American Journal of
Obstetrics and Gynecology volume 125 number 8
CLINICAL
AUGUST 15, 1976
OPINION
This section reports opinion on the handling of clinical situations, i.e., the clinical diagnosis and management of certain disease entities. Papers should range from eight to twenty typed pages, including illustrations, tables, and figures which clarify the author’s management. References are limited to six citations. Mail to Frederick P. Zuspan, M.D., Editor.
Potencies of oral contraceptives RICHARD
A. EDGREN,
F. M. STLJRTEVANT, Ann Arbor,
Michigan,
PH.D. PH.D.
and Chicago, Illinois
Oral contraceptives are combinations of estrogens and progestogens or, in the case of the mini-pills, progestogens alone. With speciJic test procedures in laboratory animals or human .subjects, it is possible to assign potency evaluations to the components relative to the progestational, estrogenic, or antiestrogenic activities of the progestogen or to the estrogen&potencies of the estrogenic component. It might even be possible to quantify the synergistic effects of the estrogen on th,e progestational agent. Unfortunately, however, it is impossible‘ now to amalgamate such assay results into single estimates of the potencies of the combinations (either the combination products per se or the combination tablets of sequential products). For example, an over-all estrogenic potency of a combination preI)aration mould involve the integration of contributions from the estrogen itselfplus the estrogenic products of metabolism of the progestogen minus the antagonistic effect of the progestational agent, zf any. These factors cannot now be quantij?ed independently, much less merged into a single figure of clinical signijicance. Further, even if it were possible to produce such an estimate, it is unlikely that the evaluation would be meaning/L1 in relation to any putative side effect or adverse reaction, i.e., the alleged thrombogenir effects of oral contraceptives cannot currently be related directly to any rneaJure of potency that mill allour prediction of these clinical conditions from laboratory models. ‘4ny evaluation of the potentia,l of a given contraceptive to produce a specific side effort alill depend upon data generated with speci$c regard to that adverse reaction and the individual product in question.
From
Parke,
Reprint
Re.warch Ann
Dauis
W Company and Searle Laboratories.
requests: Dr. Richard A. Edgren, and Development Division, 2800
Arbor,
Michigan
A LT H o u G H oral contraceptives have been subjected to clinical evaluation for two decades, have been marketed for 15 years, and have been uniquely scrutinized for possible adverse effects for more than a
Endocrinolog?r, Plymouth Rd.,
48106.
1029
1030
Edgren and Sturtevant
decade, little in the way of significant danger to the contraceptor has been demonstrated for these materials. Our opinion, expressed here, appears to be supported by the recent report of the Royal College of General Practitioners.’ However, continued suspicions are reflected by some authors and these problems are frequently related to the “potency” of specific contraceptive preparations or their components. We shall not concern ourselves here with the reality, or lack thereof, of causal association of any given untoward reaction and the oral contraceptives: WC and others have discussed this problem elsewhere and, we believe, proof remains unavailable for serious conditions. Wr shall, however, consider the problem of oral contraceptive potency. We feel that any simple listing of commercial preparations in order of potency, whether it be progestational, estrogenic, or some combination, would be simplistic and that any effort to relate side effects in terms of such a listing is likely to be misleading.
Some bask definitions Oral contraceptives include three types of preparations: (1) the conventional contraceptives that require the administration of an estrogen and a progestational agent simultaneously for a portion of the menstrual cycle (2) the sequential contraceptives that require administration of estrogen alone for the first portion of the cycle followed by a period of administration of estrogen-progestogen combination for the last few days before withdrawal of medication, and (3) a series of progestogen-alone contraceptives, or “mini-pills,” which involve continuous progestogen administration, unrelated to the cycle. In (1) and (2) above, contraception presumably results from blockade of ovulation, which can be largely accounted for by the estrogenic components. This blockade of ovulation is apparently a tertiary effect: The primary effect appears to be at the level of the hypothalamus, where the estrogen inhibits the releasing hormone LRF. This material functions in releasing luteinizing hormone (LH) from the pituitary. LH stimulates ovulation. Thus, the actual antiovulatory effect of the estrogen is three stages away from the point of action of the estrogen itself. Most investigators believe that this is the primary contraceptive action of the estrogen-containing oral contraceptives. In the case of the sequential agents, where only estrogen is administered at the probable time of ovulation, the contraceptive effect must depend entirely upon estrogenic effects, presumably ovulation blockade. Of course, other activities could occur and must be considered. For example, during the first few days post
coitum, estrogens will accelerate or inhibit (dose dependent) the transport of the egg through the oviduct. Animal studies suggest that low doses XX elerate transport of the eggs, which arrive in the uterus too early for nidation. The blockage of transport (tul~al lock) occurs only at high dose levels in some species. ‘l-he postcoital use of diethylstilbestrol. which has been discussed extensively in the United States over the past few months. may reflect these effects. Howcvct-. sine r massive doses of diethylstilbestrol or rthin\l cstrndioi are required in women. it is difficult to believe [hat tht 50 to 100 pg of estrogen administered in 111051 01.ilI contraceptives could have this effect. AII iuntinidator\ effect, resulting front activity at the Ir\t*l cbi’ thr (‘nclometrium, is also possible but poorly tlocumcntctl. In summarv. we believe that the antiovulator.\ ctfeet of the estrogenic agents is the- p1 inr;rl,\ ( oiltraceptivc activity ot combination and kc.qucnti.\l cotitratcptives. The role of the progestogen in the oral colur-acrptive then becomes moot. Again a role is suggested b\, the effects of the few days of progestogen in the sequential products. Cyclic mestranol or ethinyl estradiol will result in irregular menstrual patterns during withdrawal. These are usually copious and extended in period: they are uncontrolled. The administration fat 4 or 5 days of a progestational agent, prior to withdrawal, results in a more satisfactory “bleed-off‘ in these patients. The main role of the progestational agents in contraceptives is the contt-01 of thr c~ndo~mtrial bleeding pattern. i.r.. the pre(.ise c-ontrol of thy cycle. It seems likely, however. that the progestational agents also contribute something to contraception pet se. Many studies have indicated that approximatelv 95 per cent of the cycles of patients who receive ot~l contraceptives show pregnanediol excretion levels cotnmensurate with ovulation inhibition. Thus escape ovulation is suggested in approximately :i per tent of cycles. However, observed failure rates for oral co11traceptives in controlled studies are not commensurate with the hypothesis of a 5 per cent escape ovulation. The pregnancy rates with the sequent& establish the rate of pregnancy to be expected exclusively from estrogen effects, i.e., a rate of no more than one 10 two per 100 woman-years. Mini-pills are associated with even higher pregnancy rates than the sequentials. Their mode(s)-of-action are unclear; it was originally believed that they had little antiovulatory action. It now appears that pituitary block is evident in 50 per cent or more of “cycles” on progestogen-only contraceptives.2, ’ However, the main contraceptive effect appears to br at the level of
Volume Number
125 8
cervical mucus, which fails to show normal midcycle liquifaction under treatment. The drawback to this type of therapy is the high rate of menstrual abnormality. In large-scale, long-term studies, some 60 to 80 per cent of patients and 30 to 50 per cent of cycles show abnormal bleeding patterns. Practical experience led to the composition of oral contraceptives containing combinations of estrogens and progestogens and it would seem that neither component independently provides a fully satisfactory contraceptive. The use of oral contraceptives over the past 20 years has been accompanied by a number of difficulties, some real and some imagined. Our puritanical background may be reflected in some of the objections to the use of oral contraceptives and in the horrified finger-pointing associated with minor side effects. However, certain major problems may be associated with the oral contraceptives, at least in a statistical sense. The most crucial, at least now, appears to be thromboembolic phenomena. The history of this problem need not be discussed here. Earlier statistical data on thromboembolic phenomena were from retrospective, case-control (“trohoc”3a) studies, and led to two suggestions or extrapolations: (1) that contraceptors had a higher rate of thrombotic episodes than women who were not on oral contraceptives, and (2) the higher the dose of estrogen the higher the frequency of episodes. The deficiencies in trohoc methods need no further discussion here, particularly with respect to the presumed correlation of dosage with incidence of episodes. In an effort to resolve these problems, it appeared desirable to some commentators to have a listing of oral contraceptives in order of “estrogenic potency.” In this statement, we shall survey the data on the oral contraceptive preparations, which will demonstrate that no linear series of potency or activity relationships can be defined, and that no relationships can be drawn between rates of thrombotic episodes or for any coincidental adverse occurrence and the relative potencies of the drugs as usually defined. Three separate considerations are germane to this type of listing: (1) it would seem critical to understand the relative potencies of the various progestational agents, (2) it would be important to know the estrogenicity of these agents, and (3) the estrogen antagonistic actions of most of the progestogens must be understood. Most of the oral contraceptives are combinations of an estrogen with a progestogen that has certain estrogenic effects; dealing with the potential additivity of the component estrogen plus the estrogenicity of the progestogen becomes critical. Further, most of the progestogens are also antiestro-
Potencies of oral contraceptives
1031
gens, at least on certain targets; the influence of this antagonism on the over-all estrogenic activities of a combination needs consideration. These interactions are not simple problems due to variations among different target organs (for example, at a single dose combination testosterone will inhibit the action of estrone on the rat vagina but add to the estrogenic effect on the uterus). Also, the progestogens are not competitive inhibitors of the estrogens at the estrogen receptor in the uterus. We are unable at this time to define the precise nature of the antagonism in the uterus where it has been intensively studied. The consideration of any possible progestational modification of any putative thrombogenic effect of the estrogen simply compounds hypothesis with speculation. Before continuing with this problem, let us ask the question, what is meant by “potency”? From a very strict, purely pharmacologic pointed of view, potency may be defined as being simple quantitative biological differences between substances that are otherwise qualitatively identical. Technically, the potency of any given drug must be related to another drug (called the “standard”) and is evaluated by measuring the separation of the parallel dose-response curves. The relative potency so calculated is valid only so long as the following variables, among other variables, are identical: (1) the species and often strain of animal (race in man?), (2) the target organ or tissue involved, (3) the specific pharmacodynamic response of the organ or tissue, (4) the temporal variables, i.e., time of assessment following dosing at a specific time of day (and season, etc., if relevant), and (5) the route of, and vehicle for, drug administration. The slopes of the dose-response curves must not differ significantly and randomization must be assured. Assays may be quantitative or quantal. parametric or nonparametric.
