Oral contraceptives and carbohydrate metabolism

Oral Contraceptives and Carbohydrate Metabolism P. W. ADAMS 1~. W. OAKLEY

Thirty years ago Ingle (1942) reported changes in glucose excretion in normal and adrenalectomised rats given stilboestrol. Nevertheless, the oral contraceptive steroids (OC) were introduced, and subsequently became widely used, at a time when very little was known of their metabolic effects in man. The work of Wynn and his colleagues on the related anabolic steroids (Landon et al, 1962), and the observation by Waine et al (1963) that Enovid caused changes in glucose tolerance, were followed by intensive study of OC and carbohydrate metabolism, which is reflected in the large number of papers published on this subject between 1966 and 1970. Exact characterisation of these changes induced by OC and interpretation of their significance has, however, proved difficult. Problems which have been encountered have included :-(i) The lack of reliable and easily interpretable indices of carbohydrate tolerance. (ii,) Ignorance of the long-term implications of mildly impaired carbohydrate tolerance induced by OC. (iii) The complicating factor of weight gain, a common OC side effect, which also influences carbohydrate metabolism. (iv) Differences between the various oestrogenic and progestational steroids used in OC preparations, such that findings in women on various OC preparation may not all be the same. (v) Uncertainty as to whether oestrogen-progestogen preparations exert effects which may be predicted from the behaviour of the two components administered separately. (vi) Uncertainty as to whether findings derived from normal women can be applied to abnormal ones, in particular established diabetics. (vii) The loss rate from long-term prospective follow-up studies, owing to the high mobility within the community of women of child-bearing age. This review will attempt briefly to outline our present knowledge of the effects of currently available oestrogen-progestogen and low-dose-progestogen OC preparations on carbohydrate metabolism, and to discuss theories which have been advanced as to the mechanisms of the effects described. Clinics in Endocrinology and Metabolism--Vol.

1, No. 3, November 1972.

697

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P . W . ADAMS AND N. W. OAKLEY

THE CHEMISTRY OF ORAL CONTRACEPTIVE STEROIDS The development of effective contraceptive tablets followed closely upon the formulation of cheap, potent, orally active steroids with oestrogenic and progestogenic properties. It was found that excellent contraceptive and menstrual control could be achieved with a combined oestrogen-progestogen Table 1. Oral Contraceptive Formulations Commonly used in Great Britain Progestogen Type

Name

Oestrogen

Effect a Type

Norinyl-1 Ovulen 50

Mestranol 50 .ug

.~ :g

Name

Dose (rag)

Norethisterone

1 '0

B

Ethynoldiol diacetate

1 "0

B

O C~

Orthonovin 1/50

1.0

B

(~ ~

Anovlar 21

4.0

P

~ ~

Gynovlar 21 Norlestrin 21

~

Minovlar Orlest 28

o Ethinyl oestradiol 50 ~tg

Norethisterone acetate

c

Minilyn

Lynoestrenol

O

Nuvacon

Norolen

Ethinyl oestradiol 100 tag

,.~o

1"0

P

2"5

B

4.0

P

2"0

B

Orthonovin 1/80

Mestranol 80 ~tg

Norinyl-2 Orthonovin 2 mg

O O

Lynoestranol

2-5

B

Norethisterone

1 "0

O

2.0

P

2'5

O

1 '0

B

0"5

O

"o

.o

Conovid-E Previson Ovulen 1 m g

5'0 3"0

Norethynodrel Mestranol 75 Bg

Lyndiol 2-5

Mestranol 100/ag

8

Norethynodrel Ethynodiol diacetate

Demulen Orthonovin 0.5 Lyndiol

Mestranol 150 lag

Ovanon

Mestranol 80 ~g

Sequens

D

P

Megestrol acetate

Conovid Enovid

z

P

2"5

o

Volidan 21

g

3 '0

C-Quens 21

o

Mestranol 100 g g

Noretbisterone

0-5

O

Lynoestranol

5"0

B

2"5

O

2-0

O

1.5

O

Megestrol acetate

1 "0

O

Norethynodrel

2"5

O

Norethisterone

2"0

O

Chlormadinone acetate

~.~

,~OU. Serial 28

Ethinyl oestradiol 100 pg o

Feminor 21 Mestranol 100 lag Orthonovin SQ.

~.~

a p, O & B indicate progestogenic, oestrogenic and balanced preparations respectively.

ORAL CONTRACEPTIVES AND CARBOHYDRATE METABOLISM

699

pill, and most currently used OC preparations are in this form, although sequential preparations are also available. The formulations commonly used in Great Britain are shown in Table 1. The combined OC pills all contain a potent synthetic oestrogen--either ethinyl oestradiol or ethinyl oestradiol 3-methyl ether (mestranol) at a dose of 50 lag. The Medicines Commission recently advised that prescription of OC pills with a higher oestrogen content should be restricted, as they may carry an increased risk of thromboembolism. The synthetic progestogens in current use fall into different chemical categories and are used in widely varying doses. They may be classed as 'substituted progesterone' or '19-nor-testosterone' derivatives, as indicated in Table 1. The situation is complicated by the fact that norethynodrel and norethindrone (norethisterone), both of which are 17-alpha-ethinyl 19-nor compounds, exert quite strong oestrogenic effects which have been attributed to their metabolites (Paulsen, 1965). 'Substituted progesterone' derivatives (e.g. megestrol), and those without the 19-nor configuration (e.g. ethisterone) are not metabolised to oestrogenic derivatives. In addition to the combined and sequential OC preparations, the regular continuous administration of small doses of a progestogen has also been found to provide a high degree of contraceptive protection, probably by preventing fertilisation rather than by inhibiting ovulation. Chlormadinone and megestrol have both been used in this way, and depot injections of longacting progestogens are at present under trial. Chlormadinone has, however, been withdrawn from the market following its recognition as a possible mammary carcinogen. Throughout this review the term 'combined' will be restricted to preparations in which a progestogen is taken throughout the cycle, while 'sequential' will be used to describe preparation in which a progestogen is taken only during the latter part of the cycle.

METHODS OF EVALUATION Glucose tolerance is the only index of carbohydrate metabolism commonly used in clinical research or practice. The oral test is generally regarded as more physiological than the intravenous, and therefore a preferable diagnostic discriminant of diabetes, while the intravenous test has the advantages of independence from glucose absorption artefacts, and of being expressible as a single figure--the 'assimilation index'--usually designated 'k'. Both tests, with simultaneous estimation of other parameters including insulin, growth hormone, free fatty acids and pyruvate, have been widely used in OC studies. There is also information relating to glucocorticoid-primed glucose tolerance and the intravenous tolbutamide test, while the effects of OC on fasting glucose and insulin have been reported by several authors. Fasting insulin values must, however, be interpreted with caution, as many insulin assays lack precision in the fasting range.

