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Effect of duration of low-dose oral contraceptive administration on carbohydrate metabolism
Effect of duration of low-dose oral contraceptive administration on carbohydrate metabolism VICTOR WYNN, M.D., F.R.C.P., F.R.C.PATH. London, England Two hundred and ten healthy young women volunteered to take a combined oral contraceptive (OC) and to have glucose tolerance and insulin secretion measured in a projected 3-year study with roughly annual investigations. Although the dropout rate was high, glucose tolerance was noted to deteriorate progressively and insulin secretion to rise initially, but thereafter they remained constant. Eventually, insulin levels were lower than would have been expected from the prevailing glucose values. This combination of steroids produced marked insulin resistance to which the pancreas could respond by further insulin secretion. It is suggested that levonorgestrel is too strong a progestin for routine use in the combined OC, and it is recommended that its dose be reduced further or that weaker progestins such as norethindrone be used. (AM. J. OesTET. GYNECOL. 142:739, 1982.)
THE coMB 1 N Eo estrogen-progestin oral contraceptive pill (OC) is known to produce deterioration in carbohydrate tolerance ranging from mild impairment to overt diabetes mellitus in predisposed individuals. Since this effect was first defined in the 1960s, it has been the subject of more than 170 separate articles. 1 Despite this massive research effort, many uncertainties remain, and in particular, the role of the individual steroids used in contraception still needs to be clarified as does steroid interaction when combined in the OC. Exactly bow individual contraceptive steroids exert their effect on carbohydrate metabolism has proved difficult to investigate because of clinical and ethical considerations. Wynn 2 has reviewed the literature dealing with the effects of individual gonadal steroids, and Adams and co-workers 3 have described in considerable detail the biochemical effects on carbohydrate metabolism of synthetic gonadal steroids administered alone and in various combinations. They investigated the effects of the steroids on pancreatic islet cell function and on peripheral insulin resistance. In an earlier publication, Wynn and associates 4 reviewed the effects on carbohydrate metabolism of various combinations of From The Alexander Simpson Laboratory for Metabolic Research, St. Mary's Hospital, UniPersity of London. Reprint requests: Victor Wynn, M.D., F.R.C.P., F.R.C.Path., Professor of Human Metabolism, University of London, The Alexander Simpson Laboratory for Metabolic Research, St. Mary's Hospital, London, W2 !NY, England. 0002-9378/82/060739+08$00.80/0 © 1982 The C. V. Mosby Co.
oral contraceptives with estrogen content varying from 100 to 300 !J,g per pill and with varying amounts and types of progestin. Pills containing the largest amounts of estrogen (75 Mg or more of mestranol or ethinyl estradiol) produced the most marked impairment of glucose tolerance associated with suppressed insulin responses; pills containing the gonane progestin, levonorgestrel, were associated with the most pronounced hyperinsulinism and insulin resistance. Pills containing estrane-derived progesdns, such as norethindrone, were less insulinogenic than the norgestrel-containing pills with the same amount of estrogen. The progestins of the pregnane series (megestrol or chlormadinone acetate) when combined with estrogens had no effect on insulin secretion. Despite these studies, which have helped to clarify the main action on carbohydrate metabolism of oral contraceptives, one aspect has received remarkably little attention: the effect of duration of use. Obviously, the ideal oral contraceptive should be available for prolonged use; many women have now been using the "pill" for more than 10 years. Studies of the effect of duration of treatment on metabolic and other parameters are clearly important. Spellacy and associates, 3 using a cross-sectional (i.e., cases versus controls) study design, have described marked impairment of glucose tolerance in long-term OC users. In a group of 31 women of an average age of 39 years, who took a combined OC containing 0.1 mg of mestranol and 2 mg of norethindrone for a mean period of 9.5 years, 39% (12 patients) had clearly ab· 739
740
Marcil J:,_ EJK~ :\m j. Obstet. (;•.ncml.
Wynn
Table I. Patient characteristics: Glucose and insulin variables (mean ± SD) flA!IGAt
2
173
Pre On l
3
86
3.2
Pre
24.4 ± 5.5
102.7 ± 14.9
609 ± 106
'~62 + 161
- 100
108 ± 89
24.8 ± 5.5
102.8 ± 13.6 661 ± 128
'll3 + 166 . - 109
167 ±ILl
NS:j:
§
25.0 ± 5.6
102.8 ± 14.9
592 ± 114
On 1
3.0
25.3 ± 5.6
102.7 ± 13.7
641 ± 119
On 2
I4.7
26.3 ± 5.5
103.4 ± 14.3
667 ± 98
~
§
263 + 178 - 106 308 + 166 -108 322 + I97 - 122
39
Pre
24.8 ± 5.6
103.9 ± 14.5
609 ± 118
On 1
2.8
25.1 ± 5.7
I03.4 ± 14.0
655 ± I21
On2
13.5
26.I ± 5.6
I04.0 ::!:: I3.2
664::!:: 88
On3
25.4
27.0 ± 5.6
104.3 ± I5.1
693 ± II6
285 + 327 + 332 + 324-
167 105 I54 I05 I96 123 206 126
NS
5
17
Pre
152 ± 100 I7I ± 84 §
NS
4
93 ± 88
26.5 ± 6.7
98.5 ±
8.7
598 ± I22
On 1
2.7
26.6::!:: 6.5
97.8 ± 8.8
658 ± I23
On2
I3.1
27.5 ± 6.6
99.7 ± 10.0
659 ± 87
On3
25.2
28.5::!:: 6.8
99.2 ± 11.3
719::!:: II7
On 4
36.9
29.6 ± 6.7
98.I ±
732 ± I24
7.8
NS
247 + 149 - 93 28I + I33 ~ 90 136 28I + - 91 258 + 108 - 76 27I + 109 - 78
194 + 138 -
80 9.1'i +- l :il - ' -
88
195 + 240 + -244 + -
161 2.75 + 4.39 - 1.69 88 134 1 98 ... 2.26 ... - 1.06 86 I67 1 63 + l.S/ . - 0.80 99
~
~~~
223 +
I54 ± I02
9"7 + 139 -~ - 90
I73::!:: 84
948 +In ~ - 102 ') + 174 AS- 102
* 95 ± 85 I49 ± 92 I70 ± 98 2I6 ± 98 225 ± II8 §
+ i.2~) 1.78 -- 0.99
§
107± 94
193 ± 100
') 28 + 3.37 ~- 1.36
2.75
~
3
·~ 7
- l.:J5 ') 24 + 2.93 -· -- !.27 I 69 - 1. 57 . - 0.81 1 50 +-· l.c) 4 . - 0.76
NS I90 + 214 + 219 + -
112 70 109 72 Ill 74 203 + 99
66
206 + j 12 - 73 :'\JS
2 29 + 3.22 . - 1.34 !69+2.I3 . - 0.94 + 2.17 162 -0.93 l lti + 1. 39 . - 0.63 I II + 0.87 . 0.49
*Number. tMeans of log-transformed data. :j:Not significant. §p < 0.001 compared with control. liP< 0.01.