Progestational potency The classic methods of comparing progestational potency, the Clauberg test in rabbits or the SwyerGreenblatt delay-of-menses test in human beings, focus on these restrictions as critical problems. In the Clauberg test, all qualitative evaluations of histologic development of the endometrial glands, and the slopes of the dose-response curves, must be identical among progestogens for potency to be meaningful. When slopes are nonparallel, potency estimates become meaningless; however, arbitrary decisions are often made. The differences in slopes of dose-response curves for protestogens in the Clauberg test have been evident for years. In the Swyer-Greenblatt test, we are
1032
Edgren and Sturtevant Am.
Table
I. Postponent
of menstruation
assays: Various
No. of observations
Norethisterone Norethisterone acetate Norethynodrel Norethynodrel + mestranol (Enovid) Provera Provera + mestranol Megestrol acetate Megestrol acetate + mestranol Melengestrol acetate Melengestrol acetate + mestranol 17a-vinyl-19-nortestosterone (SC464 1) t 7 a-vinyl- 1Q-nortestosterone + mestranol 2 I-fiuoro,A6,6-methyl-I7a-acetoxyprogesterone (X10230) + mestranol Ethynodiol diacetate Ethynodol diacetate + mestranol Gestovis Gestovis + mestranol Enol luteovis Enol luteovis + mestranol Didrogesterone Didrogesterone + mestranol
89 51
Postponement
of menstruation
4.25 1() .5 20
16 28 4 21 30
?I.:4 >lO 22.3 > I0 I .8 > I0 2.5 > IO
51 17 16 12 13 4
9 32 7 22 1 4 9 4
*From Swyer and Little: J. Reprod. Fertil. Suppl. 5,63, 1968. The nomenclature II.
15. 1976 Gvnecol.
progestogens*
DmLg
Table
.Auguat .I. Obstet.
in the original has been retained
assay on Norgestrel* Response
Dose (mg.)
No. of subjects
Positive
1 11
1 5
13 3
4 I
Negative
Cr, psitivr
0 6 9 2
EDm 4 mg. (no. of observations 28) 2 + 0.1 mestranol 1 + 0.1 mestranol 0.5 + 0.1 mestranol 0.25 + 0.1 mestranol 0.2 + 0.1 mestranol 0.125 + 0.1 mestranol 0.1 + 0.1 mestranol
10 14 13 17
10
0
100
14
0
LOO
11 13
2 4
x5
2
2
0
11
6
5
55
3
0
?I
0
76.5
ED,, 0.125 mg. (no. of observations 70) *From Swyer and Little: J. Reprod. Fertil. Suppl. 5, 63, 1968. in no position to assume qualitative identity among the compounds tested by Swyer and Little.* (All discussions on the Swyer-Greenblatt test will be based upon data published by Gerald Swyer and his associate Valerie Little; other people have employed the test differently than they and, therefore, the data are not comparable for comparative potency evaluations.) Within the limitations of the test, too few data are available to determine whether slopes are nonparallel. However, despite the reservation, this is the only available, critical pharmacologic method for comparing the human potency of progestogens on the endometrium. We reproduce here as Table I a listing of progestational
agents as evaluated by Swyer and Little.4 Although the results could be manipulated in several ways, they show that the potencies of the progestogens vary considerably and that the addition of an estrogen alters the “progestational” potency. In most cases this alteration is an increase in potency, i.e., a decrease in the EDJ, of a compound when estrogen is added. Unfortunately, these data are not entirely self-consistent and not infrequently inadequate data are available to allow a satisfactory evaluation of potency. The addition of 0.1 mg. of mestt-anol is not always followed by a similar increase in potency of the progestogen. For example, norethynodrel appears to have an approximate EDeo of
Volume 125
Potencies of oral contraceptives
Number8
Table III. Potency comparisons
in various Vaginal
tests for estradiol-17P,
sfnears
% patency uterine
Rat cmpaund
I day
Estradiol-17fi Id-Homoestradiol “Propyl” estradiol
100 30 30
18-homoestradiol,
and “propyl”
1033
estradiol*
growth
Rat P&Y
Mouse
3 &Y
7 day
Moue
100 1 0.5
100 1.25 0.33
100 > 1.8
100 67 4.8
100 co.1 CO.1
Vaginal
opening
100 10 3
oviduct
growth
100 10,000.0 >10,000.0
*From Jones and Edgten:
vaginal Y 5 7% confidence limits (/A@
3.3-10.0 5.8-18.3 2.3-435.9 133.4-651.3 267.0-1,681.g 671.3-10,935.4 123.0-3.548.0
Fertil. Steril. 24: 284, 1973.
compound has almost one third the potency of estradiol. In the mouse uterine growth test, the potency for 1Shomoestradiol is 0.1 per cent of the potency of estradiol-17P; in the vaginal opening test the compound has 10 per cent of the potency of estradiol. The implication is clear from these data: no single testing procedure gives a series of potencies for the estrogens that is necessarily consistent with other tests and the potency evaluations will vary greatly from tissue to tissue, organ to organ, and species to species. Therefore, one must look spec$cally at the target one wishes to evaluate. With respect to thromboembolism, we do not think that the fact that mestranol is less or more potent than ethinyl estradiol in a pituitary blocking or a uterine growth test has any relevance to the alleged potential of the compounds to produce thromboses. Thus, thromboembolic phenomena must be considered as a separate entity, unrelated to other measures of estrogenicity, until correlations have been demonstrated. However, the direct induction of experimental thrombosis by estrogens has not been reported. In addition to this confusion relative to the potency of the estrogenic component of the oral contraceptives is the problem of the estrogenic contribution of the progestational agent. Recently a series of studies was published on a broad range of progestational agents and other steroids that produce vaginal keratinization in rats when administered by the oral route.7 Since uterine growth can be stimulated by progesterone, testosterone, and a broad range of other steroids, it is not specific and should not be considered as an “estrogenic” response. The vaginal effects, however, appear specific. Ethinyl estradiol, the standard, was the most potent steroid of the series studied, and all progestogens were weakly active, with the exception of progesterone and norgestrel (Table IV). These data
Table IVB. Estrogenic potency relative to ethinyl estradiol”
Ethinyl estradiol Mestranol Lynestrenol Norethynodrel Norethindrone acetate Ethynodiol diacetate Norethindrone Methyltestosterone Hydrocortisone Progesterone Norgestrel *Corrected-f&m 1973.
