone. Kalkhoff, Jacobson and Lemper (1970) found both the fasting plasma insulin and the plasma insulin response to oral glucose or intravenous tolbutamide to be increased after administration of intramuscular progesterone daily for six days. The progestogen studies, however, have all been with low-dose medication and it is possible that larger doses, as used in combined oral contraceptive preparations, may affect glucose tolerance, either directly, or as a result of metabolism of the progestogen to oestrogenic substances. It may be noted that the 19-nortestosterone-derived progestogens are structurally similar to some synthetic anabolic steroids. Both oral and intravenous glucose tolerance are impaired by methandienone (Al-17a-methyl testosterone) administration, but the fasting blood sugar is lowered (Landon et al, 1962). Elevated fasting and postglucose blood pyruvate levels have been observed during mestranol administration (Doar, Wynn and Cramp, 1969) but not during treatment with 0.5 mg megestrol acetate (Adams and Wynn, 1972).

METABOLIC SIDE-EFFECTS OF ORAL CONTRACEPTIVES

51 1

It is unknown whether the changes in carbohydrate and intermediary metabolism are due to a primary effect of the contraceptive steroids or secondary to increased circulating levels of other hormones such as cortisol, thyroxine and growth hormone. Growth hormone has been considered important in this respect (Yen and Vela, 1968) but the pattern of change of plasma glucose, blood pyruvate and plasma insulin levels produced by administration of growth hormone does not resemble that found during oral contraceptive administration (Doar et al, 1969a). Furthermore, marked deterioration of oral glucose tolerance has been noted in several subjects during therapy, in the absence of raised growth hormone levels (Maw and Wynn, 1972). The pattern of metabolic change is also dissimilar from that found in subjects with thyrotoxicosis (Doar et al, 1969b) or normal subjects receiving tri-iodothyronine (Stamp et al, 1969). Almost identical changes of oral glucose tolerance-test plasma glucose and blood pyruvate levels are found in non-obese women receiving combined oral contraceptive medication, non-obese women on glucocorticoid therapy and obese non-diabetic subjects (Doar and Wynn, 1970). The latter workers have suggested that glucocorticoid excess may be responsible for the abnormalities in all three situations. Although the major part of the plasma cortisol elevation during oestrogen therapy is due to an increase in the protein bound fraction, non-protein bound plasma cortisol levels are also raised (Sandberg, Rosenthal and Slaunwhite, 1969; Burke, 1969). Furthermore, the proteinbound fraction, previously thought to be biologically inactive, may have effects in certain tissues with protein permeable vascular beds such as the liver (Keller, Richardson and Yates, 1969). The situation is different in obesity in that plasma cortisol levels are normal, but the cortisol production rate is commonly elevated (Schteingart and Conn, 1965). Daily cortisol catabolism by the liver is increased and the excessive hepatic exposure to glucocorticoid might be responsible for the altered carbohydrate and intermediary metabolism. The impairment of glucose tolerance during oral contraceptive therapy superficially resembles that seen in the later stages of pregnancy (Kalkhoff et al, 1964). The fasting plasma glucose, however, is lowered in pregnancy.

VITAMINS The metabolism of L-tryptophan involves several pyridoxal phosphate dependent enzyme systems (Figure 4). The sxipernatant kynureninase which produces 3-hydroxyanthranilic acid from 3-hydroxykynurenine is more sensitive to the lack of pyridoxal phosphate than other enzymes of the pathway requiring this co-factor. A series of detailed studies by Rose and his colleagues has revealed that women taking oestrogen-containing oral contraceptives have abnormalities of tryptophan metabolism which resemble those found in vitamin B6 deficiency. These changes include increased excretion of 3-hydroxykynurenine, xanthurenic acid, and 3-hydroxyanthranilic acid following an oral L-tryptophan load. Direct measurement of urine 4-pyridoxic acid excretion, the major excretory product of vitamin B6, suggested definite

512

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pyridoxine deficiency in 7 of a group of 31 women receiving combined oral contraceptives (Rose et al, 1972). Similar changes in L-tryptophan metabolism have been found during oestrogen administration, pregnancy and glucocorticoid therapy. Progestogens, however, are without effect. The abnormalities are reversed by prior treatment with pyridoxine, and it has been postulated that pyridoxine deficiency may arise in women receiving oestrogenL - Tryptophan

Y

Tryptophan Oxygenase

5 - Hydroxytryptophan

Kynurenlne 5 - Hydroxytryptamine (Serotonin)