normal glucose tolerance curves: The mean blood glucose value at 1 and 2 hours was greater than 200 mg/ 100 ml, and at 3 hours it exceeded 180 mg/100 mi. In contrast, in a group of 31 women who took a sequential type of OC (0.08 mg mestranol for 20 days combined with 2 mg of chlormadinone acetate for the last 5 days) for a mean period of 6.5 years, only one (3%) had an abnormal glucose tolerance curve. This study showed clearly the importance of OC formulation, but the authors also felt that the duration of use was implicated in the effect on glucose tolerance. lt is probably more valid to study a defined cohort of women over a number of years, but this has proved difficult. Indeed, only one such study has been reported in which a significant number of women were observed for as long as 3 years, during which time oral glucose tolerance and plasma insulin levels were measured.6-8 In this investigation, Spellacy and co-workers studied 148 women at 6 months (the number of sub-
jects at the start of the investigation is not stated). After 1 year, 67 subjects were available for investigation, and after 3 years the number of available subjects was 28. The OC used was Ovulen (0.1 mg mestranol and 1.0 mg ethynodiol diacetate). This study documented a progressive deterioration of glucose tolerance with marked hyperinsulinism. At 3 years. 17% of the women (five cases) had abnormal glucose tolerance as judged by the Wilkerson score system, whereas none of these subjects had abnormal glucose tolerance curves before taking the OC. These data are of considerable interest and importance, but one should note that within 3 years the rate of attenuation among the subjects was very high (80%). The reasons for this are not discussed by the authors. The present study involved an unselected cohort of young women referred because they wished to take OCs and were willing to have their carbohydrate metabolism studied. The pill chosen for investigation con-
\'olume 142 Number 6, Pan 2
Duration of OC treatment and carbohydrate metabolism
741
Table II. Tally of subjects throughout the series Series 2
3 4 5
·rota!
No.(%) 173 86 39 17
(82) (40) (18) (8)
Lust to follow-up 23 35 18
10 89 (42)
Total no. lost to study
Stopped for minor side effects 8 2 3
13
(6)
tained :w J.l.g of ethinyl estradiol and 150 J.l.g of levonorgestrel. At the time the study commenced, this pill had the lowest estrogen-progestin content available in the United Kingdom.
Subjects Two hundred and ten women were recruited into the study and gave their informed consent. The patients were mostly young and of low parity (mean, 0.4; range, 0 to 5). The great majority were near their ideal body weight (Table I), but approximately 10% were obese (bodv weight > 120% of ideal body weight, Documentia Geigy tables). None was more than 150% of ideal body weight. Eighty-one percent of the women were white, Wlc were black, 7% were Indian, and 3o/c ,,·ere of Mongolian origin. None of the women had taken drugs known to have metabolic effects, and none had known metabolic or endocrine illnesses.
Methods Oral glucose tolerance tests (OGTTs) were carried out after an overnight fast of at least 12 hours. The women ll'ere g-i,·en written instructions to ensure a carbohnlrate intake of at least 200 gm daily for 3 days before the test. The dose of glucose was I grn/kg body weight, and ,·enous samples were taken at 30-minute imerYals for 3 hours. Plasma glucose and insulin were measured bv methods described elsewhere. 0 · 10 The area under the glucose tolerance curve (GA) or insulin cun·e (lA) and the incremental area under these curves (i.e .. the area under a curve above the baseline value, IGA and IIA, respectively) were derived to give single indices of glucose tolerance and insulin secretion.' The following analYsis places greater emphasis upon the incremental area (IGA, IIA) as a better index of glucose dissimilation and of insulin secretion because in this index the variable component of the fasting value is eliminated. Study design. After the initial OGTT, the women began raking the OC (30 J.l.g ethinyl estradiol, 150 p..g lenmorgestrel), and arrangements were made to repeat the investigation after intervals of approximately :~. 15, 2.f, and 36 months. This arrangement provided investigations referred to as series 2, 3, 4, and 5, respectively.
16 10 17 9 56 (26)
19 5
15
24 (11)
26
39 87 47 22
5 (10)
195
(92)
Table III. GA in six subjects advised to stop OC use GA on OC (mo)
GA offOC
GA beforeOC
855 (3) 1,341 (3) 994 (12) 1.055 ( 12)
784 876
3 4
593 950 834 624
5
549
6
672
528 (3) 957 (25) 767 (3) 765 (12) 1.418 (34)
Case
2
(rrw)
(8) (6)
871 (12) 670 (14)
773 (10) 835 (17) 475 (30)
Statistics. Standard statistical methods were used, including Student's t test for paired data. The distribution of the IA and IIA calculated for each subject was positively skewed. Logarithmic transformation was used to render the distribution more normal. The mean insulin area and incremental insulin area were derived from the antilogarithms of the means of the corresponding logarithmic variable. The ratio IIA/ IGA for each subject was estimated. This variable indicated change of insulin secretion relati\e to the pre\ ailing glucose value. The distribution of the IIA/IGA ratio was also positivelv skewed, and a logarithmic transformation was used as described above. This study prm·ided a series of four tests at timed intervals (series 2. 3, .f. and 5). Using regression techniques, the linear component of the trend across each of the series was examined for GA, IGA. and the IIA/ IGA ratio.
Results Patient characteristics ~mean age and mean percentage of ideal body weight; the number of subjects in each series: mean duration of OC use (months): and mean GA, IGA, lA, IIA, and IIA/1GA ratio] are shown in Table I. With each series there was a substantial decrease in the number of subjects. The reasons for this high rate of attenuation are listed in Table I I. Eighty-nine subjects were lost to follow-up. including 23 who failed to attend ;3 months after the initial examination. This high dropout rate ( 42'7c) no doubt reflects the young age of the subjects and their social mobility, but it also probably includes a number of sub-
742
Wynn i\J11.
\larch I !1. J 91-l:! j. Obstt't (~ynecul.