15, 1976
Gynecol.
of various
Pottvq C%)
compound
.August
Am. J. Obstet.
steroids 9 5 % cnnjiduw limit.7
100.0 52.1 2.6
2.1 0.9 0.4 0.3 0.0 0.0 0.0 0 .o
0.2724-1.0585
0.0112-0.0881 0.0100-0.0455 0.0043-0.0223 0.0016-0.0088 0.0013-0.0053
Jones and Edgren: Fertil. Steril. 24: 284,
may suggest conversion of the ptogestogen to an estrogen in viva. However, how does one employ these data? How does one come to a rational evaluation of the “estrogenicity” of a contraceptive agent? Does one add to the estrogenic content a percentage of the progestogen that may convert to estrogen or have estrogenic activities? For example, if we take the Lo-Estrin l/20 combination, this material contains 20 pg of ethinyl estradiol as the estrogen. It also contains 1,000 pg of norethindrone acetate. According to the potency estimates in Table IV, norethindrone acetate has 0.9 per cent (call it 1 per cent for the sake of the argument) of the potency of ethinyl estradiol. One per cent of 1 mg. is 10 pg. Therefore, is the combination norethindrone acetate plus ethinyl estradiol in the l/20 combination the clinical equivalent of giving 30 gg ofethinyl estradiol? When one adds mestranol to this, the confusion continues. Enovid-E contains mestranol as the basic estrogen in a dose of 100 Fg. This is, according to Table IV, the equivalent of approximately 50 pg of ethinyl estradiol. Korethynodrel has approximately 2 per cent of the potency of ethinyl estradiol, so the norethynodrel, 2.5 mg. in Enovid-E, would be the equivalent of 50 pg of ethinyl estradiol. Therefore, is the combination Enovid-E the clinical equivalent of giving 100 pg of ethinyl estradiol? The answer to these two questions regarding Lo-Estrin and Enovid-E is. certainly, “No.” But, of course, the exercises in the preceding paragraph presuppose that tat vaginal studies project to clinical effects. It would appear that this is not true from Goldzieher’s observations on human pituitary blockade. It should be evident at this point that it is not possible to make a meaningful evaluation of the estrogenic contributions of either the estrogen itself or the
Volume Number
125 8
Table
V.
Potencies of oral contraceptives
Antiestrogenic
effects of various
1035
steroids* Uterine
Steroid
Mouse
vaginal
smear
Antiestrone
growth Antiestriol
Standard:
Progesterone Testosterone Estrone
1OOS-I 200
100s 20
I
Acetoayprogesterone
1
A I
1
derivatives:
Medroxyprogesterone acetate Chlormadinone acetate Megestrol acetate
A
-
290
130 -
60a
-
Nortestostmones:
Norethindrone Norgestrel Norethynodrel Ethynodiol diacetate
730 7,400
-
800 >3,300
1
1 a
-
A A I
*From Edgren, Jones, and Peterson: Fertil. Steril. 18: 238, 1967. +Key to symbols; A = active; a = active, literature report; I = inactive; S = standard. Table
VI.
Potencies
of progestogens* Potency Progestatianal
Steroid
Progesterone Chlormadinone Norethisterone Norgestrel (Racemate)
(72)
Antiestrogenic
100 3,500
8 915
($6)
Contraceptive
dose/day t (fig)
100 130 730 7,400
500 350 75
*From Edgren: J. Reprod. Med. 2: 79, 1974. tFor
Pearl
index
of 2 to 3 in large-scale
studies
of progestogens
progestational component to the effects of a given combination on a specific end-point of estrogenic action. It would seem that each product will have to be considered on its own merits and its effects restricted to only one end-point of action.
Antiestrogenic action Further difficulty arises from the interaction of the progestogen with the estrogen. Most of the progestational agents commonly used as components of oral contraceptives are estrogen antagonists, but the meaning of this at a biochemical level has not been clearly defined. Biologically, it is abundantly clear that the administration of an estrogen is followed by certain biologic effects, apparently in all species of mammals. The most clearly defined are uterine growth, vaginal cornification, and pituitary blockade. The first two, the uterine growth and the vaginal changes, may be reversed by the simultaneous administration of certain compounds, notably the progestational agents that are being considered here. On the other hand, studies on hemicastrated rats, which are believed to measure the blockade of the pituitary, do not indicate an antiestrogenic effect. Further, the Ramirez-McCann rat,
as mini-pills.
employed for the measurement of luteinizing hormone-releasing factor, requires large doses of both estradiol and progesterone to block totally the release of gonadotropins; if progesterone were blocking the effect of the estrogen it would cause release of the luteinizing hormone and the preparation would not be suitable for this type of assay. In contradistinction, Goldzieher seemed to believe that the progestational agent will potentiate the effect of the estrogen in women. Therefore, we must be highly specific and define the target that we are considering before any potency evaluation that might be meaningful can be attempted. The antiestrogenic potencies of a number of progestational agents have been evaluated with standardized testing procedures (Table V). The antiestrogenic potencies appear to relate closely to the mini-pill contraceptive doese (Table VI). However, we see no way of merging these data for clinical purposes.
An example It would be desirable if one could evolve an “estrogenic index” for these materials that would add to the estrogen component itself the estrogenic con-
1036
Edgren and Sturtevant
40
3 $30 c’ .e P .2
: 20 3 e *--a D--l *.-,*-1L--
IO
I
,
.0003
,
Ethlnyl estmdiol Mestronol EnovidE Enovid 5 Ovrol Notlestrin IO
I
.mi
003
1
.Ol
.03
*-b *---
Drug dose (fraction of pil I) Fig. 1. Oral contraceptives with linear regression lines parallel to that of ethinyl estradiol. (From Chihal, Peppler, and Dickey: AM. J. OBSTET. GYNECOL. 121: 77, 1975.)
40
c---s l -mb L+--
I
Norinyl I/50 Norinyl I/80 Ovulen Ethinyl estradiol Demulen
,
.ooo3
I
001
,003
.Ol Drug dose (fraction of pill)
.03
00 I
003
--
.Ol 03 Drug dose(froction of o ~111)
-.-I I
Fig. 3. Oral contraceptives with linear regression lines not parallel to that of either ethinyl estradiol or Korinvl-1 + 50. (From Chihal, Peppler, and Dickey: AM. J. Ossr~ r. GYNI:COL.. 121: 77, 1975.)
1
IO-
I
7
I
Norlestrin 2 5 Ethinyl estrodioi Norinyl l/50
I
Fig. 2. Oral contraceptives with linear regression lines parallel to that of Norinyl-1 + 50. (From Chihal, Peppler, and Dickey: AM. J. OBSTET. GYNECOL. 121: 77, 1975.)