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Reproducibility of the oral glucose tolerance test has been studied by McDonald, Burnham and Lewis (1969) and West et al (1964), who have drawn attention to the marked day-to-day variation of individual tests. For this reason, large series of carefully controlled glucose tolerance tests are needed to characterise changes induced by OC. It is, moreover, difficult to compare results from different centres. Variables which hinder such comparisons include pre-test dietary preparation, glucose dose, capillary or venous blood samples, reducing sugars estimated, and the methods used for analysis of the values obtained. The latter include single glucose points (usually at 2 hours), multiple points, and measurement of the area under the glucose curve. A single post-prandial glucose estimation, which might be a practical and useful screening test for OC-induced diabetes is, unfortunately, capable of detecting only about 70 per cent of patients with diabetes diagnosable by conventional oral glucose tolerance criteria (Mitchell and Strauss, 1964). Intravenous glucose tolerance tests have been used widely for OC studies. The assimilation index k has usually been calculated on the assumption that, at least for a short period of time during the test, the glucose value is falling exponentially towards zero--the 'absolute' k value of Hamilton and Stein (1942). Interpretation of the i.v. test has recently been reviewed by Butterfield, Abrams and Whichelow (1971). Most workers studying OC have used the 'absolute' index, although the area under the curve has been used for i.v. as well as for oral tests (Yen and Vela, 1968; Wynn and Doar 1969a). Various methods have been used for measuring insulin changes during oral and i.v. glucose tolerance tests, including estimation of total insulin area (Yen and Vela, 1968) the rise in insulin following glucose (Spellacy et al, 1968), and the mean insulin value (Spellacy, Carlson and Birk, 1967). One further measurement (Beck and Wells, 1969) is the insulinogenic index (Selzer et al, 1967; Beck and Wells, 1969). This relates the insulin response to the blood glucose rise, following a glucose load. Tolbutamide tests have been evaluated in terms of glucose fall and insulin output (Davidson and Holzman 1971) and steroid-primed tests have been interpreted either by conventional oral glucose criteria (Di Paola et al, 1968) or, in the case of our own studies (Adams et al, 1971), following the maximum insulin stimulation protocol of Ryan, Schwartz and Nibbe (1971), using the peak insulin response. In general, there are two ways in which the effect of OC on glucose tolerance can be assessed. The first is by noting the number of instances in which OC induces an abnormal tolerance test; the second is by calculating the significance of differences between studies on and off OC. The first method suffers from the disadvantage of requiring definitions of normality and abnormality which must be of an arbitrary nature; the second allows the recognition of significance in the case of trivial, but consistent differences, particularly when patients act as their own controls. These considerations should be kept in mind when evaluating the clinical studies reported later in this review.

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CARBOHYDRATE METABOLISM IN WOMEN ON COMBINED AND SEQUENTIAL PREPARATIONS Fasting blood glucose and insulin Elevated fasting blood glucose levels have been reported on combined OC by Gershberg, Javier and Hulse (1964) during administration to 59 women for over 12 months, and after 3 months in a longitudinal study in both latent diabetic and normal women by Goldman and Eckerling (1970). Insulin levels were not measured. Spellacy et al (1967) found that the fasting insulin levels were increased after six cycles of Enovid in 32 women, though when the same group investigated 93 women after 12 months' treatment with the same preparation no significant change in fasting insulin levels could be detected (Spellacy et al, 1968). Several longitudinal studies using combined OC have shown no change in either fasting blood glucose or insulin levels; these studies include those of Starup, Date and Deckert (1968) and Wynn and Doar (1969a), the latter having studied 91 women taking several different preparations. Closer analysis of the fasting plasma glucose data of Wynn and Doar (1969b) revealed that although there was no significant change in the group as a whole, the change in fasting plasma glucose observed following the administration of OC, showed a close negative correlation with the preOC plasma glucose value. Thus, high values tended to fall, and low values to rise on OC, a finding consistent with a neutral OC effect in a uniform population, and one which implies that OCs reduce the scatter of fasting glucose values. Yen and Vela (1968) found little change in fasting blood glucose levels, but in one series of tests there was a significant fall in 23 women taking a sequential OC preparation. Similar results were reported by Spellacy, Carlson and Schade (1968b) in a longitudinal study of 35 women taking a sequential OC. In both studies fasting plasma insulin levels were elevated. A recent analysis of our own results, separating obese from non-obese women, showed a significant fall of glucose and rise of insulin for both groups when combined OC were given. (Wynn et al, 1972).

Oral glucose tolerance tests Only a minority of studies have employed both oral and i.v. glucose tolerance tests in the same subject as a means of assessing carbohydrate metabolism; as the response to these tests may differ, they must be considered separately. Most workers have demonstrated an effect of OC on oral glucose tolerance, but Taylor and Kass (1968), in a highly selected group of 21 women, showed no change in glucose tolerance followilag up to 12 months OC administration, and Danowski et al (1968) found no change after 14 months in 17 women. Unaltered glucose tolerance and insulin responses were found by Pi-Sunyer and Oster (l 968) in a longitudinal study of the effect of Enovid administration for only 1 month and by Boshell et al (1968) in a longitudinal study of a group of 231 mainly postmenopausal women on OC for 6 and 12 months. Yen and Vela (1968) found unchanged glucose tolerance but increased insulin responses, and therefore increased insulin: glucose ratios, in 23 women after 3 months on OC. Why these investigators found no change in oral

702

P.W. ADAMSAND N. W. OAKLEY

glucose tolerance on administration of OC is not clear. It is possible that, in the case of Pi-Sunyer and Oster (1968) short duration of exposure may have been of some relevance, while Taylor and Kass (1968) may have influenced their findings by very strict selection of their patients. Other investigators have reported an incidence of abnormality varying from 13 to 77 per cent according to the clinical material and the methods of testing. Abnormal glucose tolerance (but without insulin measurements) have been reported by Yen and Vela (1969) in 17 of 34 postmenopausal women after 6 months on OC, in 6 of 15 women after 3 to 43 months by Halling, Michals and Paulsen (1967), and in 35 of 61 women by Peterson, Steel and Coyne (1966) after 3 months to 7 years on OC. Gershberg, Javier and Hulse (1964) studied 59 women taking OC for 3 to 38 months and noted that the blood glucose levels became progressively more abnormal during a 2-hour test, so that by 2 hours 46 per cent of the women had abnormal values. In a longitudinal study of 91 women Wynn and Doar (1969a) found that oral glucose tolerance deteriorated in 78 per cent, 13 per cent of the total developing chemical diabetes after 3 months on OC, while Spellacy et al (1970a) found that of 59 women taking a combined OC for 8 years, 39 per cent had relatively impaired, and a further 39 per cent, abnormal glucose tolerance. Insulin measurements have shown variable responses during oral tests, reflecting differences in duration of OC administration and metabolic status of the women investigated. Wynn and Doar (1969a), Spellacy et al (1970) and Javier, Gershberg and Hulse (1968) have all demonstrated hyperinsulinism associated with abnormally elevated glucose levels during oral tests. The peak insulin value tends to be delayed, and the greatest abnormality is seen during the latter part of the test, when glucose levels are also most abnormal. Javier et al (1968) found that, in women studied for up to 12 months, impaired glucose tolerance was associated with concomitant hyperinsulinism, though thereafter the 30 minute plasma insulin response decreased progressively as the duration of OC therapy increased. Some latent diabetic patients can be identified by the appearance of abnormal glucose tolerance and impaired insulin secretion during a steroid-stressed glucose tolerance test, the initial insulin response being blunted in such patients (Kalkhoff, Richardson and Stoddard, 1968). Women on OC have been found to have a high incidence of abnormal steroidstressed glucose tolerance tests, with marked similarity of the glucose-insulin profile to that found in latent diabetic patients tested in the same way. Di Paola et al (1968) found abnormal tests in 67 per cent and Javier et al (1968) in 88 per cent of women on OC when also glucocorticoid-primed. Kalkhoff, Kim & Stoddard (1969) found that 10 women with normal glucose tolerance on OC all developed abnormal tests when glucocorticoid-stressed, and that they showed no further augmentation of insulin response during such a test. These findings suggest that OC with the synergistic action of prednisone can lead to chemical diabetes. In summary, therefore, abnormal oral glucose tolerance, when present in women taking OC is characterised by elevated blood glucose levels during the latter part of the test, associated with a blunted early insulin response but

ORAL CONTRACEPTIVES AND CARBOHYDRATE METABOLISM

703

subsequent hyperinsulinism. This glucose-insulin profile resembles that found in maturity onset diabetes (Perley and Kipnis, 1966; Selzer et al, 1967), and, as in that condition, there is an increased incidence of abnormal glucocorticoid-stressed carbohydrate tolerance.

