Advances in Contraception. 1993;9:187-194. O 1993 Kluwer Academic Publishers. Printed in the Netherlands

Inhibition of ovulation by a triphasic gestodene-containing oral contraceptive

J. SPONA (1,2), U. LACHNIT-FIXSON (3), B. DUSTERBERG (3) and K. DOBIANER (2)

(1) Division of Molecular Endocrinology, First Department of Obstetrics and Gynecology; (2) Ludwig Boltzmann-Institute for Experimental Endocrinology, Division of Cellular Endocrinology, University of Vienna, Austria (3) Department of Fertility Control, Schering AG, Berlin, Germany

Abstract

The minimal effective dose of gegtodene for inhibition of ovulation was studied in 30 female volunteers. Daily doses of 10/zg to 50/zg gestodene were given orally for 21 days. A control cycle prior to treatment and a treatment cycle were monitored for LH, FSH, estradiol, progesterone and cervical score. At a daily dose of 40/zg of gestodene, 6/7 volunteers exhibited inhibition of ovulation and 1/7 had a cycle with luteal insufficiency. Ovulation was inhibited in all volunteers on 50 /zg gestodene, suggesting that the minimum dose required to inhibit ovulation was 40 /zg gestodene. Cervical score was blunted even at 10 /zg gestodene. Similarly, 20 volunteers were treated with coated tablets containing ethinylestradiol/gestodene at 30/50 /zg for 6 days, 40/70 #g for 5 days and 30/100/zg for 10 days. This triphasic gestodene-containing preparation inhibited ovulation in all 20 females. In one cycle in which follicle development was observed only 43 pg estradiol/ml was secreted. Data from this investigation suggest that this triphasic gestodene-containing OC has a high contraceptive efficacy.

Introduction

The development of OCs during the past 10 years has been pursued by two main routes: 1) new dose schedules that allow the reduction of the progestogen component without sacrificing cycle control. Introduction of the triphasic pill contributed to the high standard of the modern OC [1], 2) the development of new progestogens. The strong progestogenic activity of the low-dose compounds resulted in improved metabolic profiles of combination preparations. The development of gestodene [2] and of desogestrel [3] was carried out to achieve these goals. Both compounds are derivatives of 19-nortestosterone. Gestodene was found to exhibit the endocrine- pharmacologic prof'des essential for its use in an OC [4]. This led to the development

188 Sporta et al.

of a monophasic gestodene-containing preparation [5]. The present paper describes the investigation of the borderline dose for inhibition

of ovulation by gestodene and its use in a triphasic preparation.

Materials and methods

In total, 50 volunteers participated in the studies. All women were given extensive verbal information on the study, its aims, possible

risks, and personal restrictions during the study. Subjects with any of the usual contraindications for OCs were excluded from the investigation.

Ovulation inhibition dosage for gestodene was determined in 30 volunteers, aged from 20 to 28, with normal cycles. After a control cycle they were given a daily oral dose of 10, 20, 30, 40 or 50/zg gestodene, respectively, from day 5 to day 25 of the cycle. During the control cycle and the cycle under investigation LH, FSH, estradiol and progesterone serum levels were determined. In addition, cervical score was recorded.

Similarly, 20 volunteers aged from 20 to 28 were recruited to investigate inhibition of ovulation by a triphasic gestodene-containing preparation, comprising 6 coated tablets containing 30/zg EE plus 50/zg gestodene, 5 coated tablets containing 40/zg EE plus 70/zg gestodene and 10 tablets containing 30/zg EE plus 100/zg gestodene. A control cycle was investigated before the triphasic preparation was given from day 5 through day 25 of the treatment cycle. LH, FSH, estradiol and prolactin were estimated.

Grading of ovarian activity was based on the biochemical parameters. Four groups were defmed: inhibition of ovulation with or without follicular development, luteal insufficiency, and ovulation. In 10/20 volunteers, abdominal ultrasound examinations were carried out in order to corroborate results obtained by the hormone assays.

Hormone assays were carried out by radioimmunoassay. LH was determined by materials obtained from Sorin, France. The assay of FSH was done by materials provided by Behring, Germany. Estradiol, progesterone and prolactin was estimated by materials obtained from Diagnostic Products Corporation, USA. Intra-assay and inter-assay coefficients of variation were between 5 and 8%, respectively.

