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Ann. N.Y. Acad. Sci. 997: 158–162 (2003). © 2003 New York Academy of Sciences.doi: 10.1196/annals.1290.018

How Low Can You Get?

M. BRINCAT, Y. MUSCAT BARON, AND R. GALEA

University of Malta, Department of Obstetrics and Gynaecology,Medical School G’Mangia, Malta

ABSTRACT: Since the early 1960s the side effects of oral contraceptives havebeen known to be related to the high doses (50 �g) of ethinyl estradiol used. Re-search has focused on reducing the dose of both the estrogen and progestincomponents to reduce these side effects. While reducing the dose of both com-ponents, the contraceptive efficacy has to be maintained so as to retain a satis-factory Pearl index. These requirements appear to have been attained with 24-day regimen of a low-dose pill (15 �g of ethinyl estradiol and 60 �g of geste-done) as one part of an open-label noncomparative multicenter study. This pa-per reports our unit’s results, which indicate that the low-dose pill promises toreduce contraceptive-related side effects, to encourage better compliance, andas corollary, to retain a satisfactory Pearl index

KEYWORDS: oral contraceptives; birth control; progestin; estrogin; gesogen

The oral contraceptive pill is one of the most frequently used and efficient methods ofbirth control. The pill was developed in the mid-1950s, when it was first used at highdoses of 50 mg ethinyl estradiol throughout the 21-day pill cycle. The contraceptiveefficacy of this form of pill was immediately realized; however, in the early 1960s,some side effects in the main arterial and venous thromboembolism began to appear.1,2

A sequential pill was later developed, initially concentrating on reducing the doseof the estrogen component. The first sequential pill contained 7 days of ethinylestradiol followed by 21 days of an ethinyl estradiol–progestogen combination.

Some vascular effects persisted, and further efforts were made to change theprogestin component. Changes in progestin formulation were also accompanied bya reduction in dose. Moreover, the relative androgenicity of the progestin componenthas become an important differential in selecting an oral contraception preparation.3

Both monophasic and biphasic formulations were produced. The estrogen com-ponent varied from 35 µg to 20 µg. To compensate for the reduction in the estrogencomponent, the progestin element had to be kept somewhat elevated, varying from1000 µg norethistherone to 75 µg gestodene (FIG. 1). From the success of the bipha-sic preparations it was realized that further reduction in the progestin component waspossible.5,6 It must be mentioned, however, that there is limited evidence as to theside-effect profile of the biphasic contraception pill.7 The stage had been reached

Address for correspondence: Professor M. Brincat, University of Malta, Department ofObstetrics and Gynaecology, Medical School, G’Mangia, Malta. Voice: +356-21223035 or +356-25952015.

mpbrincat@keyworld.net

159 ANNALS NEW YORK ACADEMY OF SCIENCES

where very low doses of ethinyl estradiol and low-dose gestogens had beenproduced. The low-dose monophasic pill came into being.

Our unit contributed to a multicenter study comparing various low-dose oral con-traceptive pill preparations. The formulations differed from each other in the type ofgestogen used and the doses of both the gestogens and ethinyl estradiol employed.The trial included both qualitative and quantitative data enhancing the understandingof the contraceptive used.4

The comparative model employed included different progestogens with the sameethinyl estradiol dose. Alternatively, the same progestin with varying ethinyl estra-diol doses was also implemented. A comparison was also sought between the 21-dayand the 24-day regimens. The incidence of intermenstrual bleeding was assessed inthe 21-day regimen, utilizing 30 µg ethinyl estradiol combined with desogestrel orgestodene. Both breakthrough bleeding and spotting was less in the 75-µg gestodenearm compared to 150 µg desogestrel.8 Intermenstrual bleeding was also assessed in670 women taking 20 µg ethinyl estradiol and 75 µg gestodene over 6 months.Approximately 18% of women complained of intermenstrual bleeding during thefirst month. This progressively decreased over the 6-month period (FIG. 2).9 Irregu-lar bleeding induced by steroidal contraception is thought to be due to aberrant endo-metrial vascular development caused by the induction of angiogenic growthfactors.10

A further reduction in the dose of ethinyl estrodiol and gestodene was tried on a24-day regimen. The doses were reduced to 15 µg ethinyl estradiol and 60 µggestodene. This 24-day regimen was used in an open-label, noncomparative multi-center study performed in five European countries (Belgium, Denmark, France,Italy, Switzerland, and the UK).

Contraceptive efficiency of the low-dose 24-day regimen indicated a Pearl indexof 0.214. Three pregnancies occurred among 1424 women completing 18,223cycles. These three contraceptive failures had a common denominator, whereby thewomen involved indicated voluntary or involuntary interruption of pill taking. Onewoman became pregnant 17 days after voluntarily stopping the pill. Another womanmissed five pills during cycle 5 and seven pills in cycle 6. The third woman missedone pill on day 18 of the tenth cycle.11

FIGURE 1. Currently available formulations.

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Cycle control with the 24-day low-dose regimen was normal in 71% of cycles.Spotting or intermenstrual bleeding occurred in 22% of cycles, whereas amenorrheawas noted in 7% of the cycles assessed. Forty-six percent of women with amenor-rhea had only one missed menstruation, whereas 40% of amenorrheic women expe-rienced 2–6 cycles of absent menstruation (FIG. 3).