Table IV. Significance of linear component of trend across each series GA Series
I
:~
5.65 4.10 3.83
4
I
IGA
p
I
p <0.001 p <0.001 p <0.01
7.60 5.31 5.02
l
3 hr 1/A !IGA
p
I
p <0.001 p <0.001 p <0.001
ii.IG 6.57
jects who stopped taking the OC for a variety of reasons, including side effects which they failed to report to us. Fifty-six subjects (26%) stopped OC use because of minor side effects, including weight gain, headache, depression, diminished libido, breakthrough bleeding. amenorrhea, and nausea. Twenty-four subjects ( 11 o/c) requested a change of OC for gynecologic reasons, and 20 subjects ( 1or:;) stopped using the oc because they did not require it. Thirteen subjects (6%) were advised by a physician to stop taking the OC. The total number ol subjects lmt to the study, therefore, was 195 (92%). This ven high rate is characteristic of longitudinal studies of this t\pe and explains why so few reports use this method. The I:~ subjects advised to stop the OC constitute an important group. Four had a sustained (but reversible) rise in blood pressure after I year of OC usc, and one subject developed an abnormal electrocardiogram. Two subjects dneloped deep vein thrombosis after 2 years of use, and one deyeJoped superficial venous thrombosis. Six subjects dneloped abnormal glucose tolerance while taking OCs and were advised to discontinue their usc. Results from these subjects are given in Table II I. B\ our laboratorv methods, 95"{ of healthy young women han· a glucose tolerance area (GA) below 800. The normal inucmental area is below :-WO. These data have been established by the study of about 600 control won1en. 1 A GA exceeding I ,000 is found only in a subject whose biochemical data would conform to the modern criteria for the diagnosis of diabetes. 11 A (;A between HOO and 1,000 defines a group of subjects with impaired glucose tolerance. 11 It should be pointed out that as the ;l\·erage weight of these subjects was 59.4 kg, the an~ragc dose of glucose administered (59 gm) would be about half the standard dose administered during an OGTT (I 00 gm) in most clinics in the United States; hence, ghtcose values would be somewhat lower in our (United Kingdom) studies compared to studies in the United States, especially toward the latter half of the test. Similarly. insulin secretory responses would be rather lower than would be expected in tests with a I 00 gm glucose test load. Of the subjects who developed abnormal glucose tolerance, in Case I the abnormality was minor, but the patient decided to discontinue use of the OC after dis-
4.71
I
2 hr IIAIIGA
p
I
p <0.001 p <0.001 p <0.001
5.49 6.61 4.68
T
p p <0.00! p <0.001 p <0.001
cussion with the attendant physician. Patient 2 had obviously impaired glucose tolerance before starting the OC, and this deteriorated into the diabetic range within :~ months of beginning OC use and impro\-ed on discontinuation. Patient:~ had mildlv impaired ()(;TT before starting the OC with obvious deterioration in glucose tolerance at I year. Patient 1 had normal glucose tolerance before starting OC usc and a diabetic glucose tolerance after 12 months, which ITHTted to normal on stopping the OC. Pat iellt 5 had a normal test before starting the OC but a markedly impaired OGTT after 2 years of pill use. Case() is of considerable importance because the patient had a normal OGTT bef()n· taking the OC: but after :~ vears had developed a diabetic glncose tolerance pattern. This n·1·ertcd to normal after discontinuing the OC. This subjen wished to JTCOIIlmence OC:. but within 6 months of its administration. the prnionsh observed diabetic glucose tolerance pattern recurred. Because the glncose tolerance abnollllality in l'aticm 6 occurred at the series 5 analysis when there were onh a small number of cases ( 17), it was decided to rem on· her entirelv from the series to prevent her case from having an undue ad verse effect on the glucose tolerance data for this group. Table I shows that the mean \alues for (;A and l(~A increased progressively during the :~ rears. At :~ \ears, GA was 22';( greater and IGA nfi',j greater than at the initial test. On the other hand, lA increased br 12"1, after~ months of OC use, but thereafter the1 c 11as no further increase. IIA increased bv the same amo1mt ( 12'1r). There was a progressive decrease (from 2.29 to 1.11) in the IIA/IGA ratio throughout the seric,. Table IV shows the significance of the lineal· component of I he trend across each series for GA, I CA. and II A/I GA. The changes were all highly significant. The internal consistency throughout the series is imponant, since had this not been the case, subject 1 ariation might have rendered interpretation of tlw data difficult if not impossible because of progressiYe attenuation of the cohort of women. Fig. I shows, in diagrammatic form, the increase in GA and )(;A with duration of pill usc. Fig. 2 shows the parameters of insulin secretion, lA and IAA. and Fig. ~ presents the change in the II:\/ IGA ratio. This ratio had been calculated lor two ti111c
Duration of OC treatment and carbohydrate metabolism
Volume 142 Number 6. Part 2
3
2
Series 700
4
743
5
ISO Q.UCOSE AREA (Units)
100
550 500
200
INCREMENTAL GLUCOSE AREA (Units)
150 100
~
50 N:
173
n••
~
39
n
17
Fig. l. Mean glucose tolerance throughout the series. N =!\;umber: **p < 0.01; ***p < 0.001.
350 300 250 INSULIN AREA (Units)
200
150~-L~L---WW~U---~~~~---L~~wwu._____________
Series 300
2
3
5
250
INCREMENTAL INSULIN AREA (Units)
200
150~~~~~wu~~--~~~~--~~~~~-----------
N=
170
13
31
17
Fig. 2. Mean insulin secretion throughout the series. N = Number; **p < 0.01; ***p < 0.001.
intervals (2 hours and 3 hours) of the OGTT in order to determine whether a difference could be shown in the relationship between insulin and glucose in the early versus the later part of the test. No change in the relationship was found. The fact that GA and IGA increased progressively with time while lA and IIA rose initially but subsequently remained roughly constant indicates that the initial hyperinsulinemic response is followed by increasing peripheral insulin resistance without further pancreatic islet cell stimulation. This results in progressive deterioration of glucose tolerance.
Reference has already been made to the six subjects whose glucose tolerance tests showed marked deterioration and who were therefore advised to stop taking the OC. The removal from the study of these subjects reduced the observed OC effect of impaired glucose tolerance in the present analysis, unless one assumes that patients whose glucose tolerance deteriorated under observation would have improved with further administration of the OC. This has not been my experience in the study of several hundred women taking OCs. Certainly, removal of Case 6 substantiallv reduced
744
Wynn Ant.
1·4
2HOUI
1·0
• • • • • IIMJIIA
0·6 Series
J.
March 15, 19~:.' Obstet. Gynec:ol.
~~----'--'-f&.-U......_____._.__..J.....i...UI~i._______ 2
3
4
5
2·6
2-2
3HOUR
1·4
1·0 ~6L--Lum~~~~L---~MUWW~--~AL~~~----------
N:
170
13
31
f7
Fig. 3. Mean IIA/ IGA ratio during 2 hours and 3 hours of the oral glucose tolerance test throughout the series. N = Number; **p < 0.01: ***p < 0.001.