Intravenous glucose tolerance tests Studies using i.v. glucose tolerance tests as the method for assessing carbohydrate metabolism in women on OC have, in general, given a lower percentage of abnormal tests than when an oral glucose load has been used. This may merely reflect the relative insensitivity of methods used for interpreting the i.v. test. Starup et al (1968), in a longitudinal study of 27 women, found no change in k value or insulin response after 12 months on OC. Yen and Vela (1968) found that although after 3 months on a sequential OC blood glucose levels and total areas during i.v. glucose tolerance tests were unchanged, yet the insulin response, and therefore the insulin: glucose ratio, was increased. Spellacy et al (1968b) also used a sequential OC in a longitudinal study of 35 women and found that, after 6 months exposure, blood sugar levels were lower, but insulin levels higher, than pre-OC. Vermeulen, Daneels and Theiry (1970) studied 15 women before and after 12 months on a combined OC preparation, and also found unaltered k values, but increased insulin responses. On the other hand, impaired i.v. glucose tolerance was found in 25 women after only 19 days on a combined OC pill by Spellacy and Carlson (1966), the insulin levels also being increased. Posner et al (1967a) and Posner et al (1967b) found a significant fall in k value in 9 per cent of women after 3 months on OC, and Spellacy et al (1968a) found that the mean total glucoses for a group of 93 women increased by 6.6 per cent and mean total insulin by 35 per cent twelve months after starting a combined OC. It is possible that the discrepancies between the results are due to the use of different OC preparations at different dosages, as well as to different methods of assessing and interpreting the results. Starup et al (1968) used a lower dose of Mestranol (100 gg) than Spellacy & Carlson (1966) who used 150 gg, while the two groups used OC containing megestrol and norethynodrel respectively as the progestogen. Similarly, Vermeulen et al (1970) used only 50 gg of ethinyl oestradiol, with megestrol. Moreover, neither of the two studies using sequential OC preparations revealed any change in i.v. glucose tolerance. Clinch, Turnbull and Khosla (1969) reported that i.v. glucose tolerance was improved by Norinyl-1, but they based this conclusion on an increase in k value, in the face of elevated blood glucose values on OC. This apparent paradox could be explained on the basis of an altered volume of distribution of the glucose load on OC, but certainly the k value by itself is not always the best way of expressing the results of intravenous tests, as has been pointed out by Doar and Wynn (1969) when reporting slight deterioration in glucose tolerance by area but not by k in their own patients on Norinyl-1.

704

P . W . ADAMS AND N. W. OAKLEY

Oral and intravenous tests The investigations summarised above suggest that the oral glucose tolerance test is a more sensitive index of impaired carbohydrate tolerance than the intravenous test. This thesis is to some extent supported by studies in which direct comparisons have been made between the two types of test on normal subjects under the stress stimulus of both pregnancy and OC administration. Benjamin and Casper (1967) tested 144 women during the third trimester of pregnancy and found that the oral test was frequently abnormal in the presence of a normal i.v. test, but the reverse was rare. There have been few reports in which both oral and i.v. tests have been carried out on the same women off and on OC. Buchler and Warren (1966), in a study of five post-menopausal women given OC for 30 days, found that four developed impaired oral glucose tolerance whereas i.v. tolerance remained unaltered in all five. Yen and Vela (1969) found, again in a small group of postmenopausal women, that although oral glucose tolerance on OC became abnormal in 50 per cent, intravenous tolerance invariably remained normal. Wynn and Dour (196%) have carried out the most extensive and carefully controlled study of this kind, and reported results of oral and i.v. tests on 91 women tested before and during OC administration, 39 women tested on OC and after this had been stopped, and 22 tested twice on OC. Of 83 women with normal oral tests pre-OC, 11 (13 per cent) became abnormal on OC, while of 25 abnormal on OC, 14 (56 per cent) became normal when it was stopped. The mean intravenous test k value was, however, not significantly altered by starting OC, although it was significantly improved by stopping OC in the second group. The apparent lack of sensitivity of the i.v. test was overcome by showing that the area under the i.v. glucose curve was increased in 70 per cent of women given OC, without significant change in the peak glucose value. Furthermore, a significant correlation was found between the changes in oral and i.v. glucose areas following exposure to OC. Plasma insulin levels rose during the latter half of the i.v. tests, in correspondence with the elevated glucose values, and in a manner similar to that observed during oral tests. In summary, therefore, it seems likely that the insensitivity of the i.v. test is a reflection of the inadequacy of the methods conventionally used for evaluation of the test, rather than an indication of any fundamental physiological difference between the ways in which i.v. and 0ral glucose tolerance are influenced by OC. Other tests of carbohydrate metabolism

It has been suggested that OC administration is characterised by excessively elevated plasma insulin levels for the prevailing blood glucose concentration, implying that OC induce insulin resistance. Other tests to confirm this finding have been devised, but there is little evidence that they provide any information additional to that which can be obtained from glucose tolerance tests. Such tests include insulin sensitivity tests, arginine infusion and i.v. tolbutamide tests.

ORAL CONTRACEPTIVESAND CARBOHYDRATEMETABOLISM

705

Spellacy (1969) failed to show resistance to the hypoglycaemic effect of exogenous insulin in women on OC. Vela and Yen (1969) used an arginine infusion, which stimulates insulin and growth hormone secretion without a great change in blood glucose. They found that in a group of women on Ovulen, there was an increased insulin response, without any abnormality of the glucose pattern. It has been known for some years that the female growth hormone response to arginine is often greater than that observed in the male, and that the male response can be augmented by the administration of oestrogens (Frantz and Rabkin, 1965). The observations suggest that oestrogens directly or indirectly sensitise endocrine glands to the stimulatory action of arginine. The relative insulin insensitivity could have been due to an augmented growth hormone response. The intravenous tolbutamide test has been used by two groups of workers. Kalkhoff et al (1969) found that OC caused an increased insulin response to tolbutamide, and an elevated blood glucose nadir, while Davidson and Holzman (1971) also reported that OC administration was followed by a reduced depression of blood glucose after tolbutamide, but with no change in insulin response, although there was a rise in growth hormone before and during the test. This suggests that one effect of combined OC may be to induce growth hormone-mediated insulin resistance. Unsuccessful attempts have been made to devise special tests to detect the high-risk woman. Javier et al (1968) found that the prednisone glucose tolerance test was unreliable, as some women who had abnormal tests pre-OC became normal on OC and vice versa. Adams et al (1971) used the maximum insulin stimulation technique of Ryan et al (1971); this involves giving i.v. glucagon and tolbutamide 2 hours after a 100 g glucose load. This stimulus is followed by a massive release of insulin in normal subjects, the release being even greater if the subject has been treated with prednisone. Tests were carried out with and without prednisone, pre-OC and after 3 months on OC. Neither the change in oral glucose tolerance, nor the change in maximal insulin response, after prednisone, gave a reliable index as to which individual subjects would develop impaired glucose tolerance on OC, although statistically significant predictive correlations were demonstrated.

FACTORS THAT MAY MODIFY EFFECT OF OC ON CARBOHYDRATE M E T A B O L I S M Many factors have been examined that might predispose to abnormal carbohydrate metabolism in association with the use of OC. Unfortunately it is difficult to study one variable in isolation in a clinical study, and this may have contributed to the different findings reported.

