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Clinical pharmacology of contraceptive steroids report on a workshop conference held in Igls, Austria May 4–7, 1978
CONTRACEPTION
CLINICAL PHARMACOLOGY OF CONTRACEPTIVE STEROIDS Report on a Workshop Conference held in Igls, Austria* May 4-7, 1978 J. Hammerstein', K. Fotherby*, J.W. Goldzieher3, E.D.B. Johansson4, U. Schwartz'
' Division of Gynecologic Endocrinology, Sterility and Family Planning, Department of Obstetrics & Gynecology, Klinikum Steglitz, Freie Universitat Berlin, Germany ' Department of Steroid Biochemistry, Royal Postgraduate Medical school, Hammersmith Hospital, London W 12, Great Britain 3 Southwest Foundation for Research San Antonio, Texas, U.S.A. ' Department of Obstetrics Uppsala, Sweden
Accepted
for publication
* Sponsored
by Organon,
and Education,
& Gynecology,
University
Hospital,
July 2, 1979
Munich,
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Fed. Rep. Germany
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CONTRACEPTION
INTRODUCTION Steroidal contraceptives have now been administered for more than 20 years,- and world usage was recently estimated at over 80 million women. Considerinq the larqe number of papers already published concerning these potent drugs,one would expect our understanding of the clinical pharmacology of contraceptive steroids to be comprehensive and sound. Yet, rather the opposite appears to be true. Information regarding the pharmacokinetics of synthetic estrogens and progestins is still sparse. Until recently the evaluation of these substances depended primarily on the administration of radioactively labelled compounds, an approach hampered by limited specificity, limited applicability It was only within the past four and ethical constraints. years that suitable methodology, mainly radioimmunoassay techniques, have been developed to permit widespread analyses of the levels of steroidal contraceptives in humans and to At present relatively evaluate their pharmacokinetics. little is known about the exact influence of a multitude of factors governing the bioavailability and metabolic fate of synthetic steroids, e.g. drug formulation, route of administration, absorption processes, entero-hepatic recycling, binding to plasma proteins, catabolic events, modes of excretion, etc. less data are available on the Even relationships between steroidal pharmacokinetics and such variables as ethnic background, nutrition, climate, disease drugs, states, simultaneous administration of non-contraceptive etc. Knowledge concerning the pharmacodynamics of antifertility The entire agents also remains incomplete and controversial. spectrum of effects upon the primary and secondary target None of the tissues has not been assessed conclusively. currently available contraceptive steroids may be considered satisfactorily characterized in this respect. Diverqent opinions exist on how to define "estrogenic" and Disagreement prevails on which "progestatibnal" activities. parameter to choose for potency estimation of a given compound. The mode of action of steroidal contraceptives at the cellular level has not yet been fully investigated. Basic pharmacokinetic and pharmacodynamic studies are essential in understanding the mechanisms of hormonal In addition, it is of utmost clinical fertility control. importance to find out the relationship between pharmacologic parameters and the occurrence of adverse reactions in women exposed to steroid contraceptives. This might then lead to
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CONTRACEPTION the development of contraceptive regimens associated with a lesser incidence of side effects as well as the establishment of screening methods to identify women at risk who should be excluded from hormonal contraception. In view of the limited understanding and, in some instances, controversial results in this field,a workshop on "The Clinical Pharmacology of Contraceptive Steroids" was held in Igls, Austria, May 4-7, 1978. Twenty-four investigators from Europe, North and South America, and India gathered to critically review the information presently available and to discuss areas of future research. The following moderators' report Of the summarizes the pertinent aspects of this symposium. major review articles presented, those by H. Adlercreutz et -- al. ("Steroid Absorption and Entero-Hepatic Recycling"), M.F. El Etrebv -et al. ("Suitabilitv of the Beaqle Doq as a Test Model for the Tumorigenic Potential of Contraceptive Steroids"), H. Ludwig ("Oral Contraceptives and Blood Coaqulation"), and H. Schaefer et al. ("Contraception via Topicai Application?") are publisheriii-full in this issue.
Pharmacokinetics
of Oral Contraceptives
Basic information concerning the pharmacokinetics of oral contraceptive steroids has recently become available. However, data on the time course of drug levels in blood, lymph, various tissues, bile, urine and feces are restricted to only a few compounds: moreover, they provide little insight into the actual metabolic pathways of contraceptive steroids in man. Progress in this area is hindered by the lack of reliable and practical assay procedures. Most of the earlier observations were based on the administration of labelled substances and subsequent determination of total radioactivity recovered from various body fluids and/or tissues. Such an approach was of limited applicability: also, findinqs were often difficult to evaluate since a number of metabolites were usually measured The advent in addition to the biologically active substance. of radioimmunoassay (RIA) technology facilitated pharmacologic investigations on a wider scale. However, RIAs may yield misleading results unless positive proof of specificity is established. This has seldom been attained since most of the metabolites of synthetic estrogens and progestins are yet to be identified and because most of the intermediary products are Therenot available as standards for validation experiments. fore, RIA data still have to be interpreted with caution due to possible interference from metabolites of the parent compound. This is particularly true for methods that do not include chromatoqraphic separation. Interference from unknown metabolites
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may substantially increase with time elapsed after administration, e.g. 12-24 hours after ingestion,the original substance may be present in much lower concentrations than its metabolites (R. Fotherby). The need for quality control of synthetic steroid RIAs was stressed, preferably on an international basis. Procedures based on gas chromatographymass fragmentography (MF) are not necessarily more sensitive than RIA, yet their high specificity provides a means of checking RIA reliability. H. Adlercreutz reported that plasma values for megestrol acetate and medroxyprogesterone acetate measured by RIA were up to 100% higher than those determined by Ml?; however, this did not appear to be the case with respect to norethindrone (R. Fotherby). At present MF may be the technique of choice for detailed pharmacokinetic studies. Another promising approach appears to be the development of highly specific enzymatic assays. Recent advances in methodology will hopefully facilitate the isolation and characterization of synthetic steroid metabolites. Although a number of intermediary products of ethynyl estradiol, norgestrel, and - to a lesser extent norethindrone are known, many still need to be identified. It is of interest to note that a metabolite rather than the original compound may be responsible for the intended therapeutic effect, e.g. it has been documented that lynestrenol is rapidly transformed to norethindrone which then appears to Thus, the function as the active contraceptive principle. endocrine potency of the metabolites themselves and their possible influence on the pharmacokinetics and biological activities of the parent steroid will have to be investigated. All participants of the workshop concurred that drug companies should be persuaded to synthesize metabolites to allow for An additional objective of systematic research in this area. future studies would be the determination of interactions between synthetic estrogens and progestins as the phannacokinetics may differ depending on whether they are administered alone or in combination. In the past little attention has been paid to the bioavailability of contraceptive steroids and its determinants, e.g. drug formulation, absorption processes, immediate metabolism in the intestinal tract and the liver (so-called "first passage effect"), entero-hepatic recycling, binding to Until recently the plasma proteins and adipose tissue. dosages employed were so high that a reduction in bioavailability did not lead to any perceptible loss of efficacy. However, with the increasing use of low-dose preparations this issue is becoming more important; especially, since it may be possible to reduce dosages even further by developing appropriate formulations with better bioavailability.