the reported effect on glucose tolerance and glucose/ insulin ratio in the series 5 data. Study of the trend of GA and IGA showed that OCs affected the group as a whole rather than a few individuals with extreme values. For example, of the In subjects completing the series 2 test, initially only 5% had a GA greater than 800, and none had a GA greater than 1,000. At 3 months, 13% had an area greater than 800, and 2.3% (four cases) had one greater than 1,000. At 15 months, 25 months, and 37 months, respectively, 10%, 20%, and 30% of subjects had a GA greater than 800. Comment
Impairment of glucose tolerance and alteration in insulin secretion are untoward effects of many drug therapies, including glucocorticoids, diuretics, and a number of hypotensive drugs, such as diazoxide, ,B-adrenoceptor blocking drugs, the a2-adrenoceptor agonist, clonidine, certain neuroleptics, some anticonvulsants, microtubule inhibitors, organic calcium antagonists, and others. 1 The oral contraceptive group of compounds is, however, probably the most important because of widespread use, administration to healthy subjects with minimal or no supervision, and the possibility of continuous administration for many years. It is apparent now that the progestin component modified by the coincident administration of the estrogen is responsible for the effect on glucose tolerance. 2 • 4 Earlier studies tended to implicate the estrogen in this effect, but it is now clear that estrogen administered alone or
in combination with weak progestins, such as the pregnane-derived progestins (chlormadinone, megestrol). has little or no effect on carbohydrate wlerance. The tendency during the past several years to lower the dose of estrogen in the OC because of its venous thromboembolic effect 11 has been accompanied by a change in prescribing, perhaps most noticeable in the United Kingdom, in which the strong progestin levonorgestrel has replaced the weaker compound norethindrone. While the low-estrogen levonorgestrel pill is a good oral contraceptive from a gynecologic point of view, studies such as the one reported here suggest that it may not be the best combination. After using the combined pill [30 J.tg equine estrogen (EE) and 150 J.tg levonorgestrel)], the cohort of women described herein showed definite and progressive deterioration of glucose tolerance and a decrease in the insulin/ glucose ratio. Studies in progress of two similar cohorts of women in which the pill consists of 20 J.tg of EE and I mg of norethindrone or the progestin alone do not show progressive deterioration of glucose tolerance or change in insulin/glucose ratio over a period of 2 years (to be published). It would appear from these studies that levonorgestrel, at any rate in a dose of 150 J.tg daily, is too strong a progestin for prolonged administration when combined with estrogen. This conclusion is confirmed by another analysis in which peripheral insulin activity and pancreatic islet ceU function were measured by dynamic methods. 3 The importance of duration of therapy in producing changes in glucose metabolism and insulin secretion is well demonstrated
Volume 142 Number 6, Part 2
Duration of OC treatment and carbohydrate metabolism
in the present study. The effect of duration of therapy is often overlooked in OC studies, contributing to the plethora of conflicting reports in the literature. The question may be asked whether the metabolic effects produced by OCs are important and in particular whether the effects on glucose tolerance and insulin metabolism are clinically relevant. Obviously, if women are precipitated into frank diabetes or some other recognizable clinical syndrome, such as hypertension, then the OC effect is important. These problems, fortunately, occur infrequently. What is more difficult to assess is the overall clinical importance of more limited changes of metabolic parameters, such as glucose tolerance and insulin secretion. There is a great deal of evidence that hyperglycemia is a significant risk factor in the development of coronary heart disease 12 and that the level of glucose tolerance impairment at which this becomes significant is surprisingly low. 13 It does not follow that because the OC causes glucose tolerance impairment, it acts as an atherogenic risk factor. On the other hand, it cannot be wise to ignore the risk. More than 20 publications now show an increased risk of cardiovascular disease in women taking OCs. 1 ~· '" Recently, one published report showed that after 10 years of continuous use, an increased risk of myocardial infarction up to 2.5-fold can be demonstrated in women between the ages of 40 to 49 years who stopped taking the OCs years before.'" With this evidence of an adverse clinical effect of OC administration on the cardiovascular system, it is clearly important to study the impact of OCs on all metabolic parameters that might have a bearing on the etiology of the unwanted cardiovascular effects, with the hope of devising safer OCs. Indeed, one experienced investigator goes so far as to list OCs in order of a supposed atherogenic risk, as judged by effects on various biochemical parameters, such as glucose tolerance, insulin secretion, serum lipids, blood clotting, and other hematologic indices, and effects on the renin-angiotensin system and hypertension. 17 As the evidence for an effect of OC use on the incidence of cardiovascular disease has accumulated, the importance of the progestin in this context has become more apparent. 18- 20 The progestins are known to have greatest effect on glucose tolerance and insulin secretion,~· 21 high-density lipoproteins, 22 - 24 and blood pressure .19 • 20
We must look critically at OC formulation yet again, realizing that excessive estrogenic activity is undesirable because of its thromboembolic effects and effects on blood clotting, and that excessive progestin produces changes in biochemical parameters thought to be implicated as cardiovascular risk factors. The ideal OC must be a compromise. It seems unnecessary in most women to use more than 30 to 35 p,g of estrogen, and it would appear that even 150 p,g of levonorgestrel is excessive for administration lasting more than 2 years. Probably a pill containing I mg of norethindrone would have a less untoward metabolic effect than one containing 150 p,g of levonorgestrel, assuming the estrogen dose is the same in both cases (30 to 35 p,g). There may, of course, be a gynecologic disadvantage in the use of such an OC, but it is not suggested that one pill will be suitable for all women. Those women who need the additional progestin to a\'Oid breakthrough bleeding and to achie,·e better cycle control can weigh the benefits of the levonorgestrel-containing pill against the metabolic disadvantages. For the majority of women, a less potent progestin than levonorgestrel would appear to be preferable. Combined OCs cause many changes in metabolic parameters which may have clinical significance in producing unwanted side effects, the most obtrusive of which, in Western societies at least, involve the cardiovascular system. It is suggested that the ideal OC will be a combination of estrogen and progestin which will produce the least metabolic disturbance. In the present report changes in glucose and insulin secretion have been studied longitudinally over a period of 3 years of administration of an OC containing 30 p,g of ethinyl estradiol and 150 p,g of levonorgestrel to a defined cohort of women. Progressive deterioration of oral glucose tolerance was found in association with early hyperinsulinism and the development of insulin resistance with a decrease in insulin secretion relative to the prevailing glucose level. It is concluded that levonorgestrel, even at the relatively low dose of 150 p,g, when combined with 30 p,g of ethinyl estradiol has untoward effects on carbohydrate metabolism. It is recommended either that the levonorgestrel level be reduced further in the OC or that the weaker progestin norethindrone be used in the combined pill.
REFERENCES I. Furman, B. L.: Impairment of glucose tolerance pro-
duced by diuretics and other drugs, Pharmacol. Ther. 12:613, 1981.
745
2. Wynn, V.: Effects of progesterone and progestins on carbohydrate metabolism, in Mauvais-Jarvis, P., editor: Progesterone and Progestins, New York, 1981, Plenum Press.
746
March L'l,
Wynn Am
,), .\dams. P. W., Godsland, L, Melrose. j, et al.: ·rhe influence of oral contraceptive formulation on carbohydrate and lipid metabolism, J. Pharmacother. 3:54, 1980. l. Wynn, V., Adams, P. W, Godsland, I., et al.: Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism, LatKet 1: 10·15, 1979. 5. Spellacy,\\'. \1., Buhi, W. C, Spellacv, C. E., et al.: Glucose, insulin, and growth hormone studies in long-term users of oral contraceptives, AM. J. 0BSTET. GYNECOL. 106:1 T), 1970. 6. Spellacy, W. :'\., Buhi, W. C., Birk, S. A., eta!.: Studies of ethynodiol diacetate and mestranol on blood glucose and plasma insulin, Int. J. Fertil. 16:55, 1971. 7. Spellacv, \V. N, Buhi, W. C., Birk, S. A., et al.: Studies of ethynodiol diacerate and mestranol on blood glucose and plasma insulin, Contraception 3:185, 197 I 8. Spellacy, W.l'\., Buhi, W. C., and Birk, S. A.: Three-year prospecti1e study of carbohydrate metabolism in women using (hulen, South. Med. J. 70:1188, 1977. 9. Wynn, V .. and Doar,J. W. H.: Some effects of oral conI racepth·es on carbohydrate metabolism, Lancet 2:71 !1. 1961). 10. Wvnn, \'.,and Doar, J. \\7. H.: Some effects of oral contraceptin:s on carbohydrate metabolism, Lancet 2:761, I ~~6~1 II. Keen. H .. Jarrett. R.J.. and Alberti, K. G . .\.1. .\.'L: Diabetes
mellitus: A new look at diagnostic criteria, Diabetologia I6:2H:~. 1979. !2. Kcen, H .. Jarrett, R.J.. Fuller.J. H .. et al.: Diabetes mellitu,, energy consumption, and arterial disease, in Pernow, H., and Carlson, L A., editors: Metabolic Risk Factors in lschaemic Cardiovascular Disease, New York. 19Hl, Raven Press. 1:1. Fuller, J H .. Shipley, .\.'1. J., Rose, G .. et al.: Coronaryheart-disease risk and impaired glucose tolerance: The Whitehall study. Lancet 1:1373, 1980. 14. \'essev. M. P.: Female hormones and Yascular disease-
1!1 .
16.
17.
18 .
19. 20.
21.
