July 1980, Volume 1, Number 1 Northwestern University 1040 Passavant Pavilion 303 East Superior Street Chicago, Illinois 60611 Editor: Gerald I. Zatuchni, M.D., M.Sc. Managing Editor: Kelley Osb--n This publication is supported by AID/DSPE-C-0035 RESEARCH FRONTIERS IN FERTILITY REGULATION review of past and current This report is the premiere issue of a series designed to present a comprehensive regulat'on and contraceptive develop­ research information and experience on selected major topics in fertility with the best possible summary ment. The aim of the series is to provide the scientific and technical community six times annually. As new of the state of the art with regard to each topic. The reports will appear approximately updated and rei-sued. developments occur in this rapidly changing field, the reports will be appropriately without charge by specific request to Additional copies of this publication and future issues may be obtained PARFR at the indicated address. LONGACTING STEROIDAL CONTRAEPTIVE . r Lee R. Bek, Ph.D. Donald R. Cowar, Ph.D. "ValeieZ. PS Asocae rfesor. Associate Diedor .ewh~mVr Obs Depatmen ofObstrcs Appflsd Sence Research Depa ivieWtof nufhem Ruwarh -It and Gorym"oo Universiyof Alabma Birmingham, Alabama UniversitfAlabarm BRalvignhamn *~zam of minimal intervention and The need for effective, safe, and easy-to-use contracep- The therapeutic concept through the programmed deliv­ tives has not diminished with the advent of the pill and how it can be achieved is illustrated in Figure 1. the intrauterine device (IUD). On the contrary, concern ery of steroidal contraceptives levels of a hypothetical regarding the safety of conventional contraceptives con- The curves compare blood conventional or improved dellv­ tinues to stimulate new research. One approach to the steroid following either delivery isby the oral improvement of the effectiveness, safety, and acceptabil- ery. In this example, conventional is achieved by the use of ity of steroidal contraceptives is to develop long-acting route, and improved delivery which provides programmed preparations and methods of delivery which provide an injectable formulation of the drug necessary for con­ medication. This rationale is based on the release. The blood level programmed by a narrow zone. Values in knowledge that side effects of steroid hormones are traception is represented dose constitute over­ dose-dependent. Accordingly, the degree of risk changes excess of the optimal therapeutic potential for dose-dependent in proportion to the dose. The preferred dose isone that medication with a greater values below the effective range evokes contraception with minimal risk. side effects, whereas Z OVERDOSE WITH cnF RISK OF SIDE W EFFECTS L- THE RANGE I - --- -­-­ OF MINIMAL - .INTERVENTION ~RISK UNDERDOSEOF WITH REGNANCY 1It ORAL PATTERN Figure 1. Blood levels of ahypotheti­ 8 ORLED PREGNANCY cal steroid following either oral ad­ or programmed deliv­ 1 2 3 4 5 6 7 8 9 10 11 12 ministration TIME ery. F A. Long-Acting Contraceptives E Figure 2. Long-acting steroidal contraceptive systems under current development. A. Injectable depot formulations. B. Non-biodegradable subdermal Implants, capsules, and rods. C. Medicated intrauterine devices. D. Medicated intravaginal devices. E. Medicated intracervical devices. F. Biodegradable systems. D C can result in contraceptive failure. Minimal intervention (C,D,E); and biodegradable systems that release fertility control occurs when the steroid is maintained steroids by diffusion and/or erosion of a biodegradable within the therapeutically effective dose range. Oral ad- polymer (F). ministration results in immediate high blood levels that decrease with time, and repetitive doses must be given Two different approaches have been used in the attempt at frequent intervals to keep the blood levels within the to achieve minimal intervention fertility control, the systems engineering effective zone. This results in blood steroid fluctuations, pharmacologic approach, and the represented by the pe;'ks of which exceed what is necessary for con- approach. The pharmacologic approach, compounds hav­ traception. injectable steroids, involves the use of ing iatrinsic chemical properties which provide slow re­ The injectable controlled-release system meters the iease. These include solubility of the drug in the body steroid into the blood at a controlled rate designed to fluid at the injection site, affinity for receptors in the maintain the blood level in the desired range, thereby body fluid and tissues, and rate of metabolism and achieving minimal intervention fertility control. Control- excretion from the body. The systems engineering ap­ led release allows for reduction in the total amount of pro.ch utilizes inert drug