Original research article

Toxicology of progestogens of implantable contraceptives for women

Alexander Jordan*Division of Reproductive & Urologic Drug Products, Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD, USA

Abstract

There are currently four progestogens used in implantable contraceptives marketed or tested in clinical trials: levonorgestrel in Norplantand Jadelle, etonogestrel (3-keto-desogestrel) in Implanon, nestorone in Elcometrine, and nomegestrol acetate in Uniplant and Surplant.Each progestogen was evaluated for hormonal activity and for safety in a wide variety of tests in vitro and in animals prior to their use inwomen. All four progestogens underwent pre-clinical testing that generally followed the format for animal testing of steroidal contraceptivespublished by the World Health Organization and the US Food and Drug Administration (FDA) [1]. Most of the progestogens have beentested for genotoxicity in bacterial and mammalian cultured cells and in rodents. All were tested for toxicity in short- and long-termtoxicology studies in rodents and dogs or monkeys, and all were tested for their effects on reproduction and fetal development. In most cases,the progestogens were tested for carcinogenicity in two rodent species, rats and mice. Early clinical trials in small numbers of womenprovided additional safety data prior to the exposure of large numbers of women in Phase 3 clinical trials. The published data and datasubmitted to the FDA demonstrate that the implantable progestogens have no significant or unusual toxicities and have a similar safetyprofile to the progestogens found in the approved oral contraceptives. © 2002 Elsevier Science Inc. All rights reserved.

Keywords: Progestogen; Implant; Contraception; Levonorgestrel; Etonogestrel; Nestorone; Nomegestrol acetate; Toxicology

1. Introduction

Subdermal contraceptive implants deliver steroidal pro-gestogens from polymer capsules or rods placed under theskin. The hormone diffuses out slowly over a period of 1–5years and effectively bypasses first-pass liver metabolism.Advantages of implants over oral contraceptives includehigh effectiveness without user involvement and low dosewithout the use of estrogens. The first implant to be mar-keted was the Norplant system containing levonorgestrel.The contraceptive efficacy of Norplant is high, with a cu-mulative pregnancy rate of 1.1 per 100 women at 5 years[2]. Jadelle (first called Norplant-2) was designed to releasethe same dose of levonorgestrel but from two rods instead ofsix capsules. There are three other progestogens in implantscurrently marketed: nestorone (Elcometrine), etonogestrel(Implanon) and nomegestrol acetate (Uniplant, Surplant).Because of confidentiality concerns, pre-clinical and clinicalsafety data submitted to governmental agencies has, for themost part, not been published and is not available. However,data submitted to the US Food and Drug Administration

(FDA) and reviewed for an approved New Drug Applications(NDA) is releasable through the Freedom of Information Act,and a discussion of the data are presented below.

2. Levonorgestrel (Norplant, Jadelle)

There are two types of levonorgestrel Silastic implants,capsules (Norplant) and covered rods (Jadelle). Norplantconsists of a set of six Silastic capsules, which releaselevonorgestrel for at least 5 years. The six capsules haverelease rates of 85, 50, and 30 ug/day at the first, ninth, andsixtieth month of use. After 60 months, the recommendedduration of use, there is still 69% of the original steroid loadstill left in the capsules to act as a safety margin for womenwho may not have the implants removed on time [2].

Levonorgestrel is an approved oral contraceptive and isalso the L-isomer and active moiety of D,L-norgestrel. Boththe L and D,L steroids are in a number of approved oralcontraceptives. Levonorgestrel binds with high affinity tothe progesterone, androgen, mineralocorticoid and glu-cocorticoid receptors, but not to the estrogen receptor [3].However, levonorgestrel does have strong antiestrogeniceffects that can decrease sperm penetration of cervical mu-cus [2,4].

1 From reviews of data submitted to the US FDA to support NDA.* Tel.: �1-301-827-4250; Fax: �1-301-827-4267.E-mail address: jordan@cder.fda.gov (A. Jordan).

Contraception 65 (2002) 3–8

0010-7824/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.PII: S0010-7824(01)00283-9

In addition to the large safety data base with D,L-norges-trel, toxicity studies with the isomer were conducted asadditional support of safety. Prior to its use in implants,levonorgestrel was examined for toxicity by the oral routeof administration in a number of animal species. One yearoral toxicity studies of levonorgestrel were conducted infemale rats and cynomolgus monkeys. In rats, doses from0.5 ug/kg to 25 mg/kg per day produced few drug-relatedeffects. There was an increase in body weight and a de-crease in uterine and pituitary weights only at the high dose.An increase in liver weight correlated microscopically withincreased glycogen and fat deposition. No microscopic cor-relates with the decreased pituitary or uterine weights werefound. No other drug-related postmortem findings werenoted [5].

