Contraception

46:477-488,

1992

EXPERIENCE AND PHARMACOLOGICAL CONTRACEPTIVE CONTAINING 20~ OESTROGEN

CLINICAL

EFFECTS

OF AN ORAL

K. Fotherby

Address for correspondence: Dr K Fotherby, Royal Postgraduate Medical School, Ducane Road, London W12 ONN.UK

ABSTRACT The performance of a new low-dose oral contraceptive (Me&on) containing only 2t&g ethinyloestradiol combined with 15Ol.tgdesogestrel is reviewed. Eight multicentre clinical trials have been completed and provide information on 10,672 women studied over 73,477 cycles. The high efficacy of Mercilon was indicated by the fmding that only 10 pregnancies were reported; nine of these occurred in women who omitted to take Mercilon on a number of days and only one in a woman who took all the tablets according to instructions. Cycle control was good: as with all oral contraceptives, the incidence of breakthrough bleeding and spotting was highest in the first treatment cycle and by the sixth treatment cyclethe values were usually < 5% and c 7%. More than 80% of women had regular cycles. Side effects were few, the most common being headache, nausea and breast tenderness with incidences in the sixth treatment cycle of less than 2% 6% and 6%, respectively. There were no significant changes in body weight or blood pressure. Pharmacodynamic investigations showed no adverse effects. Only 1 of 5 studies found an increased response to a glucose tolerance test compared to the pretreatment test. In 8 of 10 studies, serum HDL-C concentrations increased on treatment and this was associated with increases in apoproteins Al and A2. Serum triglyceride levels also increased but no change occurred in serum cholesterol or LDL-C levels. Haematological factors were assessed in 8 studies and only minor changes were observed. Serum binding protein (SHBG, CBG, caeruloplasmin) concentrations increased and serum androgen levels decreased. Measurements of blood FSH, LH, oestradiol and progesterone indicated adequate inhibition of ovulation. Mercilon is the only oral contraceptive containing 20 pg ethinyloestradiol to have high efficacy, to have no adverse pharmacodynamic effects and, importantly, to produce an acceptable bleeding pattern not significantly different from that of oral contraceptives with a higher content of ethinyloestradiol.

INTRODUCTION Since the inttoduction of the oestrogen-progestogen combined oral contraceptive (COC) in 1960. there has been a marked reduction of the dose of both components. In the case of the progestogen,this reduction has been accomplished by the synthesis of more potent and particularly mom selective compounds. Most COCs currently used contain about 3Opg ethinyloestradiol (EE) as the oestrogen. Attempts to develop a CGC containing less than 3Opg EE were not successful until preliminary trials (1) demonstrated that a combination of 2Opg with 15Opg of the progestogen desogestrel (DSG) could be both efftcacious and acceptable; the pregnancy rate was low and the bleeding pattern appeared acceptable. This paper reviews the subsequent clinical and pharmacological investigations performed with this combination (trade-name Mercilon) and assesses how it compares with existing COCs. Submitted for publication August 17, 1992 Accepted for publication September 9, 1992

Copyright

Q 1992 Butterworth-Heinemann

478

Contraception CLINICAL STUDIES

A large number of clinical trials have ken performed with Mercilon (2-10). These have encompassed multicentre trials in a number of European countries as well as two international multicentre trials. Altoeethcr these trials provide information on 10,672 women studied over 73,477 cycles of use (Table I ) -

Table I _Multicentrc trials of Mercilon (N and Cycles denote total number of subjects and cycles of treatment) Study (ref)

Country

Lammcrs (2) Benagiano (3) Op ten Berg (4) Kahn-Nathan (5) De Grandi (6) Picard (7) Snow&n (8) Kirkman (9) Lammers (10)

International IJY International France Switzerland Belgium UK International Belgium