carriers to control the rate of steroid administered over a prolonged period of time, drug release. Although the degree of cor, rol may vary and reduces the chance of human error by eliminating from one carrier to the next, the systems approach can the need for repetitive self-administration, be distinguished from the plharmacologic approach on The methods which have been employed to achieve neitherthe basisa bodyof a norcontrolled-release a drug component. mechanism which is using steroidal hor­ minimal intervention fertility control mones are illustrated in Figure 2. These include: steroi- Long-acting steroidal contraceptive systems can be dal preparations selected for slow release and injectabil- further classified as those designed for systemic or local ity (A); subdermal implants in the form of Silastic cap- delivery. The implant and injectable systems, as well as sules and rods containing progestogens which diffuse medicated intravaginal devices, are designed for sys­ slowly from the implant (B); medicated devices which temic delivery; whereas medicated intrauterine and in­ release steroids locally in the uterus, vagina, and cervix tracervical devices are intended for local delivery. The 2 rationale for local delivery is to reduce the steroid load A comparison of 6- and 3-month treatment regimens, the target organ. ,,sing 300 and 150 mg MPA respectively, revealed 40% even further by direct delivery to drug-related dropouts in the 6-month group, compared tou oly 25% in th group 4) a ( 1 The effort to develop new long-acting steroidal formula- tonly 6- ind 3-month r oup interal ( 111) tions and improved delivery systems for existing com- compared 6- and 3-month treatment intervals (450 and pounds represents a goal-oriented task which includes and found a greater preg­ both applied and basic research of a diverse nature. The 150 mg MPA respectively) vs. purposebpurped of thisthscommicaiearh and communication isoto reviewreiewe the atestateTf of 0.1069)nancy rate during with 220,530 the longer-acting woman months system of use.(0.4943 steroidal contraceptive the art relating to long-acting systems, with emphasis on systems that have the poten- The major side effect of MPA is irregular bleeding. tial to provide minimal intervention fertility control. Bleeding often increases at first, but decreases with repeated injections, leading to amenorrhea. in one study, 35% of 272 women became amenorrheic during Injectable Depot Formulations therapy (79), and another study reports a 50% incidence of amenorrhea after 3 years of continuous therapy The first contraceptive steroids were syn- (103). Side effects other than bleeding irregularities thetic progestogens which had to be adminis- which have been reported include decreases in libido, tered at frequent intervals because they had short weight changes, edema, and headaches (29). biologic half-lives. The synthesis and screening of new compounds led to the discovery of structures having Blood levels following injection of 150 mg of MPA longer durations of action which made administration by reached a mean value of 3.57 ng/ml by one week injection an attractive alternative to oral contraception, post-treatment and declined to 0.6 ng/ml by 12 weeks levels in the 10 to 25 ng/ml range at 5-20 Two progestogens, mcdroxyprogesterone acetate (MPA) (72). Blood decreased to 5 to 10 ng/ml by 30 and norethindrone enanthate (NET-EN) emerged from days post-treatment followed by a more gradual decline this early work as promising injectable formulations. days post-treatment, 260 (72, 73). The minimum blood level of Upjohn Pharmaceuticals developed MPA under the through day to inhibit ovulation is 0.5-1 ng/ml. trade name Depo-Provera, and Schering AG developed MPA necessary NET-EN under the trade name Noristat. Other proges- Delay in return to fertility may be a side effect of MPA togens which have been administered by injection in- treatment. Conception or return to normal menses oc­ clude hydroxyprogesterone caproate (Delalutin, curred following discontinuation of treatment (250 mg Squibb), dihydroxyprogesterone acetophenide (Dela- MPA every 3 months) within four to seven months in droxate, Squibb), levonorgestrel undecylate (Schering 183 women following 38,599 months of use (78). In AG), and levonorgestrel nonanoate (Schering AG). another study, 50% of the women desiring pregnancy months post-treatment (79). Medroxyprogesterone acetate (MPA) was first used for conceived at 7 to 12 an 80% pregnancy rate within treatment of habitual abortion and endometriosis. A McDaniel (88) reported Pardthaisong (89) claim that single dose (Ig to 4 g) of MPA for the treatment of 12 months. McDaniel and MPA contraception is no premature labor was found to protect against pregnancy return to fertility