tribution of the progestational component and subtract the antiestrogenic effect of the progestogen. This is not possible. Evaluations of these materials will have to be based on their own merits. It would seem to us that the only meaingful approach to a comparative study of oral contraceptives and stroke or thomboembolic phenomena, cancer, or any other untoward condition that might be associated with the use of a given product would have to be based on logistic, life table, or incidence data on the specific
condition under consideration. A preconceived, established rating of estrogenicity or progestational potency cannot contribute meaingfully. Various workers have made efforts to evaluate oral contraceptives in terms of relative “estrogenicity,” relative progestational “dominance,” etc. These evahtations are more wishful thinking than science. Ho~jever, few clinicians would deny that the over-all clinical effect of Enovid, for example, is folliculoid, whereas that of a norgestrelor Ilorethindrorlc-contaiIling contraceptive appears to be primarily progestational and/or androgenic. However. such generalization from clinical impression is a poor solutiotl to o\lL problem. Recently, an attempt was made to compare oral contraceptives for their “estrogenic” potencies.“’ Thr broad conclusions reached are untenable for the following reasons. First, these workers used mouse uterine weights for definition and e\.aluation of estrogenic effects. The uteri of rats and mice respond to progestatonal agents and androgens, as well as to estrogens. Therefore, the uterine growth I-esponse is not specific, does not necessitate that a compound is estrogenic in the usual sense, and could therefore he misleading. Second, the authors’ methods are questionable: they bought commercial preparations and the tablets were ground up to form slurries, which were then administered orally to mice. ‘Ten tablets were pooled to form the initial samples and final amounts were dilutions of these initiai slurries. We cannot believe that accurate dilutions are possible in these circumstances. Third, each mouse received massive
Potencies of oral contraceptives
amounts of excipients, binders, bulk materials, etc., relative to the steroids that it received. Fourth, in a highly sensitive assay of activity, slight deviations in the original tablets, which are within tolerable limits for human use, could produce gross errors in the animal study. Fifth, the ethinyl estradiol and mestranol were obtained from sequential tablets; therefore, the ratios of extraneous to steroidal materials was greater for these tablets and less for the combination tablets. The results of this study” are displayed in Figs. 1 to 3. which show two sets of dose-response curves with regard to slope. The data suggest that the Enovid combinations, Ovral and Norlestrin (1 mg.) show dose-response curves that are parallel to ethinyl estradiol and mestranol, while Norinyl l/50, Norinyl 1180, Ovulen and Demulen show dose-response curves that are different from their estrogenic components. One combination, Norlestrin 2.5, had a slope that was parallel to neither of these two major groups. The first conclusion one reaches is that potency re!ationships among the groups cannot be drawn in any meaningful fashion; whereas it is possible to evaluate the potency of Enovid-E, Enovid-5, Ovral, or Norlestrin in terms of ethinyl estradiol or mestranol, deriving potency estimates for Norinyl 1150. Norinyl l/80. Ovulen, Demulen, or Norlestrin 2.5 in terms of either of the standard estrogens is meaningless. Further, drar\?ng a relationship between the two Enovid products, for example. and Demulen would be ridiculous. One over-all problem in this type of analysis is inherent in the data of Figs. 2 and 3. Here are two groups of compounds with dose-response curve slopes more shallow than that of the standard. The data suggest that at lower doses the uterotropic action of the progestational agents may synergize with the uterotropic activity of the estrogen, whereas the antiestrogenic effect of the progestogen is apparent at the higher doses. This kind of interaction was common in a number of our (R. A. E.) early studies involving the interactions of’ androgens, progestogens, or corticoids with estrogens. However (and here is the critical point as far as we are concerned), where on the curve do human beings fall? If one of these materials be given to a woman. does she fall on the curve at the lower level kvhere the compounds may synergize or does she fall on the curve at the higher dose levels where the progestogens appear to inhibit the estrogen? In our opinion, this study lo is really not relevant to the estrogenicity of contraceptives in human subjects. REFERENCES
1, Royal College of General tives and Health, London,
Practitioners: Oral Contracep1974, Pitman Medical.
1037
Conclusions We do not feel that it is currently scientifically possible to answer the question of oral contraceptive “potency,” nor do we believe that a solution would provide clinically meaningful answers. No laboratory or clinical measure of “potency” will predict specific side effects with useful precision, except, of course, data based upon the side effect itself. While this statement holds for the component, estrogen and progestogen, it is ever more valid with respect to One cannot ignore the mutual the combination. interactions of the progestational and estrogenic components, ignore the complications of varying estrogen/progestogen ratios, and then extrapolate from an organ or biochemical response in laboratory animals or human beings to a clinical situation (e.g., thromboembolism incidence) that is not itself observable directly, that is not demonstrable experimentally, and that is posited solely upon the basis of retrospection,” voluntary physician reporting, and sales figures. ‘I Such reasoning has led to governmental action against oral contraceptives containing more than 50 pg of “estrogen” in Great Britain and Sweden. Qualified recognition was accorded by the FDA.12 While these actions may perhaps be supported as efforts to err on the “safe side,” the basic data do not meet the test of scientific validity and, further, spurious incorporation of “potency” data will not solve the immediate problem, i.e., the evaluation of safety of the oral contraceptives for their users. *Dr. Richard P. Dickey, who disagrees with the thesis presented here, has kindly pointed out that we deal summarily with the prospective studies of the Royal College.’ This is not our intention. Some months ago, in a detailed reanalysis of the data in the Royal College report, one of us (F. M. S.) noted that the evaluation of the grand totals on reported morbidity (Table 13.2, p. 85, of reference I) did not exclude predisposing factors in ihe evaluation of the standardized rate and that this table urovided the denominator for estimated incidences of idiopaihic venous thrombosis listed in tables 7.3 (p. 45) and 7.5 (p.‘46). This point was called to the attention of Dr. Clifford Kav. Chairman of the Executive Committee of the Oral Contraception Study of the Royal College. Dr. Kay, in a letter to La&t (June’21, 1975,‘~. 1380, has now corrected and LIDdated Table 7.3: however. the orieinal Table I
7.5 still reflects’cases of idiopathic thrombosis p& womanyears contributed by women with and without predisposing conditions, and still refers to different estrogens combined with varying amounts of different progestogens. Thus, in our Table 7.5 cannot be interpreted as demonstrating opinion, any dose-response relationship between “estrogens” and thrombosis.
2. Moghissi, K. S.: Morphologic women treated with continuous Fertil. Steril. 23: 739, 1972.
changes in the ovaries of microdose progestogens,
038
Edgren
and Sturtevant
3. Zanartu, J.. et al.: Low-dosage oral progestogens to control fertility. I. Clinical investigation, Obstet. Gynecol. 43: 87, 1974. 3a. Feinstein, A. R.: Clinical biostatistics. XX. The epidemiologic trohoc, the ablative risk ratio, and “retrospective” research, Clin. Pharmacol. Ther. 14: 291, 1973. 4. Swyer, G. I. M., and Little. V.: Clinical assessment of relative potency of progestogens. J. Reprod. Fert. Suppl. 5, 63, 1968. 5. Goldzieher, J. W., de la Pena, A., Chanault, C. B., and Woutersz, T. B.: Comparative studies of the ethynyl estrogens used in oral contraceptives. II. Antiovulatory potency, AM. J. OBSTET. GYNECOL. 122: 619, 1975. 6. Edgren, R. A., Jones, R. C.. and Peterson, D. L.: A biological classification of progestational agents, Fertil. Steril. 18: 238, 1967.
Intrauterine
Asphyxia
in the Developing
7. Jones, R. C., and Edgren, R. A.: The effects of various steroids on the vaginal histology in the rat, Fertil. Steril. 24: 284, 1973. 8. Edgren, R. A., Jones, R. C.. and Peterson, I>. L.: ‘l‘he estrogenic effects of a series of 13fl-substituted compounds related to estradiol-17P Eur. J. Steroids 2: 19. 1967. 9. Edgren, R. A.: Progestagens as contraceptives, J. Reprod. Med. 2: 79, 1974. 10. Chihal, H. J. W., Peppler, R. D., and Dickey, R. P.: Estrogen potency of oral contraceptive pills, A&t. J. OBSTET. GYNECOL. 121: 77, 1975. 11. Inman, W. H. W., Vessey, M. P., Westerholm, B., aud Engelund, A.: Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs, Br. Med. J. 2: 203, 1970. 12. FDA Current Drug Information, April 24, 1970.
Fetal Brain
“Intrauterine Asphyxia in the Developing Fetal Brain,” a symposium, co-sponsored by the Department of Pediatrics, University of California, San Diego, California, and the Institute for Pediatric Service of the Johnson Bc Johnson Baby Products Company, will be held at the Town and Country Hotel, San Diego, September 9-12, 1976. The Chairman is Louis Gluck, M.D. An international faculty of neonatologists, pediatricians, obstetricians, and other specialists will discuss the important aspects of intrauterine asphyxia as it affects the developing fetal brain. For further information, write: Steven Sawchuk, M.D., 501 George St., New Brunswick, New Jersey 08903.