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CONTRACEPTION Entero-hepatic metabolism of steroids constitutes a major part of their general metabolism. These compounds undergo numerous reactions prior to absorption catalyzed by enzymes in the intestinal mucosa, enzymes secreted into the intestinal lumen or bacterial enzymes. Preliminary data show that ampicillin may reduce absorption of ethynvl estradiol and subsequently lead to decreased plasma-levels, while the opposite effect was observed after combined oral administration of ampicillin and megestrol acetate (H. Adlercreutz). Intestinal disease has also been Further documented to influence steroid metabolism in man. studies on the physiology and pathophysioloqy of the enterohepatic circulation of contraceptive hormones are, therefore, indicated. There was considerable discussion regarding the impact of the first liver passage on pharmacokinetics and pharmacodynamics. Hypothetically, by-passing the intial enterohepatic passage should increase the bioavailability of contraceptive steroids and also decrease the incidence of E. De Jaqer presented data liver-mediated side effects. indicating that lipophilic estrogen esters, e.g. estradiol decanoate, could be prepared which after oral intake are abosrbed unchanged via the lymphatic system, thus escapinq Similar results may be immediate hepatic inactivation. obtained by choosing non-oral routes of administration. H. Adlercreutz suggested that the first passage effect observed with oral medication is primarily due to metabolic changes occurring in the intestinal tract rather than in the liver. Other factors related to bioavailability also require Only preliminary studies have been more investigation. carried out concerninq the binding of synthetic hormones to plasma proteins, e.g. -ethynyl estradiol sulfate appears to bind to albumin, whereas 1-norqestrel appears to bind to SHBG primarily. This is important not only in regard to biological activity, but also for the interaction of steroid contraIn addition, little is ceptives and endogenous hormones. known about the binding of antifertility aqents to human tissues: in particular, the role played by adipose tissue in the storage and metabolism of these drugs remains unclear. Various noncontraceptive drugs may influence the metabolism of contraceptive steroids by enzyme induction, impairment of entero-hepatic circulation, hepatic tissue damage; e.g. Rifampin markedly enhances the metabolism of ethynyl estradiol resulting in reduced contraceptive efficacy (H.M. Bolt). It was acknowledged that information concerning the interaction between synthetic estrogens and proqestins and other drugs should be extended.
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Finally, it is important to conduct pharmacokinetic studies in different parts of the world as J.W. Goldzieher presented evidence showing significant variations in the kinetics and metabolism of ethynyl estrogens depending on the ethnic group chosen for investigation. Pharmacokinetics
of Non-Oral
Contraceptives
The pharmacokinetics of contraceptive steroids are stronqly affected by the mode of administration. Major differences in metabolism and biological activity are observed depending on whether a compound is given orally or by various parenteral routes. Intravenous administration provides a basic reference method; it was stressed, however, that the pharmacokinetics of a particular agent must be investigated under clinically relevant conditions, e.g. employing the formulation marketed and the route of administration normally used. Little is known in regard to the impact of the temporal mode of administration on pharmacodynamics, i.e. bolus administration resulting in fluctuating plasma concentrations as opposed to constant release mechanisms leading to steady blood values. Preliminary data, mostly derived from animal studies, suggest that a pulsatile time course of Plasma steroid levels is less effective in In addition, the terms of endocrine potency (P. Neumann). sequence of administration of different compounds may influence drug action via modulations in receptor synthesis. During the past 15 years various non-oral routes of hormonal contraception have been utilized in an attempt to byThe pharmacologic pass the first entero-hepatic passage. aim was an increase in bioavailability to facilitate a reduction of the minimum dose required for contraceptive efficacy and to decrease the incidence of liver-mediated adverse reactions. Pharmacokinetic data on subdermal implantation, topical, intravaginal and intranasal application of steroid contraceptives are scarce as these methods have not yet achieved widespread acceptance. Intramuscular injection of proqestins constitutes the only parenteral mode of hormonal contraception which has been more Most of the relevant depot preparations thoroughly evaluated. exhibit similar patterns of phannacokinetic behaviour: a sharp initial peak is followed by gradually declining plasma levels; the actual time course varies depending on the drug An increase in dosage, as injected and its vehicle. demonstrated with norethindrone enanthate, causes an auqmentationof theinitial segment of the serum level, while serum levels thereafter remain similar to administration of lower drugs; administration of amounts of norethindrone enanthate exceeding the minimum effective contraceptive dose apparently does not increase the duration of ovulation inhibition It is yet unknown whether the early rise CU. Goebelsmann).
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and/or prolonged presence of minute amounts of circulating hormone are responsible for its biological actions. Binding to plasma proteins represents one of the determinants of the bioavailability of proqestin injectables. Thus, 19-nortestosterone derivatives not only have a high affinity for sex-hormone binding globulin (SHBG), but also decrease directly the hepatic synthetis of this carrier protein. Plasma levels of total 19-nor compounds are, therefore, an unreliable parameter for pharmacodynamic studies; no absolute relationship between plasma concentration and inhibition of ovulation has been demonstrated so far (E.D.B. Johansson). Cyproterone acetate was shown to exert biological depot effects both after oral and intramuscular administration While the majority of pharmacokinetic indices (L. Moltz). differed, the half lives of disappearance were identical for It was suggested that this both modes of administration. behaviour might be due to a predominant storage of the 17acetoxyproqesterone derivative in adipose tissue. Subcutaneous implantation of pure crystalline pellets of estradiol (25-100 mg) at 6-month intervals has been used as a means of fertility control since 1969 (R.B. Greenblatt); withdrawal bleeding must be induced monthly with an oral progestin. The high contraceptive effectiveness of this non-oral approach (Pearl index of 1.4) documents the increased biological potency of estradiol when the immediate metabolism Detailed during the first entero-hepatic passage is avoided. pharmacokinetic data regarding this mode of application is not available at present. Subdermal implantation of progestin-containing silastic Polymers results in contraceptive depot effects exceeding those of the techniques referred to above (E. Coutinho). The duration of effectiveness depends largely on the release it varies from less than one rates of the various compounds; year (lynestrenol) to 3-5 years (norethindrone, norgestrel). The site of implantation appears to be important: locating the depot in adipose tissue seems to prolong bioavailability, although this effect might be overrated. Interpopulational differences in pharmacokinetics, as observed after oral administration of ethynyl estrogens, are apparently lacking in regard to proqestin implants (E.D.B. Johansson). Intravaginal application of progestins alone or combined with an estrogen has been investiqated as an alternative to oral fertility control since 1979. (Il.Goebelsmann; B-D-B. The steroids are released from Silastic contraJohansson). ceptive vaginal rings (CVR). An initial burst of plasma
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CONTRACEPTION hormone concentrations is observed following CVR insertion; they subsequently fall to relatively stable values. The actual time course and plasma levels depend on the type and dosage of steroid as well as the material and design of the CVR. Intravaainal rather than oral administration leads to an increase in bioavailability: 0.2 mg of estradiol applied intravaginally elicits the same effect as 4 mg given orally (E.D.B. Johansson), and 0.02 to 0.03 mg of ethynyl estradiol contained in vaqinal tablets are twice as potent as the corresponding oral formulation in regard tb inhibition of ovulation (U. Schwartz). The occurrence of metabolic alterations appears to be influenced by the type of low-dose estrogen applied intravaginally: estradiol (CVR) does not induce elevations in serum triglycerides or transcortin W. Goebelsmann),while ethynyl estradiol (vaginal tablets) retains its stimulatory effects upon hepatic transcortin synthesis (U. Schwartz). Preliminary information obtained in monkey experiments, though controversial, seems to indicate that steroids administered intranasally inextremely minute amounts may block ovulation and suppress spermatogenesis (A. Kumar). Transfer of compounds into the cerebrospinal fluid was suggested to depend on the particle size delivered by the spraying device. A multi-center Phase I study organized by WHO is under way to examine the applicability of this approach to humans. Compared to combined oral contraceptives, fewer and/or less pronounced metabolic side effects are observed after parenteral administration of steroids: however, epidemiologic data concerning this topic are scarce. The problem most commonly associated with non-oral long-term progestin contraThe participants ception is that of breakthrough bleeding. of the workshop agreed that basic studies regarding the mechanism governing endometrial stability are needed. The participants also concurred that research in the area of non-oral hormonal contraception should be intensified in regard to the investigation of possible changes in metabolic pathways depending on the mode of administration, determination of the sites of steroid metabolism, studies of the mode of action (e.g. pharmacodynamic effects of pulsatile signals vs. constant dose), definition of proper dosages, and epidemiologic analysis of adverse reactions (e.g. changes in the vaginal flora following CVR application, carcinogenic potential of CVR regarding cervix and endometrium).