3 - Hydroxykynurenlne

Xanthurenlc Acid

Kynurenlnase1~ 3 - Hydroxyanthrani[ic Acid

Quinollnlc Acid

Nicotinic Acid Ribonucleotide

N'- Meth ilnlcofinamlde

Figure 4. Pathways of L-tryptophan metabolism. * = a pyridoxal-phosphate-dependent enzyme system. containing oral contraceptives by induction of hepatic tryptophan oxygenase, causing an increased turnover of the tryptophan-nicotinic acid ribonucleotide pathway. This would be expected to reduce the amount of serotonin formed from tryptophan via 5-hydroxytryptophan. Tryptophan oxygenase is probably the rate-limiting enzyme of this pathway, and the increased hepatic activity of this enzyme in oral contraceptive users may be secondary to increased glucocorticoid levels. Oestrogens may also interfere with the activity of pyridoxal phosphate-dependent enzymes by competition with the coenzyme for sites on the apo-enzyme molecule (Mason and Gullekson, 1960).

METABOLIC SIDE-EFFECTS OF ORAL CONTRACEPTIVES

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The current amine hypothesis proposes that concentrations of certain monoamines, including 5-hydroxytryptamine (serotonin) and noradrenaline in parts of the brain are related to mood, and there is evidence that these levels are reduced in depression. The changes in tryptophan metabolism described above would tend to reduce serotonin formation from tryptophan and might have a bearing on the depression that has been described in some subjects receiving oral contraceptives. A few uncontrolled studies have indicated that pyridoxine administration may alleviate depression occurring in oral contraceptive users. Such therapy is supposed to relieve the partial block of decarboxylation of tryptophan to tryptamine, a pyridoxal phosphate dependent step, and thereby increase serotonin formation. It might be expected, however, that the increased tryptophan oxygenase activity would continue to drain tryptophan away down the nicotinic acid ribonucleotide pathway. Circulating levels of tyrosine, the amino-acid precursor of noradrenaline, are also reduced during combined oral contraceptive administration (Rose and Cramp, 1970), possibly as a result of increased activity oftyrosine aminotransferase (Braidman and Rose, 1971). Other factors almost certainly play a role in regulating the levels of brain amines. Cortisol, for example, increases the activity oftryptophan hydroxylase and contraceptive steroids also influence the level of monoamine oxidase activity, an enzyme important in amine degradation, in certain tissues. The net effect of these influences on brain amine levels in women receiving oral contraceptives is difficult to assess. Serum vitamin B12 levels are reduced during combined oral contraceptive administration and also in pregnancy (Shojania, 1971; Briggs and Briggs, 1972), but treatment with medroxyprogesterone acetate alone is without effect. The serum BI2 binding capacity was found to be elevated during pregnancy and oral contraceptive administration (Bianchine et al, 1969), thus excluding altered vitamin B12 transport as an explanation for these findings. Furthermore, Schilling tests carried out in four subjects with low serum B12 levels were normal (Shojania, 1971), indicating that combined oral contraceptives did not impair absorption of this compound. Shojania, Hornady and Barnes (1969) reported reduced serum and red cell folate levels and increased urine FIGLU excretion after histidine-loading in women receiving oral contraceptives. While these initial findings were not confirmed by others (Stephens et al, 1972), reports of megaloblastic anaemia due to folate deficiency in women receiving these compounds have appeared. Adult coeliac disease, however, was not convincingly excluded in any of these subjects. Streiff (1970) found that oral doses of monoglutamyl folate and polyglutamic folate (the dietary form of folic acid) produced similar rises of serum folate in control women; the rise with polyglutamic folate, however, was considerably less in women receiving oral contraceptives. Polyglutamic folates are normally broken down by folate conjugase in the small intestine to the monoglutamyl form, which is then absorbed. Streiff postulated that the activity of folate conjugase was reduced during oral contraceptive medication, thereby causing a relative malabsorption of dietary folate. Later studies (Stephens et al, 1972), however, have failed to demonstrate inhibition of this enzyme by gonadal steroids in vitro. Furthermore, absorption of polyglutamic folate in women receiving oral contraceptives was normal,

514

J.w.H.

DOAR

providing that the subjects were presaturated with monoglutamyl folate. These workers suggested that contraceptive steroids may alter the rate of folate clearance from the blood, rather than impair the absorption of dietary folate. The clinical significance of these changes in vitamin B12 and folate metabolism is unknown. There have been few studies of circulating levels of other vitamins during oral contraceptive medication. Gal, Parkinson and Craft (1971) reported increased circulating vitamin A and carotenoid levels, and proposed that these may reflect a rise in the specific vitamin-A-binding a-globulin.