N

Cycles

1684 1068 1173 3242 786 2073 293 255 98

25,970

Pregnancies Method failure Patient failure 1

3

7,127 6,111 16,251 4,053 10,975 1,501 1,019 0,470

2 1 2 1

In most of the trials, subjects recorded the days on which they omitted to take the Pill and,despite omissions by a large number of women,pregnancies were remarkably few. Of the ten pregnancies reported, only one occurred in a woman who took all the pills according to instructions, and thus was classified as a method failure. The other 9 pregnancies were patient failures: 2 due to d&rhea, 2 in women who had extended the pill-free interval to eight days,and the remaining 5 due to the omission of multiple consecutive tablets. lbe Pearl Index for method failure of Mercilon was 0.02 and for patient failure 0.16. Cycle control was good. As with all COCathe incidence of breakthrough bleeding (BTB) and spotting was highest in the first cycles of use and then rapidly decreased to reach stable levels by about the fourth cycle. Tableg gives the available data on the.cycle control in cycle 3 and cycle 6 in those studies in which a minimum of 400 women were enrolled. Over 80% of women maintained regular cycles without BTB or spotting during the trials. Spotting was defined as any bleeding starting during tablet intake requiring no or maximally one sanitary pad per day, BTB as bleeding starting during tablet intake and reqdring two or more pads per day.

Tablell. Irregular bleeding in cycle 3 and cycle 6 (% of women, N = number of women) Study (rcf)

Lammers(2) Benagiano (3) Gp ten Berg (4) Kahn-Nathan (5) De Grandi (6) Picard (7)

N

1684 1068 1173 3242 786 2073

Cycle 3 None 81 94 77 79 86 84

BTB

Spotting

9 2 15 5

10 4 9 16 14

7

9

Cycle 6 None 87 97 82 86 93 93

BTB

Spotting

6 1 12 2

7 2 7 12 7

2

5

479

Contraception

The recorded incidence of BTEtvaried, with low values recorded in some trials, e.g. l-2% in cycle 6 in trials in Italy, France and Belgium (35.7) and somewhat higher vahres in the international trials: 6 and 12% reqectively,(2,4). In genera&with Me&on, as with otber COCs, a larger pmportion of women experienced episodes of spotting than of BTB. The incidence of absent withdrawal bleeding in the pill-free interval was negligible in all studies. The prevalence of minor side effects during treatment was low in the various studies (Table llQ.Those most often reported were breast tenderness, headache and nausea. The prevalence of the various side effects repented during treatment was generally no higher than that present in the cycle before treamrent. The outlying higher prevalences of headache and breast tenderness in the French study (5) can be explained by pretreatment prevalences of 24 and 31%~espectively. Ten cases of superticial thrombophlebitis were reported, the relationship between these events and the CCC use is considered doubtfull. For example, in two of the caseathe condition resolved during continued CCC use and in some other casesqedisposing factors (eg,varicose veins) were present prior to treatment. Serious side effects (including deep venous thrombosis) were not reported in any of the studies.

TableIUMinor side effects in cycle 3 and cycle 6 (% of women, N = number of women) Study (ref)

Lammers (2) Benagiano (3) Op tenBerg(4) KahnNathan(5) De Grandi (6) picard (7)

N

1684 1068 1173 3242 786 2073

Cycle 3 Breast Nausea Headache tenderness 3 :

7 :

8 4 3

17 7 6

5 4 7 19 11 6

Cycle 6 Breast Nausea Headache tenderness

2

5

I 4 1 1

5 15 6 2

5 4 3 15 6 4

Changes in body weight were minor, the only group to show a slight increase was women aged less than 19 years. In this group,a mean body weight increase of 0.3 kg after 12 cycles of use can be attributed to an effect of mutual growth (2). In all the trialsblood pressure was monitored but only minor non-significant changes were observed. No change in blood pressure was detected in 434 women of over 30 years of age using Mercilon for up to 4 years (11). A detailed analysis of blood pressure in subjects using Mercilon was reported by Dieben and Van Beok (12) who analysed data from 1657 women using Mercilon for up to 24 cycles; 929 of these women had either not previously used COCs or their previous use had stopped more than two months prior to commencement of the study. Mean changes in blood pressure from pretreatment levels were calculated monthly and no significant changes were observed. Five women discontinued due to an increase in blood pressure and 2 of these had previously had hypertension in pregnancy. A further 14 of tbe women had a history of hypertension in pregnancy but did not experience any increase in blood pressure whilst using Mercilon. Most of the multicentre clinical trials were designed to be of specific duration so that an evaluation of continuation rates may not be valid. Of more value is an analysis of the percentage of women who discontinued the use of Mercilon during the fast 6 cycles of beament either for cycle control reasons or side effects. This information is shown in TableIY The difference in discontinuation rates between the various studies was to be expected and is the consequence of differences both in the design of the studies and in the patient counselling medmds in use in tbe clinics that took part in them. The rates in TableIVshow that after 6 cycles,usually less than 5% of women had discontinued for irregular bleeding or for side effects. These figures are similar to those reported in trials with other COCs (13-16).

