LOW-DOSE LYNESTRENOL AS A CONTRACEPTIVE METHOD*

J. Prslc", M . D .
P.M. Kic'ovic', M.D.

Family Planning Service, Medical Center

Os] jek, Yugoslavia

and

Organon Scientific Development Group

Medical Unit
Ozs, The Netherlands

ABSTRACT

The use of a continuous low-dose of lynestrenol as an oral contraceptive

has been investigated in a total of 274 women during 2702 cycles. A daily
dose of 0.5 mg** was found to give a satisfactory contraceptive protection; a
total of two pregnancies occurred giving a general failure rate of 0.88 per 100
women-yeors.

The computer analysis showed that the cycle length was moreorless a
normal one in 80 per cent of participants after 6 cycles. Irregular bleeding
occurred in 244 out of 2702 cycles (9%). The incidence of spotting was higher
in the initial cycles, decreasing with the duration of treatment. Less women
experienced break-through bleeding. The method was acceptable to most of the
subjects and slde-effects, other than menstural irregularity, were minimal.

* Read at the VIIth World Congress of Obstetrics and Gynecology Moscow,

August 12 to 18, 19~3.
** Trade name Exlution (Organon, Oss, The Netherlands)
Accepted for publication on September 7, 1973

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CONTRACEPTION

The observation of Martinez-Manautou et al. (11) on the effectiveness of

continuous daily doses of 0.5 mg chlormadlnone acetate initiated a new era
in the field of contraception. Thereafter, several investigators confirmed their
observation investigating different progestogens (1-10, 12) but efficacy indices
and frequency of cycle disturbances showed marked variations. The present
communication deals with the evaluation of lynestrenol as a contraceptive ad-
ministered daily in a dose of 0.5 mg.

MATERIALS AND METHODS

Lynestrenol tablets were taken daily by 274 women, all of proven fertil-
ity, during 2702 cycles. The longest observation time was 20 cycles (Figure1).

The age range was 19-40 (Figure 2), 84.3% being under 35. The aver-
age weight of subjects was 64 kg.

At the first visit a full medical, gynaecologlcal and obstetrical history was
carefully taken and a routine physical and gynaecological examination were per-
formed in all cases. Each woman was provided with tablets (packed in strips
of 35 tablets) and a personal record card to keep a daily record of tablets taken
and bleeding episodes occurring during treatment. With this kind of mlnl-pill
a it is sometimes rather difficult to make a clear-cut distinction between a "men-
struatlon" and a break-through bleeding. Taking into account the menstrual
pattern of the woman before she started to take medication, the intensity of the
bleeding episodes and the intervals between them, it was arbitrarily decided
whether a bleeding should be considered as a BTB or as a menstruation. It is
possible that the number of BTB's given in this report is, to a certain extent,
too high or too low. All data on the treatment cycles were recorded on special
forms and evaluated by computer analysis.

RESULTS

Acceptability

The method was acceptable to most of the subjects and slde-effects, other
than menstrual irregularity, were minimal. Thirty-four women (12.4%) dropped
out of the trial: 7 because of break-through bleeding, 6 because of amenorrhea,
2 became pregnant, 2 because of intercurrent !llness (not related to the treat-
ment) and 17 for purely social and unrelated causes. Neither liver disturbances
nor thromboembollc disorders were detected during the control study.

316 OCTOBER 1973 VOL. 8 NO. 4

 CONTRACEPTION

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OCTOBER 1973 VOL. 8 NO. 4 317

CONTRACEPTION

Figure 2 - Age distribution

Cases
100
96

75

65

58

50

35

25 ~

12
8

I <19 20-24 25-29 30-34 35-39 > 40

Years

318 OCTOBER 1973 VOL. 8 NO. 4

 CONTRACEPTION

Contraceptive efficacy

Two pregnancies occurred during the study giving a general failure rate
(Pearl index) of 0.88 per 100 woman-years (with a 95% confidence interval of
0.1 - 3.2). (In the over--all computer analysis of several clinical trials with
this drug, the mean cycle length during the first 6 months of treatment was
29.6 days. Accordingly, 1 woman-year was considered as 12 cycles). One
woman had taken tablets regularly, and her pregnancy was thought to represent
a "method failure" and resulted in a Pearl index of 0.44 per 100 women-years
(with a confidence interval of 0.01 - 2.5). The other subject was a typical "patient
failure" following omission of tablets.