Age Glucose tolerance is known to deteriorate with age; Buchler and Warren (1966) found that five postmenopausal women became diabetic when given Enovid, and Spellacy et al (1968a), in a longitudinal study of the effect of combined OC on i.v. glucose tolerance in 93 premenopausal women, found a

706

P.W. ADAMSAND N. W. OAKLEY

positive correlation between the change in plasma glucose and insulin levels following the introduction of Enovid and the age of the subject. Other workers have failed to find any correlation between the incidence of OC-induced blood glucose abnormalities and age (Peterson et al, 1966; Wynn and Doar 1969a). Weight It is well established that obesity is associated with impaired glucose tolerance and hyperinsulinism (Bagdade, Bierman and Porte 1967). Taylor and Kass (1968), who found no change in carbohydrate metabolism during up to 12 months OC administration, and Yen and Vela (1968) who found no change in plasma glucose levels but significant hyperinsulinisrn on OC, excluded obese subjects from their studies. Other investigators (Di Paola et al, 1968; Gershberg et al, 1964; Posner et al, 1967a and Spellacy et al, 1970a) found no correlation between weight and changes in carbohydrate metabolism on OC. Boshell et al (1968) found that of five obese women with normal tests off OC, four developed abnormal tests on OC. In a study of the effects of obesity, Doar and Wynn (1970) investigated oral glucose tolerance in matched groups of women without diabetes, subdivided by weight, and whether or not they were on OC. The obese control women had mildly impaired glucose tolerance, which was identical to that found in non-obese women on OC; the combination of obesity and OC administration resulted in a further significant deterioration in the tests. An identical pattern of responses was found in the pyruvate levels, giving support to the observations of change in glucose tolerance when obesity and OC administration coexist. The same investigators, however, (Wynn and Doar 1969a) failed to find any correlation between the degree of obesity and change in glucose tolerance in a longitudinal study of women following exposure to OC. These findings could be due to the small number of obese subjects in the latter study. There is clearly a need for further studies on the relationship between obesity and OC-induced carbohydrate intolerance.

Family history of diabetes Diabetes mellitus is in part genetically determined, but, as yet, the mode of inheritance is not clear. Moreover, the significance of a family history of this condition is difficult to establish as the definition of a positive family history is arbitrary, and the validity of any assessment depends on the patient's knowledge of their own family. Starrup et al (1968) and Taylor and Kass (1968) studied women with no family histories of diabetes, and failed to demonstrate changes in carbohydrate metabolism with administration of OC. Neither Spellacy et al (1968a) nor Wynn and Doar (1969a) were able to correlate family history of diabetes with the incidence of glucose intolerance on OC. However, Gershberg et al (1964) and Peterson et al (1966) found an increased percentage of abnormal tests on OC in women with positive family histories, while Di Paola et al (1968) made a similar observation using the prednisone-stressed glucose tolerance test.

ORAL CONTRACEPTIVES AND CARBOHYDRATE METABOLISM

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Parity No relation has been found between parity and vulnerability to OC-induced carbohydrate intolerance in the few studies in which this has been considered (Spellacy et al, 1968a; Di Paola et al, 1968; Wynn and Doar, 1969a). Potential and latent diabetes As diabetes can be unmasked by steroid stress, investigators have studied the effect of OC on women with potential diabetic features such as xtelivery of a large baby, unexplained fetal death, glycosuria of pregnancy, or with definite latent diabetes. Attempts have been made to correlate these historical features with the glucose tolerance response to OC. Javier et al (1968) found a significant correlation between abnormal glucose tolerance on OC and both previous big babies and previously impaired glucose tolerance during the third trimester of pregnancy. Spellacy et al (1968a) made a similar observation. Beck and Wells (1969) compared 14 control women with 12 women who had abnormal oral glucose tolerance during the third trimester of pregnancy, and prednisone-glucose tolerance test post partum; after 3 months on OC, 50 per cent of the latent diabetic women, but none of the control group, showed deterioration in glucose tolerance. Szabo, Cole and Grimaldi (1970) studied a similarly selected group of 15 women; five of these were given OC and the remainder followed as controls. All those given OC, but only 3 out of 10 controls showed impaired glucose tolerance during the period of follow-up. Goldman and Ovadia (1969) found that oestrogen administration was associated with a greater reduction in k value in latent diabetic than in normal women. Wynn and Doar (1969a) did not find such a marked effect of OC in seven chemical diabetic women, after 3 months on OC--only one showing a marked deterioration in glucose tolerance. From these studies it seems that abnormal tests are particularly likely to appear during OC administration in women with latent diabetes. The stress of short term OC treatment does not appear to be so great as that to which women are exposed during the third trimester of pregnancy, but this may not be true when experience of longer follow-up on OC is available. Day of pill cycle Results of studies of carbohydrate metabolism during the proliferative and luteal phases of the normal menstrual cycle have given variable results, but the balance of evidence seems to indicate no difference between phases. This is the conclusion of Py6r/il/i, Py/Sr/il/i and Lampinen (1967), Spellacy et al (1967a) and Larsson-Cohn, Tengstr6m and Wide (1969). On the other hand, Jarrett and Graver (1968) found glucose tolerance to be improved during the proliferative phase. The timing of testing of subjects in relation to the cycle on combined OC has been found to show no correlation with glucose tolerance (Wynn and Doar, 1966, 1969a). In summary, many factors affect the manner in which a woman responds to OC administration, but none enables the woman who is going to develop diabetes on the pill to be recognised with certainty. The most constant association with abnormal carbohydrate intolerance on OC is that of latent diabetes, while the potential diabetic also carries an increased risk. It also seems that obesity may increase the effect of the pill on glucose tolerance.

708

P . W . ADAMS AND N. W. OAKLEY THE EFFECTS OF DIFFERENT GONADAL STEROIDS

Experimental studies It is not clearly established whether the effects of PC on carbohydrate metabolism are due entirely to the oestrogen, or progestogen, or whether the combination of the two steroids is additive or synergistic. Unfortunately, few studies in women have used single steroids, and animal experiments have yielded conflicting results, possibly reflecting species variations (Haist, 1965). Animal experiments are usually short term, and it is therefore unwise to extrapolate from them to effects in women who may be on PC for many years. In general, animal studies have shown that oestrogens improve rather than exacerbate experimental diabetes, duration of exposure being an important variable. Studies on the rat have been reviewed by Rodriguez 0965). He noted that the frequency of diabetes after partial pancreatectomy is higher in male than in female rats and the incidence of pancreatic diabetes in female rats is greatly increased by ovariectomy. He also found that diethyl stilboestrol has a biphasic effect; first there is increased glycaemia and glycosuria in the partially pancreatectomised rat, but after about a month a protective effect supervenes. Oestrogen administration has been shown to cause hypertrophy and hyperplasia of the pancreatic islets in a number of species, which probably explains the late protective effect of oestrogens in the rat. It was found that oestradiol cured 50 per cent of rats with alloxan diabetes, a property not shared by other steroids tested, or by chlorpropamide. Beck (1969) studied monkeys and found that mestranol was more diabetogenic than ethinyl oestradiol, but nevertheless believed that mestranol was insulinogenic, owing to possession of a partial positive charge at C5, not present in ethinyl oestradiol. It seems likely that mestranol is more strongly insulin-antagonistic than ethinyl oestradiol, which would be consistent with some of the clinical observations. The progestogens used in P C have various types of chemical structure, as summarised earlier in this review. Progesterone itself causes glycosuria in partially pancreatectomised rats (Ingle, Beary & Purmalis 1953). Beck (1969) has also carried out structure-function studies on progestogens, in monkeys. Most progestogens show insulin-antagonistic properties--perhaps reflecting their chemical similarity to cortisol. The proposed insulinogenic properties of a partial positive charge at C5 are, however, also found in progesterone itself, norethynodrel, norethindrone (norethisterone) chlormadinone and megestrol. It is known that C6 unsaturation reduces the gluconeogenic effect of cortisol. This may explain why chlormadinone, a C6 unsaturated compound, increases the i.v. k value of monkeys when given alone. Megestrol is also a C6 unsaturated steroid. Clinical studies provide some support for Beck's hypotheses, but more observations on individual steroids will be needed before they can be regarded as proven.