Contraception

480

TableN.Discontinuations during the ftrst 6 cycles (% of women, N = number of women) Study (ref) Lammers (2) Benagiano (3) Gp ten Berg (4) Kahn-Nathan (5) De Grandi (6) Picard (7)

N 1684 1068 1173 3242 786 2073

Cycle control

Side effects

3.0 1.3 5.8 3.7 2.0 6.2

4.2 1.4 4.2 11.2 2.8 8.6

A small-scale comparative clinical trial was performed in which 196 women were random&d to either Mercilon or Loestrin-20 (lmg norethisterone acetate (NETA) + 2Opg EE, the only other commercially available CGC containing less than 3Opg EE) and studied over 6 cycles. No pregnancies occurred in this trial. The incidence and the number of days of BTB or spotting was significantly higher in all cycles with Loestrin than with Mercilon and there was a higher drop-out rate because of bleeding disturbances in the Loestrin group (10).

PHARMACOLOGICAL STUDIES Pituitary-ovarian function The high efficacy of Mercilon suggests adequate suppression of hypothalamic-pituitaryovarian function and this has been confiied by direct investigations. FSH, LH and oestradiol concentrations in blood were suppressed in a group of 12 women (17) from whom blood samples were obtained weekly during a pretreatment cycle and the first and third treatment cycles,and also in a study performed over 6 cycles on 39 women (18). In an intensive comparative study of 56 women divided into 8 groups treated with various COCs, ovarian activity was evaluated by serial ultrasonography and serum hormone analyses during a pretreatment cycle and during the fmt and third treatment cycles (19). The ovarian suppression in the women receiving Mercilon did not differ from that in the other groups, where the CGCs used contained doses of 30-35pg EE in combination with the progestogens widely used today. In another comparative study of 14 adolescents with ovarian hyperandrogenism, there was no difference in the degree of FSH and LH suppression between subjects receiving Mercilon or Marvelon (20). De Leo (21) measured pituitary responsiveness to GnRh in 10 women treated for 6 cycles with Mercilon; FSH response appeared to be affected to a greater extent than LH, but basal levels of both FSH and LH were suppressed. A preliminary study in which endometrial biopsies were obtained prior to treatment and tbreemonthly thereafter (22) showed that endometrial gland atrophy and stromal d&dual&ion did not differ between women using Mercilon and those using higherdose oesirogen CGCs. No change occurred in serum prolactin levels on using Mercilon nor is there any change in the prolactin response to TRH. Lipid metabolism In view of the potential importance of changes in lipid metabolism in relation to the development of cardiovascular disease, a number of detailed studies into the effects of Mercilon on lipid and lipoprotein metabolism have been performed. These are summarized in TableV.. No significant changes have been found in total cholesterol, LDL-C and HDL2-C. Due to technical problems in the measurement of the HDL subfractions, results of studies assessing them generally need to be accepted with caution. Almost all studies show an increase of total HDLC during use of Mercilon. These increases in HDL-C are supported by increases in apoproteins Al and A2, the major apoproteins of HDL. Although none of the studies showed a change in the serum levels of LDL-C, some investigators found an increase in apoptotein B, the major apoprotein of LDL.

481

Contraception

Table V. Changes in lipid and lipoprotein metabolism with Mercilon (For lipoproteins,assessment relates to lipoprotein-cholesterol; t, significant increase; =, no change; TC, total cholesterol; N, number of women; Dur, duration of use in cycles) Study

N

Kloosterbocr (24) Kloosterboer (24) Song Si (28) sirtori (23) Fioretti(26) Bertolini (27) Falsetti (18) Miccoli (29) Tuimala (25) Petersen (30)

10 10 12 10 17 18 39 19 12 12

Dur TC Trig1 LDL HDL HDL2 HDL3 ApoAl 3= 3=7== 3= 6~ 6= 6 6~ 6= 12 = 12=

T

=

t t t -l= f

= = = = = =

7

=

; t t T 7 t t

ApoA2 ApoB

7 =

=

=

t

; t f t =

= =

;

=

=

T r 7

t -r = ; 7 =

t

Carbohydrate metabolism Impairment of glucose tolerance and increased levels of insulin are thought to be associated with an increased risk of cardiovascular disease. The studies summarized in Table VIshow that carbohydrate metabolism was not affected by use of Mercilon.No change in fasting serum glucose or insulin concentrations occurred in up to 12 months treatment and only one of 5 studies showed a slight increase in the glucose and insulin response to a glucose tolerance test; this study also found an increase in fasting C-pcptide levels (31). No significant changes occurred in the serum levels of glycosylated proteins, a reliable indicator that serum glucose levels were not increased in tbe weeks preceding the assessment.