In female monkeys, oral doses of 25 ug/kg to 2.5 mg/kgper day produced a dose-related increase in body weight, aprolonged prothrombin time, and a decrease in serum cho-lesterol at the high dose. At the two highest doses, there wasdecidual transformation of the uterine endometrium, in-creased glandular secretion in the cervix, decreased mucosalkeratinization of the vagina, follicular atresia, and absenceof corpora lutea. No other histopathological effects werenoted [6].

Levonorgestrel has been examined for toxicity whengiven parenterally in a number of animal species. Whenimplanted subcutaneously (sc) in female cynomolgus mon-keys for 2 years at doses releasing approximately 14 to 50ug/monkey/day, levonorgestrel had no effect on survival,and there were no adverse tissue reactions at the implanta-tion site. No tumors were found in any of the monkeys. Theuteri and ovaries from the high-dose group weighed lessthan those of controls. There were no ophthalmologicalchanges or changes in urinalysis. Changes in clinical chem-istry consisted of an increased hematocrit and hemoglobinand decreased cholesterol and triglycerides. There were nogrossly observable indications of pathology.

In another study, levonorgestrel-releasing intrauterinedevices (IUDs) were fixed to the uterine lumen of monkeysby a suture in the myometrium and were left in place for 1year. The only systemic effect noted was a slight decrease inthromboplastin time. Uterine effects included decreasedweight, a marked decidual reaction with glandular atrophy,as well as some necrosis of superficial layers of endome-trium. Cervical morphology was normal, with one animalshowing pallisading of the endocervical gland nuclei. Therewas no evidence for any hyperplasia of endo- or exo-cervical epithelium.

Levonorgestrel has been examined for genotoxicity in anumber of systems and did not increase point mutations inthe Ames salmonella/microsome test with and without ametabolic activating system [7]. The steroid was also neg-ative in a mammalian mutagenesis assay in mouse lym-phoma cells an in vitro chromosomal aberration assay inChinese hamster ovary cells and in an in vivo micronucleustest in mice.

Levonorgestrel was tested for carcinogenicity by theparenteral route of administration in rats and by oral dosingin dogs and monkeys. When administered to rats in animplant releasing an estimated 5 ug/rat/day for 2 years,levonorgestrel did not alter survival rates. Treatment re-sulted in an increase in body weight and a decrease inuterine and ovarian weight. There were no differences be-tween treated and control groups in the number of rats thatdeveloped tumors or the total number of tumors. There was aslight increase in adrenal tumors (3/58 vs. 7/63 control/treated,respectively), and a treatment-related decrease in endome-trial stromal tumors (14/61 vs. 2/63 control/treated, respec-tively). Nontumor lesions occurred equally in both groups.

Doses of 0.01, 0.05, and 0.125 mg/kg/day were givenorally to beagles for 7 years. The number of mammarynodules increased with time in both control and treatedgroups. At the end of 7 years, the number of beagles withnodules and the total number of nodules were no differentbetween control and treated animals. Malignant mammarynodules developed in 9/32 dogs of the control group, 1/16 inthe low-dose group, 0/16 in the mid-dose group, and 6/16 inthe high-dose dogs [8].

In a separate study with a much higher dose of 0.5mg/kg/day, the incidence of mammary nodules increasedsignificantly during treatment, with 9 of 11 surviving dogshaving a total of 108 nodules after 7 years compared to 5/10control dogs having a total of only 8 nodules. The majorityof the nodules were simple and complex adenomas, with nomalignancies [8].

When given to rhesus monkeys at oral doses of 10, 50,and 250 ug/kg/day for 10 years, levonorgestrel did notinduce palpable mammary nodules or overt toxicity.

Polydimethylsiloxane rods containing levonorgestrelwere implanted in the uteri of rabbits for 24 months. Theexpected levonorgestrel release rate was 25 ug/day. Twenty-nine treated and 33 controls survived to the end of the study.The incidence of endometrial neoplasia of 17.2% in thegroup treated with levonorgestrel was significantly less thanthe 42.4% incidence observed in the control does. No en-dometrial neoplasia was found in the eight does with serumlevonorgestrel concentrations greater than 0.12 ng/mL.Only one of the five tumors in the levonorgestrel-treatedgroup occurred in the uterine horn containing the levonorg-estrel implant [9]. When estradiol was combined withlevonorgestrel in Silastic rings sutured into the vagina ofrabbits, a release rate of 98 ug/day levonorgestrel and 45ug/day estradiol produced a marked decidual reaction of theendometrium in 16 of 23 test rabbits. In 14 of these rabbits,malignant tumors developed that were composed of ana-plastic cells that invaded the uterine walls, lymphatics, andin 4 of 13 rabbits that survived 2 years of treatment, thetumors metastasized to the lungs. No tumors were seen inrabbits given the Silastic rods without steroids [10].