Cycle control

Natural cycle length distribution, shown in Figure 3, indTcates that in

269 out of 274 women (98.1%) cycles lasted from 24 to 33 days.

Cycle length distribution during the treatment is shown in Figure 4. The

histogram of the data is based on the computer analysis of the cycle length
variation per woman and per cycle. The cycle length of the first treatment
cycle deviated by not more than +_ 4 days or less from the cycle length prior
to treatment in 71 per cent of the women. In the sixth cycle this figure was
about 82 per cent and remained between 80 - 88 per cent throughout cycles
7 - 15. Although in initial cycles, the percentage of women with either
shortened or prolonged cycles was relatively low, the incidence gradually de-
clined further throughout the trial. Nevertheless, the incidence ranged between
3 - 8 per cent for the three categories of changed cycle length.

Oligo-amenorrhea appeared in 114 out of 2702 cycles (4.2%). Only in

30 cycles (1.1%) did amenorrhea last for more than 60 days.

Analysis of the menstrual pattern revealed that, although in mast cycles

there were no changes, a tendency towards a decreased amount of flow per-
sisted throughout all cycles (Table I).

On the other hand duration of flow, shown in Table II, was prolonged in
most subjects.

There were marked decreases in both dysmenorrhea and the premenstrual

tension syndrome in most cases where these had existed before treatment.

Irregular bleedlngs
Irregular bleeding is well known to be the biggest problem during low-dose

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CONTRACEPTION

Figure 3 - N a t u r a l cycle length distribution

Cases
138

125"

100,

75-
67

50-
42

25-

I 3 16 6

20-23 24-25 26-27 28-29 30-31 32-33 34-35

Cycle length in days

320 OCTOBER 1973 VOL. 8 NO. 4

 CONTRACEPTION ~

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O C T O B E R 1973 VOL. 8 NO. 4 321

CONTRACEPTION

TABLE I

Amount of flow compared wlth the natural cycle*

Decreased No Change Increased

Cycle 1 73 (26.6%) 172 (62.4%) 29 (11.0%)

Cycle 5 69 (30.1%) 110 (56.1%) 17 (13.9%)

Cycle 10 50 (31.6%) 97 (61.3%) 11 (7.1%)

Cycle 15 25 (31.2%) 49 (61.2%) 6 (7.6%)

*Total number and percentage of women in each category for

representative cycles is shown.

TABLE II

Duration of flow, compared with the natural menses

(percentage of women)

Prolonged for
Shortened for
>2 days 1-2 d a y s Unchanged 1-2 days :'2 days

Cycle 1 3.5 25.4 26.3 33.6 11.2

Cycle 5 4.8 26.1 22.5 28.4 18.2

Cycle 10 2.6 23.3 25.4 39.4 9.3

Cycle 15 3.7 11.2 27.5 51.3 6.2

322 OCTOBER 1973 VOL. 8 NO.

 CONTRACEPTION

gestagen treatment. Data on break-through bleeding and spotting are shown in

Table III. The incidence of spotting was higher than the incidence of break-
through bleeding. The frequency of irregular bleeding decreased during treat-
ment. Irregular bleeding was acceptable to most of the women; only 7 (2.5%)
dropped out because of prolonged break-through bleeding.

Other side-effects

All other side-effects were minimal, far less than with conventional prep-
arations. Nausea, headache, breast tenderness, etc. occurred only occasional-
ly, while some changes in weight were found in 13 per cent of women in the
first cycle and 10.6 per cent in the second cycle. After the second cycle
changes in weight almost disappeared.

