Progestogen potency in oral contraceptive pills

Bonnar

dose estrogen may potentiate or reduce the estrogen effects. The low-dose OC formulations in current use produce significantly less change in the hemostatic system than do preparations that contain 50 J.Lg of estrogen. The estrogen/progestogen combinations also increase fibrinolytic activity, which most probably balances the increase in coagulation activity, thus preserving the dynamic equilibrium between coagulation and fibrinolysis. Current research is aimed at finding low-dose formulations of estrogen/progestogen that will produce the least change in the hemostatic system and in other metabolic processes. This appears to be the most logical way of minimizing the risk of vascular complications and thus increasing the safety of oral contraception for the millions of women who use this method of fertility control. I would like to thank Dr. Ali Sabra, Leisha Daly, and Eilis Carroil for their excellent teamwork in these research studies.

October I 98 7 Am J Obstet Gynecol

REFERENCES I. Shapiro S. Oral contraceptives-a time to take stock. N Englj Med 1986;315:450-l. 2. Stadel BV. Oral contraceptives and cardiovascular disease. N Englj Med 1981;305:612-8, 672-7. 3. Bocaz JA, Barja P, Bonnar J, et a!. Differences in coagulation and hemostatic parameters in normal women of childbearing age from different ethnic groups and geographical locations. Task Force on Oral ContraceptivesWHO Programme of Research, :Development and Research Training in Human Reproduction. Thromb Haemost 1986;55:390-5. 4. Belsey MA, Russel Y, Kinnear K. Cardiovascular disease and oral contraceptives: a reappraisal of vital statistics data. Fam Plann Perspect 1979;2:84-9. 5. Beller FK, Ebert C. Effects of oral contraceptives on blood coagulation. A review. Obstet Gynecol Surv 1985;40: 425-36. 6. Notelovitz M. Oral contraception and coagulation. Clin Obstet Gynaecol 1985;28:73-83. 7. Sabra A, Bonnar J. Haemostatic system changes induced by 50 meg and 30 meg estrogen/progestogen oral contraceptives. J Reprod Med !983;28(suppl):85-9l.

Progestogen potency in oral contraceptive pills Michael D. G. Gillmer, M.D. Headington, Oxford, United Kingdom The most important target organs for combined oral contraceptive preparations are the anterior pituitary gland and the uterus. The long-term unopposed administration of estrogen produces endometrial hyperplasia and amenorrhea, which are unacceptable to most women and their medical advisors. Cyclic administration of progestogens in combination with the estrogen, however, produces predictable endometrial shedding and achieves a regular and acceptable bleeding pattern in most women. This was the main reason that the "delay of menses" test was adopted as the earliest clinical means of comparing the relative potencies of progestogens that were administered orally. Recently attempts have been made to compare the potency of progestogens on the other organ systems by the extrapolation of data derived from studies on the endometrium. This is inappropriate, inasmuch as the effects Of progestogens and estrogens independently and in combination differ greatly depending on the target organ. In this article, the literature on this controversial subject is reviewed. (AM J OssrET GYNECOL 1987;157:1048-52.)

Key words: Oral contraceptives, progestogen potency, delay of menses test, lipid metabolism To appreciate fully the confusion that currently surrounds the concept of the potency of progestogen, it is necessary to know the early history of the tombined oral contraceptive (OC).

History of the combination pill The first 19-norprogestogen, norethisterone, was synthesized in October 1952, and the U.S. patent for the drug was filed a month later by Carl Djerassi on

From the john Radcliffe Maternity Hospital.

