Ovarian activity suppression by two different low-dose triphasic oral contraceptives

ELSEVIER

Ovarian Activity Suppression by Two Different Low-Dose Triphasic Oral Contraceptives Janneke van der Does,* Niek Exalto,* Thorn Dieben,t In an open, randomized study in an outpatient clinic of a large teaching hospital, thirty-one female volunteers with regular cycles and established ovulation by ultrasonography were given one of two triphasic oral contraceptives containing ethinylestradiol combined with levonorgestrel or desogestrel during six cycles of treatment. The main outcome measures were transvaginal ultrasonography and serum E, and P measurements in pill cycles 1, 3 and 6. No ovarian activity was found in 10 subjects. Among the remaining 21 women who showed ovarian activity, most follicle-like structures developed in the pill-free week and decreased in size or disappeared in the first pill week. One women taking triphasic desogestrel had evidence of a luteinized unruptured follicle and one women taking triphasic levonorgestrel had a possible ovulation. The latter women also showed symptoms of lower abdominal pain. A statistically significant difference in ovarian activity between the two oral contraceptives could not be established. The two triphasic oral contraceptives suppressed ovarian activity to the same degree. A trend was seen towards increasing ovarian activity with duration of use in both treatment groups. CoNTRAcEPnoN 1995;52:357-361

and Herjan Coelingh

Benninkt

to normal follicular growth, the growth rate of these FLSs is slower.’ These FLSs usually arise during the pill-free interval and most of them disappear during the first pill-week.5,6 FLSs of a pre-ovulatory size and larger have been described.‘t6 In case of ovarian activity during oral contraceptive use, estradiol production is usually increased.‘t2 The formation of functional ovarian cysts has been reported during use of phasic OCs.’ In other publications, no difference in ovarian activity was found during phasic OCs as compared to low-dose monophasic OCS.‘,~,~ The aim of the present study was to compare ovarian activity over a six-month period during treatment with two low-dose triphasic OCs containing ethinylestradiol (EE) combined with levonorgestrel (LNG) or desogestrel (DSG). Activity was assessed by ultrasonographic investigation (US] of the ovaries and semm E, and P measurements.

Material

and Methods

Subjects

desogestrel, levonorgestrel, triphasic oral contraceptives, ovarian activity

KEY WORDS:

Introduction ral contraceptives (OCs) have an inhibitory effect on ovarian activity and the quality of cervical mucus and endometrium. Low-dose OCs, however, do not completely suppress ovarian function. Ovarian activity has been observed by ultrasonographic detection of follicle-like structures (FL%) during oral contraceptive cycles.14 Compared

0

*Department of Obstetrics and Gynecology of the Spaarne Ziekenhuis, Haarlem, the Netherlands, and tMedical Research and Development Unit of NV Organon, Oss, the Netherlands Name and address for correspondence: Dr. N. Exalto, Spaarne Ziekenhuis, Department of Obstetrics and Gynecology, van Heythuyzenweg 1, 2003 BR Haarlem, the Netherlands Tel: 23-5141516; Fax 23-5340486 Submitted for publication July 10, 1995 Revised September 18, 1995 Accepted for publication September 19. 1995

0 1995 Elsevier Science Inc 655 Avenue of the Americas,

New

York, NY 10010

Healthy female volunteers between 20 and 35 years of age entered the study. All women had a regular menstrual cycle between 24 and 35 days and did not use OCs in the two months prior to treatment. Their last pregnancy ended more than two months earlier and they had stopped breastfeeding for longer than three months. After explanation of the study, the volunteers gave their written informed consent. Study Design

In the screening cycle, US was performed twice a week from day 9 (* 1) until postovulatory signs were observed.g P and E2 were then measured as well. With an additional US in the last week of the screening cycle, persistent follicular activity was excluded. In the subsequent cycle, the volunteers started using one of the two study drugs after randomization. The treatment was continued for 6 months. Ovarian activity was monitored by US performed ISSN OOIO-7824/95/$9.50 SSDI 001 O-7824(95)00228-6

358

van der Does et al.

Contraception 1995;52:357-361

Table 1. Classification of ovarian activity from Hoogland and Skouby” Ovarian Activity

ord vaginal bleeding patterns and adverse events. To evaluate adequate compliance, the time of pill-intake was recorded every day. Ovarian activity was graded according to the classification reported by Hoogland and Skouby,” which was slightly modified (Table 1). Mean and maximum E, levels of the two treatment groups were compared using a non-parametric Wilcoxon test. To assess the association between maximum FLS size and maximum E, levels, Spearman Rank coefficients were calculated by treatment group and by cycle.

