THE EFFECTON POLLICULARGROWTHAND LUTEAL FUNCTION OF “MISSINGTEE PILL” A comparison between a monophasic and a triphasic combined orai contraceptive

R-M. Landgren, G. Csemiczky Department of Obstetrics and Gynecology, Karohnska Hospital, S-l 04 0 1 Stockholm, Sweden

ABSTRACT The effects on follicular growth and hormonal indices of the deliberate omission of two low-dose combined oral contraceptives, a monophasic (30 pg ethinylestradiol + 1SO J.Qdesorgestrel) and a triphasic (30 pg ethinylestradiol + 50 pg levonorgestrel for 6 days, followed by 40 ug ethinylestradiol + 7S pg levonorgestrel for 5 days and 30 K ethinylestradiol + 125 pg levonorgestrel for 10 days) combination during the first three days of one contraceptive pill cycle was studied in two groups of 10 women each. Follicular growth was followed by ultrasound scanning and plasma levels of estradiol, and progesterone were measured every other day until day 19 of the contraceptive pill cycle. In each group, ovulation occurred in one subject and 4 women reacted with follicular activity only, while 5 women on the monophasic and 3 on the triphasic formulation exhibited complete ovarian suppression. Two subjects on the triphasic preparation showed follicular growth followed by insufficient luteal function. Thus, the risk of escape ovulation when the pill-free interval is prolonged to 10 days in women taking low-dose combined oral contraceptive pills, is low (l/ 101. Submitted for publication October Accepted for publication December

FEBRUARY 1991 VOL. 43 NO. 2

24, 1990 21, 1990



INTRODUCTION An important prerequisite for a better understanding of the likely consequences of occasional non-compliance in oral contraception is the careful assessment of follicular growth and of the hormonal consequences of deliberate pill omission. It is now well established that in many women on current low-dose combined oral contraceptives, there is a variable degree of restoration of endogenous ovarian function during the pill-free interval ( I). Not only do the levels of gonadotrophins and estradiol rise (2, 31, but also in many women serial ultrasound scanning of the ovaries shows regular return of follicular activity (4 j. A few studies have been performed on the hormonal consequences of deliberate pill omission, From earlier studies (5,6), we concluded, that 150 ug levonorgestrel combined with 30 pg ethinylestradiol remained an effective contraceptive pill, when 2 tablets were omitted for 2 consecutive days at various phases of the cycle.When 35 women missed the combination of 1.O mg norethisterone + 30 pg ethinylestradiol for two consecutive days between cycle days 5 and 17 (7). elevated ovulatory-like plasma progesterone levels were found in almost one-third of the subjects. In one of our earlier studies (61, the critical part of pill omission in the contraceptive pill cycle seems to be when the pillfree interval is prolonged. Therefore, the purpose of this study was to study the effect of prolonging the pill-free interval from 7 to 10 days on follicular growth and hormonal indices in women taking either a monophasic combined oral contraceptive containing 30 pg ethinylestradiol + 150 clg desorgestrel. or a triphasic combination (6 days 30 pg ethinylestradiol + 50 pg levonorgestrel; 5 days 40 pg ethinylestradiol + 75 ug levonorgestrel; 10 days 30 ug ethinylestradiol + 125 pg levonorgestrelj.

MATERIAL AND METHODS Clinical material Twenty apparently healthy women with a history of regular menstrual cycles volunteered for the study. They were instructed to use mechanical means of contraception for the duration of the study. Some clinical data are presented in Tables I and II. Ethical aspects The study has been approved by the Ethical Committee of the Karolinska Hospital and the Swedish Drug Regulatory Authority.