1048

behalf of Syntex. In August 1953, nearly a year later, Frank B. Colton of Searle filed the patent for norethynodrel. Although it was known that norethynodrel was converted to norethisterone by weak acids and that this conversion almost certainly occurred in the stomach after ingestion, commercial reasons led to the choice of norethynodrel as the preparation that was used in the first studies of the OC pill. According to Vaughan, 1 the reason given for this decision was that norethisterone had been shown to produce testicular enlargement in rats, and it was feared that this compound might have masculinizing effects. However, Pincus, who played a

Progestogen potency in OC

Volume 157 Number 4, Part 2

major part in the early studies on the pill, was closely associated with Searle, and it is not altogether surprising that he and his associates favored the Searle compound in clinical trials. Thus even the very earliest stages in the development of the OC pill were marked by confusion about the relative actions of its progestogen components. Further confusion followed the discovery that norethynodrel contained an estrogen contaminant, mestranol. When this contaminant was eliminated, cycle control, which had previously been satisfactory, became unpredictable and breakthrough bleeding occurred. The estrogen was therefore reintroduced in an amount that was equivalent to 1.5% of the progestogen dose. Thus it is apparent that the resulting "combination pill" Enovid, which contained 10 mg of norethynodrel and 150 fLg of mestranol, was essentially a product of chance. This early experience with the pill clearly demonstrated an interaction between the estrogen and the progestogen components on the endometrium, an interaction that has frequently been ignored when progestogens such as levonorgestrel and desogestrel have been compared with the earlier products that were derived from norethisterone.

Emergence of potency as an issue Until recently, the relative potency or bioactivity of the constituents of OCs had been of little interest to clinicians. In 1983 the publication by Pike et a!. 2 of data that linked the risk of breast cancer to the progestogen content of the pill, and in particular the "potency" of the progestogens in different preparations, has, however, focused attention on this issue. Of the innumerable target organs for the steroids in combination OC preparations, the anterior pituitary gland and the uterus are clinically the most important. The initial doses of estrogen and progestogen "chosen" for the pill appeared to inhibit ovulation effectively, but in practice it was difficult to assess "potency" by comparing the effects of different progestogens on the ovulatory process. In addition, it soon became apparent from the early clinical trials that irregular bleeding was unacceptable to women taking the pill and that this effect on the endometrium was likely to be as important a factor to the success of the pill as its ability to prevent pregnancy. The delay of menses test The endometrial effects of the pill were relatively easy to measure in clinical practice; therefore it was logical that the earliest efforts to compare the potency of progestogen in women relied on the so-called delay of menses test. This originated from an observation by Greenblatt et al. 3 that if women with normal menstrual cycles were given a progestogen, but not an estrogen,

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togens on the endometrium cannot be extrapolated to the breast. Although studies are in progress to clarify the effect of the pill on this target organ (Anderson TJ, personal communication), their results are not yet available.

The future This brief review cannot examine the many effects of OCs on end-organs, but certain general points can be made. New combinations of estrogen and progestogen must be "designed" not only to be highly effective in inhibiting ovulation and altering cervical mucus and endometrium but also in achieving optimal cycle control with minimal metabolic perturbation. This involves careful study of as many measurable end points as possible, including lipid and carbohydrate metabolism and coagulation processes. It will never be possible to assess all effects on end-organs and some chances will have to be taken, as they were with Enovid. Several questions remain to be answered. For example, do the increases in high-density lipoprotein cholesterol (in particular the high-density lipoprotein 2 subfraction) that have been observed with recent formulations protect the patient from atherogenic disease? Does it matter that most of these preparations continue to produce significant alterations in coagulation factors17 and other proteins such as sex hormone-binding globulin? 18 Do minor alterations in metabolic processes matter if values remain within the normal range? Are the biologic effects of OCs related to the highly variable circulating concentrations of the individual components that have been observed 7· 19-21 (Figs. 3 and 4), and, if so, should efforts be made to tailor the "pill dose" to the needs of each person? This would presumably mean that it would be more appropriate for those

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women who experience poor cycle control while taking low-dose preparations to take the older high-dose preparations. It will take many years to answer these questions and until then we will have to accept our very incomplete understanding of "progestogen potency" and the pill.