Results

Gestodene borderline dose

Inhibition of ovulation by single daily doses of gestodene was studied in five groups of volunteers, who were given between 10 and 50 /zg gestodene. Patterns of cycles observed were classified as: ovulatory; non-ovulatory with or without follicle development; and cycles with luteal insufficiency. The classification was based on patterns of LH, FSH, estradiol and progesterone serum levels. Follicle development was registered by increases of estradiol serum levels above 30 pg/ml. Most cycles in

Inhibition of Ovulation by a Triphasic Gestodene-Containing OC 189

which follicle development was observed had estradiol serum levels in the range of preovulatory levels or even higher (Figure 1). No LH peak could be found in anovulatory cycles with follicular development. Small and/or short rises of post- ovulatory progesterone serum levels above 1.6 og/ml but below 3 ng/ml were used to classify cycles with luteal insufficiency (Figure 2). At doses below 30/zg.gestodene a high incidence of ovulatory cycles was noted (Table 1). At a daily dose of 30 /zg gestodene 11/12 (92%) volunteers exhibited inhibition of ovulation, but a high incidence (72%) of cycles with follicle development was found at this dose. At the 40 ~g dose 6/7 (86%) volunteers had anovulatory cycles and in 4/6 (67%) anovulatory cycles follicular development was observed. One cycle was noted with luteal insufficiency.

30

20

10

I Control cycle 1 30 #g Gestodene

LH miU/ml

FSH rniU/ml

I 301 2O

1 0 - v

�9 17t3-Estradiol pg/ml 600 -

400 -

200 -

Progesterone ng/ml

1 5 -

1 0 -

5 -

1 2 -

8 -

4 -

Day

/m Cervical score

~LItlll l l l t l l l l l I J ~ l l l l l l L 4 8 12 16 20 24 28 4 8 12 16 20 24 2~

Figure 1. Patterns of hormone serum levels and cervical score noted in a volunteer with follicular development during treatment with 30/~g gestodene

190 Spona et a~

Control cycle 10 p.g Gestodene

�9 LHmiU/ml 30 . / _ . _ ~ 2O

10-

�9 FSH miU/ml

30

20

10

�9 178-Estradiol pg/ml

600

400

200

�9 Progesterone ng/ml

15

5

�9 Cervical score

8

4

I l l l l l t l l l l l l r J J J t l I I J l l l a t J l l l l l l ~ l ~ l l l

Day 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32

Figure 2. Hormone serum levels and cervical score in a volunteer with luteal insufficiency during treatment with 10 /zg gestodene

Ovulation was inhibited in all volunteers with the 50/zg dosage, and 2/7 (29%) females had follicular development at this dose. Grading of ovarian activity during oral application of various daily doses of gestodene is summarized in Table 1. These data define a borderline dose of approximately 40/zg gestodene for inhibition of ovulation.

It is noteworthy that cervical function was inhibited even at the lowest gestodene dose studied. As can be seen from Figure 1, the cervical score was reduced to values of anovulatory cycles at a daily dose of 10/zg.

Inhibition of Ovulation by a Triphasic Gestodene-Containing OC 191

Table 1. Patterns of cycles in 30 volunteers during application of daily doses of gestodene ranging from 10/zg to 50/zg. Treatment started on day 5 and ended on day 25 of the cycle

Borderline doses of gestodene for inhibition of ovulation

Number of Subjects

Dose ~ug)

10

20

30

40

50

Total Number of Subjects

2

2 12

7

7

Inhibition of Ovulation

-11

6

7

Follicular Maturation

Luteal Insufficiency

Normal Cycle

1 1

Triphasic gestodene

The triphasic preparation inhibited ovulation in all cycles studied (Figure 3). In 1/20 volunteers, follicular development was shown by a rise of estradiol to 43 pg/ml serum. In 10 cases the biochemical findings were corroborated by sonographic examinations (data not shown). In addition, the cervical score was diminished to values observed in anovulatory cycles. During treatment with the triphasic gestodene preparation, fluctuating levels of prolactin were observed. There were no alterations exceeding the normal range or those of the pretreatment cycle (Figure 4).

D i s c u s s i o n

Introduction of the triphasic principle allowed a dose reduction of older generation progestageus without sacrificing cycle control [6]. Dose reduction was aimed at lowering possible side-effects caused by the synthetic steroids administered. Efforts to minimize the adverse side-effects of oral contraceptives have also focused on the synthesis of new steroids used in low-dose formulations. This led to the development of the new generation progestagen gestodene which was found to exhibit an improved pharmacological and endocrine profile in comparison with older-generation progesta- gem [7,8]. The main progress with this compound was its enhanced progestagenic activity but decreased residual androgenic activity when compared to older-generation progestagens, as shown in animal pharmacology model systems [8]. The improved pharmacologic profde found in animal models could be corroborated in clinical studies using a monophasic oral contraceptive containing 30 #g ethinylestradiol and 75/zg gestodene [9].