Table 1. Age, weight, height and index of obesity in 20 women recruited for the investigation of the effects of “missing the pill”; Mea&D and (range) Characteristic

Monophasic pill users

Triphasic pill users

Age (years)

27.4 f 4.8 (23 - 38)

28.1 ? 5.0 (20 - 34)

Weight (kg)

55.2 2 5.5 (43 - 641

59 .1 ? 4.7 (54 - 69)

Height (cm)

164.9 ? 3.9 (159 - 172)

169.9i4.1 (163-176)

0.203 t 0.17 (0.174 - 0.235)

0.205 + 0.0 14 (0.193 - 0.235)

Index of obesitya)

a) Calculated as (weight/height21

x 100 (8)

Table II. Previous reproductive study

events in 20 women admitted to the


Monophasic pill users 2 1 none r3

Triphasic pill users 2 1 none r3

Live births







Still births


















Design of study The subjects were randomly allocated to one of two treatment regimens, either a triphasic pill (30 pg ethinylestradiol + SO pg levonorgestrel for the first 6 days, followed by levonorgestrel75 ethinylestradiol 40 pg for 5 days and levonorgestrel 125 pg + ethinylestradiol 30 pg for 10 days 1 or a low-dose combined pill (desorgestrel 150 pg + ethinylestradiol 30 t.tgO.The pills were kindly provided by Schering Nordiska AB, Nacka, Sweden, and Organon AB, Vistra Friilunda, Sweden. These pills were taken for a minimum of three months prior to admission to the study in cycles consisting of 2 I days of pill administration followed by a pill-free period of 7 days. Then the pill-free period was prolonged from 7 to 10 days.

FEBRUARY 1991 VOL. 43 NO. 2


Ultrasound monitoring was performed every other day starting on the first day of the pill taking (after the omission) until: 1) ovulation seemed to have occurred: or 21 a shrinkage of the follicle was seen; or 3) no signs of follicular activity had been seen on pill day 15. Follicle diameters were measured. Blood samples were taken at the time of ultrasound monitoring and thereafter on two occasions, on pill days 17 and 19. Radioimmunoassay OZestradiol and progesterone The levels of estradiol and progesterone were measured in all samples using a rapid radioimmunoassay method (9). Classification

of hormonal


The ovarian reaction of the subjects was classified according to the classification system described by Landgren and Diczfalusy(IO) (Table III). A to D,where Type A indicates no follicular or luteal activity as evidenced by peripheral estradiol and progesterone levels; type B is characterized by a marked follicular activity but no luteal function; type C is normal follicular function associated with an inadequate rise in luteal activity; and Type D represents normal cyclic function as reflected by normal estradiol and progesterone levels. Table III. Classification of ovarian reaction to steroidal contraceptives according to Landgren and Diczfalusy( 101 Reaction type

Follicular maturation*

Luteal function** None None Inadequate Normal

None Marked

Normal Normal f


As reflected by peripheral estradiol levels As reflected by peripheral progesterone levels RRSULTS

The degree of ovarian follicular development of the two groups of women during the study cycle is shown in Table IV. The data of Table IV indicate that one woman ovulated in each group whereas S of the women taking the monophasic pill and 3 women in the triphasic group reacted with complete suppression of ovarian activity. There was no significant difference between the two treatment groups in ovarian reaction.


FEBRUARY 1991 VOL. 43 NO. 2


Table IV. The degree of ovarian follicular development in 20 women “missing the pill” when taking a monophasic or a triphasic oral contraceptive Ovarian reactiona)

Monophasic pill users (n-10)

A R C D a)

5 4 0 1

Triphasic pill users (n-10) 3 4 2 1

According to the classtiication by Landgren and Diczfalusy ( 10).

The follicle diameters during the study cycle from the first day of pill taking after omission of the first three pills are shown in Figure I. There is a wide inter-individual variation within the two treatment groups. Still, the regression coefficients differ for the combined pill takers (R-0.2 12) and for the subjects taking the triphasic combinations (R-0.6031, the equations of the regression lines being Y- 6.824 + 0.245X and Y- 4.819 + 0.609 X, respectively. There was less suppression of the follicular development during the prolonged pill-free interval in the triphasic group. No significant difference in the decrease in follicular diameter was found between the two groups during pill-taking.

Monophasic Triphasic

Figure 1. Follicular diameter (arithmetic means and SD) in 10 women taking a monophasic (indicated by open circles) contraceptive pill and in 10 taking a triphasic (indicated by closed circles) contraceptive pill when the first t.hree pills of the cycle were “missed”.