Gillmer

October 1987 Am J Obstet Gynecol

REFERENCES 1. Vaughan P. The pill on trial. Harmondsworth, Middlesex, England: Penguin Books, 1972. 2. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983;2:926. 3. Greenblatt RB, Jungck EC, Barfield WE. A new test of efficacy of progestational compounds. Ann NY Acad Sci 1958;71:717. 4. Swyer GIM, Sebok L, Barns DF. Determination of the relative potency of some progestogens in the human. Proc R Soc Med 1960;55:435. 5. Dickey RP, Stone SC. Progestational potency of oral contraceptives. Obstet Gynecol 1976;47:106. 6. Fotherby K. Biological activity of progestogens in humans. BrJ Fam Plann 1985;11(suppl):10. 7. Goldzieher JW. Use and misuse of the term potency with respect to oral contraceptives. J Reprod Med 1986; 31 (suppl):533. 8. Greenblatt RB. Progestational agents in clinical practice. Med Sci 1967;May 37. 9. Swyer GIM. Potency of progestogens in oral contraceptives-further delay of menses data. Contraception 1982; 26:23. 10. Swyer GIM. The development of potency tests. Eur J Obstet Gynecol Reprod Bioi 1984;4(suppl 2):S110. 11. Grant EC. Hormone balance and oral contraceptives. J Obstet Gynaecol Br Commonw 1967;74:908. 12. Ferinj. Orally active progestational compounds. Human

13. 14. 15. 16. 17. 18.

19. 20. 21.

studies: effects on the utero-vaginal tract. In: Tausk M, ed. International encyclopaedia of pharmacology and therapeutics. Oxford: Pergamon Press, 1972; vol 2: 245-73. Drill VA. Oral contraceptives. New York: McGraw-Hill, 1966. Wahl P, Walden C, Knopp R, et a!. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl J Med 1983;308:862. Fotherby K. Effect of oral contraceptives on serum lipids and cardiovascular disease. Br J Fam Plann 1985;11:86. Anderson TJ. Mitotic activity in the breast. Eur J Obstet Gynecol Reprod Bioi 1984;4(suppl 2):Sll4. Bonnar J, Sabra AM. Oral contraceptives and blood coagulation. J Reprod Med 1986;31(suppl):551. Hammond GL, Langley MS, Robinson PA, Nummi S, Lund L. Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel. Fertil Steril 1984;42:44. Back DJ, Breckenridge AM, Orme M, Rowe P. Clinical pharmacology of oral contraceptive steroids: drug interactions. Eur J Obstet Gynecol Reprod Bioi 1980;1:126. Fotherby K. Variability of the pharmacokinetic parameters for contraceptive steroids. J Steroid Biochem 1983; 19:817. Goldzieher JW, Dozier TS, De Ia Pena A. Plasma levels and pharmacokinetics of ethynyloestrogens in various populations. Contraception 1980;21: 1.

Phasic approach to oral contraceptives Ralph W. Hale, M.D. Honolulu, Hawaii Oral contraceptives were initially very high in estrogen and progestogen and had a uniform dosage schedule throughout the entire cycle. These early oral contraceptives were associated with high rates of side effects and complications. As a result, the hormone levels have been gradually reduced to attain the minimal amount necessary for contraception while most of the undesired side effects and complications have been eliminated. Recently, a new approach has been added. This mechanism consists of altering the dose of estrogen or progestogen or both during the month and is referred to as the phasic approach. The newest phasic pills now use a triphasic approach. Three basic formulations of the triphasic pill have been developed. In two of the three formulations, the progestogen level is altered, whereas the estrogen level remains stable; in the third formulation, both estrogen and progestogen are changed. Multiple clinical studies of the triphasics, such as ethinyl estradiol and levonorgestrel, prove that there is a significant reduction in the incidence of side effects and complications related to oral contraception. (AM J OBSTET GYNECOL1987;157:1052-8.)

Key words: Oral contraceptives, triphasics, reduction of side effects Ovulation is a complex interaction of multiple neuroendocrine and hormonal events (Fig. 1). 1 Interruption of this relationship results in anovulation and infertility! Ifthe interruption is voluntary, its mechanism should be as free as possible from undesirable side effects and complications. From the Department of Obstetrics and Gynecology, john A. Burns School of Medicine, Kapiolani-Children's Medical Center.

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In the early and mid-1950s, researchers developed steroidal medications that were effective in interrupting these ovulation pathways and producing a state of anovulation and temporary infertility. These medications were first marketed in the early 1960s and used a 19nortestosterone compound with a synthetic estrogen. The original formulation contained 9.85 mg of norethynodrel acetate and 0.150 mg of mestranol. How-