The present data show that gestodene inhibits ovulation at a minimal daily dose lower than that described for levonorgestrel (approximately 50 #g) [10] or for desogestrel (60/zg) [3]. The cervical score was suppressed even at the lowest dose level (10/zg gestodene) studied in the present investigation. This implies inhibition of

192 Spona et aL

sperm penetration as a back-up mechanism contributing to the contraceptive efficacy of the triphasic gestodene preparation. These data also suggest that gestodene can be used at an extremely low dose in a progestagen-only oral contraceptive.

30

20 15 10 5

�9 FSH miU/ml 3O 25 2O 15 10

4 �9 178-Estradiol ng/I

200 :i 100

�9 Progesterone ~g/I

60 ~

4O ao 2 o - l O -

Con t ro l cyc le Tr iphas ic G e s t o d e n e

LH miU/ml

�9 Cervical function

10 - '~: '=

5 "

. . . . . . .

- 5 - 0 - 0 1 15 -15-10 -5 0 5 10 1

Day 0 = LH Peak days

Figure 3. Inhibition of ovulation by triphasic gestodene. Hormone serum levels and cervical score observed in 20 volunteers

The present investigation indicates that the triphasic gestodene-containing oral contraceptive has a high efficacy in inhibiting ovulation. A recent publication on a long-term clinical trial with triphasic gestodene is in support of this notion. The study was performed in 1933 women for 30 763 cycles and resulted in a Pearl index of 0.09 [11]. Furthermore, data of the present investigation suggest that this preparation

Inhibition of Ovulation by a Triphasic Gestodene-Containing OC 193

causes a low incidence of follicular development. Previously, the effects of low-dose combined oral contraceptives on ovarian function were assessed by ultrasound examinations and peripheral endocrine parameters [12]. The investigators reported that triphasic gestodene suppressed ovarian function to a significantly greater extent than other low-dose preparations, such as monophasic norethisterone, monophasic cyproterone acetate, and triphasic levonorgestrel.

Contro l cyc le Tr iphas ic Ges todene

HPRL ~tg/I

30 25 20 15- 10- 5 -

I 1 / I I I I

- 15 -10 -5 0 5 10 15 Day 0 = LH Peak

I I | I I I I

-15 -10 -5 0 5 10 15 days

Figure 4. Prolactin serum levels in 20 volunteers on triphasic gestodene

The results of the present study were corroborated by recent multicenter clinical trials in which high contraceptive efficacy of the triphasic gestodene was noted [13]. The use of the present preparation produced excellent cycle control. Spotting and breakthrough bleeding dropped below the pretreatment incidence after three months of use [13]. The rate of breakthrough bleeding was similar to or better than that previously published for other low-dose triphasic regimens [14]. The slowly increasing doses of gestodene during the various phases and the increase in estrogen during the second phase mimic the cyclical variations in hormone levels of normal natural cycles. This and the improved pharmacologic-endocrine profde of gestodene may be favorable for better development and transformation of the endometrium.

Data of the present study and results of previous investigations suggest that the triphasic gestodene-containing preparation has a high contraceptive efficacy.

References

1. Lachnit-Fixson U. Development and clinical evaluation of triphasic oral contraception. In: Elstein M, ed. Update on triphasic oral contraception. Amsterdam: Excerpta Medica. 1982;37-53.

2. Hofmeister H, Annen K, Laurent H, Petzoldt K, Wiechert R. Synthesen yon Gestoden. Drug Res. 1986;36:781-3.

3. Cutlberg G, Lindstedt G, Lundberg P-A, Stefferson K. Central and peripheral effects of desogestrel 16-60 /zg daily for 21 days in healthy female volunteers. Acta Obstet Gynecoi Scand. 1982;111(suppl):47-54.

4. Diisterberg B, Beier S, Schneider WHF, Spona J. In: Breckwoldt M, Diisterberg B, eds. Gestodene a new direction in oral contraception. Carnforth: The Parthenon Publishing Group Ltd. 1988;13-29.

194 Spona et al.

5. Eistein M. Gestodene: Development of a new gestodene-eontaining low-dose oral contraceptive. Carnforth: The Parthenon Publishing Group Ltd. 1987.

6. Lachnit-Fixson U. The rationale for a new triphasic contraceptive. In: Greenblatt RB, ed. The development of a new triphasic oral contraceptive. Lancaster. MTP Press Ltd. 1980:23-30.

7. Spona J, Schneider WHF, Biegimayer C, Schroeder R, Pirker 1L Ovulation inhibition with different doses of levonorgestrel and other progestagens: clinical and experimental investigation. Acta Obstet Gynecol Scand. 1979;88:7-15.

8. Elger W, Steinbeek H, Schillinger E, Losert W, Beier S. Endocrine-pharmacological profile of gestodene. In: Elstein M, ed. Gestodene: Development of a new gestodene-containing low-dose oral contraceptive. Carnforth: The Parthenon Publishing Group Ltd. 1988:19-33.