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Pharmacodynamic
Effects
on Primary
Target Organs
Estrogens and progestins elicit a broad spectrum of reactions at the uterine, ovarian and hypothalamo-hypophyseal levels. These effects differ qualitatively and quantitatively depending on numerous factors, e.g. the target organ and pharmacologic endpoint selected for analysis, variables in steroid administration(type of compound, dosage, route and sequence of administration, duration of exposure, etc.), the choice of experimental subject (species, age, parity, weight, clinical history, socio-economic background, etc.). In addition, the response of any given organ system is influenced by numerous pharmacokinetic determinants mainly related to the bioavailability of the substance under investigation (e.g. degree of absorption and entero-hepatic metabolism, binding to plasma proteins, compartmental distribution, storage and excretion). Thus, uncertainties arise as to the actual Within exposure of the target organ to a particular hormone. the tissue, cellular considerations take over (e.g. binding affinities to cytoplasmatic and nuclear receptors, induction of receptor synthesis, duration of receptor occupancy at various intracellular sites). Therefore, even within one organ system, systemic factors which present the steroid to the target tissue as well as the cellular kinetics of steroidreceptor binding and turnover must be evaluated. In view of the heterogeneity of effectslit becomes understandable that there is no unifying concept concerning the exact definition of "estrogenic" and Vprogestational" activity: consequently, the choice of appropriate methods for potency measurements remqins a topic of continued controversy. Estimation of uterotropic action is a classical procedure for assessing steroidal activity. For c?inical investigation of uterine tissue response,only endometrium is usually available. Donors must be either ovariectomized or belong Recruitment to the qroup of patients with qonadal dysqenesis. of such-vol;ntee&s is associat&l with c&.&iderable difficulties, and this explains in part the limited amount of data publish&i. Estrogens are found to exert a spectrum of activities on the uterus which differ qualitatively from one compound to another depending on the-criteria us& (e.g. en&n&trial proliferation, uterine weight gain, blood flow augmentation, water imbibition). Thus, it is almost impossible to find one general underlying denominator for the varied effects. The action of "weak" or "impeded" estrogens such as estriol may be best explained at present by their kinetic behaviour at the cellular level which is characterized by rapid turnover of cytoplasmatic receptor; as a corollary, estrogens which are tightly bound to cytosol or nuclear receptors produce a different time course of reactions. For clinical purposes, only histological evaluation of endometrial reponse appears
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CONTRACEPTION to be of some practical value: however, it does not provide more than a crude estimate of estrogenic potency since the quantification of estrogen-induced proliferation is inaccurate and prone to bias. No methodological breakthrough has been accomplished in this area during recent years. Clinical testing of progestational strength of contraceptive steroids at the uterine level is hampered by similar problems. Among the most widely applied techniques are the delay of menses test (prevalent in Anglo-Saxon countries) and the determination of the dose required for the transformation of a proliferative to a secretory endometrium (commonly used in continental Europe). As these procedures assess different properties the divergent results obtained in comparative studies of identical steroids are not acetate rates high in surprising; e.g. medorxyprogesterone terms of potency regarding its transformation dose, but 10~ according to the delay of menses test (J. Nevinny-Stickel, The participants of the workshop agreed R.B. Greenblatt). that progestational potency estimates based on either paraSimilar meter should, therefore, be interpreted with caution. reservations apply to methods measuring endometrial enzyme induction (E. De Jager) and myometrial response following wroaestin administration (E. Coutinho). Also, only limited information may be gained‘from determining the -in vitro inhibition of sperm miaration in cervical mucus due to the low sensitivity-of this bioassay. Assessment of suppressive and/or stimulatory actions of contraceptive steroids on the hypothalamo-hypophyseal axis Pituitary further confounds the issue of endocrine potency. LH and FSH synthesis and release are fnfluenced in an extremely complex fashion by estrogenic and progestational Most clinical studies compounds, both natural and synthetic. Since have employed combination-type oral contraceptives. it is well known that the pituitary-inhibiting action of these steroids may be synergistic, it is virtually impossible to identify the relative contributions of the compounds given. In addition, the effect is not only dependent on the dose, but on the duration of hormonal exposure as well as on the level of hypophyseal activity which in turn is related to the previous levels of estrogenic and progestional influences. Evaluation of the acute response of plasma gonadotropin concentrations to estrogen and progestin administration represents only one phase of this phenomenon, while continuous exposure as in contraceptive regimens is a substantially different situation. Thus, daily doses of 0.05 or even 0.08 mg of mestranol or ethynyl estradiol given without progestin may at first stimulate and only after a few months addition of progestational agents diminish gonadotropins; causes an immediate and dramatic increase in the pituitaryLH-RH stimulation tests inhibiting action (J-W, Goldzieher).