Obstetrics and Gynecology volume 125 number 8
CLINICAL
AUGUST 15, 1976
OPINION
This section reports opinion on the handling of clinical situations, i.e., the clinical diagnosis and management of certain disease entities. Papers should range from eight to twenty typed pages, including illustrations, tables, and figures which clarify the author’s management. References are limited to six citations. Mail to Frederick P. Zuspan, M.D., Editor.
Potencies of oral contraceptives RICHARD
A. EDGREN,
F. M. STLJRTEVANT, Ann Arbor,
Michigan,
PH.D. PH.D.
and Chicago, Illinois
Oral contraceptives are combinations of estrogens and progestogens or, in the case of the mini-pills, progestogens alone. With speciJic test procedures in laboratory animals or human .subjects, it is possible to assign potency evaluations to the components relative to the progestational, estrogenic, or antiestrogenic activities of the progestogen or to the estrogen&potencies of the estrogenic component. It might even be possible to quantify the synergistic effects of the estrogen on th,e progestational agent. Unfortunately, however, it is impossible‘ now to amalgamate such assay results into single estimates of the potencies of the combinations (either the combination products per se or the combination tablets of sequential products). For example, an over-all estrogenic potency of a combination preI)aration mould involve the integration of contributions from the estrogen itselfplus the estrogenic products of metabolism of the progestogen minus the antagonistic effect of the progestational agent, zf any. These factors cannot now be quantij?ed independently, much less merged into a single figure of clinical signijicance. Further, even if it were possible to produce such an estimate, it is unlikely that the evaluation would be meaning/L1 in relation to any putative side effect or adverse reaction, i.e., the alleged thrombogenir effects of oral contraceptives cannot currently be related directly to any rneaJure of potency that mill allour prediction of these clinical conditions from laboratory models. ‘4ny evaluation of the potentia,l of a given contraceptive to produce a specific side effort alill depend upon data generated with speci$c regard to that adverse reaction and the individual product in question.
From
Parke,
Reprint
Re.warch Ann
Dauis
W Company and Searle Laboratories.
requests: Dr. Richard A. Edgren, and Development Division, 2800
Arbor,
Michigan
A LT H o u G H oral contraceptives have been subjected to clinical evaluation for two decades, have been marketed for 15 years, and have been uniquely scrutinized for possible adverse effects for more than a
Endocrinolog?r, Plymouth Rd.,
48106.
1029
1030
Edgren and Sturtevant
decade, little in the way of significant danger to the contraceptor has been demonstrated for these materials. Our opinion, expressed here, appears to be supported by the recent report of the Royal College of General Practitioners.’ However, continued suspicions are reflected by some authors and these problems are frequently related to the “potency” of specific contraceptive preparations or their components. We shall not concern ourselves here with the reality, or lack thereof, of causal association of any given untoward reaction and the oral contraceptives: WC and others have discussed this problem elsewhere and, we believe, proof remains unavailable for serious conditions. Wr shall, however, consider the problem of oral contraceptive potency. We feel that any simple listing of commercial preparations in order of potency, whether it be progestational, estrogenic, or some combination, would be simplistic and that any effort to relate side effects in terms of such a listing is likely to be misleading.
Some bask definitions Oral contraceptives include three types of preparations: (1) the conventional contraceptives that require the administration of an estrogen and a progestational agent simultaneously for a portion of the menstrual cycle (2) the sequential contraceptives that require administration of estrogen alone for the first portion of the cycle followed by a period of administration of estrogen-progestogen combination for the last few days before withdrawal of medication, and (3) a series of progestogen-alone contraceptives, or “mini-pills,” which involve continuous progestogen administration, unrelated to the cycle. In (1) and (2) above, contraception presumably results from blockade of ovulation, which can be largely accounted for by the estrogenic components. This blockade of ovulation is apparently a tertiary effect: The primary effect appears to be at the level of the hypothalamus, where the estrogen inhibits the releasing hormone LRF. This material functions in releasing luteinizing hormone (LH) from the pituitary. LH stimulates ovulation. Thus, the actual antiovulatory effect of the estrogen is three stages away from the point of action of the estrogen itself. Most investigators believe that this is the primary contraceptive action of the estrogen-containing oral contraceptives. In the case of the sequential agents, where only estrogen is administered at the probable time of ovulation, the contraceptive effect must depend entirely upon estrogenic effects, presumably ovulation blockade. Of course, other activities could occur and must be considered. For example, during the first few days post
coitum, estrogens will accelerate or inhibit (dose dependent) the transport of the egg through the oviduct. Animal studies suggest that low doses XX elerate transport of the eggs, which arrive in the uterus too early for nidation. The blockage of transport (tul~al lock) occurs only at high dose levels in some species. ‘l-he postcoital use of diethylstilbestrol. which has been discussed extensively in the United States over the past few months. may reflect these effects. Howcvct-. sine r massive doses of diethylstilbestrol or rthin\l cstrndioi are required in women. it is difficult to believe [hat tht 50 to 100 pg of estrogen administered in 111051 01.ilI contraceptives could have this effect. AII iuntinidator\ effect, resulting front activity at the Ir\t*l cbi’ thr (‘nclometrium, is also possible but poorly tlocumcntctl. In summarv. we believe that the antiovulator.\ ctfeet of the estrogenic agents is the- p1 inr;rl,\ ( oiltraceptivc activity ot combination and kc.qucnti.\l cotitratcptives. The role of the progestogen in the oral colur-acrptive then becomes moot. Again a role is suggested b\, the effects of the few days of progestogen in the sequential products. Cyclic mestranol or ethinyl estradiol will result in irregular menstrual patterns during withdrawal. These are usually copious and extended in period: they are uncontrolled. The administration fat 4 or 5 days of a progestational agent, prior to withdrawal, results in a more satisfactory “bleed-off‘ in these patients. The main role of the progestational agents in contraceptives is the contt-01 of thr c~ndo~mtrial bleeding pattern. i.r.. the pre(.ise c-ontrol of thy cycle. It seems likely, however. that the progestational agents also contribute something to contraception pet se. Many studies have indicated that approximatelv 95 per cent of the cycles of patients who receive ot~l contraceptives show pregnanediol excretion levels cotnmensurate with ovulation inhibition. Thus escape ovulation is suggested in approximately :i per tent of cycles. However, observed failure rates for oral co11traceptives in controlled studies are not commensurate with the hypothesis of a 5 per cent escape ovulation. The pregnancy rates with the sequent& establish the rate of pregnancy to be expected exclusively from estrogen effects, i.e., a rate of no more than one 10 two per 100 woman-years. Mini-pills are associated with even higher pregnancy rates than the sequentials. Their mode(s)-of-action are unclear; it was originally believed that they had little antiovulatory action. It now appears that pituitary block is evident in 50 per cent or more of “cycles” on progestogen-only contraceptives.2, ’ However, the main contraceptive effect appears to br at the level of
Volume Number
125 8
cervical mucus, which fails to show normal midcycle liquifaction under treatment. The drawback to this type of therapy is the high rate of menstrual abnormality. In large-scale, long-term studies, some 60 to 80 per cent of patients and 30 to 50 per cent of cycles show abnormal bleeding patterns. Practical experience led to the composition of oral contraceptives containing combinations of estrogens and progestogens and it would seem that neither component independently provides a fully satisfactory contraceptive. The use of oral contraceptives over the past 20 years has been accompanied by a number of difficulties, some real and some imagined. Our puritanical background may be reflected in some of the objections to the use of oral contraceptives and in the horrified finger-pointing associated with minor side effects. However, certain major problems may be associated with the oral contraceptives, at least in a statistical sense. The most crucial, at least now, appears to be thromboembolic phenomena. The history of this problem need not be discussed here. Earlier statistical data on thromboembolic phenomena were from retrospective, case-control (“trohoc”3a) studies, and led to two suggestions or extrapolations: (1) that contraceptors had a higher rate of thrombotic episodes than women who were not on oral contraceptives, and (2) the higher the dose of estrogen the higher the frequency of episodes. The deficiencies in trohoc methods need no further discussion here, particularly with respect to the presumed correlation of dosage with incidence of episodes. In an effort to resolve these problems, it appeared desirable to some commentators to have a listing of oral contraceptives in order of “estrogenic potency.” In this statement, we shall survey the data on the oral contraceptive preparations, which will demonstrate that no linear series of potency or activity relationships can be defined, and that no relationships can be drawn between rates of thrombotic episodes or for any coincidental adverse occurrence and the relative potencies of the drugs as usually defined. Three separate considerations are germane to this type of listing: (1) it would seem critical to understand the relative potencies of the various progestational agents, (2) it would be important to know the estrogenicity of these agents, and (3) the estrogen antagonistic actions of most of the progestogens must be understood. Most of the oral contraceptives are combinations of an estrogen with a progestogen that has certain estrogenic effects; dealing with the potential additivity of the component estrogen plus the estrogenicity of the progestogen becomes critical. Further, most of the progestogens are also antiestro-
Potencies of oral contraceptives
1031
gens, at least on certain targets; the influence of this antagonism on the over-all estrogenic activities of a combination needs consideration. These interactions are not simple problems due to variations among different target organs (for example, at a single dose combination testosterone will inhibit the action of estrone on the rat vagina but add to the estrogenic effect on the uterus). Also, the progestogens are not competitive inhibitors of the estrogens at the estrogen receptor in the uterus. We are unable at this time to define the precise nature of the antagonism in the uterus where it has been intensively studied. The consideration of any possible progestational modification of any putative thrombogenic effect of the estrogen simply compounds hypothesis with speculation. Before continuing with this problem, let us ask the question, what is meant by “potency”? From a very strict, purely pharmacologic pointed of view, potency may be defined as being simple quantitative biological differences between substances that are otherwise qualitatively identical. Technically, the potency of any given drug must be related to another drug (called the “standard”) and is evaluated by measuring the separation of the parallel dose-response curves. The relative potency so calculated is valid only so long as the following variables, among other variables, are identical: (1) the species and often strain of animal (race in man?), (2) the target organ or tissue involved, (3) the specific pharmacodynamic response of the organ or tissue, (4) the temporal variables, i.e., time of assessment following dosing at a specific time of day (and season, etc., if relevant), and (5) the route of, and vehicle for, drug administration. The slopes of the dose-response curves must not differ significantly and randomization must be assured. Assays may be quantitative or quantal. parametric or nonparametric.