SERUM PROTEINS

The circulating levels of many serum proteins are changed during combined oral contraceptive medication (Lancet, 1970). Some of the most striking alterations are to be seen in the increase of certain globulin-carrier proteins, such as transcortin, thyroxine-binding globulin, transferrin, and caeruloplasmin. Other proteins affected include those acting as substrates in the blood coagulation, fibrinolytic and renin-angiotensin systems. Some workers have found a slight reduction of serum albumin levels during oral contraceptive medication, and this fall does not appear to be due to expansion of the extracellular fluid volume. Varying effects on immunoglobulins have been reported. While Laurell, Kullander and Thorell (1967) found decreased serum IgA and IgG levels, Horne et al (1970) found a slight rise of lgG concentration. These studies, however, differed both in the type of oral contraceptive used and the duration of medication. Similar changes in serum proteins occur during oestrogen therapy (Doe et al, 1967) but not during administration of chlormadinone acetate (Laurell, Kullander and Thorell, 1969) or medroxyprogesterone acetate (Powell et al, 1970). However, Briggs and Briggs (1970) found ethinyloestradiol to be without effect on serum total-iron-binding-capacity, whereas a significant rise occurred during norethisterone and norgestrel administration. The effects usually appear rapidly. For example, concentrations of transcortin quadruple during the first 2 weeks of oestrogen medication, with little change thereafter. When the oestrogen is withdrawn, levels return to baseline over 3 to 4 weeks with 40 per cent of tile fall occurring in the first week (Doe et al, 1967). These studies emphasise the importance of taking the day of the cycle into account when studies are made of circulating compounds which are bound to carrier proteins. It is remarkable that as little as 20 Ixg/day of ethinyloestradiol will produce a detectable rise in serum transcortin. Whether the changed serum protein levels result from altered rates of production or degradation is unknown. The liver is the major source of all serum proteins except the immunoglobulins, and the finding of increased smooth endoplasmic reticulum by electron microscopy in biopsy specimens from oral contraceptive users may be relevant (Perez et al, 1969), although other workers have found no change (Kleiner, Kresch and Arias, 1965).

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BLOOD COAGULATION AND FIBRINOLYSIS Interest in this field has been stimulated by the increased incidence of thromboembolism in women receiving oral contraceptives. The sequence of biochemical reactions leading to blood coagulation is complex, and there appear to be two distinct pathways by which prothrombin may be activated to thrombin. In the intrinsic system, triggered by factor XII, all the components are contained in the blood, whereas the extrinsic system is initiated by release of tissue thromboplastin. Both systems share a final common pathway at the level of factor X. Although the levels of many of these factors can be measured, the relationship of such determinations to the development of thromboembolism is not clear. Combined oral contraceptive administration has been found to increase levels of factors VII and X, and reduce the prothrombin time (Poller, Thomson and Thomas, 1971). These tests probably reflect the activity of the extrinsic system. The cephalin time, an overall index d'f the intrinsic system, was also reduced in these studies. Some, but not all workers have observed a modest rise of fibrinogen levels (Howie et al, 1970). These changes do not occur during low-dose progestogen (chlormadinone acetate) therapy (Poller et al, 1971). Platelet aggregation is accelerated during combined oral contraceptive medication and a significant but smaller change was found after two years' treatment with chlormadinone acetate (Poller et al, 1971). The oestrogen component is thought to be more important in the genesis of these changes and it may be relevant that oestrogen therapy shortens the bleeding time and corrects abnormal platelet adhesiveness in von Willebrand's disease. Studies of platelet electrophoretic behaviour have shown striking changes during combined oral contraceptive medication (Hampton, 1969; Bolton, Hampton and Mitchell, 1968). The platelet response to ADP is increased, whereas that to noradrenaline remains normal, a pattern resembling that found in platelets from subjects with arterial disease. It appears that the abnormal platelet behaviour, which can be induced by oestrogen but not progestogen alone, is due to an abnormality of low-density lipoprotein lecithin. The effects of oral contraceptives on fibrinolysis are somewhat uncertain. The subject is well reviewed by Dugdale and Masi (1969) who consider that fibrinolysis is generally increased during combined oral contraceptive medication, a situation contrasting with that of pregnancy in which fibrinolysis is reduced. The technique of thromboelastography has been used by Poller and his colleagues as a measure of overall intrinsic clotting, platelet function and fibrinolysis. Studies with women receiving combined oral contraceptives again showed changes consistent with accelerated clotting. Similar changes, although to a lesser extent, were also observed in women receiving long-term, low-dose chlormadinone acetate (Poller et al, 1971). Although the changes in clotting factors during combined oral contraceptive medication are less marked than those found in the third trimester of pregnancy, they cannot be regarded as desirable. It is likely that the majority of women are affected to some extent, but the incidence of venous thrombosis