191-i~
.J. ObMet. (~vneml.
an epidemiological overview, Br. J. Fam. Plann ..'>uppi. 6:1, 1980. .\.bnn,J. 1., and Vessev, M.P.: Trend;; in cardiO\ascubr disease mortality and oral contracepth·es, Br. J. Fam. Plann. 6:99, 1981. Slone, D .. Shapiro, S .. Kaufman, D. \\., t'l aL: Risk of nwocardial infarction in relation to current and cli~con ti~ued use of oral contraceptives, :\. Engl. J Med. 305:420, )981. Briggs. M. H.: Recent biological studies in relation to Jm, dose hormonal contraceptives. Br. J. Fam. Plann. 5:25. 1979. .\.!ann, J. !.: Progestogen:. in eardiO\a>cular disease: An introduction to the epidemiologic data. AM . .J. 0BSTE'I GYNECOL. 142:752, 1982. Meade, T. W.: Effects of progestogens on the cardiO\as· cular system, AM. J. 0BSTET. GYNECOL. 142:776, 191-!2. Kav. C. R.: Progestogens and arterial dis.ease-EYidence from the Roval College of General Practitioners· study, AM. J. 0BSTET, GYNECOL. 142:762. l9S2. Kalkhoff, R. K.: Metabolic effects, of progesterone, AM. J. 0BSTET. GYNECOL, J42:n5, )982.
22. Knopp. R. f~f.. \'Vaiden, C. E., \Vahl, P. \V., er aL: Effects
of oral comraceptives on lipoprotein triglvceride and chole~rerol: Relationships to estroge,. and progestin potenq. A.M. J. OssTH. Gnn:cm.. 142:725, 1982. 23. Oster, P., .~rab, L., Kohlmeier. ;'vf., ets.
THE coMB 1 N Eo estrogen-progestin oral contraceptive pill (OC) is known to produce deterioration in carbohydrate tolerance ranging from mild impairment to overt diabetes mellitus in predisposed individuals. Since this effect was first defined in the 1960s, it has been the subject of more than 170 separate articles. 1 Despite this massive research effort, many uncertainties remain, and in particular, the role of the individual steroids used in contraception still needs to be clarified as does steroid interaction when combined in the OC. Exactly bow individual contraceptive steroids exert their effect on carbohydrate metabolism has proved difficult to investigate because of clinical and ethical considerations. Wynn 2 has reviewed the literature dealing with the effects of individual gonadal steroids, and Adams and co-workers 3 have described in considerable detail the biochemical effects on carbohydrate metabolism of synthetic gonadal steroids administered alone and in various combinations. They investigated the effects of the steroids on pancreatic islet cell function and on peripheral insulin resistance. In an earlier publication, Wynn and associates 4 reviewed the effects on carbohydrate metabolism of various combinations of From The Alexander Simpson Laboratory for Metabolic Research, St. Mary's Hospital, UniPersity of London. Reprint requests: Victor Wynn, M.D., F.R.C.P., F.R.C.Path., Professor of Human Metabolism, University of London, The Alexander Simpson Laboratory for Metabolic Research, St. Mary's Hospital, London, W2 !NY, England. 0002-9378/82/060739+08$00.80/0 © 1982 The C. V. Mosby Co.
oral contraceptives with estrogen content varying from 100 to 300 !J,g per pill and with varying amounts and types of progestin. Pills containing the largest amounts of estrogen (75 Mg or more of mestranol or ethinyl estradiol) produced the most marked impairment of glucose tolerance associated with suppressed insulin responses; pills containing the gonane progestin, levonorgestrel, were associated with the most pronounced hyperinsulinism and insulin resistance. Pills containing estrane-derived progesdns, such as norethindrone, were less insulinogenic than the norgestrel-containing pills with the same amount of estrogen. The progestins of the pregnane series (megestrol or chlormadinone acetate) when combined with estrogens had no effect on insulin secretion. Despite these studies, which have helped to clarify the main action on carbohydrate metabolism of oral contraceptives, one aspect has received remarkably little attention: the effect of duration of use. Obviously, the ideal oral contraceptive should be available for prolonged use; many women have now been using the "pill" for more than 10 years. Studies of the effect of duration of treatment on metabolic and other parameters are clearly important. Spellacy and associates, 3 using a cross-sectional (i.e., cases versus controls) study design, have described marked impairment of glucose tolerance in long-term OC users. In a group of 31 women of an average age of 39 years, who took a combined OC containing 0.1 mg of mestranol and 2 mg of norethindrone for a mean period of 9.5 years, 39% (12 patients) had clearly ab· 739
740
Marcil J:,_ EJK~ :\m j. Obstet. (;•.ncml.
Wynn
Table I. Patient characteristics: Glucose and insulin variables (mean ± SD) flA!IGAt
2
173
Pre On l
3
86
3.2
Pre
24.4 ± 5.5
102.7 ± 14.9
609 ± 106
'~62 + 161
- 100
108 ± 89
24.8 ± 5.5
102.8 ± 13.6 661 ± 128
'll3 + 166 . - 109
167 ±ILl
NS:j:
§
25.0 ± 5.6
102.8 ± 14.9
592 ± 114
On 1
3.0
25.3 ± 5.6
102.7 ± 13.7
641 ± 119
On 2
I4.7
26.3 ± 5.5
103.4 ± 14.3
667 ± 98
~
§
263 + 178 - 106 308 + 166 -108 322 + I97 - 122
39
Pre
24.8 ± 5.6
103.9 ± 14.5
609 ± 118
On 1
2.8
25.1 ± 5.7
I03.4 ± 14.0
655 ± I21
On2
13.5
26.I ± 5.6
I04.0 ::!:: I3.2
664::!:: 88
On3
25.4
27.0 ± 5.6
104.3 ± I5.1
693 ± II6
285 + 327 + 332 + 324-
167 105 I54 I05 I96 123 206 126
NS
5
17
Pre
152 ± 100 I7I ± 84 §
NS
4
93 ± 88
26.5 ± 6.7
98.5 ±
8.7
598 ± I22
On 1
2.7
26.6::!:: 6.5
97.8 ± 8.8
658 ± I23
On2
I3.1
27.5 ± 6.6
99.7 ± 10.0
659 ± 87
On3
25.2
28.5::!:: 6.8
99.2 ± 11.3
719::!:: II7
On 4
36.9
29.6 ± 6.7
98.I ±
732 ± I24
7.8
NS
247 + 149 - 93 28I + I33 ~ 90 136 28I + - 91 258 + 108 - 76 27I + 109 - 78
194 + 138 -
80 9.1'i +- l :il - ' -
88
195 + 240 + -244 + -
161 2.75 + 4.39 - 1.69 88 134 1 98 ... 2.26 ... - 1.06 86 I67 1 63 + l.S/ . - 0.80 99
~
~~~
223 +
I54 ± I02
9"7 + 139 -~ - 90
I73::!:: 84
948 +In ~ - 102 ') + 174 AS- 102
* 95 ± 85 I49 ± 92 I70 ± 98 2I6 ± 98 225 ± II8 §
+ i.2~) 1.78 -- 0.99
§
107± 94
193 ± 100
') 28 + 3.37 ~- 1.36
2.75
~
3
·~ 7
- l.:J5 ') 24 + 2.93 -· -- !.27 I 69 - 1. 57 . - 0.81 1 50 +-· l.c) 4 . - 0.76
NS I90 + 214 + 219 + -
112 70 109 72 Ill 74 203 + 99
66
206 + j 12 - 73 :'\JS
2 29 + 3.22 . - 1.34 !69+2.I3 . - 0.94 + 2.17 162 -0.93 l lti + 1. 39 . - 0.63 I II + 0.87 . 0.49
*Number. tMeans of log-transformed data. :j:Not significant. §p < 0.001 compared with control. liP< 0.01.