Progestational potency The classic methods of comparing progestational potency, the Clauberg test in rabbits or the SwyerGreenblatt delay-of-menses test in human beings, focus on these restrictions as critical problems. In the Clauberg test, all qualitative evaluations of histologic development of the endometrial glands, and the slopes of the dose-response curves, must be identical among progestogens for potency to be meaningful. When slopes are nonparallel, potency estimates become meaningless; however, arbitrary decisions are often made. The differences in slopes of dose-response curves for protestogens in the Clauberg test have been evident for years. In the Swyer-Greenblatt test, we are
1032
Edgren and Sturtevant Am.
Table
I. Postponent
of menstruation
assays: Various
No. of observations
Norethisterone Norethisterone acetate Norethynodrel Norethynodrel + mestranol (Enovid) Provera Provera + mestranol Megestrol acetate Megestrol acetate + mestranol Melengestrol acetate Melengestrol acetate + mestranol 17a-vinyl-19-nortestosterone (SC464 1) t 7 a-vinyl- 1Q-nortestosterone + mestranol 2 I-fiuoro,A6,6-methyl-I7a-acetoxyprogesterone (X10230) + mestranol Ethynodiol diacetate Ethynodol diacetate + mestranol Gestovis Gestovis + mestranol Enol luteovis Enol luteovis + mestranol Didrogesterone Didrogesterone + mestranol
89 51
Postponement
of menstruation
4.25 1() .5 20
16 28 4 21 30
?I.:4 >lO 22.3 > I0 I .8 > I0 2.5 > IO
51 17 16 12 13 4
9 32 7 22 1 4 9 4
*From Swyer and Little: J. Reprod. Fertil. Suppl. 5,63, 1968. The nomenclature II.
15. 1976 Gvnecol.
progestogens*
DmLg
Table
.Auguat .I. Obstet.
in the original has been retained
assay on Norgestrel* Response
Dose (mg.)
No. of subjects
Positive
1 11
1 5
13 3
4 I
Negative
Cr, psitivr
0 6 9 2
EDm 4 mg. (no. of observations 28) 2 + 0.1 mestranol 1 + 0.1 mestranol 0.5 + 0.1 mestranol 0.25 + 0.1 mestranol 0.2 + 0.1 mestranol 0.125 + 0.1 mestranol 0.1 + 0.1 mestranol
10 14 13 17
10
0
100
14
0
LOO
11 13
2 4
x5
2
2
0
11
6
5
55
3
0
?I
0
76.5
ED,, 0.125 mg. (no. of observations 70) *From Swyer and Little: J. Reprod. Fertil. Suppl. 5, 63, 1968. in no position to assume qualitative identity among the compounds tested by Swyer and Little.* (All discussions on the Swyer-Greenblatt test will be based upon data published by Gerald Swyer and his associate Valerie Little; other people have employed the test differently than they and, therefore, the data are not comparable for comparative potency evaluations.) Within the limitations of the test, too few data are available to determine whether slopes are nonparallel. However, despite the reservation, this is the only available, critical pharmacologic method for comparing the human potency of progestogens on the endometrium. We reproduce here as Table I a listing of progestational
agents as evaluated by Swyer and Little.4 Although the results could be manipulated in several ways, they show that the potencies of the progestogens vary considerably and that the addition of an estrogen alters the “progestational” potency. In most cases this alteration is an increase in potency, i.e., a decrease in the EDJ, of a compound when estrogen is added. Unfortunately, these data are not entirely self-consistent and not infrequently inadequate data are available to allow a satisfactory evaluation of potency. The addition of 0.1 mg. of mestt-anol is not always followed by a similar increase in potency of the progestogen. For example, norethynodrel appears to have an approximate EDeo of
Volume 125
Potencies of oral contraceptives
Number8
Table III. Potency comparisons
in various Vaginal
tests for estradiol-17P,
sfnears
% patency uterine
Rat cmpaund
I day
Estradiol-17fi Id-Homoestradiol “Propyl” estradiol
100 30 30
18-homoestradiol,
and “propyl”
1033
estradiol*
growth
Rat P&Y
Mouse
3 &Y
7 day
Moue
100 1 0.5
100 1.25 0.33
100 > 1.8
100 67 4.8
100 co.1 CO.1
Vaginal
opening
100 10 3
oviduct
growth
100 10,000.0 >10,000.0
*From Jones and Edgten:
vaginal Y 5 7% confidence limits (/A@
3.3-10.0 5.8-18.3 2.3-435.9 133.4-651.3 267.0-1,681.g 671.3-10,935.4 123.0-3.548.0
Fertil. Steril. 24: 284, 1973.
compound has almost one third the potency of estradiol. In the mouse uterine growth test, the potency for 1Shomoestradiol is 0.1 per cent of the potency of estradiol-17P; in the vaginal opening test the compound has 10 per cent of the potency of estradiol. The implication is clear from these data: no single testing procedure gives a series of potencies for the estrogens that is necessarily consistent with other tests and the potency evaluations will vary greatly from tissue to tissue, organ to organ, and species to species. Therefore, one must look spec$cally at the target one wishes to evaluate. With respect to thromboembolism, we do not think that the fact that mestranol is less or more potent than ethinyl estradiol in a pituitary blocking or a uterine growth test has any relevance to the alleged potential of the compounds to produce thromboses. Thus, thromboembolic phenomena must be considered as a separate entity, unrelated to other measures of estrogenicity, until correlations have been demonstrated. However, the direct induction of experimental thrombosis by estrogens has not been reported. In addition to this confusion relative to the potency of the estrogenic component of the oral contraceptives is the problem of the estrogenic contribution of the progestational agent. Recently a series of studies was published on a broad range of progestational agents and other steroids that produce vaginal keratinization in rats when administered by the oral route.7 Since uterine growth can be stimulated by progesterone, testosterone, and a broad range of other steroids, it is not specific and should not be considered as an “estrogenic” response. The vaginal effects, however, appear specific. Ethinyl estradiol, the standard, was the most potent steroid of the series studied, and all progestogens were weakly active, with the exception of progesterone and norgestrel (Table IV). These data
Table IVB. Estrogenic potency relative to ethinyl estradiol”
Ethinyl estradiol Mestranol Lynestrenol Norethynodrel Norethindrone acetate Ethynodiol diacetate Norethindrone Methyltestosterone Hydrocortisone Progesterone Norgestrel *Corrected-f&m 1973.