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in oral contraceptive users is very low, being in order of 3-2/1000 women per annum. Investigations of blood coagulation and fibrinolysis in subjects who have developed venons thrombosis while receiving oral contraceptives are indicated. Such studies, if carried out after oral contraceptives had been discontinued, might reveal abormalities and suggest screening tests by which women at risk could be excluded from oral contraceptive programmes.

BLOOD PRESSURE

Combined oral contraceptive administration causes hypertension in some women. Usually the rise in blood pressure is modest, but most physicians are now familiar with occasional cases of severe, rapidly progressive hypertension. There have been few carefully controlled longitudinal studies of the effects of oral contraceptives on blood pressure, and no studies of the effects of long-term medication. Weir et al (1971) found the mean systolic pressure to rise in 50 of 66 women studied at 1 year by an average of 6.6 mm Hg. There was no significant change in the mean diastolic pressure, and in no case did the blood pressure rise to 140/90 or more. The change in systolic pressure was not associated with a past history of hypertension in pregnancy or renal disease, nor with a family history of hypertension or weight gain. Striking changes in the renin-angiotensin system occur during combined oral contraceptive administration (Crane, Harris and Winsor, 1971) and resemble those found in pregnancy. Plasma-renin substrate levels are consistently increased during oestrogen and combined oral contraceptive therapy, but medroxyprogesterone acetate and norethisterone are without effect. Renin activity is also increased but the renin concentration is usually unchanged or reduced, presumably as a result of negative feedback on the juxtagtomerular cells. Saruta, Saade and Kaplan (1970) found that renin concentrations tended to be higher in women who were hypertensive during oral contraceptive medication, suggesting that certain subjects may fail to suppress their renin secretion. Increased levels of plasma angiotensin II were observed by Cart et al (1971), and evidence of increased aldosterone secretion has been found during administration of oestrogen or combined oral contraceptives in both normotensive and hypertensive subjects. Medroxyprogesterone acetate, however, caused a significant decrease in the excretion rate of aldosterone in normal subjects (Crane and Harris, 1969). A slight, but not statistically significant rise of plasma aldosterone levels, was found in a group of women receiving combined oral contraceptives (Weir, Tree and Fraser, 1969). While the above biochemical changes may be responsible for the rise in blood pressure seen in some women receiving oral contraceptives, their importance is difficult to assess as similar changes are also found in women who do not become hypertensive. Possibly, severe hypertension only develops when there is a failure of normal compensatory mechanisms, perhaps as a result of occult renal disease.