FEBRUARY 1991 VOL. 43 NO. 2






FEBRUARY 1991 VOL. 43 NO. 2


i j

FEBRUARY 1991 VOL. 43 NO. 2



The mean progesterone and estradiol levels were calculated for the two treatment groups in the women showing A, B or C type ovarian reaction. Figure 2 shows the progesterone levels per day and Fiiure 3 shows the estradiol levels. No significant differences between the two groups were found, with persistently low progesterone levels throughout the cycle, and a decrease in estradiol levels during the second half of the pill-cycle. Relatively high estradiol levels during the first 12 days of pill-taking were followed by low levels during pill days 14 to 19 indicating follicle shrinkage. The follicle diameters were only measured during the first 15 and they were in agreement with circulating days of pill-taking, estradiol. When the estradiol levels were compared for each day between the two groups, no significant differences were found, although a tendency towards higher levels during the first pill days was seen in the triphasic group.

The results of this study indicate, that in 10 women taking a low-dose combined oral contraceptive containing 30 pg ethinylestradiol and 150 pg desorgestrel, and in 10 women on a triphasic contraceptive pill with a content of 30 pg ethinylestradiol + 50 pg levonorgestrel for the first 6 days, followed by 40 pg ethinylestradiol + 75 ug levonorgestrel for 5 days and 30 f.tgethinylestradiol + 125 pg levonorgestrel for 10 days, the omission of a pill during three consecutive days, and thus prolonging the pill-free interval to 10 days represents only a minor risk ( 1/ 1Of for escape ovulation. This is in contrast with the well established fact that a restoration of endogenous ovarian activity occurs during the pill-free interval of 7 days in women taking low-dose combined oral contraceptives (2,3), and to the results of one of our earlier studies (51, in which 10 women taking a low-dose combined oral contraceptive containing 30 pg ethinylestradiol + 150 pg levonorgestrei were instructed to prolong the pillfree interval from 7 to 9 days. Ovulatory-like activity occurred in one woman during a 9-day pill-free interval, and in another woman who prolonged the pill-free interval to 10 days. Thus, the results of this study add information to the discussion as to whether a shortening of the pill-free interval to 5 days in low-dose combined oral contraceptive users would reduce the risk of escape ovulation, and thus make a method “safer“. The gain in this respect seems negligible. The question as to whether such a regimen would reduce the number of days with breakthrough bleedings remains to be answered. However, like other investigators ( 1, 21, we found signs of ovarian activity such as follicular growth in 4 women in each group. and follicular growth followed by insufficient luteal function in 2 women taking the triphasic pill. These ovarian reactions are well known to


FEBRUARY 1991 VOL. 43 NO. 2


occur in low-dose gestagen only users ( 10, 11, 12, 13 1. It seems as if there is a considerable gap between the appearance of ovarian activity and the occurrence of a normal ovulation, This might explain the high safety of lowdose contraceptives. The lack of difference between the two regimens may partly be explained by differences in gestagenic potency between I-NOGand desorgestrel. We have found measurable levels of NOG6 days following discontinuation of pill-taking, and a mean elimination half-life of 29 hours was calculated (41, which is in good agreement with that reported by Humpel et al. ( 14), but is higher than published by Weiner et al. ( 15). It is not unlikely that the elimination half-life of levonorgestrel is increased by simultaneous estrogen administration, which has been shown to increase SHBGlevels (161. The elimination half-life of desorgestrel, 16 hours (171, is significantly shorter than of I-NOG. Thus. the risk of pregnancy in accidental non-compliance in low-dose combined oral contraceptive users can be regarded as low, even when up to three tablets have been missed. These findings are very well in agreement with those of Killick et al, ( 18) who concluded that even increasing the pillfree interval to 11 days would not result in pill failure.

ACKNOWLEDGEYENT This study received financial support from Organon AB, Oss, The Netherlands, We are also grateful to Astrid Haggblad for preparing the manuscript.