Criteria

No ovarian activity Potential activity Non-active follicle

max. FLS ~10 mm 10 mm < FLS cl.5 mm max. FLS >I5 mm max. E, C220 pmolll max. P c.5 nmol/l max. FLS >15 mm max. E, >220 pmol/l max. P G5 nmol/l max. FLS > 15 mm max. E, >220 pmol/l max. P >5 nmol/l max. FLS > 15 mm + rupture max. E, >220 pmol/l max. P >5 nmol/l

Active follicle Luteinized unruptured follicle (LUF) Ovulation

max. FLS = diameter = progesterone.

as modified

of maximum

follicle-like

structure,

E2 = estradiol,

Results After randomization, thirty-one subjects (mean age: 27.8 years) were enrolled in the study, sixteen in the triphasic EE/DSG group (mean age: 28.6) and fifteen in the triphasic EE/LNG group (mean age: 26.9 years). Demographic variables did not reveal relevant differences. During the screening cycle, all subjects showed signs of ovulation as diagnosed by US and progesterone assessments. Twenty-eight women were investigated during cycle 1,3 and 6 as scheduled, while three women had to be assessed one cycle earlier or later. All subjects completed the study. To classify ovarian activity, definitions were used as described in Table 1. First, the maximum ovarian activity during the whole treatment period was assessed (Table 2). In 10 subjects, 6 on triphasic EE/DSG and 4 on triphasic EE/LNG, no ovarian activity was found in any of the treatment cycies studies. Five subjects showed non-active follicles (3 on triphasic EE/DSG, 2 on triphasic EE/LNG). An active follicle was found in 9 subjects, 3 on triphasic EE/DSG and 6 on triphasic EE/LNG. One woman in the triphasic EE/DSG group developed an FLS which was classified as a luteinized unruptured follicle. In the pill-free week before cycle 3, an FLS with a diameter of 24 mm was seen in the right ovary. This structure increased in size to a maximum of 66 mm on CD 10 and diminished again to 28 mm on day 21. No rupturing was seen [P on CD 10: 20.2 nmol/l; Ez had a maximum of 633 pmol/l on CD - 1). One woman in the triphasic EE/LNG group developed a follicle which ruptured and was classified as a possible ovulation. In the pill-free week before cycle

P

twice a week in cycles 1, 3 and 6 on cycle days (CD) 3,7, 10, 14, 17 and 21. P and E2 were determined once a week in cycles 1, 3 and 6 (CD 3, 10 and 17). In the pill-free week preceding treatment cycles 3 and 6, US was performed twice (CD - 5 and - 1). P and E, were determined two times that week as well (CD - 5 and - 1). The protocol was reviewed and approved by the Ethics Committee of the Spaarne Ziekenhuis. The study drugs used were Trigynon@, a triphasic 21 -day OC (6,5 and 10 days) containing EE (30,40 and 30 pg) and LNG (SO, 75 and 125 pg) manufactured by Schering AG, Berlin, Germany, and a triphasic 2 1 -day OC (7, 7 and 7 days) containing EE (35,30 and 30 kg) and DSG (50, 100 and 150 kg) manufactured by NV Organon, Oss, the Netherlands. Ultrasonography and Hormone Determination Ultrasonography (Hitachi EUB-415) was performed using a vaginal probe (5-6.5 mHz). FLSs were measured in three perpendicular planes and the mean was recorded. P and Ez were measured in serum at the laboratory of the Spaarne Hospital using a Coat-ACount Kit@, produced by Diagnostic Product Corporation (reference value for E, four days before LH peak: 220-730 pmol/l; reference value for P in the follicular and luteal phase: 0.3-5 nmol/l and 18-89 nmol/l). All patients used a bleeding calendar to recTable 2. Ovarian activity per treatment group No Activity

Triphasic EE/DSG Triphasic EE/LNG

Potential Activity

n

%

n

%

6

37.5 26.7

3 2

18.8 13.3

4

Non-active Follicle n %

n

%

n

%

3 2

3 6

18.8 40.0

1

6.3

18.8 13.3

Active Follicle

Possible Ovulation

LUF

n

%

1

6.7

Ovarian Activity and Triphasic Oral Contraceptives

Contraception 1995;52:357-361

Table

3. Ovarian activity per treatment

cycle Potential Activity

No Activity

Non-active Follicle

Active Follicle

Cycle

n

%

n

%

n

%

n

.:

12 10 9 11 7 6

75.0 62.5 56.3 73.3 46.7 40.0

i

6.3 18.8 12.5 13.3 13.3 6.7

2 1 1

12.5 6.3 6.3

1 1

Triphasic EE/DSG

6

Triphasic EE/LNG

1 3 6

359

2 2 2 1

3, an FLS with a diameter of 15 mm was seen in the right ovary. The diameter of this structure increased to a maximum of 36 mm on CD 10. The following US was performed on CD 14. There were no FLSs seen in either ovary (E, on CD 10: 826 pmol/l; P on CD 10: 5.7 nmol/l, P on CD 17: 0.5 nrnol/l). This subject was the only woman in the study to complain of lower abdominal pain. To see if ovarian activity was the same for every treatment cycle, an analysis was made using the classification of Table 1 by treatment cycle (Table 3). In some women more than one FLS 210 mm was seen. In those cases only the largest FLS was taken into account. A trend towards increasing ovarian activity during longer treatment was found in both groups. This trend seemed more pronounced in the triphasic EE/LNG group, but the difference was not statistically significant. The group median of the number of FLSs with a

3

; 5 5

20.0

Possible Ovulation

LUF

%n%n% 6.3 6.3 25.0 13.3 33.3 33.3

1

6.3 1

6.7

diameter of 25 mm was calculated by day to see in which part of the cycle most FLSs occur. The number of FLSs 25 mm increased during the pill-free interval and had its maximum at CD 3. During the rest of the pill-cycle, a gradual decrease in number of FLSs 25 mm was seen (Figure 1). It seemed that some subjects were FLS-prone: they developed FLSs in every assessment cycle while in other women an FLS was never seen. Group comparison revealed no statistically significant differences. We were also interested to know in which part of the cycle FLSs were at their maximum size. Therefore, the group median of the maximum FLS diameter was calculated by day. An increase in maximum FLS diameter was seen in the pill-free week with its maximum on CD 3, followed by a gradual decrease during the rest of the treatment cycle (Figure 2). Group comparison revealed no statistically significant differences.

10

Cycle

1

Cycle 6

Cycle 3

m6 Al

Figure 1. Median of the number of follicle-like structures (FL%) 35 mm per treatment cycle day. Triphasic EE/DSG (n = 16): A - A - A; triphasic EEILNG (n = 15): B-4-4.

rn

0

3

7

10

14

17

*

rl,

21

-5

m -1

3

7

10

14

Days of treatment

17

21

cycle

-5

-1

3

7

10

14

17

21

360

Contraception 1995:52:357-361

van der Does et at

Cycle

1

Cycle 3

Cycle 6

OL-3

7

10

14

17

21

-5

-1

3

7

14

10

17

Days of treatment

21

-5

-1

3

7

10

14

17

21

cycle

To assess if the same cyclic pattern found for the median of the number of FLSs and the group median of the maximum FLS diameter could be found for E, levels, the median of the E, level was calculated by day. E, levels increased during the pill-free week with the maximum on CD 3, and decreased during the rest of the pill cycle (Figure 3). Group comparison revealed no statistically significant differences.

Using the Spearman Rank correlation coefficient, a high correlation was found between maximum follicular diameter and maximum E2 level in both groups.

Discussion Ovarian activity during oral contraceptive use has been described before with all types of combined oral

300

250

Cycle 1

hh 0E

Cycle 3

Cycle 6

200

n 5 0 E

/

Ti i

Figure 3. Median of the maximum estradiol levels (pmol/l) per treatment cycle day. Triphasic EE/ DSG (n = 16): A-A - A; triphasic EE/LNG (n = 15): W---U---m.

I I

150

100

\

I

2

u, 50

\

\

\

k

4:x__L

oL3

‘m \

\

10

17

-5

-1

3

10

Days of treatment

17

cycle

-5

-1

3

10

17

Ovarian Activity and Triphasic Oral Contraceptives

Contraception 1995;52:357-361

two reports comparing contraceptives, 1-4 including triphasic and monophasic preparations.‘~~ No statistically significant differences in ovarian activity between triphasic and monophasic regimens was reported in these studies. In the present study, a comparison in ovarian activity between triphasic EE/LNG and triphasic EE/DSG was made as measured by FLS diameter and P and E, level. Both triphasic OCs gave a comparable level of ovarian suppression. Complete suppression of ovarian activity, however, was found in only 10 of 31 subjects: 6 out of 16 in the triphasic EE/DSG and 4 out of 15 in the triphasic EE/LNG group. Significant ovarian activity was observed in the remaining 21 subjects. Follicle growth particularly occurred during the pill-free interval reaching a maximum at day 3 of the subsequent cycle. Thereafter, most follicles decreased in size or disappeared. These observations are in agreement with previous findings in women on low-dose OCs. l--5,1’ The incidence and degree of ovarian activity was previously found not to change in a period of six months of oral contraceptive use.’ Our study is the first