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LIVER

Jaundice occasionally occurs in women receiving combined oral contraceptives. The onset is usually within four weeks of starting medication and may be preceded by anorexia, nausea and malaise. Fever, rash and arthralgia, common symptoms of infective hepatitis, however, are generally absent. The elevated serum bilirubin is mostly conjugated and serum alanine transferase, aspartate transferase, and alkaline phosphatase values increase. Liver biopsies show canalicular and hepatocellular bile stasis but little or no inflammatory reaction. When oral contraceptive medication is discontinued, a complete clinical and biochemical remission usually occurs within a few weeks. Extensive studies of the influence of oestrogens and progestogens on hepatic function have been reviewed by Song and Kappas (1969). Of particular relevance are those relating to hepatic excretory function. The standard BSP test is only occasionally abnormal during oral contraceptive medication. Kleiner, Kresch and Arias (1965), however, using a more sensitive BSP infusion technique, observed the maximum transfer rate (Tin) of BSP into bile to be considerably reduced in women receiving a mestranolnorethynodrel combination, but hepatic storage and conjugation of BSP were normal. These workers further found low doses of oestradiol (2.5 mg daily) to have no effect on BSP Tm values and suggested that the cholestatic effect of the combined contraceptive was due to the progestogen. A similar reduction of BSP Tm is also found in the last trimester of pregnancy, in the Dubin-Johnson syndrome, and during the administration of certain 17~alkylated anabolic steroids, such as methyl testosterone and 17c~-ethyl 19nortestosterone (norethandrolone). Treatment with larger doses of natural oestrogens, but within the range of total daily production of oestrogens in late pregnancy, also causes significant BSP retention in a high proportion of subjects (Palmer et al, 1969). These workers studied the effects of several natural and synthetic steroids on BSP metabolism in the rat. Impaired hepatic excretion of the dye was produced by a variety of oestrogens including stilboestrol; but progesterone, cortisol, corticosterone, norethynodrel and norethandrolone were inactive in this respect. Clinch and Tindall (1969) found stilboestrol to cause BSP retention in women during the puerperium. whereas megestrol acetate was without effect. The effects of steroids on BSP excretion cannot be consistently correlated with their anabolic, oestrogenic or progestational effects, nor with their chemical stru/cture. Factors which appear to confer a cholestatic effect include an alkyl radical on C-17, an oxo group on C-3 an d a phenolic A ring. Conflicting findings by Various investigators may have resulted from species variation and differences in dosage and routes of administration. In general, hepatic exposure to contraceptive steroids is likely to be greater following oral rather than parenteral administration. Some subjects (as many as 50 per cent according to some estimates) who develop jaundice during oral contraceptive administration, have a past history of jaundice and/or pruritus in the later stages of one or more pregnancies. This syndrome, benign intrahepatic cholestasis of pregnancy, remits

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shortly after delivery and shows a remarkable similarity to oral contraceptiveinduced jaundice in terms of clinical, biochemical and liver biopsy changes. Kreek and her co-workers have shown that such patients develop intrahepatic cholestasis when challenged with ethinyloestradiol but not during medroxyprogesterone acetate administration (Kreek, 1969). Several subjects presenting with oral contraceptive-induced jaundice have been found to have the Dubin-Johnson syndrome. In this condition there is a selective defect of hepatic excretory function which is presumably accentuated by oral contraceptive medication. It seems that while asymptomatic impairment of hepatic excretory function occurs regularly during the administration of various contraceptive steroids, clinical jaundice occurs in only a minority of subjects, who for some reason are more sensitive to the cholestatic effect of these drugs. Elevated levels of various serum enzymes, including aminotransferases, alkaline phosphatase and ornithine carbamoyltransferase have been noted during oral contraceptive therapy. These abnormalities usually occur in the first few cycles of medication and disappear with continued administration. Changes in the circulating levels of serum proteins synthesised by the liver have been discussed in a previous section. The activity of several hepatic enzymes is increased during the administration of oestrogens and/or progestogens. These include tryptophan oxygenase, various aminotransferases, glucose 6-phosphate dehydrogenase and 5-aminolaevulinic (ALA) synthetase. in certain instances, there appears to be induction of new enzyme protein since the rise in activity can be blocked by agents such as actinomycin D which inhibits nucleic acid synthesis and by puromycin which blocks protein synthesis at the ribosomal level (Kappas and Granick, 1968). Raised hepatic aminotransferase activity may be responsible for the reduced circulating levels of a variety of aminoacids during oral contraceptive medication (Craft and Peters, 1971). Exacerbation of acute intermittent porphyria and increased urinary output of porphyrins and their precursors during oral contraceptive therapy are presumably due to increased hepatic ALA synthetase activity since this enzyme is rate-limiting for porphyrin and haem-synthesis within the liver. The hepatic microsomes contain mixed-function oxidases which catalyse various oxidative detoxication conversions of many chemicals and drugs including hydroxylation, N-dealkylation, O-dealkylation, N-oxidation, sulphoxidation and phosphothianate oxidation. These reactions require NADPH and oxygen, and also depend on a haem-containing protein, cytochrome P-450. Certain steroids act as competitive inhibitors in these systems. For example, oestradiol and progesterone, compete in vitro with the microsomal metabolism of hexobarbital by rat liver (Tephly and Mannering, 1968). A large number of compounds, including several sex steroids, also affect the activity of these microsomal mixed-function oxidase systems. Juchau and Fours (1966) studied the effects of pretreatment with various steroids on the metabolism of hexobarbital by rat liver microsomes in vitro. Progesterone had no effect, but norethynodrel enhanced, and the combination of mestranol and norethynodrel reduced hexobarbital oxidation. Similar studies testing aromatic hydroxylation (substrate aniline), N-dealkylation