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reveal a reduction in hypophyseal gonadotropin release in response to combined oral contraceptives and sequential preparations, but not proqestin-only minipills and depot progestins; normalcy of reaction was restored within two weeks after discontinuation of therapy (H.D. Taubert). However, contrary findings were also reported and this topic remains controversial at present. Serum prolactin is known to be elevated by estrogens. There was some discussion regarding the possible difference between natural and synthetic estrogens. Massive, frequent doses of estriol were reported to decrease prolactin (H. Adlercreutz), while conjugated estrogens failed to It remains to be influence prolactin (R-B. Greenblatt). seen whether this constitutes a qualitative difference or A moderate rise in merely a potency-related phenomenon. basal prolactin has been documented in women using various The TRHcontraceptive formulations including minipills. induced prolactin release is also significantly augmented by the administration of low-dose and sequential oral contraceptives; it may be reduced considerably by the addition of The relative contribution of bromocriptine (H.D. Taubert). the progestational component is yet to be identified. Increased serum prolactin may be accompanied by qalactorrhea; paradoxically, inappropriate lactation may be suppressed by ascending doses of oral contraceptives (R.B. Greenblatt). The mechanism by which high estrogen concentrations counteract the lactotropic activity of prolactin apparently resides in a direct action on the mammary gland itself. It becomes evident from these data that exact defintions of estroqenic and proqestational activity are lacking at Effects evoked by any given contraceptive steroid present. may differ qualitatively and quantitatively from target tissue to target tissue and - even within a particular organ The various responses system - from parameter to parameter. do not necessarily show parallelism or form a constant ratio from one estrogen to another or one progestin to another. Thus, classical procedures for the detection of endocrine strength have largely outlived their usefulness and may actually be misleadinq unless taken as crude estimates and For example, the determination interpreted in a broad sense. of uterotropic properties does not provide an adequate, let alone a quantitative potency measurement of a contraceptive There was steroid in its full biological perspective. general agreement that the attributes "estrogenic" and "progestational" must be regarded as merely operational It was stressed that the particular action studied terms. must be specified as it cannot be extrapolated to other estroqenic or proqestational activities in any simple fashion. It was also suggested that the concept of phannacoloqic
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potency should be expanded to account not only for the therapeutic effects intended, but also for the adverse reactions elicited.Controversy existedon whether accumulating knowledge about the intracellular events underlying the transformation of hormonal sianals into snecific bioloaical action (e.g. steroid-receptorbinding and-turnover) might provide the basis for developins more reliable biochemical procedures to determine estrbgenic and progestational strength. The participants of the meeting concurred that additiona research regarding the pharmacodynamics of contraceptive agents should include the assessment of steroidal activities at the ovarian level, as hardly any data concerning this target organ are presently available. Also, attempts should be made to analyze the correlation between the doses of steroid administered, the drug levels attained in various biological fluids and tissues, and the respective reactions induced in order to define the threshold dosages for specific pharmacodynamic effects.It was also felt necessary to agree on compounds to be used as reference standards for relative potency estimates. Pharmacodynamic
Effects
on Secondary
Target Tissues
Steroid hormones exert effects which extend far beyond the reproductive system. Changes in over a hundred metabolic parameters have been recorded in women using oral contraceptives. The entire spectrum of alterations is still not known. While a multitude of publications exist on combined and sequential oral contraceptives, relatively little information is available concerning the actions of their respective components, low-dose oral progestins, longacting systemic contraceptives (injectables, sustained-release preparations) and medicated intrauterine and intravaginal devices. The medical relevance of the metabolic disturbances is, in many instances, uncertain. Most documented side effects appear to be reversible. Actual clinical disease, such as diabetes, hypertension or thromboembolism, seems to develop only in the susceptible individual. It is, therefore, Of Voluminous utmost importance to identify such women at risk. epidemiologic data, though mainly retrospective, have marked the areas of concern; there is now a definite need to conduct adequately designed studies to determine whether the associations between contraceptive steroid usage and metabolic Factors that are pertinent derangements are casual or causal. to the design of clinical pharmacologic trials and which have unfortunately been neglected by many investigators In the past
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CONTRACEPTION include population (age, parity, weight, clinical history, ethnic and socio-economic background), experimental approach (retrospective, prospective, cross-sectional), variables in steroid therapy (type, dosage, route of administration, duration and exposure) and testing procedure (static, dynamic). Based on conclusive evidence,proper and simple screening techniques will have to be developed to identify those patients who should be excluded from hormonal contraception. The participants were unable to recommend a specific set of tests which should be required before initiation of contraceptive therapy. The present lack of connection between studies evaluating the pharmacokinetics and pharmacodynamics of contraceptive steroids and enidemioloaic data elucidatina the risks of evoking adverse reactions needs to be overcome. Many of the alterations in carbohydrate, lipid and protein metabolism as well as derangements in coagulation appear to be livermediated. Again it was stressed that the significance of the first liver passage, which follows absorption from the portal vein system after oral administration, requires further investigation. Little is also known about the relevance of events at the cellular level for the occurrence of side effects, e.g. hepatic receptor binding and turnover of synthetic compounds. One of the pathophysiologic mechanisms under discussion is based on the speculation that overloading of high-affinity receptors in the primary target organs leads to occupancy of low-affinity receptors in non-target tissues such as the liver or vessel walls. As steroid metabolites rather than the parent compounds themselves might be responsible for the adverse reactions elicited, it was thought worthwhile to look for predisposing changes of steroid metabolism in the Again the meeting was unanimous in suggesting patient at risk. that drug companies should synthesize contraceptive steroid metabolites to allow for systematic research in this area. Relevance
of Pharmacologic
Animal
Studies
Although the workshop's main concern centered on the pharmacology of contraceptive steroids in women, some pertinent information obtained in animals was also presented. As could be expected, these comparative studies clearly documented the problems encountered in attempting to extrapolate from Pharmacokinetics and pharmacodynamics one species to another. of synthetic estrogens and progestins are determined by a multitude of variables,all of which may be species-specific. For example, it was shown that the rat model does not reflect the human situation in regard to release of longacting progestin esters from their depots (F. van der Veen), entero-hepatic recycling of estrogens (H.M. Bolt), endometrial enzyme induction by progestins (E. de Jager), ovulation
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CONTRACEPTION
inhibition by ethynyl estrogens (J.W. Goldzieher), and tumorigenie effects of progesti'ns on the liver (H.M. Bolt). On the other hand, certain similarities were detected between man and rabbit relating to entero-hepatic estrogen circulation and progestin-evoked changes in endometrial enzyme patterns; also, results accumulated in the baboon concerning the metabolism of ethynyl estrogens and the effects of oral contraceptives on lipoprotein metabolism resembled those in the human (J.W. Goldzieher). F. Neumann convincingly demonstrated that the beagle dog does not represent an appropriate model for assessing the mammary tumorigenicity of progestational compounds. In addition, it appears that even intra-species differences have to be accounted for, e.g. geographic influences: thus diveraent findinas were reqistered in monkey colonies located in India and Oregon-pertaining to the gonadotropin-suppressing activity of steroids administered intranasally (A. Xumar). Animal trials are undoubtedly of significant importance for developing new contraceptive modalities and for conducting However, it must long-term tolerance and toxicity studies. be stressed that animal data may only be extrapolated to the human after proving the suitability of the species model utilized for each specific pharmacologic parameter which is to be analyzed.