Syrian golden hamsters were given four weekly injec-tions of a carcinogen N-nitrosobis(2-oxypropyl)amine(NBOPA) to initiate renal tumorigenesis and then were

4 A. Jordan / Contraception 65 (2002) 3–8

given either a control diet or a diet containing 10 mg/kglevonorgestrel for 27 weeks. Another group received thelevonorgestrel diet without NBOPA. Levonorgestrel alonedid not induce renal tumors or dysplasia. Initiation withNBOPA caused nephroblastoma in 1/21 hamsters and 469dysplastic tubules. Levonorgestrel did not significantly en-hance the incidence of renal tumors in initiated animals orincrease the total number of dysplastic tubules [11].

Studies on the effect of levonorgestrel on reproductiveparameters were conducted with the progestogen alone andwith estrogens. Early studies on the effect of levonorgestrelon reproduction were conducted with levonorgestrel givenorally with ethinyl estradiol to pregnant rats and rabbitsduring the period of organogenesis. In rats [12] and rabbits[13], doses up to 50 ug/kg levonorgestrel and 30 ug/kgethinyl estradiol had no effect on embryo or fetal develop-ment. In a study in mice, time-release pellets and capsulescontaining levonorgestrel were implanted subdermally andleft in situ for periods of 2 or 3 months. Mice were inducedto ovulate, and oocytes were obtained, inseminated, andsubsequently cultured for 96 h, some in medium containinglevonorgestrel. Levonorgestrel had no adverse effect onoocyte quality and should not adversely affect early embry-onic development [14].

Levonorgestrel was administered to pregnant New Zea-land white rabbits via a Silastic IUD. There were no treat-ment-related effects on any parameter of fertility or fetaldevelopment. There were also no drug effects, includingmasculinization, on fetuses directly adjacent to the IUD.

In humans, early clinical trials demonstrated good effi-cacy. In a study with 816 women, there was a cumulativenet pregnancy rate of 0.7 per 100 through 3 years. Norplantusers experienced irregular menstruation, but with normalaverage numbers of bleeding days and of bleeding episodes.Hemoglobin levels increased moderately during implant use.The incidence of abnormally high blood pressure readings wasno greater than among users of the copper-T IUD [15].

3. Etonogestrel (Implanon)

Implanon consists of a single covered rod containing 68mg of etonogestrel, the 3-keto metabolite of desogestrel,with an initial release rate of around 60 ug/day that slowlydecreases to around 30 ug/day at the end of 2 years. Acontraceptive dose is maintained for 3 years. Maximumserum concentrations average 813 pg/mL that decline toaround 200 pg/mL after 1 year and to 156 pg/mL at the endof the third year [16]. Etonogestrel has shown no estrogenic,anti-inflammatory or mineralocorticoid activity, only weakandrogenic and anabolic activity, and strong antiestrogenicactivity [17]. The relative binding affinity of etonogestrel tothe rat uterine progesterone receptor is approximately 10times greater than progesterone [18].

Because desogestrel is converted to its unique, directlyacting metabolite 3-keto-desogestrel, the toxicology studies

using desogestrel were used to assess the safety of etono-gestrel. In addition, toxicology, genotoxicity and reproduc-tive studies, and a carcinogenicity study in rats were con-ducted for the metabolite. The results of these studies arenot available.