15, 1976
Gynecol.
of various
Pottvq C%)
compound
.August
Am. J. Obstet.
steroids 9 5 % cnnjiduw limit.7
100.0 52.1 2.6
2.1 0.9 0.4 0.3 0.0 0.0 0.0 0 .o
0.2724-1.0585
0.0112-0.0881 0.0100-0.0455 0.0043-0.0223 0.0016-0.0088 0.0013-0.0053
Jones and Edgren: Fertil. Steril. 24: 284,
may suggest conversion of the ptogestogen to an estrogen in viva. However, how does one employ these data? How does one come to a rational evaluation of the “estrogenicity” of a contraceptive agent? Does one add to the estrogenic content a percentage of the progestogen that may convert to estrogen or have estrogenic activities? For example, if we take the Lo-Estrin l/20 combination, this material contains 20 pg of ethinyl estradiol as the estrogen. It also contains 1,000 pg of norethindrone acetate. According to the potency estimates in Table IV, norethindrone acetate has 0.9 per cent (call it 1 per cent for the sake of the argument) of the potency of ethinyl estradiol. One per cent of 1 mg. is 10 pg. Therefore, is the combination norethindrone acetate plus ethinyl estradiol in the l/20 combination the clinical equivalent of giving 30 gg ofethinyl estradiol? When one adds mestranol to this, the confusion continues. Enovid-E contains mestranol as the basic estrogen in a dose of 100 Fg. This is, according to Table IV, the equivalent of approximately 50 pg of ethinyl estradiol. Korethynodrel has approximately 2 per cent of the potency of ethinyl estradiol, so the norethynodrel, 2.5 mg. in Enovid-E, would be the equivalent of 50 pg of ethinyl estradiol. Therefore, is the combination Enovid-E the clinical equivalent of giving 100 pg of ethinyl estradiol? The answer to these two questions regarding Lo-Estrin and Enovid-E is. certainly, “No.” But, of course, the exercises in the preceding paragraph presuppose that tat vaginal studies project to clinical effects. It would appear that this is not true from Goldzieher’s observations on human pituitary blockade. It should be evident at this point that it is not possible to make a meaningful evaluation of the estrogenic contributions of either the estrogen itself or the
Volume Number
125 8
Table
V.
Potencies of oral contraceptives
Antiestrogenic
effects of various
1035
steroids* Uterine
Steroid
Mouse
vaginal
smear
Antiestrone
growth Antiestriol
Standard:
Progesterone Testosterone Estrone
1OOS-I 200
100s 20
I
Acetoayprogesterone
1
A I
1
derivatives:
Medroxyprogesterone acetate Chlormadinone acetate Megestrol acetate
A
-
290
130 -
60a
-
Nortestostmones:
Norethindrone Norgestrel Norethynodrel Ethynodiol diacetate
730 7,400
-
800 >3,300
1
1 a
-
A A I
*From Edgren, Jones, and Peterson: Fertil. Steril. 18: 238, 1967. +Key to symbols; A = active; a = active, literature report; I = inactive; S = standard. Table
VI.
Potencies
of progestogens* Potency Progestatianal
Steroid
Progesterone Chlormadinone Norethisterone Norgestrel (Racemate)
(72)
Antiestrogenic
100 3,500
8 915
($6)
Contraceptive
dose/day t (fig)
100 130 730 7,400
500 350 75
*From Edgren: J. Reprod. Med. 2: 79, 1974. tFor
Pearl
index
of 2 to 3 in large-scale
studies
of progestogens
progestational component to the effects of a given combination on a specific end-point of estrogenic action. It would seem that each product will have to be considered on its own merits and its effects restricted to only one end-point of action.
Antiestrogenic action Further difficulty arises from the interaction of the progestogen with the estrogen. Most of the progestational agents commonly used as components of oral contraceptives are estrogen antagonists, but the meaning of this at a biochemical level has not been clearly defined. Biologically, it is abundantly clear that the administration of an estrogen is followed by certain biologic effects, apparently in all species of mammals. The most clearly defined are uterine growth, vaginal cornification, and pituitary blockade. The first two, the uterine growth and the vaginal changes, may be reversed by the simultaneous administration of certain compounds, notably the progestational agents that are being considered here. On the other hand, studies on hemicastrated rats, which are believed to measure the blockade of the pituitary, do not indicate an antiestrogenic effect. Further, the Ramirez-McCann rat,
as mini-pills.
employed for the measurement of luteinizing hormone-releasing factor, requires large doses of both estradiol and progesterone to block totally the release of gonadotropins; if progesterone were blocking the effect of the estrogen it would cause release of the luteinizing hormone and the preparation would not be suitable for this type of assay. In contradistinction, Goldzieher seemed to believe that the progestational agent will potentiate the effect of the estrogen in women. Therefore, we must be highly specific and define the target that we are considering before any potency evaluation that might be meaningful can be attempted. The antiestrogenic potencies of a number of progestational agents have been evaluated with standardized testing procedures (Table V). The antiestrogenic potencies appear to relate closely to the mini-pill contraceptive doese (Table VI). However, we see no way of merging these data for clinical purposes.
An example It would be desirable if one could evolve an “estrogenic index” for these materials that would add to the estrogen component itself the estrogenic con-
1036
Edgren and Sturtevant
40
3 $30 c’ .e P .2
: 20 3 e *--a D--l *.-,*-1L--
IO
I
,
.0003
,
Ethlnyl estmdiol Mestronol EnovidE Enovid 5 Ovrol Notlestrin IO
I
.mi
003
1
.Ol
.03
*-b *---
Drug dose (fraction of pil I) Fig. 1. Oral contraceptives with linear regression lines parallel to that of ethinyl estradiol. (From Chihal, Peppler, and Dickey: AM. J. OBSTET. GYNECOL. 121: 77, 1975.)
40
c---s l -mb L+--
I
Norinyl I/50 Norinyl I/80 Ovulen Ethinyl estradiol Demulen
,
.ooo3
I
001
,003
.Ol Drug dose (fraction of pill)
.03
00 I
003
--
.Ol 03 Drug dose(froction of o ~111)
-.-I I
Fig. 3. Oral contraceptives with linear regression lines not parallel to that of either ethinyl estradiol or Korinvl-1 + 50. (From Chihal, Peppler, and Dickey: AM. J. Ossr~ r. GYNI:COL.. 121: 77, 1975.)
1
IO-
I
7
I
Norlestrin 2 5 Ethinyl estrodioi Norinyl l/50
I
Fig. 2. Oral contraceptives with linear regression lines parallel to that of Norinyl-1 + 50. (From Chihal, Peppler, and Dickey: AM. J. OBSTET. GYNECOL. 121: 77, 1975.)