9. Brill K, Norpoth T, Schmitker J, Albring M. Clinical experiences with a modern low-dose oral contraceptive in almost 100 000 users. Contraception. 1991;43:101-10.

10. Spona J, Schneider WHF, Lachnit-Fixson U. Mode of action of triphasie oral contraception. In: Greenblatt RB, ed. The development of a new triphasic oral contraceptive. Lancaster: MTP Press Ltd. 1980:51-68.

11. Weber-Diehl F, Unger R, Lachnit U. Triphasic combination of ethinylestradiol and gestodene. Long-term clinical trial. Contraception. 1992;46:19-27.

12. van der Vange N. Effects of seven low dose combined oral contraceptives on ovarian function, measured by ultrasound examination and peripheral endocrine parameters. Thesis 1986; Utrecht State University, Utrecht, The Netherlands.

13. Crosignani PG, Finelli F, Pizzi C. Muitieenter clinical trials on triphasic gestodene. In: Genazzani AR, Skouby SO, eds. Triphasic Gestodene. Carnforth: The Parthenon Publishing Group Ltd. 1992:77-90.

14. Schilling LH, Bolding OT, Chenault CB et al. Evaluation of the clinical performance of three triphasic oral contraceptives: a multicenter randomized comparative trial. Am J Obstet G-ynecol. 1989;160:1264-8.

MS received 9Apr. 93. Accepted for publication 5 May 93.

Resum~

Une dose efficace minimale de gestod6ne destin6e h inhiber l'ovulation a 6t6 6tudi6e chez 30 femmes qui se sont pr&6es volontairement aux essais. Des doses journali6res de 10/zg h 50 #g de gestod/me ont 6t6 administr6es oralement pendant 21 jours. Les contr61es qui ont 6td effectu6s au cours d'un cycle t6moin pr6alable au traitement et d'un cycle de traitement portaient sur les hormones LH et FSH, l'oestradiol, la progest6rone et l'indice cervical. A une dose de 40 ~g de gestod~ne, l'ovulation 6tait inhib6e chez six-septi~me des volontaires, alors que ehez le septi/~me restant on avait constat6 une insuffisance lut~ale. L'ovulation a ~t6 inhib6e chez routes les volontaires avec une dose de 50/~g de gestod~ne, ce qui laisse penser que la dose inhibant l'ovulation se situe h 40/~g. L'indice cervical 6tait net m~.me h une dose de 10 ~g. Par ailleurs, 20 volontaires ont 6t6 trait6es avec des comprim6s enrob6s contenant de l'dthinyloestradiol/gestod~ne h 30/50 pendant 6 jours, h 40/70 pendant 5 jours et 30/100 pendant 10 jours. Cette pr6paration triphasique contenant du gestod6ne a inhib~ l'ovulation chez 20 femmes. Au cours d'un cycle o3 l'on a observ6 un d6veloppement folliculaire, ~ peine 43 pg d'oestradiol/ml ont 6t6 secr6t6s. Les r6sultats obtenus jusqu'ici sugg6rent que ce contraceptif oral triphasique contenant du gestod~ne a u n pouvoir contraeeptif 61ev6.

Resumen

Se estudi6 la dosis eficaz minima de gestod6n para inhibir la ovulaci6n en 30 voluntarias. Se dieron dosis orales diarias de 10/2g a 50/zg de gestogSn durante 21 dfas. Un ciclo de control anterior al tratamiento y un ciclo de tratamiento fueron controlados segdn indices de LH, FSH, estradiol, progesterona y cervical. A una dosis diaria de 40/ tg de gestod6n, 6/7 voluntarias presentaron inhibici6n de la ovulaci6n y 1/7 tuvieron un ciclo con insuficiencia hltea. La ovulaci6n fue inhibida en todas las voluntarias con 50/zg de gestod6n, Io cual sugiere que la dosis para inhibit la ovulaci6n era 40/zg de gestod6n. El fndice cervical era neto aun con 10 /zg de gestod6n. Del mismo modo, 20 voluntarias fueron tratadas con pastillas revestidas que contenian etinilestradiol/gestod6n a 30/50 durante 6 dias, 40/70 durante 5 dfas y 30/100 durante 10 dfas. Esta preparaci6n trifhsica con gestod6n inhibi6 la ovulaci6n en la totalidad de las 20 mujeres. En un ciclo en el que se observ6 desarrollo folicular s61o se secretaron 43 pg de estradiol/ml. Los datos de este estudio sugieren que este anticonceptivo oral trifhsico con gestod6n tiene gran eficacia anticonceptiva.