Desogestrel was extensively tested in both rats and dogsfor up to 2 years alone and in combination with ethinylestradiol (5:1 or 2.5:1 progestogen:estrogen). Desogestreldoses ranged from 5 to 625 ug/kg. Other than the expectedpharmcodynamic effects, desogestrel alone produced noconsistent toxicological findings in rats or dogs. Whengiven with estrogen, the combination produced a slightincrease in the incidence of pituitary hyperplasia and mam-mary fibroadenoma. In tests of genotoxicity, desogestrelwas negative for point mutations in the in vitro Salmonella/mammalian microsome test (Ames test) and for chromo-somal aberrations in a micronucleus test in female rats. Boththe Ames test with liver microsomes and the micronucleustest in rats would be expected to test both desogestrel andthe 3-keto metabolite for genotoxicity. Carcinogenicitystudies were conducted in mice and rats for 80 weeks and 2years, respectively. Desogestrel alone and in combinationwith ethinyl estradiol was given orally at doses of 5, 50, and500 ug/kg. In mice treated with desogestrel alone, no treat-ment related tumorigenic effects were seen. In mice treatedwith the combination of progestin and estrogen, there wasan increased incidence of pituitary enlargement with treat-ment in both males and females. The incidence of pituitaryadenoma was increased in both male and female mice in adose-related manner, and it was a contributory factor indeaths in treated mice. In the rat carcinogenicity study withdesogestrel alone, there was a dose-related increase in paleareas or foci in the lungs of both males and females. Notreatment effect on tumor incidence was seen. With thecombination of desogestrel and estrogen the incidence ofpituitary enlargement with hemorrhagic areas increasedwith dose in males. No increase in pituitary adenocarcinomawas seen in any treated group compared with controls. Inmales, there was a dose-related increase in the incidence ofmammary fibroadenoma, adenoma, and adenocarcinoma. Infemales, the only significant finding was an increase inmammary adenocarcinoma in the high-dose group com-pared with controls. Planned 7- and 10-year carcinogenicitystudies in dogs and monkeys were terminated after 3 years.The study design included interim killing and provided dataon the toxicology of desogestrel but little information oncarcinogenicity because of the relative short duration. Deso-gestrel and ethinyl estradiol (5:1 progestogen:estrogen)were administered orally at doses of desogestrel from 3 to150 ug/kg in a cyclic regimen of 21 days on drug and 7 daysoff. There were no unusual findings in dogs. In monkeys, therewas an increase in fibrinogen in the two higher-dose groupsand ductal and acinar proliferation and ductal dilation in themammary glands, primarily in the high-dose group.

Desogestrel was evaluated for its effects on fetal devel-opment. When given to pregnant rats during Days 0–15 of

5A. Jordan / Contraception 65 (2002) 3–8

gestation, desogestrel at doses of 5, 100, and 1800 ug/kg hadno effect on fetal malformations or minor anomalies. InNew Zealand white rabbits, the administration of deso-gestrel and ethinyl estradiol at 5, 10, and 20 ug/kg duringDays 1–18 of gestation increased pre-implantation losses inthe high-dose group. The number of major and minor mal-formations increased in a dose-dependent manner, but werewithin the laboratory standard range values. In rats admin-istered the combination of desogestrel and ethinyl estradiolat doses of 5, 50, and 500 ug/kg orally during Days 6–15 ofpregnancy, there was an increased incidence of uterine hem-orrhage and post-implantation loss in the high-dose group.Corpora quadrigemina, a brain defect, occurred only in thedrug-treated groups, and the effect was significant, but theincidence was within the range of the historical controls.

In early studies in women, no pregnancies occurred in514 woman-months in users of implants delivering 30 and40 ug/day of 3-keto-desogestrel. No changes were seen inplasma lipoprotein pattern or clinical chemistry during treat-ment. Ovarian cysts found during initial pelvic examinationin 11 subjects disappeared spontaneously within 7–90 days[19]. In a later study assessing efficacy in 4103 woman-years, there were no pregnancies. Implanon suppressed pro-gesterone levels, had little effect on follicle stimulatinghormone and prevented luteinizing hormone surges. Theviscosity of the cervical mucus was increased; the endome-trium was thin but not atrophic, with primarily inactivity orweak proliferation; and return of ovulation after removal ofImplanon was rapid [20].

4. Nestorone (Elcometrine)

The progestogen nestorone, previously known asST1435, is a potent 19-norprogesterone derivative that hashigh progestational activity with essentially no androgenic,estrogenic, or glucocorticoid-like activity [18]. The implantreleases 150 ug/day to maintain serum levels of 60 pg/mLthat decrease steadily to reach 30 pg/mL at 24 months. Asingle Silastic capsule containing nestorone with an activelife of 6 months has been introduced in Brazil for thetreatment of endometriosis [2].

Nestorone has not been approved by the US FDA. ThePopulation Council, sponsor of nestorone, graciously gavepermission to use in this article data submitted to the FDA.All data not referenced were from submissions from thePopulation Council to the FDA.