normal glucose tolerance curves: The mean blood glucose value at 1 and 2 hours was greater than 200 mg/ 100 ml, and at 3 hours it exceeded 180 mg/100 mi. In contrast, in a group of 31 women who took a sequential type of OC (0.08 mg mestranol for 20 days combined with 2 mg of chlormadinone acetate for the last 5 days) for a mean period of 6.5 years, only one (3%) had an abnormal glucose tolerance curve. This study showed clearly the importance of OC formulation, but the authors also felt that the duration of use was implicated in the effect on glucose tolerance. lt is probably more valid to study a defined cohort of women over a number of years, but this has proved difficult. Indeed, only one such study has been reported in which a significant number of women were observed for as long as 3 years, during which time oral glucose tolerance and plasma insulin levels were measured.6-8 In this investigation, Spellacy and co-workers studied 148 women at 6 months (the number of sub-
jects at the start of the investigation is not stated). After 1 year, 67 subjects were available for investigation, and after 3 years the number of available subjects was 28. The OC used was Ovulen (0.1 mg mestranol and 1.0 mg ethynodiol diacetate). This study documented a progressive deterioration of glucose tolerance with marked hyperinsulinism. At 3 years. 17% of the women (five cases) had abnormal glucose tolerance as judged by the Wilkerson score system, whereas none of these subjects had abnormal glucose tolerance curves before taking the OC. These data are of considerable interest and importance, but one should note that within 3 years the rate of attenuation among the subjects was very high (80%). The reasons for this are not discussed by the authors. The present study involved an unselected cohort of young women referred because they wished to take OCs and were willing to have their carbohydrate metabolism studied. The pill chosen for investigation con-
\'olume 142 Number 6, Pan 2
Duration of OC treatment and carbohydrate metabolism
741
Table II. Tally of subjects throughout the series Series 2
3 4 5
·rota!
No.(%) 173 86 39 17
(82) (40) (18) (8)
Lust to follow-up 23 35 18
10 89 (42)
Total no. lost to study
Stopped for minor side effects 8 2 3
13
(6)
tained :w J.l.g of ethinyl estradiol and 150 J.l.g of levonorgestrel. At the time the study commenced, this pill had the lowest estrogen-progestin content available in the United Kingdom.
Subjects Two hundred and ten women were recruited into the study and gave their informed consent. The patients were mostly young and of low parity (mean, 0.4; range, 0 to 5). The great majority were near their ideal body weight (Table I), but approximately 10% were obese (bodv weight > 120% of ideal body weight, Documentia Geigy tables). None was more than 150% of ideal body weight. Eighty-one percent of the women were white, Wlc were black, 7% were Indian, and 3o/c ,,·ere of Mongolian origin. None of the women had taken drugs known to have metabolic effects, and none had known metabolic or endocrine illnesses.
Methods Oral glucose tolerance tests (OGTTs) were carried out after an overnight fast of at least 12 hours. The women ll'ere g-i,·en written instructions to ensure a carbohnlrate intake of at least 200 gm daily for 3 days before the test. The dose of glucose was I grn/kg body weight, and ,·enous samples were taken at 30-minute imerYals for 3 hours. Plasma glucose and insulin were measured bv methods described elsewhere. 0 · 10 The area under the glucose tolerance curve (GA) or insulin cun·e (lA) and the incremental area under these curves (i.e .. the area under a curve above the baseline value, IGA and IIA, respectively) were derived to give single indices of glucose tolerance and insulin secretion.' The following analYsis places greater emphasis upon the incremental area (IGA, IIA) as a better index of glucose dissimilation and of insulin secretion because in this index the variable component of the fasting value is eliminated. Study design. After the initial OGTT, the women began raking the OC (30 J.l.g ethinyl estradiol, 150 p..g lenmorgestrel), and arrangements were made to repeat the investigation after intervals of approximately :~. 15, 2.f, and 36 months. This arrangement provided investigations referred to as series 2, 3, 4, and 5, respectively.
16 10 17 9 56 (26)
19 5
15
24 (11)
26
39 87 47 22
5 (10)
195
(92)
Table III. GA in six subjects advised to stop OC use GA on OC (mo)
GA offOC
GA beforeOC
855 (3) 1,341 (3) 994 (12) 1.055 ( 12)
784 876
3 4
593 950 834 624
5
549
6
672
528 (3) 957 (25) 767 (3) 765 (12) 1.418 (34)
Case
2
(rrw)
(8) (6)
871 (12) 670 (14)
773 (10) 835 (17) 475 (30)
Statistics. Standard statistical methods were used, including Student's t test for paired data. The distribution of the IA and IIA calculated for each subject was positively skewed. Logarithmic transformation was used to render the distribution more normal. The mean insulin area and incremental insulin area were derived from the antilogarithms of the means of the corresponding logarithmic variable. The ratio IIA/ IGA for each subject was estimated. This variable indicated change of insulin secretion relati\e to the pre\ ailing glucose value. The distribution of the IIA/IGA ratio was also positivelv skewed, and a logarithmic transformation was used as described above. This study prm·ided a series of four tests at timed intervals (series 2. 3, .f. and 5). Using regression techniques, the linear component of the trend across each of the series was examined for GA, IGA. and the IIA/ IGA ratio.
Results Patient characteristics ~mean age and mean percentage of ideal body weight; the number of subjects in each series: mean duration of OC use (months): and mean GA, IGA, lA, IIA, and IIA/1GA ratio] are shown in Table I. With each series there was a substantial decrease in the number of subjects. The reasons for this high rate of attenuation are listed in Table I I. Eighty-nine subjects were lost to follow-up. including 23 who failed to attend ;3 months after the initial examination. This high dropout rate ( 42'7c) no doubt reflects the young age of the subjects and their social mobility, but it also probably includes a number of sub-
742
Wynn i\J11.
\larch I !1. J 91-l:! j. Obstt't (~ynecul.