tribution of the progestational component and subtract the antiestrogenic effect of the progestogen. This is not possible. Evaluations of these materials will have to be based on their own merits. It would seem to us that the only meaingful approach to a comparative study of oral contraceptives and stroke or thomboembolic phenomena, cancer, or any other untoward condition that might be associated with the use of a given product would have to be based on logistic, life table, or incidence data on the specific
condition under consideration. A preconceived, established rating of estrogenicity or progestational potency cannot contribute meaingfully. Various workers have made efforts to evaluate oral contraceptives in terms of relative “estrogenicity,” relative progestational “dominance,” etc. These evahtations are more wishful thinking than science. Ho~jever, few clinicians would deny that the over-all clinical effect of Enovid, for example, is folliculoid, whereas that of a norgestrelor Ilorethindrorlc-contaiIling contraceptive appears to be primarily progestational and/or androgenic. However. such generalization from clinical impression is a poor solutiotl to o\lL problem. Recently, an attempt was made to compare oral contraceptives for their “estrogenic” potencies.“’ Thr broad conclusions reached are untenable for the following reasons. First, these workers used mouse uterine weights for definition and e\.aluation of estrogenic effects. The uteri of rats and mice respond to progestatonal agents and androgens, as well as to estrogens. Therefore, the uterine growth I-esponse is not specific, does not necessitate that a compound is estrogenic in the usual sense, and could therefore he misleading. Second, the authors’ methods are questionable: they bought commercial preparations and the tablets were ground up to form slurries, which were then administered orally to mice. ‘Ten tablets were pooled to form the initial samples and final amounts were dilutions of these initiai slurries. We cannot believe that accurate dilutions are possible in these circumstances. Third, each mouse received massive
Potencies of oral contraceptives
amounts of excipients, binders, bulk materials, etc., relative to the steroids that it received. Fourth, in a highly sensitive assay of activity, slight deviations in the original tablets, which are within tolerable limits for human use, could produce gross errors in the animal study. Fifth, the ethinyl estradiol and mestranol were obtained from sequential tablets; therefore, the ratios of extraneous to steroidal materials was greater for these tablets and less for the combination tablets. The results of this study” are displayed in Figs. 1 to 3. which show two sets of dose-response curves with regard to slope. The data suggest that the Enovid combinations, Ovral and Norlestrin (1 mg.) show dose-response curves that are parallel to ethinyl estradiol and mestranol, while Norinyl l/50, Norinyl 1180, Ovulen and Demulen show dose-response curves that are different from their estrogenic components. One combination, Norlestrin 2.5, had a slope that was parallel to neither of these two major groups. The first conclusion one reaches is that potency re!ationships among the groups cannot be drawn in any meaningful fashion; whereas it is possible to evaluate the potency of Enovid-E, Enovid-5, Ovral, or Norlestrin in terms of ethinyl estradiol or mestranol, deriving potency estimates for Norinyl 1150. Norinyl l/80. Ovulen, Demulen, or Norlestrin 2.5 in terms of either of the standard estrogens is meaningless. Further, drar\?ng a relationship between the two Enovid products, for example. and Demulen would be ridiculous. One over-all problem in this type of analysis is inherent in the data of Figs. 2 and 3. Here are two groups of compounds with dose-response curve slopes more shallow than that of the standard. The data suggest that at lower doses the uterotropic action of the progestational agents may synergize with the uterotropic activity of the estrogen, whereas the antiestrogenic effect of the progestogen is apparent at the higher doses. This kind of interaction was common in a number of our (R. A. E.) early studies involving the interactions of’ androgens, progestogens, or corticoids with estrogens. However (and here is the critical point as far as we are concerned), where on the curve do human beings fall? If one of these materials be given to a woman. does she fall on the curve at the lower level kvhere the compounds may synergize or does she fall on the curve at the higher dose levels where the progestogens appear to inhibit the estrogen? In our opinion, this study lo is really not relevant to the estrogenicity of contraceptives in human subjects. REFERENCES
1, Royal College of General tives and Health, London,
Practitioners: Oral Contracep1974, Pitman Medical.
1037
Conclusions We do not feel that it is currently scientifically possible to answer the question of oral contraceptive “potency,” nor do we believe that a solution would provide clinically meaningful answers. No laboratory or clinical measure of “potency” will predict specific side effects with useful precision, except, of course, data based upon the side effect itself. While this statement holds for the component, estrogen and progestogen, it is ever more valid with respect to One cannot ignore the mutual the combination. interactions of the progestational and estrogenic components, ignore the complications of varying estrogen/progestogen ratios, and then extrapolate from an organ or biochemical response in laboratory animals or human beings to a clinical situation (e.g., thromboembolism incidence) that is not itself observable directly, that is not demonstrable experimentally, and that is posited solely upon the basis of retrospection,” voluntary physician reporting, and sales figures. ‘I Such reasoning has led to governmental action against oral contraceptives containing more than 50 pg of “estrogen” in Great Britain and Sweden. Qualified recognition was accorded by the FDA.12 While these actions may perhaps be supported as efforts to err on the “safe side,” the basic data do not meet the test of scientific validity and, further, spurious incorporation of “potency” data will not solve the immediate problem, i.e., the evaluation of safety of the oral contraceptives for their users. *Dr. Richard P. Dickey, who disagrees with the thesis presented here, has kindly pointed out that we deal summarily with the prospective studies of the Royal College.’ This is not our intention. Some months ago, in a detailed reanalysis of the data in the Royal College report, one of us (F. M. S.) noted that the evaluation of the grand totals on reported morbidity (Table 13.2, p. 85, of reference I) did not exclude predisposing factors in ihe evaluation of the standardized rate and that this table urovided the denominator for estimated incidences of idiopaihic venous thrombosis listed in tables 7.3 (p. 45) and 7.5 (p.‘46). This point was called to the attention of Dr. Clifford Kav. Chairman of the Executive Committee of the Oral Contraception Study of the Royal College. Dr. Kay, in a letter to La&t (June’21, 1975,‘~. 1380, has now corrected and LIDdated Table 7.3: however. the orieinal Table I
7.5 still reflects’cases of idiopathic thrombosis p& womanyears contributed by women with and without predisposing conditions, and still refers to different estrogens combined with varying amounts of different progestogens. Thus, in our Table 7.5 cannot be interpreted as demonstrating opinion, any dose-response relationship between “estrogens” and thrombosis.
2. Moghissi, K. S.: Morphologic women treated with continuous Fertil. Steril. 23: 739, 1972.
changes in the ovaries of microdose progestogens,
038
Edgren
and Sturtevant
3. Zanartu, J.. et al.: Low-dosage oral progestogens to control fertility. I. Clinical investigation, Obstet. Gynecol. 43: 87, 1974. 3a. Feinstein, A. R.: Clinical biostatistics. XX. The epidemiologic trohoc, the ablative risk ratio, and “retrospective” research, Clin. Pharmacol. Ther. 14: 291, 1973. 4. Swyer, G. I. M., and Little. V.: Clinical assessment of relative potency of progestogens. J. Reprod. Fert. Suppl. 5, 63, 1968. 5. Goldzieher, J. W., de la Pena, A., Chanault, C. B., and Woutersz, T. B.: Comparative studies of the ethynyl estrogens used in oral contraceptives. II. Antiovulatory potency, AM. J. OBSTET. GYNECOL. 122: 619, 1975. 6. Edgren, R. A., Jones, R. C.. and Peterson, D. L.: A biological classification of progestational agents, Fertil. Steril. 18: 238, 1967.
Intrauterine
Asphyxia
in the Developing
7. Jones, R. C., and Edgren, R. A.: The effects of various steroids on the vaginal histology in the rat, Fertil. Steril. 24: 284, 1973. 8. Edgren, R. A., Jones, R. C.. and Peterson, I>. L.: ‘l‘he estrogenic effects of a series of 13fl-substituted compounds related to estradiol-17P Eur. J. Steroids 2: 19. 1967. 9. Edgren, R. A.: Progestagens as contraceptives, J. Reprod. Med. 2: 79, 1974. 10. Chihal, H. J. W., Peppler, R. D., and Dickey, R. P.: Estrogen potency of oral contraceptive pills, A&t. J. OBSTET. GYNECOL. 121: 77, 1975. 11. Inman, W. H. W., Vessey, M. P., Westerholm, B., aud Engelund, A.: Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs, Br. Med. J. 2: 203, 1970. 12. FDA Current Drug Information, April 24, 1970.
Fetal Brain
“Intrauterine Asphyxia in the Developing Fetal Brain,” a symposium, co-sponsored by the Department of Pediatrics, University of California, San Diego, California, and the Institute for Pediatric Service of the Johnson Bc Johnson Baby Products Company, will be held at the Town and Country Hotel, San Diego, September 9-12, 1976. The Chairman is Louis Gluck, M.D. An international faculty of neonatologists, pediatricians, obstetricians, and other specialists will discuss the important aspects of intrauterine asphyxia as it affects the developing fetal brain. For further information, write: Steven Sawchuk, M.D., 501 George St., New Brunswick, New Jersey 08903.