Table VI-Changes in carbohydrate metabolism with Mercilon (Glut, glucose; Ins, insulin; CKXT (AUC), area under serum cont. curve in response to oral glucose tolerance test; 7, significant increase; =, no change; N, number of women; Dur, duration of use in cycles ) Study (ref)

N

Dllr

V d Ende (31) Song Si (28) Fioretti (26) Miccoli (29) Petersen (30) Tuimala (25)

13 12 17 19 12 12

3 3 6 6 12 12

Fasting Glut Ins = = = = =

= = = = =

0Gl-I (AUC) Glut Ins ? = = = =

t = = = =

GlycosyIatcd proteins = = = =

Haematobgical factors The dose of ethinylestradiol in CGCs is related to the frequency of venous tbromboembolic complications and to the extent of changes in the haemostatic system (32-36). With the decreased dose of EE (2Opg) in Mercilon, a further reduction in the effects on haematological factors compared to those with CGCs containing 3Opg or more of EE was expected. These effects have been investigated in eight studies involving 132 women studiedfor up to 12 months. In none of tbe studies was the haemostatic system evaluated ‘in full’. Although the newer and potentially more relevant dynamic parameters like fibrinopeptide A and fibrin degradation products have been measured in some studies, they have not been assessed in combination with the more traditional coagulation and fibrinolytic factors. This is also tbe case for all other available WCs. However, the

Contraception

482

results summarized in TablevIIshow that, in contrast to CGCs containing a higher EE dose, Mercilon seems not to affect antithrombin III and to have only minimal effects on fibrinogen, fibrhropeptide A and tIbrin degradation products. A number of other haematological factors (plasminogen , t-PA activity, PAI activity and HBG ) were also measured by Jespersen et aL(38) and the authors concluded that the dynamic balance between fibrin formation and degradation was not altered and that the various changes observed were not indicative of an increased tendency to thrombosis.

TableVIIChanges in haematological factors with Mercilon (AT III, antithrombin III: Fib, fibrinogen; FDP, fibrin degradation products; FPA, fibrinopeptide A; VII, factor VII; Pr C, protein C; Pr S, protein S; Plat, platelet count; 7, significant increase; J , significant decrease; =, no change; N, number of women; Dur, duration of use in cycles ) Study (ref)

N

Dur

Inauen (37) Jespemen (38) Fioretti (26) Melis (39) Tuimala (25) Kloosterboer (24) Sirtori (23) Pinto (40)

20 12 17 31 19 10 10 13

3 12 6 6 12 3 6 6

AT III Fib FDP FPA .L =

7

= = = = =

=

t t 7 =

=

VII

PrC

PrS

‘p

J

Plat

t

=

=

= =

=

=

Serum binding proteins and androgen concentrations The effect of Mercilon on these parameters is summarized in TablemAll seven investigations showed a substantial (twofold) increase in SHBG. Serum levels of this protein are increased by oestrogen administration and this increase may be suppressed by progestogens, depending on their dose and structure. In three comparative studies (20,23,28),changes in SHBG concentrations resulting from Mercilon adminstration were not significantly different from those seen with Marvelon. Other binding proteins, for example cortisokbinding globulin (CBG) and caeruloplasmin (CP), are also stimulated by oestrogens, but this stimulation is less affected by concomitant administration of progestogens than that of SHBG. Three studies show an increase in CBG levels and two studies an increase in CP on Mercilon administration. The four investigations in which serum androgen concentrations were assayed all showed a decrease.

TableVlWhanges in serum binding protein and androgen concentrations with Mercilon (Andr, androstenedione; DHAS, dehydroepiandrosterone sulphate;?, significant increase& significant decrease; =, no change; N, number of women; Dur, duration of use in cycles )

Study (ref)

N

Dtlr

SHBG

CBG

Falsetti (18) Tuimala (25) Kloosterboer (24) Kuhl(41) Nappi (20) De Leo (21) Song Si (28)

39 12 10 18 7 10 11

6 12 3 1 6 6 3

t r t

7

; 7 t

Testosterone Free Total

Andr

DHAS

J.