Table IV. Significance of linear component of trend across each series GA Series
I
:~
5.65 4.10 3.83
4
I
IGA
p
I
p <0.001 p <0.001 p <0.01
7.60 5.31 5.02
l
3 hr 1/A !IGA
p
I
p <0.001 p <0.001 p <0.001
ii.IG 6.57
jects who stopped taking the OC for a variety of reasons, including side effects which they failed to report to us. Fifty-six subjects (26%) stopped OC use because of minor side effects, including weight gain, headache, depression, diminished libido, breakthrough bleeding. amenorrhea, and nausea. Twenty-four subjects ( 11 o/c) requested a change of OC for gynecologic reasons, and 20 subjects ( 1or:;) stopped using the oc because they did not require it. Thirteen subjects (6%) were advised by a physician to stop taking the OC. The total number ol subjects lmt to the study, therefore, was 195 (92%). This ven high rate is characteristic of longitudinal studies of this t\pe and explains why so few reports use this method. The I:~ subjects advised to stop the OC constitute an important group. Four had a sustained (but reversible) rise in blood pressure after I year of OC usc, and one subject developed an abnormal electrocardiogram. Two subjects dneloped deep vein thrombosis after 2 years of use, and one deyeJoped superficial venous thrombosis. Six subjects dneloped abnormal glucose tolerance while taking OCs and were advised to discontinue their usc. Results from these subjects are given in Table II I. B\ our laboratorv methods, 95"{ of healthy young women han· a glucose tolerance area (GA) below 800. The normal inucmental area is below :-WO. These data have been established by the study of about 600 control won1en. 1 A GA exceeding I ,000 is found only in a subject whose biochemical data would conform to the modern criteria for the diagnosis of diabetes. 11 A (;A between HOO and 1,000 defines a group of subjects with impaired glucose tolerance. 11 It should be pointed out that as the ;l\·erage weight of these subjects was 59.4 kg, the an~ragc dose of glucose administered (59 gm) would be about half the standard dose administered during an OGTT (I 00 gm) in most clinics in the United States; hence, ghtcose values would be somewhat lower in our (United Kingdom) studies compared to studies in the United States, especially toward the latter half of the test. Similarly. insulin secretory responses would be rather lower than would be expected in tests with a I 00 gm glucose test load. Of the subjects who developed abnormal glucose tolerance, in Case I the abnormality was minor, but the patient decided to discontinue use of the OC after dis-
4.71
I
2 hr IIAIIGA
p
I
p <0.001 p <0.001 p <0.001
5.49 6.61 4.68
T
p p <0.00! p <0.001 p <0.001
cussion with the attendant physician. Patient 2 had obviously impaired glucose tolerance before starting the OC, and this deteriorated into the diabetic range within :~ months of beginning OC use and impro\-ed on discontinuation. Patient:~ had mildlv impaired ()(;TT before starting the OC with obvious deterioration in glucose tolerance at I year. Patient 1 had normal glucose tolerance before starting OC usc and a diabetic glucose tolerance after 12 months, which ITHTted to normal on stopping the OC. Pat iellt 5 had a normal test before starting the OC but a markedly impaired OGTT after 2 years of pill use. Case() is of considerable importance because the patient had a normal OGTT bef()n· taking the OC: but after :~ vears had developed a diabetic glncose tolerance pattern. This n·1·ertcd to normal after discontinuing the OC. This subjen wished to JTCOIIlmence OC:. but within 6 months of its administration. the prnionsh observed diabetic glucose tolerance pattern recurred. Because the glncose tolerance abnollllality in l'aticm 6 occurred at the series 5 analysis when there were onh a small number of cases ( 17), it was decided to rem on· her entirelv from the series to prevent her case from having an undue ad verse effect on the glucose tolerance data for this group. Table I shows that the mean \alues for (;A and l(~A increased progressively during the :~ rears. At :~ \ears, GA was 22';( greater and IGA nfi',j greater than at the initial test. On the other hand, lA increased br 12"1, after~ months of OC use, but thereafter the1 c 11as no further increase. IIA increased bv the same amo1mt ( 12'1r). There was a progressive decrease (from 2.29 to 1.11) in the IIA/IGA ratio throughout the seric,. Table IV shows the significance of the lineal· component of I he trend across each series for GA, I CA. and II A/I GA. The changes were all highly significant. The internal consistency throughout the series is imponant, since had this not been the case, subject 1 ariation might have rendered interpretation of tlw data difficult if not impossible because of progressiYe attenuation of the cohort of women. Fig. I shows, in diagrammatic form, the increase in GA and )(;A with duration of pill usc. Fig. 2 shows the parameters of insulin secretion, lA and IAA. and Fig. ~ presents the change in the II:\/ IGA ratio. This ratio had been calculated lor two ti111c
Duration of OC treatment and carbohydrate metabolism
Volume 142 Number 6. Part 2
3
2
Series 700
4
743
5
ISO Q.UCOSE AREA (Units)
100
550 500
200
INCREMENTAL GLUCOSE AREA (Units)
150 100
~
50 N:
173
n••
~
39
n
17
Fig. l. Mean glucose tolerance throughout the series. N =!\;umber: **p < 0.01; ***p < 0.001.
350 300 250 INSULIN AREA (Units)
200
150~-L~L---WW~U---~~~~---L~~wwu._____________
Series 300
2
3
5
250
INCREMENTAL INSULIN AREA (Units)
200
150~~~~~wu~~--~~~~--~~~~~-----------
N=
170
13
31
17
Fig. 2. Mean insulin secretion throughout the series. N = Number; **p < 0.01; ***p < 0.001.
intervals (2 hours and 3 hours) of the OGTT in order to determine whether a difference could be shown in the relationship between insulin and glucose in the early versus the later part of the test. No change in the relationship was found. The fact that GA and IGA increased progressively with time while lA and IIA rose initially but subsequently remained roughly constant indicates that the initial hyperinsulinemic response is followed by increasing peripheral insulin resistance without further pancreatic islet cell stimulation. This results in progressive deterioration of glucose tolerance.
Reference has already been made to the six subjects whose glucose tolerance tests showed marked deterioration and who were therefore advised to stop taking the OC. The removal from the study of these subjects reduced the observed OC effect of impaired glucose tolerance in the present analysis, unless one assumes that patients whose glucose tolerance deteriorated under observation would have improved with further administration of the OC. This has not been my experience in the study of several hundred women taking OCs. Certainly, removal of Case 6 substantiallv reduced
744
Wynn Ant.
1·4
2HOUI
1·0
• • • • • IIMJIIA
0·6 Series
J.
March 15, 19~:.' Obstet. Gynec:ol.
~~----'--'-f&.-U......_____._.__..J.....i...UI~i._______ 2
3
4
5
2·6
2-2
3HOUR
1·4
1·0 ~6L--Lum~~~~L---~MUWW~--~AL~~~----------
N:
170
13
31
f7
Fig. 3. Mean IIA/ IGA ratio during 2 hours and 3 hours of the oral glucose tolerance test throughout the series. N = Number; **p < 0.01: ***p < 0.001.