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Clinical studies on individual steroids

Buchler and Warren (1966) found that diethylstilboestrol caused abnormal oral glucose tolerance in small groups of postmenopausal or latent diabetic women, and Goldman and Ovadia (1969) found that oestrogens impaired i.v. glucose tolerance in both young and old women. Insulin levels were not measured in either study. Ethinyl oestradiol was found by Py~rfil~i et al (1967) to lower the i.v. k value, while another group found that this oestrogen caused no change in glucose tolerance, but raised insulin responses, both when given alone and as part of a sequential regime (Yen & Vela, 1968; 1969). These studies excluded obese and latent diabetic women, which may explain why they are rather closer in line with the animal work of Beck than are most other reports. Di Paola, Robin and Nicholson (1970) found that ethinyl oestradiol caused no deterioration in prednisone-glucose tolerance, while there was a 57 per cent incidence of abnormality in women given mestranol; after 12 months, however, there was no increased incidence of abnormalities on mestranol--a finding which is consistent with the work of Rodriguez on rats, cited above. Javier et al (1968) also showed that mestranol caused deterioration in glucose tolerance, while Beck and Wells (1969) reported a 50 per cent incidence of abnormality in latent diabetics given a mestranol-containing OC, the characteristic feature being delayed insulin release. Gow and MacGillivray (1971) also showed a reduction in i.v. k value in postmenopausal women given mestranol. On the other hand Starup et al (1969) found that neither glucose nor insulin changed when women were given a combined OC containing mestranol and megestrol. This finding may be explained on the basis of strictly selected normal subjects and perhaps the beneficial effect of using a C6 unsaturated progestogen. The dose of oestrogen does not appear to play an important role. Mestranol at a dose of 20 gg was without effect, and increasing the dose above 40 gg did not cause any difference in carbohydrate tolerance (Di Paola et al, 1968). Similarly there was no difference between 100 lag and 200 gg of ethinyl oestradiol (Yen and Vela, 1969). These clinical studies support the view that oestrogens alone can cause resistance to insulin, and that abnormalities of glucose tolerance are more common with mestranol than with ethinyl oestradiol, though the pancreatic islet cell reserve of the subjects studied is also of great importance. The situation is probably even more complex, as Gershberg et al (1967) found that two months of mestranol significantly improved the glucose tolerance of a group of maturity-onset diabetics, without an increased insulin response. Thus, while oestrogens may precipitate diabetes in latent diabetics, yet in frank diabetics they may ameliorate it, although, unlike experimental animals, such amelioration is not always associated with normalisation of the insulin pattern. OESTROGENS.

PROGESTOGENS. Both Goldman, Ovadia and Eckerling (1968) and Yen and Vela (1969) agree that up to 3 weeks of intramuscular progesterone (100 to 300 rag) does not affect i.v. k values, while Kalkhoff, Jacobson and Lemper (1970) reported similar negative findings using the oral glucose and i.v. tolbutamide tests; the latter authors, however, reported increased insulin

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responses. Goldman et al (1968) also failed to show any change in carbohydrate tolerance after 3 weeks of i.m. medroxyprogesterone acetate. Gershberg et al (1969) gave medroxyprogesterone to latent and established diabetic women. The former showed initially increased insulin responses with unchanged glucose tolerance, but after 3 months the insulin levels fell and glucose tolerance became impaired. The established diabetics showed immediate impairment both of insulin output and glucose tolerance. The authors attributed the results to the glucocorticoid-like properties of medroxyprogesterone acetate. Spellacy et al (1970b) came to a similar conclusion when they found elevated glucose and insulin values both fasting and during an oral glucose tolerance test in women given this steroid for 6 months. Reports on the effect of 17-alpha-OH-progesterone caproate on carbohydrate metabolism are conflicting, Benjamin and Casper (1966) reporting improvement and Schreibman (1968) deterioration with this steroid. The modifying effect of progesterone derivatives on growth hormone secretion (Lawrence and Kersteins, 1970) may contribute to its influence on carbohydrate metabolism. Of the C6 unsaturated derivatives, chlormadinone and megestrol have been studied. Vermeulen, Daneels and Theiry (1970) and Larsson-Cohn et al (1969) agree that glucose tolerance is unchanged by chlormadinone in normal subjects, although only the former authors noted increased insulin responses. Beck (1970) showed early deterioration of glucose tolerance on chlormadinone in both normal and latent diabetic women; at 2½ and 5½ months, however, this had returned to normal. No insulin changes were detected. Adams and Wynn (1972) found that when megestrol acetate was substituted for combined OC in women who had developed carbohydrate intolerance, tolerance usually reverted to normal, with parallel reduction in insulin response. Py/Sr~l/i et al (1967) made a similar observation in women previously given ethinyl oestradiol for 20 days. From the work of Beck (1969) it might be predicted that 19-nor-testosterone derivatives with a relatively positive charge at C5 might be more favourable to glucose tolerance than derivatives without this configuration. Certainly, neither norethisterone acetate (Di Paoloa et al, 1970), norethisterone (Larsson-Cohn et al, 1969) nor norethisterone oenanthate (Gilfrich et al, 1969) seem to affect glucose tolerance or insulin levels after glucose. Yen and Vela (1969) and Goldman et al (1971) studied ethynodiol diacetate and found that glucose and insulin responses to intravenous glucose and arginine were unaltered. Lynoestrenol has not been studied on its own in man. The above studies suggest that while there is some clinical support for Beck's structure-effect hypotheses, yet there is no evidence that any 19-nortestosterone derivatives exert any effect on carbohydrate metabolism in man, when given by themselves. As, in general; the progestogens seem to have fewer side effects than the oestrogenic steroids, they have been used on their own in the form of the low-dose progestogen pill for continuous administration. Unfortunately, this form of contraception is less certain than a combined OC and is associated with menstrual irregularities (Mears et al, 1969), and possibly an increased incidence of breast nodules (Daniel, 1970) and ectopic pregnancy (Rozenbaum et al, 1969).

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Differences between combined and sequential OC When oestrogens and progestogens are combined in oral contraceptives their actions on carbohydrate metabolism may be additive or even synergistic; no particular combination of steroids has been reported as clearly being least likely to cause abnormalities in glucose tolerance. There have been few direct comparisons between combined and sequential OC, but results tend to show less impairment of glucose tolerance with the latter. Most studies on sequential preparations have used small numbers of subjects with a short duration of exposure to OC. Spellacy et al (1968b) and Moses and Goldzieher (1969) both showed a tendency for glucose tolerance to improve on C-quens during periods of 6 months and 2 years respectively. On the other hand Javier et al (1968) found no difference between C-quens and combined OC, abnormal tests occuring on both, while Vermeulen et al (1970), in a comparison of 17 women on a sequential OC with 15 on a combined preparation, showed that i.v. glucose tolerance was altered by neither, and insulin responses increased by both. The last two trials can be criticised on the grounds of small numbers of subjects and the comparative insensitivity of tolerance indices derived from i.v. glucose tests. Perhaps the most impressive comparative study is that of Spellacy et al (1970a) who compared oral glucose tolerance in 59 women who had been on combined OC for 8 years with that of 43 women who had been on a sequential OC (mestranol and chlormadinone) for 6 years, and found a much lower incidence of abnormalities in the sequential group. The selection of the least diabetogenic OC thus remains open, but the studies described above seem to indicate that perhaps a sequential preparation using ethinyl oestradiol and chlormadinone or megestrol acetate is a likely candidate. It should, however, be noted that according to Beck's ideas of structurefunction relationships in gonadal steroids, the progestogens used in the sequential preparations are less likely to impair glucose tolerance than those used in the combined formulations. Only one low-oestrogen combined pill (Volidan) uses a substituted progesterone derivative with the structure believed to be associated with insulinogenic activity, but with minimum antagonistic potency. It is therefore by no means certain that the sequential method of administration itself is beneficial to carbohydrate metabolism. EFFECT OF DURATION OF ADMINISTRATION In common with so many aspects of OC and carbohydrate metabolism there is disagreement concerning the effect of duration of OC administration due to the manner in which this has been assessed and the type of OC preparation studied. Wynn and Doar (1966, 1969a) in their cross-sectional and longitudinal studies of women taking combined and sequential OC found no correlation between change in glucose tolerance and duration of exposure. Fuertes-De La Haba, Vega-De Rodrigues and Pelegrina (1971), investigating 53 women who had been on OC up to 13 years, reported that only one woman of six with abnormal tests had clinical diabetes, and they concluded that the duration of administration did not correlate with the development of this con-