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CLINICAL PHARMACOLOGY OF CONTRACEPTIVE STEROIDS Report on a Workshop Conference held in Igls, Austria* May 4-7, 1978 J. Hammerstein', K. Fotherby*, J.W. Goldzieher3, E.D.B. Johansson4, U. Schwartz'
' Division of Gynecologic Endocrinology, Sterility and Family Planning, Department of Obstetrics & Gynecology, Klinikum Steglitz, Freie Universitat Berlin, Germany ' Department of Steroid Biochemistry, Royal Postgraduate Medical school, Hammersmith Hospital, London W 12, Great Britain 3 Southwest Foundation for Research San Antonio, Texas, U.S.A. ' Department of Obstetrics Uppsala, Sweden
Accepted
for publication
* Sponsored
by Organon,
and Education,
& Gynecology,
University
Hospital,
July 2, 1979
Munich,
SEPTEMBER 1979 VOL. 20 NO. 3
Fed. Rep. Germany
187
CONTRACEPTION
INTRODUCTION Steroidal contraceptives have now been administered for more than 20 years,- and world usage was recently estimated at over 80 million women. Considerinq the larqe number of papers already published concerning these potent drugs,one would expect our understanding of the clinical pharmacology of contraceptive steroids to be comprehensive and sound. Yet, rather the opposite appears to be true. Information regarding the pharmacokinetics of synthetic estrogens and progestins is still sparse. Until recently the evaluation of these substances depended primarily on the administration of radioactively labelled compounds, an approach hampered by limited specificity, limited applicability It was only within the past four and ethical constraints. years that suitable methodology, mainly radioimmunoassay techniques, have been developed to permit widespread analyses of the levels of steroidal contraceptives in humans and to At present relatively evaluate their pharmacokinetics. little is known about the exact influence of a multitude of factors governing the bioavailability and metabolic fate of synthetic steroids, e.g. drug formulation, route of administration, absorption processes, entero-hepatic recycling, binding to plasma proteins, catabolic events, modes of excretion, etc. less data are available on the Even relationships between steroidal pharmacokinetics and such variables as ethnic background, nutrition, climate, disease drugs, states, simultaneous administration of non-contraceptive etc. Knowledge concerning the pharmacodynamics of antifertility The entire agents also remains incomplete and controversial. spectrum of effects upon the primary and secondary target None of the tissues has not been assessed conclusively. currently available contraceptive steroids may be considered satisfactorily characterized in this respect. Diverqent opinions exist on how to define "estrogenic" and Disagreement prevails on which "progestatibnal" activities. parameter to choose for potency estimation of a given compound. The mode of action of steroidal contraceptives at the cellular level has not yet been fully investigated. Basic pharmacokinetic and pharmacodynamic studies are essential in understanding the mechanisms of hormonal In addition, it is of utmost clinical fertility control. importance to find out the relationship between pharmacologic parameters and the occurrence of adverse reactions in women exposed to steroid contraceptives. This might then lead to
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SEPTEMBER 1979VOL.20N0.3
CONTRACEPTION the development of contraceptive regimens associated with a lesser incidence of side effects as well as the establishment of screening methods to identify women at risk who should be excluded from hormonal contraception. In view of the limited understanding and, in some instances, controversial results in this field,a workshop on "The Clinical Pharmacology of Contraceptive Steroids" was held in Igls, Austria, May 4-7, 1978. Twenty-four investigators from Europe, North and South America, and India gathered to critically review the information presently available and to discuss areas of future research. The following moderators' report Of the summarizes the pertinent aspects of this symposium. major review articles presented, those by H. Adlercreutz et -- al. ("Steroid Absorption and Entero-Hepatic Recycling"), M.F. El Etrebv -et al. ("Suitabilitv of the Beaqle Doq as a Test Model for the Tumorigenic Potential of Contraceptive Steroids"), H. Ludwig ("Oral Contraceptives and Blood Coaqulation"), and H. Schaefer et al. ("Contraception via Topicai Application?") are publisheriii-full in this issue.
Pharmacokinetics
of Oral Contraceptives
Basic information concerning the pharmacokinetics of oral contraceptive steroids has recently become available. However, data on the time course of drug levels in blood, lymph, various tissues, bile, urine and feces are restricted to only a few compounds: moreover, they provide little insight into the actual metabolic pathways of contraceptive steroids in man. Progress in this area is hindered by the lack of reliable and practical assay procedures. Most of the earlier observations were based on the administration of labelled substances and subsequent determination of total radioactivity recovered from various body fluids and/or tissues. Such an approach was of limited applicability: also, findinqs were often difficult to evaluate since a number of metabolites were usually measured The advent in addition to the biologically active substance. of radioimmunoassay (RIA) technology facilitated pharmacologic investigations on a wider scale. However, RIAs may yield misleading results unless positive proof of specificity is established. This has seldom been attained since most of the metabolites of synthetic estrogens and progestins are yet to be identified and because most of the intermediary products are Therenot available as standards for validation experiments. fore, RIA data still have to be interpreted with caution due to possible interference from metabolites of the parent compound. This is particularly true for methods that do not include chromatoqraphic separation. Interference from unknown metabolites
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may substantially increase with time elapsed after administration, e.g. 12-24 hours after ingestion,the original substance may be present in much lower concentrations than its metabolites (R. Fotherby). The need for quality control of synthetic steroid RIAs was stressed, preferably on an international basis. Procedures based on gas chromatographymass fragmentography (MF) are not necessarily more sensitive than RIA, yet their high specificity provides a means of checking RIA reliability. H. Adlercreutz reported that plasma values for megestrol acetate and medroxyprogesterone acetate measured by RIA were up to 100% higher than those determined by Ml?; however, this did not appear to be the case with respect to norethindrone (R. Fotherby). At present MF may be the technique of choice for detailed pharmacokinetic studies. Another promising approach appears to be the development of highly specific enzymatic assays. Recent advances in methodology will hopefully facilitate the isolation and characterization of synthetic steroid metabolites. Although a number of intermediary products of ethynyl estradiol, norgestrel, and - to a lesser extent norethindrone are known, many still need to be identified. It is of interest to note that a metabolite rather than the original compound may be responsible for the intended therapeutic effect, e.g. it has been documented that lynestrenol is rapidly transformed to norethindrone which then appears to Thus, the function as the active contraceptive principle. endocrine potency of the metabolites themselves and their possible influence on the pharmacokinetics and biological activities of the parent steroid will have to be investigated. All participants of the workshop concurred that drug companies should be persuaded to synthesize metabolites to allow for An additional objective of systematic research in this area. future studies would be the determination of interactions between synthetic estrogens and progestins as the phannacokinetics may differ depending on whether they are administered alone or in combination. In the past little attention has been paid to the bioavailability of contraceptive steroids and its determinants, e.g. drug formulation, absorption processes, immediate metabolism in the intestinal tract and the liver (so-called "first passage effect"), entero-hepatic recycling, binding to Until recently the plasma proteins and adipose tissue. dosages employed were so high that a reduction in bioavailability did not lead to any perceptible loss of efficacy. However, with the increasing use of low-dose preparations this issue is becoming more important; especially, since it may be possible to reduce dosages even further by developing appropriate formulations with better bioavailability.