Guillebaud J, The forgotten pill and the paramount importance of a pill-free week. Br J Fam Plann 1987;12:35-43.


Smith SK, Kirkman RJ, Arce B. The effect of deliberate omission of Trinordiol or Microgynon on the hypothalamo-pituitary-ovarian axis. Contraception 1986;34:435-42.


Killoch S. Eyong E. Elstein M. Ovarian follicular development contraceptive cycles, Fertil Steril 1987;48:409- 13.


Malloy BG, Coulson KA, Lee JH, Waters JK. ‘Missed - pill. conception. fact or fiction? Br Med J 1985;290: 1474-S.

FEBRUARY 1991 VOL. 43 NO. 2

in oral




Wang E,Shi S, Cekan SZ,Landgren B-M,DiczfalusyE. Hormonal consequences of “Missingthe pill ‘I.Contraception 1982;26:545-66.


Landgten B-M, DiczfalusyE. Hormonal consequences of missing the phi” during the first two days of three consecutive artificial cycles. Contraception 1984;29:437-46.


Chowdhury V, Joshi UM,Gopalkrishna K,Betrabet S, Mehta S, Saxena B.N.Escape ovulation in women due to the missing of low dose combination oral contraceptive pills. Contraception 1980;22:241-7.


Khosla T, Lowe CR. Indices of obesity derived from body weight and height. Br J Prev Sot Med 1967;21:122-8.


Aso T, Guerrero R, Cekan SZ,DiczfalusyE. A rapid S-hour radioimmunoassay of progesterone and oestradiol in human plasma. Clin Endocrinol 1975:4: 173- 182 1975.


Landgren B-M, DicxfalusyE. Hormonal effects of the 300 pg norethisterone (NET)minipill. Daily steroid levels in 43 subjects during the second month of NETadministration. Contraception 1980;21:87-113.


Olsson S-E,Bakos 0. Lindgren PG,Odlind V, Wide L. Ovarian function during use of subdermal implants releasing low doses of levonorgestrel. Br J Fam Plann (submitted).


Viinikka L. Hirvonen E. Ylikorkala 0, Nummi S, Virkkunen P. Ranta T, Alapiessa U, Vihko R. Ovulation inhibition by a new low-dose progestogen. Contraception 1977;165 l-5.


Cullberg G,Lindstedt G,Lundberg P-A, Steffensen K.Central and peripheral effects of desorgestrel 15-60 pg daily for 2 1 days in healthy female volunteers. Acta Obstet Gynecol Stand 1982: 111: 2 l8.


Hnmpel M, Wendt H. Pommereke G. Weiss C , Spech U. Investigations of pharmacokinetics of levonorgestrel to specific consideration of possible first-pass effect in women. Contraception 1978;17: 207- 19 .


Weiner E, Victor A, Johansson EDB.Plasma levels of d-norgestrel after oral administration. Contraception 1976;14: 563-570.

FEBRUARY 1991 VOL. 43 NO. 2



Toddywalla V. Johannisson E, Landgren B-M,Cekan SZ,Diczfalusy E. Pharmacodynamic effects of ethinylestradiol in women using vaginal devices releasing small doses of levonorgestrel at a constant level. Contraception I983;28:2 l-39.


Vinnika L. Y&ala 0. Vihko R, Hasenech HG,Nieuwenhuyse H. Metabolism of a new synthetic progestagen ORG2969 in female volunteers. The distribution and excretion of radioactivity after an oral dose of the labelled drug. Acta Univ Oulensis IMedl 1978;38:1-9.


KillickSR,Bancroft K,Oelbaum S, Morris J, Elstein M. Extending the duration of the pill-free interval during combined oral contraception. Adv Contracep 1990;6:33-40.

FEBRUARY 1991 VOL. 43 NO. 2


The effect of follicular growth and luteal function of "missing the pill". A comparison between a monophasic and a triphasic combined oral contraceptive.

The effects of follicular growth and hormonal indices of the deliberate omission of two low-dose combined oral contraceptives, a monophasic 130 microg...
966KB Sizes 0 Downloads 0 Views