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dition. Boshell et al (1968) re-examined those subjects in their study who had developed abnormal tests when on OC for 12 months and found that continuing OC for a further year did not result in further deterioration in glucose tolerance. In contrast, other investigators have found that prolonged OC administration exerts a progressive effect on carbohydrate metabolism. Halling et al (1967) in a cross-sectional study of women taking Metrulen found that those subjects with abnormal tests had been on OC longest, and Javier et al (1968) showed in an investigation of 23 women on Enovid for up to 5 years that 85 per cent had abnormal glucose tolerance. Their findings confirmed a correlation between duration of OC administration and degree of impairment of glucose tolerance which was associated with a blunted early insulin response. On the other hand, Posner et al (1967b) found that although all their subjects showed impaired glucose tolerance within 3 months of taking Enovid, 10 women studied after 18 months showed a tendency to improve. Moses and Goldzieher (1968) found that during 2 years of C-quens, there was a tendency for glucose tolerance to improve. Di Paola (1970) confirmed this finding in a very large study of both pre- and post-menopausal women taking mestranol as either a sequential or a combined pill. Testing them before starting, and then at 3-monthly intervals, they found that there was a biphasic response. After 3 months there was a 57 per cent incidence of abnormal prednisone glucose tolerance tests, but by 12 months the incidence had fallen to preexposure levels. There was no further trend in up to 30 months' follow-up The balance of evidence suggests that duration of OC exposure influences carbohydrate metabolism. In patients with impaired pancreatic reserve there is progressive deterioration in glucose tolerance, while those with normal islet-cell function show a biphasic response to oestrogens, with initial deterioration followed by a return to normal, possibly associated with betacell hypertrophy. This mechanism could account for the differences between the findings of Javier et al (1968) and Di Paola (1970), as some latent diabetic women may have been included in the former study, for which no control pre-OC tests were available; the latter study had a very low incidence (6.4 per cent) of abnormal prednisone glucose tolerance tests before OC. It should be noted that the highly oestrogenic sequential OC preparations figure in the reports showing a biphasic response to continued OC administration, which is consistent with the animal studies on oestrogens discussed earlier (Rodriguez, 1965). REVERSIBILITY OF EFFECTS OF OC O N CARBOHYDRATE METABOLISM

Several investigations have included observations upon the reversibility of changes associated with OC administration. Peterson et al (1966) noted that two women on sequential OC with abnormal tests improved following withdrawal of OC, and Goldman, Eckerling and Ovadia (1969), having induced a high incidence of abnormal tests by 3 months' continuous Enovid administration, found that the changes were reversed 3 months after stopping the drug. There is, however, some evidence that women who develop sig-

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nificant glucose intolerance on OC may not revert completely to normal, or that they may take longer to do so than those with only minor abnormalities (Javier et al, 1968). These differences may be a function of pancreatic reserve. Thus Szabo et al (1970) reported that five latent diabetic women all developed abnormal tests on OC, and only one showed improvement, 2 to 18 months after stopping. In a detailed study of reversibility, Wynn and Doar (1969a) investigated 39 women retested four months after stopping OC. Twenty-five of the 39 women in the test group had chemical diabetes on OC, and all but one showed improvement when it was stopped, though only fourteen had achieved normal glucose tolerance at the time of testing. Insulin responses were unchanged. It appears therefore that the changes in carbohydrate metabolism induced by OC are usually reversible, but return to normal may take longer in those women with more severely affected glucose tolerance. In a small number of latent diabetic women given OC, pancreatic function may deteriorate and the changes become irreversible. EFFECT OF OC ON HORMONES WHICH INFLUENCE CARBOHYDRATE METABOLISM Cortisol Raised levels of endogenous or exogenous glucocorticoids are associated with hyperglycaemia and hyperinsulinism. Significantly raised levels of total plasma cortisol have been demonstrated in women taking OC (Metcalfe and Beaven 1963). This effect is due to oestrogens, as progesterone in large doses does not raise the plasma cortisol level (Kalkhoff et al, 1970). Oestrogens mainly increase the plasma level of protein-bound cortisol, and the mechanisms by which they do so have been reviewed by Burke (1969a); the metabolic clearance rate and degradation of cortisol are lower, whilst the levels of cortisol-binding-globulin are increased. Thus the protein-bound pool of cortisol in the plasma and extracellular fluid is increased. As protein-bound cortisol is generally not available to most tissues, attention has been given to the effect of oestrogens on plasma free cortisol. Burke (1969b) has shown that this is raised by oestrogens in a dose-dependent manner. He argued, however, that plasma free cortisol was not such a reliable index of tissue exposure to the hormone as 24-hour urinary free cortisol and he concluded that tissue exposure to free cortisol was not significantly increased by OC. However, Keller, Richardson and Yates (1969) have shown that in organs, such as the liver, with a protein-permeable vascular bed, protein-bound cortisol may be metabolically active and capable of enzyme induction. Glucocorticoids affect many aspects of intermediary metabolism, one result being a rise in plasma pyruvate (Hennes et al 1957). Wynn and Doar (1969a) have shown that blood pyruvate levels are also elevated both in the fasting state and in response to glucose, in women on OC and in a subsequent study (1970) they compared blood pyruvate changes in women on OC with those in women receiving glucocorticoids and showed a striking similarity between the two groups. They concluded that the raised levels of blood pyruvate in women on OC were an indication of increased glucocorticoid activity, probably due to oestrogens.

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Growth hormone

Since growth hormone (GH) is known to have diabetogenic effects, many investigators have studied changes in this hormone during administration of OC. Frantz and Rabkin (1965) showed that oestrogens elevated ambulatory GH levels in men to equal those found in women, and suggested that this was due to increased pituitary sensitivity to normal GH stimuli. It is unlikely that the progestogenic components of OC alter GH as studies of progesterone itself (Kalkhoff et al, 1970; Beck, 1969), and individual progestogens (Spellacy et al, 1970b; Simon et al, 1967; Beck, 1970; Yen and Vela, 1969) showed no significant changes during the administration of medroxyprogesterone acetate, chlormadinone acetate or ethynodiol diacetate. Elevated fasting GH levels and GH responses to insulin induced hypoglycaemia were found in women on Enovid by Spellacy et al (1967b); Vela and Yen (1969) found increased responses during arginine infusion and Davidson and Holzman (1971) after i.v. tolbutamide. Yen and Vela (1968) reported elevated fasting levels with normal suppression in response to hyperglycaemia. These authors believed GH to have an important role in the causation of OC induced glucose intolerance. Other workers do not believe that GH is an important factor. Maw and Wynn (1972) found elevated resting GH levels in a group of 32 women on OC, with normal suppression by oral glucose, but did not believe that the glucose intolerance observed in their subjects was due to increased GH secretion, because the GH changes did not correlate with either glucose or insulin levels in the tests concerned. Moreover, several women had very low growth hormone levels associated with impaired glucose tolerance. They also pointed out that elevated blood pyruvate levels, found in women on OC, are not found in acromegaly (Doar and Wynn, unpublished observations), or after acute administration of growth hormone (Doar, Wynn and Cramp, 1969). Aguilo et al (1970) gave oestrogens to 22 women with post partum hypopituitarism, and observed reversible, impaired glucose tolerance in 23 per cent during oestrogen therapy. The balance of evidence indicates that although the oestrogen component of OC elevates fasting GH levels, these changes are not the major cause of deterioration in carbohydrate tolerance seen in women on OC. SUMMARY