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(aminopyrine) and O-dealkylation (p-nitroanisol) showed enhanced activity after treatment with medroxyprogesterone acetate alone or combined with ethinyloestradiol. Significant changes were not found with progesterone, norethynodrel or mestranol (Jori, Bianchetti and Prestini, 1969). Contraceptive steroids, therefore, may have a dual action on hepatic drug detoxicating systems in that they appear to induce increased activity of various enzymes and may also act as competing substrates. The dose of steroid employed in these studies has often been relatively large, and the relevance of the findings to drug metabolism in women receiving oral contraceptives is difficult to evaluate. In view of the high incidence of oral contraceptive usage, it is surprising that so little is known about the influence of these steroids on drug metabolism in man. An example is the effect of oestrogen medication on cortisol metabolism. The half-life of cortisol is prolonged, probably because of reduced activity of the hepatic NADPH-linked reductase system responsible for the initial stage of cortisol catabolism (Prunty, 1964). This change accounts for the reduced urinary 17-hydroxycorticosteroid excretion found during combined oral contraceptive medication and is clinically important in that the requirement for replacement cortisol therapy is reduced in women with Addison's disease receiving oestrogen medication. MINERAL METABOLISM The actions of oral contraceptives on sodium and water metabolism are poorly understood, as the majority of studies have been carried out with natural gonadal hormones and the effects of compensatory mechanisms make the results difficult to interpret. In normal subjects, oestradiol and oestriol cause a transient natriuresis lasting for one to two days, followed by a period of sodium retention, and then a further natriuresis at about two weeks (Preedy, 1969). Increased aldosterone secretion has been reported during oestradiol medication by Katz & Kappas (1967), and these workers have suggested that oestrogens, like progesterone, may have an anti-aldosterone effect on the renal tubule, inducing an initial natriuresis. Increased renin and aldosterone secretion then cause sodium retention with overcompensation, and the later natriuresis is due to reduced aldosterone secretion. However, oestrog~n administration to subjects with cirrhosis or congestive cardiac failure causes persistent sodium and water retention. Progesterone, like oestrogens, causes an initial natriuresis in normal subjects, the magnitude of which is dose dependent (Landau and Lugibuhl, 1961), and persists rather longer than that caused by oestrogen administration. These workers also showed that this effect is dependent on the presence of aldosterone. As would be expected, a compensatory rise of urinary aldosterone excretion also occurs during progesterone administration. No studies of the long-term effects of gonadal hormones or synthetic contraceptive steroids on total body exchangeable sodium, water and potassium have been published. Oestrogen medication has a mild hypocalcaemic action in postmenopausal women (Young et al, 1968). A similar fall was found in 10 postmenopausal women with hyperparathyroidism treated with ethinyloestradiol (Gallagher and Nordin, 1972), and plasma phosl0hate and urinary calcium and hydroxy-

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proline excretion were also reduced in these patients. These workers suggested that oestrogens inhibit the peripheral actions of parathyroid hormone, particularly on bone resorption. Goldsmith and Baumberger (1967) reported lower levels of serum and urinary magnesium in a group of women receiving Enovid. Plasma copper has been reported to be increased and plasma zinc levels are reduced in oral contraceptive users (Halstead, Hackley and Smith, 1968). The clinical relevance of these effects of oral contraceptive steroids on mineral metabolism is unknown, but the changes in sodium handling may be relevant to the development of hypertension. SUMMARY

A variety of metabolic effects has been described in oral contraceptive users. Virtually all organ systems are affected, and the present review describes changes in serum lipid and lipoprotein levels, carbohydrate and intermediary metabolism, vitamins, tryptophan metabolism, serum proteins, blood coagulation and fibrinolysis, blood pressure, liver function and mineral metabolism. These biochemical disturbances are unnecessary for the anti-fertility effect, and their influence on the long-term health of the user is unknown. While the oestrogen component of the combined oral contraceptive appears to be responsible for most of the metabolic changes, the progestogen is also important. Differences between the metabolic profile of pregnancy and that observed during oral contraceptive medication emphasise that contraceptive steroids and natural gonadal hormones do not necessarily have identical biological actions. The relation of these metabolic changes to the severe side-effects of oral contraceptives, such a~ thrombo-embolic disease and hypertension is not clear. The former are found in the majority of users whereas the latter are rare. This suggests that severe clinical side-effects may occur only in subjects whose natural homeostatic mechanisms are deficient because of pre-existing organ system dysfunction.

REFERENCES

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