&

.l

&

=

.L &

.L J,

=

t 7

.L

483

Contraception DISCUSSION

Since the introduction of the combined oral contraceptive (CGC) over 30 years ago, the dose of oestrogen in the Pill has been reduced by 80% from 150 to 3Opg. Until recentlyt it was considered that the dose could not be further reduced without compromising the acceptability of the CGC. This doubt applied not to any possible loss of contraceptive efficacy but to an increased incidence of irregular bleeding, a major determinant of the acceptability of steroidal contraceptives by most women. Whilst the factors which lead to irregular bleeding am largely unknown, an empirical approach to the use of CGCs with less than 3Opg EE remained the only one. The doubt was reinforced by the results of earlier preliminary clinical trials with various oestrogen-progestogen combinations. Combinations of various doses of levonorgestrel (LNG) with 15 or 2Opg EE were tested (4244); the results suggested that although the efficacy of the combinations was satisfactory, the amount of irregular bleeding was unacceptable. Similarly, larger scale trials of various doses of NETA and EE (4546) showed that 1 mg NETA with 2Opg EE was effective but with about a 30% incidence of cycle irregularities. Despite this, the combination (Loesnin 20) was made commercially available. In a comparative randomised double-blind trial of Loestrin 20 with Microgynon (lmg LNG + 3Q.tg EE), failure rates were low and not significantly different for the two formulations but cycle control with Locstrin 20 was poor (47). Preston (48) suggested that adequate contraception could be obtained with 1Opg EE combined with NETA, provided no pills were. missed. Thusthese preliminary trials were important in showing:l) that the efficacy of the CGC could be maintained with doses of EE less that 3@tg; 2) that the efficacy was not dependent on the estrogen alone since these low doses of EK administered alone would not consistently inhibit ovulation;and 3) that a sufBciently potent progestogen was required such that low doses would interact with the oestrogen to maintain the endometrium until the end of the course of pill-taking and then allow regular withdrawal bleeding. Preliminary trials suggested that desogestrel had the required properties and that a combination of 15qSg of this progestogen and 2wg EE was an acceptable CGC (1). These preliminary findings for Mercilon are substantiated by the more extensive trials summarixed in this review. The high efficacy is shown by the low value for the Pearl Index (0.18) for a total of 5650 woman-years of use. The majority of the pregnancies which occurred appeamd to be due to patient failures rather than method failures; the Pearl Index for method failure was 0.02. The high effkacy of Mercilon is also shown by the fact that in trials in which subjects recorded missing pills, up to 8% of the women missed one or more pills per cycle. Ibis high efficacy and the direct investigations of pituitary-ovarian function reviewed above demonstrate that Mercilon produces adequate suppression of hypothalamic-pituitary-ovarian function with inhibition of ovulation. In most women,CGCs produce a regular withdrawal bleeding; often the cycles are more regular than they were before starting treatment. However, with Metcilon, in common with other CGCs, irregular bleeding tends to be more common during the initial three cycles, and particularly the fit, after starting treatment. After this time.the figures in Table II show that more than 80% of women will maintain a regular cycle. For reasons that are not clear, the incidence of BTB varied widely among the various trials with higher values in the international trials and lower in the others; the variability of spotting among trials was lower. The values for cycle disturbances appear to be similar to those found with other COCs containing higher doses of EE. A small-scale randomised double-blind trial (10) compared Mercilon with Loestrin 20 and found a much higher incidence of BTB (15.4%) and spotting (33.3%) with the latter than with Mercilon (5.2% and 13.8%) after 6 cycles. In spite of the fact that irregular bleeding is always greatest in the fmt six months of use, discontinuation rates for cycle irregularities during this period of Mercilon use were low. This also applied to the trials with the higher incidences of irregular bleeding. Non-menstruaI side effects had a low incidence in all trials and were minor, since they did not lead to discontinuation of tteatmenc the proportion of women who discontinued due to subjective side effects was even much lower than their incidence. ‘lhe proportion of women withdrawing from the Mercilon trials during the first 6 months was no higher than that observed in trials with other CO& On completion of the trial