DISCUSSION

Continuous daily administration of lynestrenol 0.5 mg provided contra-

ceptive protection with a "tablet failure" rate of 0.44 per 100 woman-years.
Therefore, when taken regularly, this progestogen is a very reliable contra-
ceptive preparation. One recent publication (12) has already shown that lynes-
trenol, with a pregnancy rate of 0 and excellent cycle control in a large
scale study, is superior when compared with other low-dose gestagen prepara-
tions (1-6, 9, 10, 13). Our data confirm this conclusion.

The frequency of break-through bleeding and spatting was relatively high

in initial cycles, but both were considered acceptable by most of the women.
The incidence of these problems was less than with other progestagens used in
continuous low dosage.

Cycle control was satisfactory in mast subjects. Side-effects were rare

and insignificant.

The acceptability of this preparation, as illustrated by a very low drop-

out rate is favorable in comparison with conventional and other low-.dose ges-
tagen preparations.

It is concluded that with the very low pregnancy rate and the very low
discontinuation rate for menstrual disturbances, acceptable variation or cycle
length and complete absence of other complaints in the majority of subjects
treated, lynestrenol is considered to be a good and safe low-dose gestagen
preparation.

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TABLE III

Percentage of Women with BTB and Spotting

Cycle 1 5 10 15

No irregular 81.1 88.8 96.7 98.8

bleeding

Breakthrough 9.4 3.2 0.7 0

bleeding

Spott|ng 9.5 8.0 2.6 1.2

BTB and Spotting 18.9 11.2 3.3 1.2

No. of Cases 274 196 158 80

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REFERENCES

1. Asbj~rn, O., Lebech, P.E., Strayer, I., and Thing, E. Low close of
gestagen as a contraceptive method. Dan. Med. Bull., 18(5):122, 1971.

2. Avendano, S., Tatum, H.J., Rudel, H.W., and Avendano, C. A

clinical study with continuous low doses of megestrol acetate for fertility
control. Amer. J. Obst. Gynec. 109:531, 1971.

3. Board, J.A. Continuous norethlndrone, 0.35 mg., as an oral contra-

ceptive agent. Amer. J. Obst. Gynec. 109:531, 1971.

4. El Mahgoub, S. and Karlm, M. Continuous low doses of clomagestone

in fertility control. J. Obstet. Gynaec. Brit. Commonwealth, 78:930,
1971.

5. Eckstein, P., Whltby, M., Fotherby, K., Butler, C., Mukherjee, T.K.,
Bumett, J.B.C., Richards, D.J., and Whitehead, T.P. Clinical and
Laboratory Findings in a Trial of Norgestrel, a Low-dose Progestogen-only
Contraceptive. Brit. Med. J., 5820:195, 1972.

6. Foss, G.L., Svendsen, E.K., Fotherby, K., and Richards, D.J.

Contraceptlve Action of Continuous Low Doses of Norgestrel, Brit. Med.
J. 4:489, 1968.

7. Foss, G.L. Oral contraception with continuous micro-dosage of nor-

gestrel. J. Reprod. Fert. Suppl. 5, 145, 1968.

8. Foss, G.L. A clinical trial of a new totally synthetic low dose progestagen.
J. Reprod. Fert. 18:59, 1969.

9. Larsson-Cohn, U. Contraceptive treatment with low-doses of gestagen

(thesis), Uppsala, 1970.

10. Lawson, J.P. and Bradshaw, F.P. Experience with norethlsterone 0.35 mg
as an oral contraceptive - a preliminary report. Current Med. Res. and
Opinion, 1:53, 1972.

11. Martinez-Manautou, J., Cortez, V., Giner, J., Aznar, R., Casasola, J.,
and Rudel, H.W. Low dose of Progestogen as an Approach to Fertillty
Control. Fert. Ster. 17:49, 1966.

12. Ravn, J. Contraception with the Lynestrenol "Mini-Pill". Arzneim.-

Forsch. 22:104, 1972.

O C T O B E R 1973 VOL. 8 NO. 4 325

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13. Zanartu, J., Rodrigues-Moore, G., Pupkin, M., Salas, O., and
Guerero, R. Antlfertility Effect of Continuous Low-dosage Oral Pro-
gestogen Therapy Brit. Med. J., 2:263, 1968.

326 OCTOBER 1973 VOL. 8 NO. 4