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CONTRACEPTION Entero-hepatic metabolism of steroids constitutes a major part of their general metabolism. These compounds undergo numerous reactions prior to absorption catalyzed by enzymes in the intestinal mucosa, enzymes secreted into the intestinal lumen or bacterial enzymes. Preliminary data show that ampicillin may reduce absorption of ethynvl estradiol and subsequently lead to decreased plasma-levels, while the opposite effect was observed after combined oral administration of ampicillin and megestrol acetate (H. Adlercreutz). Intestinal disease has also been Further documented to influence steroid metabolism in man. studies on the physiology and pathophysioloqy of the enterohepatic circulation of contraceptive hormones are, therefore, indicated. There was considerable discussion regarding the impact of the first liver passage on pharmacokinetics and pharmacodynamics. Hypothetically, by-passing the intial enterohepatic passage should increase the bioavailability of contraceptive steroids and also decrease the incidence of E. De Jaqer presented data liver-mediated side effects. indicating that lipophilic estrogen esters, e.g. estradiol decanoate, could be prepared which after oral intake are abosrbed unchanged via the lymphatic system, thus escapinq Similar results may be immediate hepatic inactivation. obtained by choosing non-oral routes of administration. H. Adlercreutz suggested that the first passage effect observed with oral medication is primarily due to metabolic changes occurring in the intestinal tract rather than in the liver. Other factors related to bioavailability also require Only preliminary studies have been more investigation. carried out concerninq the binding of synthetic hormones to plasma proteins, e.g. -ethynyl estradiol sulfate appears to bind to albumin, whereas 1-norqestrel appears to bind to SHBG primarily. This is important not only in regard to biological activity, but also for the interaction of steroid contraIn addition, little is ceptives and endogenous hormones. known about the binding of antifertility aqents to human tissues: in particular, the role played by adipose tissue in the storage and metabolism of these drugs remains unclear. Various noncontraceptive drugs may influence the metabolism of contraceptive steroids by enzyme induction, impairment of entero-hepatic circulation, hepatic tissue damage; e.g. Rifampin markedly enhances the metabolism of ethynyl estradiol resulting in reduced contraceptive efficacy (H.M. Bolt). It was acknowledged that information concerning the interaction between synthetic estrogens and proqestins and other drugs should be extended.
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Finally, it is important to conduct pharmacokinetic studies in different parts of the world as J.W. Goldzieher presented evidence showing significant variations in the kinetics and metabolism of ethynyl estrogens depending on the ethnic group chosen for investigation. Pharmacokinetics
of Non-Oral
Contraceptives
The pharmacokinetics of contraceptive steroids are stronqly affected by the mode of administration. Major differences in metabolism and biological activity are observed depending on whether a compound is given orally or by various parenteral routes. Intravenous administration provides a basic reference method; it was stressed, however, that the pharmacokinetics of a particular agent must be investigated under clinically relevant conditions, e.g. employing the formulation marketed and the route of administration normally used. Little is known in regard to the impact of the temporal mode of administration on pharmacodynamics, i.e. bolus administration resulting in fluctuating plasma concentrations as opposed to constant release mechanisms leading to steady blood values. Preliminary data, mostly derived from animal studies, suggest that a pulsatile time course of Plasma steroid levels is less effective in In addition, the terms of endocrine potency (P. Neumann). sequence of administration of different compounds may influence drug action via modulations in receptor synthesis. During the past 15 years various non-oral routes of hormonal contraception have been utilized in an attempt to byThe pharmacologic pass the first entero-hepatic passage. aim was an increase in bioavailability to facilitate a reduction of the minimum dose required for contraceptive efficacy and to decrease the incidence of liver-mediated adverse reactions. Pharmacokinetic data on subdermal implantation, topical, intravaginal and intranasal application of steroid contraceptives are scarce as these methods have not yet achieved widespread acceptance. Intramuscular injection of proqestins constitutes the only parenteral mode of hormonal contraception which has been more Most of the relevant depot preparations thoroughly evaluated. exhibit similar patterns of phannacokinetic behaviour: a sharp initial peak is followed by gradually declining plasma levels; the actual time course varies depending on the drug An increase in dosage, as injected and its vehicle. demonstrated with norethindrone enanthate, causes an auqmentationof theinitial segment of the serum level, while serum levels thereafter remain similar to administration of lower drugs; administration of amounts of norethindrone enanthate exceeding the minimum effective contraceptive dose apparently does not increase the duration of ovulation inhibition It is yet unknown whether the early rise CU. Goebelsmann).
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and/or prolonged presence of minute amounts of circulating hormone are responsible for its biological actions. Binding to plasma proteins represents one of the determinants of the bioavailability of proqestin injectables. Thus, 19-nortestosterone derivatives not only have a high affinity for sex-hormone binding globulin (SHBG), but also decrease directly the hepatic synthetis of this carrier protein. Plasma levels of total 19-nor compounds are, therefore, an unreliable parameter for pharmacodynamic studies; no absolute relationship between plasma concentration and inhibition of ovulation has been demonstrated so far (E.D.B. Johansson). Cyproterone acetate was shown to exert biological depot effects both after oral and intramuscular administration While the majority of pharmacokinetic indices (L. Moltz). differed, the half lives of disappearance were identical for It was suggested that this both modes of administration. behaviour might be due to a predominant storage of the 17acetoxyproqesterone derivative in adipose tissue. Subcutaneous implantation of pure crystalline pellets of estradiol (25-100 mg) at 6-month intervals has been used as a means of fertility control since 1969 (R.B. Greenblatt); withdrawal bleeding must be induced monthly with an oral progestin. The high contraceptive effectiveness of this non-oral approach (Pearl index of 1.4) documents the increased biological potency of estradiol when the immediate metabolism Detailed during the first entero-hepatic passage is avoided. pharmacokinetic data regarding this mode of application is not available at present. Subdermal implantation of progestin-containing silastic Polymers results in contraceptive depot effects exceeding those of the techniques referred to above (E. Coutinho). The duration of effectiveness depends largely on the release it varies from less than one rates of the various compounds; year (lynestrenol) to 3-5 years (norethindrone, norgestrel). The site of implantation appears to be important: locating the depot in adipose tissue seems to prolong bioavailability, although this effect might be overrated. Interpopulational differences in pharmacokinetics, as observed after oral administration of ethynyl estrogens, are apparently lacking in regard to proqestin implants (E.D.B. Johansson). Intravaginal application of progestins alone or combined with an estrogen has been investiqated as an alternative to oral fertility control since 1979. (Il.Goebelsmann; B-D-B. The steroids are released from Silastic contraJohansson). ceptive vaginal rings (CVR). An initial burst of plasma
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CONTRACEPTION hormone concentrations is observed following CVR insertion; they subsequently fall to relatively stable values. The actual time course and plasma levels depend on the type and dosage of steroid as well as the material and design of the CVR. Intravaainal rather than oral administration leads to an increase in bioavailability: 0.2 mg of estradiol applied intravaginally elicits the same effect as 4 mg given orally (E.D.B. Johansson), and 0.02 to 0.03 mg of ethynyl estradiol contained in vaqinal tablets are twice as potent as the corresponding oral formulation in regard tb inhibition of ovulation (U. Schwartz). The occurrence of metabolic alterations appears to be influenced by the type of low-dose estrogen applied intravaginally: estradiol (CVR) does not induce elevations in serum triglycerides or transcortin W. Goebelsmann),while ethynyl estradiol (vaginal tablets) retains its stimulatory effects upon hepatic transcortin synthesis (U. Schwartz). Preliminary information obtained in monkey experiments, though controversial, seems to indicate that steroids administered intranasally inextremely minute amounts may block ovulation and suppress spermatogenesis (A. Kumar). Transfer of compounds into the cerebrospinal fluid was suggested to depend on the particle size delivered by the spraying device. A multi-center Phase I study organized by WHO is under way to examine the applicability of this approach to humans. Compared to combined oral contraceptives, fewer and/or less pronounced metabolic side effects are observed after parenteral administration of steroids: however, epidemiologic data concerning this topic are scarce. The problem most commonly associated with non-oral long-term progestin contraThe participants ception is that of breakthrough bleeding. of the workshop agreed that basic studies regarding the mechanism governing endometrial stability are needed. The participants also concurred that research in the area of non-oral hormonal contraception should be intensified in regard to the investigation of possible changes in metabolic pathways depending on the mode of administration, determination of the sites of steroid metabolism, studies of the mode of action (e.g. pharmacodynamic effects of pulsatile signals vs. constant dose), definition of proper dosages, and epidemiologic analysis of adverse reactions (e.g. changes in the vaginal flora following CVR application, carcinogenic potential of CVR regarding cervix and endometrium).