484

Contraception

period,many women expressed a desire to continue with Mercilon; in one international trial (4).an evaluation after six months of use showed that about 90% of the women were satisfied or very satisfted with Mercilon. Mercilon does not appear to have any adverse effects upon metabolism. No significant changes occurred in the fasting blood glucose and insulin levels or in their response to a glucose tolerance test with up to 12 cycles of use. Similarly no changes occurred in the serum concentrations of cholesterol and LDL-C; in view of this consistent tinding, it is surprising that in some studies,levels of apoprotein B were increased. In common with other COCkserum triglycerides were increased; the significance of this in relation to the development of cardiovascular disease is still controversial. In spite of the low oestrogen dose, HDL-C and its major apoproteins, Al and A2, were increased, increased levels of HDL-C with no change in total cholesterol or LDL-C are considered to be a beneficial effect, potentially reducing the risk of development of cardiovascular disease. Increases in serum triglycerides and HDL-C are oestrogenic effects and the findings indicate that desogestrel does not counteract the effect of the low dose of EE in Mercilon. This conclusion is further substantiated by the increases observed in CBG and particularly SHBG in women using Mercilon (TableVmLSerumconcentrations of both of these proteins are increased by oestrogen administration and the increase in SHBG, but not that of CBG, can be inhibited by progestogens. The increases in SHBG were such as to suggest that little.if any, antagonism of the oestrogen effect by desogestrel occurred. The increased concentrations of SHBG lead to a higher amount of serum testosterone being bound to this protein with a consequent reduction in the amount of biologically active free testosterone. Reduction of the oestrogen content of CGCs from more than 5Ot.tgEE to 5Opg EE or less led to a reduced incidence of venous tbromboembolism and to reduced impact on the haemostatic system (34.39. For the dose reduction to 2Ottg,no epidemiological data on thrombo~embolisrnare available yet, nor will they be in the next few years. Thereforeconclusions at present can only IX made on the basis of changes in haematological factors in women using CGCs. For a number of reasons,these factors are difficult to evaluate. Firstly,technical problems exist in respect to their measurement and different results may be obtained depending on the methodology employed. Secondly,all the factors exist in a delicate equilibrium and changes in one or two of the components of the haemostatic system may be. compensated by changes in other components which restore the haemostatic balance. Tbirdly~few laboratories can assay a sufficient number of the factors to obtain a complete overview andfourthly, the interpretation of the findings, in respect to the extent of the changes produced by CGCs and their possible connection with the risk of developing thromboembolic disease, is obscure. The studies performed so far with Mercilon would suggest that there were no significant changes in the haemostatic system. Any changes which do occur in haematological factors in women using CGCs are usually ascribed to the oestrogen but may be modified to some degree by the progestogen. The results with Mercilon seem promising. However, further studies are needed, particularly comparative trials with CGCs containing a higher cestrogen content, to provide proof that the reduction of the EE dose in Mercilon has minimised changes in the haematological factors. Results of one such trial have ken published: in cross-over trial of desogestrel combined with either 20 or 5Ottg EE, Inauen (37) found that the high-dose oestrogen combination produced a more pronounced activation of the coagulation system. Changes in many metabolic parameters in women using CGCs result from an interaction between the oestrogenic and progestogenic activities of the components, the changes produced by the oestrogen often being antagonised by the anti-cestrogenic activity of the progestogen. That desogestrel has weak activity in this respect is illustrated by the findings that it did not suppress increases,e.g. in HDL-C and SHBG resulting from the low dose of EE in Mercilon. Howeveq in other respects,the interaction between the oestrogenic and progestogenic components is a synergistic one and this is illustrated by the suppression of pituitary-ovarian activity in women using Mercilon. Ovulation is inhibited even though the dose of EE is not sufficient by itself to

Contraception

485

consistently inhibit ovulation but its suppressive action is augmented by the dose of desogestrel. This is important since, although CGCs may exert a number of different anti-fertility effects, their main contraceptive activity is ascribed to the inhibition of ovulation by suppressing pituitary gonadotrophin release. A number of the pharmacodynamic investigations have been comparative ones of Mercilon with other CGCs. Of particular interest are those trials which have compared Mercilon with Marvelon. No differences between these two CGCs were found for carbohydrate metabolism (28). serum levels of antitbrombin III (24) or SHBG (20,23). In two studies (28,4l),however,the increase in SHBG with Marvelon was greater than with Mercilon. In one study (28). HDL-C was increased by Marvelon but not by Mercilon,aldrough both increased equally the serum concentrations of apoprotein A, the major apoprotein of HDL. Any new COC must satisfy certain criteria: 1) it must have high contraceptive efficacy;2) it must be acceptable in that its use leads to a high incidence of regular cycles and a minimal incidence of irregular bleeding and minor subjective side effects; 3) it must not produce any serious side effects,although this aspect can usually only be determined by epidemiological studies once the CGC is in widespread use; and 4) it must not produce any major changes in metabolic processes which might be adverse. From an analysis of the currently available data,Mercilon appears to satisfactorily meet these. criteria. During the 1960’s the CGCs in use contained up to 15Opg oestrogen, during the 1970’s most contained no more than 5Opg EE,whilst the most widely used CGCs during the 1980’s contained only about 3Opg EE. It seems likely that the 1990’s will be the decade of the 2Opg EE pill.