Oral contraceptives may induce glucose intolerance and hyperinsulinism. There is evidence to suggest that oestrogens contribute to the effect, although they may exert a stimulatory effect on the pancreas under certain circumstances; most progestogens probably exert an insulin-antagonistic effect, but the exact action depends upon the hormone. There may well be synergism between the two hormonal compounds of the combined pill in some, if not all, instances. It seems clear that the highest incidence of OC-induced glucose intolerance occurs in subjects with poor pancreatic islet cell reserve, and many conflicting reports can be attributed to varying prevalence of latent or potential diabetics in the populations studied. There is no definite evidence that sequential and

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combined OC differ in their ability to affect carbohydrate tolerance, although there is an impression that sequential preparations are preferable. This may, however, be due to the choice of hormones selected for their formulation. Low-dose progestogen OC do not appear to affect glucose tolerance. The mechanisms whereby OC alter carbohydrate metabolism have still not been clearly established. Many believe that the elevation of growth hormone observed with oestrogen administration is the primary cause, as this hormone is antagonistic to insulin and is insulinogenic. This effect is probably due, at least in part, to mobilisation of free fatty acids which inhibit glucose utilisation by peripheral tissues. Attractive as this explanation is, it cannot be considered to be the only mechanism, as intolerance due to OC is still observed in women with low or absent growth hormone levels, growth hormone changes do not always correlate with changes in glucose metabolism, and the changes in blood pyruvate levels found in women on OC are not found in acromegalics or subjects given growth hormone; moreover, free fatty acid levels are not elevated in women on OC (Wynn and Doar 1969a). The similarity of glucose, insulin and pyruvate patterns observed in nonobese women on OC and on glucocorticoids, and the synergistic effect of oestrogen and glucocorticoids indicate that they share a common metabolic effect. Oestrogens increase the level of circulating protein-bound cortisol to which the liver is sensitive. It has, for instance, been shown that oestrogens induce hepatic enzymes such as tryptophan oxygenase and alanine aminotransferase, and that this effect is mediated via the adrenals (Braidman and Rose, 1971). It is possible that this is a result of induction of adenyl cyclase leading to increased levels of cyclic AMP within the hepatic cells. In this situation, enhanced hepatic glucose release will occur leading to hyperinsulinism. That combined OC may be more likely to impair carbohydrate metabolism than oestrogen alone may be due both to the glucocorticoid-like action of some progestogens and also to the effect of the oestrogenically active compounds to which some of them are metabolised. Oestrogens may have complex secondary effects on glucose metabolism by influencing the metabolism of tryptophan along the nicotinic acid methyl ribonucleotide pathway, certain metabolites of which can influence glucose homeostasis. Thus 3-hydroxyanthranilic acid inhibits oxidative phosphorylation (Quagliariello et al, 1964) and quinolinic acid inhibits phosphoenylpyruvate carboxykinase and hence gluconeogenesis (Ray, Foster and Lardy, 1966). Although the steroid-mediated effect of oestrogens induces the ratelimiting enzyme tryptophan oxygenase (Braidman and Rose, 1971), a direct effect blocks the formation of excessive amounts of 3-hydroxyanthranilic acid and hence probably quinolinic acid (Rose et al, 1972). The balance of evidence suggests that the main cause of the alterations in carbohydrate metabolism due to OC is a big cortisol-mediated increase in hepatic gluconeogenesis; the changes of growth hormone secretion, and possibly other metabolic pathways such as that of tryptophan and lipogenesis, may contribute to the effects but are probably of lesser importance. We should like to end this review with some practical conclusions derived from the reports summarised in the preceding pages but, in the absence of reliable information as to the long term effects of OC-induced carbohydrate

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intolerance, this is a difficult task. Certainly the precipitation of perm a n e n t clinical diabetes is an undesirable side effect of OC, and for this reason an alternative m e t h o d of contraception is to be preferred in latent diabetics; the same is probably true o f potential diabetics--that is women with a suggestive obstetric history, or a very strong family history o f diabetes. These are the two groups at most serious risk f r o m OC effects. In particular, abnormal glucose tolerance during the third trimester of pregnancy should be a warning against the subsequent use o f OC. I n growth-onset diabetics, who require insulin and have little or no endogenous production of this hormone, it might be argued that no h a r m can come f r o m use of OC. With regard to carbohydrate metabolism, this is p r o b a b l y true, but it has been generally agreed that OC administration is associated with elevated serum triglyceride and cholesterol concentrations; this suggests that it might not be wise to give O C to clinical diabetics, at least for long periods, as they are k n o w n to be liable to premature vascular disease. A most difficult problem is to k n o w to what extent provision should be made for detection of impaired glucose tolerance in w o m e n given OC who are not recognised as potential diabetics. Urine testing is of little value, and post-prandial blood glucose estimations will not detect all chemical diabetics. It is clearly not possible to carry out glucose tolerance tests on all normal w o m e n given OC. In addition to w o m e n at particular risk, as mentioned above, groups which might be singled out for special surveillance are the obese and those who show rapid weight gain on OC, and those who develop hypertension on OC. These groups seem to be particularly likely to develop carbohydrate intolerance.

ACKNOWLEDGEMENTS The authors wish to thank Professor Victor Wynn, whose work is quoted throughout this review, for his help and encouragement during the preparation of the manuscript; also the Medical Research Council for their Continued support, and Miss Mary Davies for secretarial assistance. :~ REFERENCES

Adams, P. W. et al (1971) The effect of oral contraceptives and glucocorticoids on insulin response to intensive islet-cell stimulation. Communication to 7th Annual Meeting, European Association for the Study of Diabetes. Southampton. Adams, P. W. & Wynn, V. (1972) The effects of a progestogen oral contraceptive, megestrol acetate, on carbohydrate and lipid metabolism. Journal of Obstetrics and Gynaecology of the British Commonwealth. (In press). Aguilo, F. Jr et al (1970) Effect of oestrogen therapy on glucose tolerance in Sheehan's syndrome. Clinical Research, 18, 672. Bagdade, J. D., Bierman, E. L. & Porte, D. (1967) The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and non diabetic subjects. Journal of Clinical Investigation, 64, 1549-1557. Beck, P. (1969) Effects of gonadal hormones and contraceptive steroids on glucose and insulin metabolism. In Metabolic Effects of Gonadal Hormones and Contraceptive Steroids, ed. Salhanick, H. R., Kipnis, D. M. & Van de Wiele, R. L. p. 67-125. New York: Plenum Press.