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Pharmacodynamic
Effects
on Primary
Target Organs
Estrogens and progestins elicit a broad spectrum of reactions at the uterine, ovarian and hypothalamo-hypophyseal levels. These effects differ qualitatively and quantitatively depending on numerous factors, e.g. the target organ and pharmacologic endpoint selected for analysis, variables in steroid administration(type of compound, dosage, route and sequence of administration, duration of exposure, etc.), the choice of experimental subject (species, age, parity, weight, clinical history, socio-economic background, etc.). In addition, the response of any given organ system is influenced by numerous pharmacokinetic determinants mainly related to the bioavailability of the substance under investigation (e.g. degree of absorption and entero-hepatic metabolism, binding to plasma proteins, compartmental distribution, storage and excretion). Thus, uncertainties arise as to the actual Within exposure of the target organ to a particular hormone. the tissue, cellular considerations take over (e.g. binding affinities to cytoplasmatic and nuclear receptors, induction of receptor synthesis, duration of receptor occupancy at various intracellular sites). Therefore, even within one organ system, systemic factors which present the steroid to the target tissue as well as the cellular kinetics of steroidreceptor binding and turnover must be evaluated. In view of the heterogeneity of effectslit becomes understandable that there is no unifying concept concerning the exact definition of "estrogenic" and Vprogestational" activity: consequently, the choice of appropriate methods for potency measurements remqins a topic of continued controversy. Estimation of uterotropic action is a classical procedure for assessing steroidal activity. For c?inical investigation of uterine tissue response,only endometrium is usually available. Donors must be either ovariectomized or belong Recruitment to the qroup of patients with qonadal dysqenesis. of such-vol;ntee&s is associat&l with c&.&iderable difficulties, and this explains in part the limited amount of data publish&i. Estrogens are found to exert a spectrum of activities on the uterus which differ qualitatively from one compound to another depending on the-criteria us& (e.g. en&n&trial proliferation, uterine weight gain, blood flow augmentation, water imbibition). Thus, it is almost impossible to find one general underlying denominator for the varied effects. The action of "weak" or "impeded" estrogens such as estriol may be best explained at present by their kinetic behaviour at the cellular level which is characterized by rapid turnover of cytoplasmatic receptor; as a corollary, estrogens which are tightly bound to cytosol or nuclear receptors produce a different time course of reactions. For clinical purposes, only histological evaluation of endometrial reponse appears
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CONTRACEPTION to be of some practical value: however, it does not provide more than a crude estimate of estrogenic potency since the quantification of estrogen-induced proliferation is inaccurate and prone to bias. No methodological breakthrough has been accomplished in this area during recent years. Clinical testing of progestational strength of contraceptive steroids at the uterine level is hampered by similar problems. Among the most widely applied techniques are the delay of menses test (prevalent in Anglo-Saxon countries) and the determination of the dose required for the transformation of a proliferative to a secretory endometrium (commonly used in continental Europe). As these procedures assess different properties the divergent results obtained in comparative studies of identical steroids are not acetate rates high in surprising; e.g. medorxyprogesterone terms of potency regarding its transformation dose, but 10~ according to the delay of menses test (J. Nevinny-Stickel, The participants of the workshop agreed R.B. Greenblatt). that progestational potency estimates based on either paraSimilar meter should, therefore, be interpreted with caution. reservations apply to methods measuring endometrial enzyme induction (E. De Jager) and myometrial response following wroaestin administration (E. Coutinho). Also, only limited information may be gained‘from determining the -in vitro inhibition of sperm miaration in cervical mucus due to the low sensitivity-of this bioassay. Assessment of suppressive and/or stimulatory actions of contraceptive steroids on the hypothalamo-hypophyseal axis Pituitary further confounds the issue of endocrine potency. LH and FSH synthesis and release are fnfluenced in an extremely complex fashion by estrogenic and progestational Most clinical studies compounds, both natural and synthetic. Since have employed combination-type oral contraceptives. it is well known that the pituitary-inhibiting action of these steroids may be synergistic, it is virtually impossible to identify the relative contributions of the compounds given. In addition, the effect is not only dependent on the dose, but on the duration of hormonal exposure as well as on the level of hypophyseal activity which in turn is related to the previous levels of estrogenic and progestional influences. Evaluation of the acute response of plasma gonadotropin concentrations to estrogen and progestin administration represents only one phase of this phenomenon, while continuous exposure as in contraceptive regimens is a substantially different situation. Thus, daily doses of 0.05 or even 0.08 mg of mestranol or ethynyl estradiol given without progestin may at first stimulate and only after a few months addition of progestational agents diminish gonadotropins; causes an immediate and dramatic increase in the pituitaryLH-RH stimulation tests inhibiting action (J-W, Goldzieher).