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Alapiessa U, Lok D. Clinical studies with a new, low-dose oral contraceptive combination containing 0.150 mg desogestrel and 0.020 mg etbinylestradiol. Acta Obstet Gynecol Stand 1987; suppll44: 744.

2.

Lammers P, Gp ten Berg M. Phase III clinical trial with a new oral contraceptive containing 150 mcg desogestrel and 20 mcg ethinylestradiol. Acta Obstet Gynecol Stand 1991; 70: 497500.

3.

Benagiano G, Primiero FM. Multicenter clinical trial of an oral contraceptive with desogestrel plus 20 mcg etbinylestradiol in Italy. In: Newton JR, ed. Mercilon, a new era in low-dose oral contraception. Carnforthz Parthenon Publishing Group, 1990~55-63.

4.

Op ten Berg M. International multicenter clinical trial of an oral contraceptive containing 28 mcg ethinylesttadiol and 150 mcg desogestrel (Mercilon). In: Newton J, Gp ten Berg M, eds. Optimizing the estrogen dose in oral contraceptives. Camforth: Parthenon Publishing Group, 1992: 33-38.

5.

Kahn-Nathan J, Lapousterle C. Reaultats d’une etude multicentrique nationale d’un contraceptif oral contenant 20 mcg ethinyl-estradiol et 150 mcg d&ogesrrel. Reproduction et hormones 1991: no 1: 15-20.

6.

De Grandi P. Personal communication

7.

Picard J. Personal communication

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Snowden R. Personal communication

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Kirkman RJE. Clinical comparison of two low-dose oral contraceptives in women older than 30 years. Advances in Contraception 1991; 7 (suppl2): 63-76.

10.

Lammers P, Atsma WJ, Van den Heuvel M, Picard J. Double-blind comparative acceptability study with two combined oral contraceptives containing 20 mcg ethinylestradiol plus desogestrel or norethistemne acetate. In: Newton J, Gp ten Berg M, eds. Optimizing the estrogen dose in oral contraceptives. Camforth: Parthenon Publishing Group, 1992: 67-74.

11.

Steffensen K. Evaluation of an oral contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol in women aged 30 years or older. Acta Obstet Gynecol Stand 1987; Suppll44: 23-27.

12.

Dieben TOM, Van Be& A. Desogestrel-containing oral contraceptives and blood pressure. Atzneimittel-ForschunglDrug Research 1986; 36: 1678-1680.

13.

Rekers H. Multicemre trial of a monophasic oral contraceptive containing ethinyl estradiol and desogestrel. Acta Obstet Gynecol Stand 1988; 67: 171-174.

14.

Woutersz TB, Butler AJ, Cohen M, Korba VD, Canavan RC. A low-dose triphasic oral contraceptive. Fertility and Sterility 1987; 47: 425430.

15.

Woutersz TB. A new ultra-low-dose combination oral contraceptive. 1 28: 81-84.

16.

Bilotta P, Favilli S. Clinical evaluation of a monophasic ethinylestradiol desogestrelcontaining oral contraceptive. Arzneimittel-Forschung/Drug Research, 1988; 38: 932-934.

17.

Rozenbaum H, Degrelle H. Quality of inhibition of ovarian hormone production by a combined oral contraceptive containing 20 mcg ethinylestradiol and 150 mcg desogestrel per tablet. In: Newton J, Gp ten Berg M, eds. Optimizing the estrogen dose in oral contraceptives. Carnforth: Parthenon Publishing Group, 1992: 59-65.

18.

Falsetti L, Schivardi MR. Prandini BD. A new low-dose estrogen oral contraceptive combination: effect on endocrine parameters and lipid status. Contraception 1987; 36: 489-497.

19.

Benagiano G. Personal communication.

20.

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