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Beck, P. (1970) Comparison of the metabolic effects of chlormadione acetate and conventional contraceptive steroids in man. Journal of Clinical Endocrinology, 30, 785-791. Beck, P. & Wells, S. A. (1969) Comparison of the mechanisms underlying carbohydrate intolerance in subclinical diabetic women during pregnancy and during postpartum oral contraceptive steroid treatment. Journal of Clinical Endocrinology and Metabolism, 29, 807-818. B~njamin, F. & Casper, D. J. (1966) Alterations in carbohydrate metabolism induced by progesterone in cases of endometrial carcinoma and hyperplasia. American Journal of Obstetrics & Gynecology, 94, 991-996. Benjamin, F. & Casper, D. J. (1967) Comparative validity of oral glucose and intravenous glucose tolerance tests in pregnancy. American Journal of Obstetrics & Gynecology, 97, 488-492. Boshell, B. R. et al (1968) The effects of oral contraceptives on glucose tolerance. Journal of Reproduction & Fertility. Supplement 5, 77-88. Braidman, I. P. & Rose, D. P. (1971) Effects of sex hormones on three glucocorticoidinducible enzymes concerned with amino acid metabolism in rat liver. Endocrinology, 89, 1250-1255. Buchler, D. & Warren, J. C. (1966) Effects of estrogen on glucose tolerance. American Journal of Obstetrics & Gynecology, 95, 479-483. Burke, C. W. (1969a) The effect of oral contraceptives on cortisol metabolism. Journal of Clinical Pathology, 23, Supplement 3, 11-18. Burke, C. W. (1969b) Biologically active cortisol in plasma of oestrogen treated and normal subjects. British Medical Journal, ii, 798-800. Butterfield, W. J. H., Abrams, M. E. & Wichelow, M. J. (1971) The 25-g intravenous glucose tolerance test: a critical appraisal. Metabolism, 20, 255-265. Clinch, J., Turnbull, A. C. & Khosla, T. (1969) Effect of oral contraceptives on glucose tolerance. Lancet, i, 857-858. Daniel, G. R. (1970) Chlormadinone contraceptive withdrawn (letter). British Medical Journal, i, 303. Danowski, T. S. et al (1968) Glucose tolerance prior to and during therapy with contraceptive steroids. Clinical Pharmacology & Therapeutics, 9, 223-227. Davidson, M. B. & Holzman, G. (1971) Effect of oral contraceptive agents (OCA) on metabolic and hormonal responses to tolbutamide. Clinical Research, 19, 370. Di Paola, G. et al (1968) Oral contraceptives and carbohydrate metabolism. American Journal of Obstetrics & Gynecology, 101, 206-216. Di Paola, G., Robin, M. & Nicholson, T. (1970) Estrogen therapy and glucose tolerance test. American Journal of Obstetrics and Gynecology, 107, 124-132. Doar, J. W. H. & Wynn, V. (1969) Oral contraceptives & glucose tolerance (letter). Lancet, i, 1156. Doar, J. W. H. & Wynn, V. (1970) Effects of obesity, glucocorticoid, and oral contraceptive therapy on plasma glucose and blood pyruvate levels. British Medical Journal, i, 149-152. Doar, J. W. H., Wynn, V. & Cramp, D. G. (1968) Blood pyruvate and plasma glucose levels during oral and intravenous glucose tolerance tests in obese and non-obese women. Metabolism, 17, 690-701. Doar, J. W. H., Wynn, V. & Cramp, D. G. (1969) Studies of venous blood pyruvate and lactate levels during oral and intravenous glucose tolerance tests in women receiving oral contraceptives. In Metabolic Effects of Gonadal Hormones and Contraceptive Steroids, ed. Salhanick, H. R., Kipnis, D. M. & Van de Wiele, R. L., p. 178-192. New York: Plenum Press. Frantz, A. G. & Rabkin, M. T. (1965) Effects of estrogen and sex difference on secretion of human growth hormone. Journal of Clinical Endocrinology, 25, 1470-1480. Fuertes-De La Haba, A., Vega-De Rodriguez, G. & Pelegrina, I. (1971) Carbohydrate metabolism in long-term oral contraceptive users. Obstetrics & Gynecology, 37, 220224. Gershberg, H., Javier, Z. & Hulse, M. (1964) Glucose tolerance in women receiving an ovulatory suppressant. Diabetes, 13, 376-383. Gershberg, H. et al (1967) Improvement of glucose tolerance with estrogen treatment in maturity-onset diabetes. Diabetes, 16, 525.

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Gershberg, H. et al (1969) Effects of medroxyprogesterone acetate on serum insulin and growth hormone levels in diabetics and potential diabetics. Obstetrics & Gynecology, 33, 383-389. Gilfrich, H. J. et al (1969) Norethisterone, oenanthate, investigation of a long acting parentcral contraceptive. Deutsche medizinische Wochenschrift, 94, 2473-2477: Goldman, J. A. & Eckerling, B. (1970) Glucose metabolism during the menstrual cycle. Obstetrics & Gynecology, 35, 207-210. Goldman, J. A., Eckerling, B. & Ovadia, J. L. (1969) The effect of pseudopregnancy by ovulatory suppressants on the glucose tolerance in women. Fertility & Sterility, 20, 393-399. Goldman, J. A. et al (1971) Blood glucose and plasma insulin levels with ethynodiol diacetate oral contraceptive. Journal of Obstetrics & Gynaecology of the British Commonwealth, 78, 255-260. Goldman, J. A. & Ovadia, J. L. (1969) The effect of estrogen on intravenous glucose tolerance in women. American Journal of Obstetrics & Gynecology, 103, 172-178. Goldman, J. A., Ovadia, J. L. & Eckerling, B. (1968)Effect of progesterone on glucose tolerance in women, lsrael Journal of Medical Sciences, 4, 878-882. Gow, S. & MacGillivray, I. (1971) Metabolic, hormonal and vascular changes after synthetic oestrogen therapy in oophorectomized women. (1971) British Medical Journal, ii, 73-77. Haist, R. E. (1965) Effects of steroids on the pancreas. Methods in Hormone Research, 4, 193-233. Hailing, G. R., Michals, E. L. & Paulsen, C. A. (1967) Glucose intolerance during ethynodiol diacetate-mestranol therapy. Metabolism, 16, 465-468. Hamilton, B. & Stein, A. F. (1942) The measurement of intravenous blood sugar curves. Journal of Laboratory and Clinical Medicine, 27, 491-497. Hennes, A. R. et al (1957) The effect of adrenal steroids on blood levels of pyruvic and alpha-ketoglutaric acids in normal subjects. Metabolism, 6, 339-345. Ingle, D. J. (1942) The relationship of the diabetogenic effect of diethylstilbesteral to the adrenal cortex in the rat. American Journal of Physiology, 138, 577-582. Ingle, D. J., Beary, D. F. & Purmalis, A. (1953) Comparison of the effect of 11 beta,hydroxyprogesterone and of 11 beta, 17 alpha,-dihydroxyprogesterone upon the glycosuria of the partially depancreatised rat. Metabolism, 2, 510-512. Jarrett, R. J. & Graver, H. J. (1968) Changes in oral glucose tolerance during the menstrual cycle. British Medical Journal, ii, 528-529. Javier, Z., Gershberg, H. & Hulse, M. (1968) Ovulatory suppressants, estrogens and carbohydrate metabolism. Metabolism, 17, 443-456. Kalkhoff, R. K., Jacobson, M. & Lemper, D. (1970) Progesterone, pregnancy and the augmented plasma insulin response. Journal of Clinical Endocrinology, 31, 24-28. Kalkhoff, R. K., Kim, H. J. & Stoddard, F. J. (1969) Acquired subclinical diabetes mellitus in women receiving oral contraceptive agents. In Metabolic Effects of Gonadal Hormones and Contraceptive Steroids, ed. Salhanick, H. R., Kipnis, D. M. & Van de Wiele, R. L. p. 193-203. New York: Plenum Press. Kalkhoff, R. K., Richardson, B. L. & Stoddard, F. J. (1968) Defective plasma insulin response during prednisolone glucose tolerance tests in subclinical diabetic mothers of heavy infants. Diabetes, 17, 37-47. Keller, N., Richardson, U. I. & Yates, F. E. (1969) Protein binding and the biological activity of corticosteroids. In vivo induction of hepatic and pancreatic alarnine aminotransferase by corticosteroids in normal and oestrogen treated rats. Endocrinology, 84, 49-62. Landon, J. et al (1962) Effects of anabolic steroid, methandienone, on carbohydrate metabolism in man. Metabolism, 11, 501-512. Larsson-Cohn, U., Tengstr6m, B. & Wide, L. (1969) Glucose tolerance and insulin response during daily continuous low dose oral contraceptive treatment. Acta endocrinologica, 62, 242-250. Lawrence, A. M. & Kersteins, L. (1970) Progestin in the medical management of active acromegaly. Journal of Endocrinology, 30, 646-652. McDonald, G. W., Burnham, C. E. & Lewis, W. F. (1969) Reproducibility of glucose tolerance in 101 non-diabetic women. Public Health Reports (Washington), 84~ 353-357.

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