one to demonstrate

a trend

towards

increasing

ovarian activity

in the later pill cycles. This was more pronounced in the triphasic EE/LNG group, but the difference was not statistically significant. In the present study it did seem that some women were “follicle-prone” since FLSs were seen in every treatment cycle studied. Recent studies do not suggest that some women are more prone than others to develop FLSs during oral contraceptive use. l1 If, however, women have ovarian activity in more than one contraceptive cycle, the FLSs are larger.’ In one out of 93 cycles studied, a possible ovulation was observed, as suggested by the disappearance of a growing follicle and raised P levels. Possible ovulation has also been found by van der Vange,’ whereas Killick13 showed that FLSs developing during OC use may indeed have the potential to ovulate. However, in our case, P levels were comparatively low and follicular collapse is not always associated with ovulation.” Actual contraceptive failure is even less likely as this would additionally require adequately timed changes in cervical penetrability and endometrial receptivity, which was never demonstrated under these conditions.“J’3

Functional sometimes

ovarian associated

cysts during with

serious

phasic pelvic

OC use, pain, have

361

been described before.’ In our study only one subject complained of lower abdominal pain, the subject with the possible ovulation. Other subjects never complained of pelvic pain in the presence of larger FLSs. It can be concluded that triphasic EE/LNG and

triphasic EE/DSG suppressed ovarian activity to the same degree as assessed by ultrasonography and Ez and P levels. Ovarian activity increased of use in both treatment groups.

with

duration

References 1. van der Vange N. Ovarian activity during low-dose oral contraceptives. In: Chamberlain G, ed. Contemporary Obstetrics and Gynaecology. London: Butterworths, 1988:315-26. 2. Killick SR, Eyong E, Elstein M. Ovarian follicular development in oral contraceptive cycles. Fertil Steril 1987;48:409-13. 3. Doyen J, Schaaps JP, Lambote RR. Suivi echographique et hormonal des ovaries sous contraception orale minidosee. Contracept Fertil Sex 1987;15:529-33. 4. Young RL, Snabes MC, Frank ML, Reilly M. A randomized, double-blind, placebo-controlled comparison of the impact of low-dose and triphasic oral contraceptives on follicular development. Am J Obstet Gynecol 1992;167:678-82. 5. Molloy BG, Coulson KA, Lee JM, Watters JK. “Missed pill conception,” fact or fiction. Br Med J 1985;290: 1474-5. 6. Tayob Y, Robinson G, Adams J, Nye M, Whitelaw N, Shaw RW et al. Ultrasound appearance of the ovaries during the pill-free interval. Br J Fam Planning 1990; 16: 94-6. 7. Caillouette JC, Koehler AL. Phasic contraceptive pills and functional ovarian cysts. Am J Obstet Gynecol 1987;156:1538-42. 8. Grimes DA, Godwin AJ, Rubin A, Smith JA, Lacarra M. Ovulation and follicular development associated with three low-dose oral contraceptives: a randomized controlled trial. Obstet Gynecol 1994;83:29-34. 9. Hackeloer BJ, Sallam HN. Ultrasound scanning of ovarian follicles. Clin Obst Gyn 1983;10:603-20. 10. Hoogland HJ, Skouby SK. Ultrasound evaluation of ovarian activity under oral contraceptives. Contraception 1993;47:583-90. 11. Hamilton CJCM, Hoogland HJ. Longitudinal ultrasonographic study of the ovarian suppressive activity of a low-dose triphasic oral contraceptive during correct and incorrect pill intake. Am J Obstet Gynecol 1989;161: 1159-62. 12. Queenan JT, O’Brien GD, Bains LM et al. Ultrasound scanning of ovaries to detect ovulation in women. Fertil Steril 1980;34:99-105. 13. Killick SR. Ovarian follicles during oral contraceptive cycles: their potential for ovulation. Fertil Steril 1989; 52:580-2.