Approximately 12% of women participating in the 24-day low-dose pill studydiscontinued the pill because of the occurrence of certain events. Fifty-nine women(3.9%) discontinued this pill because of metrorrhagia, whereas 1.5% of womeninterrupted their pill taking because of amenorrhea. Twenty-three (2.2%) womenstopped the pill because of headaches. Other causes for 24-day regimen pill discon-tinuation included weight gain, breast pain, and nausea. Menorrhagia and inter-menstrual bleeding have been the most frequently quoted causes of pilldiscontinuation.12

FIGURE 2. Intermenstrual bleeding with GTD 75/EE 20. Cycle control characteristics(n = 670 women). (From Dusterberg et al.9 Reproduced by permission.)

FIGURE 3. Cycle control with a low-dose, 24-day regimen of GTD 60 µg/EE 15 µg.Cycle bleeding characteristics (n = 17,051 cycles). (From Gestodene Study Group.11 Repro-duced by permission.)

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After the aforementioned study, an open-labeled multicenter study comparing thelow-dose 24-day ethinyl estradiol/gestodene regimen to the 21-day ethinyl estradiol/desogestrel regimen. A total of 1074 women were recruited for this study for a totalof six cycles.

The Pearl index in the gestodene 60-µg/ethinyl estradiol 15-µg 24-day regimenagain remained low. One woman became pregnant after having missed five pills dur-ing cycle 5. In this arm, 539 women completed 2982 cycles, for a Pearl index of0.242.13

Study events leading to discontinuation of the pill were rare in both the ethinylestradiol/gestodene and ethinyl estradiol/desogestel arms. The most common rea-sons for discontinuation were headache/migrane, nausea and vomiting, amenorrhea,and breast pain. Nausea and vomiting and breast pain were significantly more com-mon events for discontinuing the ethinyl estradiol/desogestrel pill.11

Estradiol-related side effects appear to be attenuated due to a reduction in ovarianestradiol secretion. Sullivan et al., however, have shown that ovarian estradiol secre-tion is diminished in both the 21- and 24-day regimens compared to pre- and post-pill treatments.14 The reduction in ovarian estradiol secretion appeared most markedin the 24-day 15-µg ethinyl estradiol/60-µg gestodene arm (FIG. 4).

Normal cycle control was significantly lower in the gestodene 60-µg/ethinylestradiol (15-µg) arm compared to the desogestrel 75-µg/ethinyl estradiol arm. Bothintermenstrual bleeding and amenorrhea were less in the desogestrel/ethinyl estra-diol group.11

Although initially 38% of women complained of breakthrough bleeding or spot-ting with the gestodene (60-µg)/ethinyl estradiol (15-µg) pill 24-day regimen, cyclecontrol improved significantly as the trial progressed. In fact, by cycle 18, only 10%of women complained of breakthrough bleeding or spotting while using thegestodene (60-µg)/ethinyl estradiol (15-µg) 24-day regimen (FIG. 5). This may bedue to slow, but progressive restoration of the endometrial balance.11

In conclusion, the 24-day regimen of gestodene (60-µg)/ethinyl estradiol 15 µgprovides the lowest dose oral contraceptive available on the market. With its low

FIGURE 4. Estradiol secretion. (From Sullivan et al.14 Reproduced by permission.)

162BRINCAT: HOW LOW CAN YOU GET?

estrogen content, it leads to fewer estrogen-related side effects and reduces hormon-al fluctuations. These advantages encourage compliance, which is an importantfactor in maintaining the birth control efficacy of an oral contraceptive.

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2. MIDDELDORP, S., J. ROSING & H.R. BOUMEN BULLEN. 2001. Effects of second and thirdgeneration oral contraceptives on haemostasis. New Tijdischr. Geneeskd. 145: 252–256.

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9. DUSTERBERG, B., H. ELLMEN, U. MULLEN, et al. 1996. A three-year clinical investiga-tion of efficacy, cycle control, and tolerability of a new low dose monophasic oralcontraceptive containing gestodene. Gynecol. Endocrinol. 10: 33–39.

10. REES, M.C., M.K. OEHLER & R. BICKNELL. 2000. Steroids and the endometrium. Curr.Med. Chem. 7: 543–560.

11. GESTODENE STUDY GROUP. 1999. Eur. J. Contra Reprod. Health Care.12. COLLI, E., D. TONG, R. PENHALLEGON & F. PARAZZINI. 1999. Reasons for contraceptive dis-

continuation in women 20-39 years old in New Zealand. Contraception 59: 227–231.13. MINESSE REGISTRATION FILE.14. SULLIVAN, H., H. FURNISS, J. SPONE & M. ELSTEIN. 1999. Effects of 21-day and 24-day

oral contraceptive regiment containing gestodene (60 microg/and ethyl estradiol (15microg) on ovarian activity. Fertil. Steril. 72: 115–120.

FIGURE 5. 60/15: cycle control. Breakthrough bleeding and/or spotting.