the reported effect on glucose tolerance and glucose/ insulin ratio in the series 5 data. Study of the trend of GA and IGA showed that OCs affected the group as a whole rather than a few individuals with extreme values. For example, of the In subjects completing the series 2 test, initially only 5% had a GA greater than 800, and none had a GA greater than 1,000. At 3 months, 13% had an area greater than 800, and 2.3% (four cases) had one greater than 1,000. At 15 months, 25 months, and 37 months, respectively, 10%, 20%, and 30% of subjects had a GA greater than 800. Comment
Impairment of glucose tolerance and alteration in insulin secretion are untoward effects of many drug therapies, including glucocorticoids, diuretics, and a number of hypotensive drugs, such as diazoxide, ,B-adrenoceptor blocking drugs, the a2-adrenoceptor agonist, clonidine, certain neuroleptics, some anticonvulsants, microtubule inhibitors, organic calcium antagonists, and others. 1 The oral contraceptive group of compounds is, however, probably the most important because of widespread use, administration to healthy subjects with minimal or no supervision, and the possibility of continuous administration for many years. It is apparent now that the progestin component modified by the coincident administration of the estrogen is responsible for the effect on glucose tolerance. 2 • 4 Earlier studies tended to implicate the estrogen in this effect, but it is now clear that estrogen administered alone or
in combination with weak progestins, such as the pregnane-derived progestins (chlormadinone, megestrol). has little or no effect on carbohydrate wlerance. The tendency during the past several years to lower the dose of estrogen in the OC because of its venous thromboembolic effect 11 has been accompanied by a change in prescribing, perhaps most noticeable in the United Kingdom, in which the strong progestin levonorgestrel has replaced the weaker compound norethindrone. While the low-estrogen levonorgestrel pill is a good oral contraceptive from a gynecologic point of view, studies such as the one reported here suggest that it may not be the best combination. After using the combined pill [30 J.tg equine estrogen (EE) and 150 J.tg levonorgestrel)], the cohort of women described herein showed definite and progressive deterioration of glucose tolerance and a decrease in the insulin/ glucose ratio. Studies in progress of two similar cohorts of women in which the pill consists of 20 J.tg of EE and I mg of norethindrone or the progestin alone do not show progressive deterioration of glucose tolerance or change in insulin/glucose ratio over a period of 2 years (to be published). It would appear from these studies that levonorgestrel, at any rate in a dose of 150 J.tg daily, is too strong a progestin for prolonged administration when combined with estrogen. This conclusion is confirmed by another analysis in which peripheral insulin activity and pancreatic islet ceU function were measured by dynamic methods. 3 The importance of duration of therapy in producing changes in glucose metabolism and insulin secretion is well demonstrated
Volume 142 Number 6, Part 2
Duration of OC treatment and carbohydrate metabolism
in the present study. The effect of duration of therapy is often overlooked in OC studies, contributing to the plethora of conflicting reports in the literature. The question may be asked whether the metabolic effects produced by OCs are important and in particular whether the effects on glucose tolerance and insulin metabolism are clinically relevant. Obviously, if women are precipitated into frank diabetes or some other recognizable clinical syndrome, such as hypertension, then the OC effect is important. These problems, fortunately, occur infrequently. What is more difficult to assess is the overall clinical importance of more limited changes of metabolic parameters, such as glucose tolerance and insulin secretion. There is a great deal of evidence that hyperglycemia is a significant risk factor in the development of coronary heart disease 12 and that the level of glucose tolerance impairment at which this becomes significant is surprisingly low. 13 It does not follow that because the OC causes glucose tolerance impairment, it acts as an atherogenic risk factor. On the other hand, it cannot be wise to ignore the risk. More than 20 publications now show an increased risk of cardiovascular disease in women taking OCs. 1 ~· '" Recently, one published report showed that after 10 years of continuous use, an increased risk of myocardial infarction up to 2.5-fold can be demonstrated in women between the ages of 40 to 49 years who stopped taking the OCs years before.'" With this evidence of an adverse clinical effect of OC administration on the cardiovascular system, it is clearly important to study the impact of OCs on all metabolic parameters that might have a bearing on the etiology of the unwanted cardiovascular effects, with the hope of devising safer OCs. Indeed, one experienced investigator goes so far as to list OCs in order of a supposed atherogenic risk, as judged by effects on various biochemical parameters, such as glucose tolerance, insulin secretion, serum lipids, blood clotting, and other hematologic indices, and effects on the renin-angiotensin system and hypertension. 17 As the evidence for an effect of OC use on the incidence of cardiovascular disease has accumulated, the importance of the progestin in this context has become more apparent. 18- 20 The progestins are known to have greatest effect on glucose tolerance and insulin secretion,~· 21 high-density lipoproteins, 22 - 24 and blood pressure .19 • 20
We must look critically at OC formulation yet again, realizing that excessive estrogenic activity is undesirable because of its thromboembolic effects and effects on blood clotting, and that excessive progestin produces changes in biochemical parameters thought to be implicated as cardiovascular risk factors. The ideal OC must be a compromise. It seems unnecessary in most women to use more than 30 to 35 p,g of estrogen, and it would appear that even 150 p,g of levonorgestrel is excessive for administration lasting more than 2 years. Probably a pill containing I mg of norethindrone would have a less untoward metabolic effect than one containing 150 p,g of levonorgestrel, assuming the estrogen dose is the same in both cases (30 to 35 p,g). There may, of course, be a gynecologic disadvantage in the use of such an OC, but it is not suggested that one pill will be suitable for all women. Those women who need the additional progestin to a\'Oid breakthrough bleeding and to achie,·e better cycle control can weigh the benefits of the levonorgestrel-containing pill against the metabolic disadvantages. For the majority of women, a less potent progestin than levonorgestrel would appear to be preferable. Combined OCs cause many changes in metabolic parameters which may have clinical significance in producing unwanted side effects, the most obtrusive of which, in Western societies at least, involve the cardiovascular system. It is suggested that the ideal OC will be a combination of estrogen and progestin which will produce the least metabolic disturbance. In the present report changes in glucose and insulin secretion have been studied longitudinally over a period of 3 years of administration of an OC containing 30 p,g of ethinyl estradiol and 150 p,g of levonorgestrel to a defined cohort of women. Progressive deterioration of oral glucose tolerance was found in association with early hyperinsulinism and the development of insulin resistance with a decrease in insulin secretion relative to the prevailing glucose level. It is concluded that levonorgestrel, even at the relatively low dose of 150 p,g, when combined with 30 p,g of ethinyl estradiol has untoward effects on carbohydrate metabolism. It is recommended either that the levonorgestrel level be reduced further in the OC or that the weaker progestin norethindrone be used in the combined pill.
REFERENCES I. Furman, B. L.: Impairment of glucose tolerance pro-
duced by diuretics and other drugs, Pharmacol. Ther. 12:613, 1981.
745
2. Wynn, V.: Effects of progesterone and progestins on carbohydrate metabolism, in Mauvais-Jarvis, P., editor: Progesterone and Progestins, New York, 1981, Plenum Press.
746
March L'l,
Wynn Am
,), .\dams. P. W., Godsland, L, Melrose. j, et al.: ·rhe influence of oral contraceptive formulation on carbohydrate and lipid metabolism, J. Pharmacother. 3:54, 1980. l. Wynn, V., Adams, P. W, Godsland, I., et al.: Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism, LatKet 1: 10·15, 1979. 5. Spellacy,\\'. \1., Buhi, W. C, Spellacv, C. E., et al.: Glucose, insulin, and growth hormone studies in long-term users of oral contraceptives, AM. J. 0BSTET. GYNECOL. 106:1 T), 1970. 6. Spellacy, W. :'\., Buhi, W. C., Birk, S. A., eta!.: Studies of ethynodiol diacetate and mestranol on blood glucose and plasma insulin, Int. J. Fertil. 16:55, 1971. 7. Spellacv, \V. N, Buhi, W. C., Birk, S. A., et al.: Studies of ethynodiol diacerate and mestranol on blood glucose and plasma insulin, Contraception 3:185, 197 I 8. Spellacy, W.l'\., Buhi, W. C., and Birk, S. A.: Three-year prospecti1e study of carbohydrate metabolism in women using (hulen, South. Med. J. 70:1188, 1977. 9. Wynn, V .. and Doar,J. W. H.: Some effects of oral conI racepth·es on carbohydrate metabolism, Lancet 2:71 !1. 1961). 10. Wvnn, \'.,and Doar, J. \\7. H.: Some effects of oral contraceptin:s on carbohydrate metabolism, Lancet 2:761, I ~~6~1 II. Keen. H .. Jarrett. R.J.. and Alberti, K. G . .\.1. .\.'L: Diabetes
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