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reveal a reduction in hypophyseal gonadotropin release in response to combined oral contraceptives and sequential preparations, but not proqestin-only minipills and depot progestins; normalcy of reaction was restored within two weeks after discontinuation of therapy (H.D. Taubert). However, contrary findings were also reported and this topic remains controversial at present. Serum prolactin is known to be elevated by estrogens. There was some discussion regarding the possible difference between natural and synthetic estrogens. Massive, frequent doses of estriol were reported to decrease prolactin (H. Adlercreutz), while conjugated estrogens failed to It remains to be influence prolactin (R-B. Greenblatt). seen whether this constitutes a qualitative difference or A moderate rise in merely a potency-related phenomenon. basal prolactin has been documented in women using various The TRHcontraceptive formulations including minipills. induced prolactin release is also significantly augmented by the administration of low-dose and sequential oral contraceptives; it may be reduced considerably by the addition of The relative contribution of bromocriptine (H.D. Taubert). the progestational component is yet to be identified. Increased serum prolactin may be accompanied by qalactorrhea; paradoxically, inappropriate lactation may be suppressed by ascending doses of oral contraceptives (R.B. Greenblatt). The mechanism by which high estrogen concentrations counteract the lactotropic activity of prolactin apparently resides in a direct action on the mammary gland itself. It becomes evident from these data that exact defintions of estroqenic and proqestational activity are lacking at Effects evoked by any given contraceptive steroid present. may differ qualitatively and quantitatively from target tissue to target tissue and - even within a particular organ The various responses system - from parameter to parameter. do not necessarily show parallelism or form a constant ratio from one estrogen to another or one progestin to another. Thus, classical procedures for the detection of endocrine strength have largely outlived their usefulness and may actually be misleadinq unless taken as crude estimates and For example, the determination interpreted in a broad sense. of uterotropic properties does not provide an adequate, let alone a quantitative potency measurement of a contraceptive There was steroid in its full biological perspective. general agreement that the attributes "estrogenic" and "progestational" must be regarded as merely operational It was stressed that the particular action studied terms. must be specified as it cannot be extrapolated to other estroqenic or proqestational activities in any simple fashion. It was also suggested that the concept of phannacoloqic
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potency should be expanded to account not only for the therapeutic effects intended, but also for the adverse reactions elicited.Controversy existedon whether accumulating knowledge about the intracellular events underlying the transformation of hormonal sianals into snecific bioloaical action (e.g. steroid-receptorbinding and-turnover) might provide the basis for developins more reliable biochemical procedures to determine estrbgenic and progestational strength. The participants of the meeting concurred that additiona research regarding the pharmacodynamics of contraceptive agents should include the assessment of steroidal activities at the ovarian level, as hardly any data concerning this target organ are presently available. Also, attempts should be made to analyze the correlation between the doses of steroid administered, the drug levels attained in various biological fluids and tissues, and the respective reactions induced in order to define the threshold dosages for specific pharmacodynamic effects.It was also felt necessary to agree on compounds to be used as reference standards for relative potency estimates. Pharmacodynamic
Effects
on Secondary
Target Tissues
Steroid hormones exert effects which extend far beyond the reproductive system. Changes in over a hundred metabolic parameters have been recorded in women using oral contraceptives. The entire spectrum of alterations is still not known. While a multitude of publications exist on combined and sequential oral contraceptives, relatively little information is available concerning the actions of their respective components, low-dose oral progestins, longacting systemic contraceptives (injectables, sustained-release preparations) and medicated intrauterine and intravaginal devices. The medical relevance of the metabolic disturbances is, in many instances, uncertain. Most documented side effects appear to be reversible. Actual clinical disease, such as diabetes, hypertension or thromboembolism, seems to develop only in the susceptible individual. It is, therefore, Of Voluminous utmost importance to identify such women at risk. epidemiologic data, though mainly retrospective, have marked the areas of concern; there is now a definite need to conduct adequately designed studies to determine whether the associations between contraceptive steroid usage and metabolic Factors that are pertinent derangements are casual or causal. to the design of clinical pharmacologic trials and which have unfortunately been neglected by many investigators In the past
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CONTRACEPTION include population (age, parity, weight, clinical history, ethnic and socio-economic background), experimental approach (retrospective, prospective, cross-sectional), variables in steroid therapy (type, dosage, route of administration, duration and exposure) and testing procedure (static, dynamic). Based on conclusive evidence,proper and simple screening techniques will have to be developed to identify those patients who should be excluded from hormonal contraception. The participants were unable to recommend a specific set of tests which should be required before initiation of contraceptive therapy. The present lack of connection between studies evaluating the pharmacokinetics and pharmacodynamics of contraceptive steroids and enidemioloaic data elucidatina the risks of evoking adverse reactions needs to be overcome. Many of the alterations in carbohydrate, lipid and protein metabolism as well as derangements in coagulation appear to be livermediated. Again it was stressed that the significance of the first liver passage, which follows absorption from the portal vein system after oral administration, requires further investigation. Little is also known about the relevance of events at the cellular level for the occurrence of side effects, e.g. hepatic receptor binding and turnover of synthetic compounds. One of the pathophysiologic mechanisms under discussion is based on the speculation that overloading of high-affinity receptors in the primary target organs leads to occupancy of low-affinity receptors in non-target tissues such as the liver or vessel walls. As steroid metabolites rather than the parent compounds themselves might be responsible for the adverse reactions elicited, it was thought worthwhile to look for predisposing changes of steroid metabolism in the Again the meeting was unanimous in suggesting patient at risk. that drug companies should synthesize contraceptive steroid metabolites to allow for systematic research in this area. Relevance
of Pharmacologic
Animal
Studies
Although the workshop's main concern centered on the pharmacology of contraceptive steroids in women, some pertinent information obtained in animals was also presented. As could be expected, these comparative studies clearly documented the problems encountered in attempting to extrapolate from Pharmacokinetics and pharmacodynamics one species to another. of synthetic estrogens and progestins are determined by a multitude of variables,all of which may be species-specific. For example, it was shown that the rat model does not reflect the human situation in regard to release of longacting progestin esters from their depots (F. van der Veen), entero-hepatic recycling of estrogens (H.M. Bolt), endometrial enzyme induction by progestins (E. de Jager), ovulation
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inhibition by ethynyl estrogens (J.W. Goldzieher), and tumorigenie effects of progesti'ns on the liver (H.M. Bolt). On the other hand, certain similarities were detected between man and rabbit relating to entero-hepatic estrogen circulation and progestin-evoked changes in endometrial enzyme patterns; also, results accumulated in the baboon concerning the metabolism of ethynyl estrogens and the effects of oral contraceptives on lipoprotein metabolism resembled those in the human (J.W. Goldzieher). F. Neumann convincingly demonstrated that the beagle dog does not represent an appropriate model for assessing the mammary tumorigenicity of progestational compounds. In addition, it appears that even intra-species differences have to be accounted for, e.g. geographic influences: thus diveraent findinas were reqistered in monkey colonies located in India and Oregon-pertaining to the gonadotropin-suppressing activity of steroids administered intranasally (A. Xumar). Animal trials are undoubtedly of significant importance for developing new contraceptive modalities and for conducting However, it must long-term tolerance and toxicity studies. be stressed that animal data may only be extrapolated to the human after proving the suitability of the species model utilized for each specific pharmacologic parameter which is to be analyzed.
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