Nestorone was given to rats in a subdermal implantreleasing approximately 85 �g steroid/day for 90 days.Other than the expected pharmacodynamic effects, therewere few adverse effects in this study. A similar study wasperformed in female rabbits. Subdermal implants releasingup to 550 �g/day of nestorone for 90 days had few effectsother than progestational and glucocorticoid-like activity.

Long-term toxicity of nestorone was examined in studiesin rats and cynomolgus monkeys. Female rats were given

subdermal implants releasing approximately 11, 15, and 48ug/day of steroid for 1 year. A control group received notreatment, and a placebo group was given Silastic implantswithout steroid. There were no drug-related deaths. Bodyweight was significantly greater than controls in the twohigher-dose groups after 3 weeks of treatment. Histopatho-logical examination did not reveal any evidence of local orsystemic toxicity. The incidence of mammary gland neo-plasms and overall tumor incidence was similar in treatedand control groups.

Four groups of female cynomolgus monkeys were givensubdermal implants releasing approximately 30, 87, and 395ug/day of nestorone for 1 year and compared to a controlgroup given empty implants. Menstrual cycles remainednormal in the control monkeys, but essentially stoppedwithin 10 days after nestorone implantation in all threetreated groups. Occasional evidence of menstruation orbreakthrough bleeding was seen in treated animals. Uterineweights increased in a dose-dependent manner and corre-lated with the degree of myometrial hypertrophy seen his-tologically. Hormonally induced changes in the ovaries,uterus, cervix, and vagina were seen in all treated groups.No glucocorticoid-like effect was noted in this study. Otherthan the endocrine effects noted, there were no adverseconsequences of nestorone treatment.

There were two studies with orally administered nestor-one. A study in rats for 26 weeks and a study in baboons for6 months. Despite the high doses administered (up to 10mg/kg/day), there were no treatment-related effects. Theseresults reflect the poor bioavailability of nestorone whengiven orally and demonstrate the necessity for parenteraldelivery of this progestogen.

Nestorone was examined for potential genotoxicity inthree tests and did not produce gene mutations or affectchromosomal integrity. When administered by intraperito-neal injection at doses up to 2000 mg/kg, nestorone had noeffect on the number of micronucleated polychromaticerythrocytes in the bone marrow of male and female mice.Nestorone did not produce chromosomal aberrations in hu-man peripheral lymphocytes in vitro and did not increasethe number of mutations in the in vitro bacterial reversemutation (Ames) assay.

Nestorone is currently being tested for carcinogenicity in a2-year study in rats and in a 6-month study in transgenic mice.

Nestorone was examined for its effects on the developingfetus in two animal studies. When injected sc to pregnantrats during Days 6 to 15 of gestation at doses of 10, 50, and250 ug/kg/day, nestorone treatment had no effect on fertilityindexes or on fetal development. When injected sc to rabbitsduring Days 6 to 18 of pregnancy at doses of 10, 50, and250 ug/kg/day, nestorone induced complete resorption inone high-dose doe and tended to increase embryo deaths inthat group. There were no treatment-related effects on fetaldevelopment.

Nestorone was implanted into 26 healthy women for aperiod of 2 years. No hormonal side effects were reported.

6 A. Jordan / Contraception 65 (2002) 3–8

Irregular bleeding patterns were common, but well tolerated[21]. In a similar study, nestorone had no effect on totalcholesterol, high- or low-density lipoprotein cholesterol, ortriglycerides. Blood pressure and liver enzymes and elec-trolytes remained unchanged [22]. In a later study, nestor-one was implanted into 70 healthy women of proven fertil-ity. No pregnancy occurred in 1570 woman-months. Noabnormal changes were observed in plasma lipoproteins orother clinical chemistry parameters during treatment. Theimplants were well tolerated, with the most frequent com-plaint being irregular bleeding. Enlarged follicles foundduring pelvic examination in eight participants disappearedspontaneously in 10 days to 6 weeks [23].

5. Nomegestrol Acetate (Surplant, Uniplant)

Uniplant is a single Silastic capsule containing 38 mgnomegestrol acetate. The initial release rate is approxi-mately 100 ug/day and the duration is 12 months. Nomeges-trol acetate is a 19-norprogesterone derivative that binds tothe androgen and progesterone receptors and has moderateantiestrogenic and anti-androgenic activity. Nomegestrolacetate exerts no estrogenic, glucocorticoid, mineralo- orantimineralo-corticoid effects [24].

Nomegestrol acetate seems to have fewer metabolic sideeffects than nortestosterone derivatives. In adult female rats,megestrol acetate, a 17� hydroxyprogesterone derivative,induced significant increases in glucose, total and high-density lipid cholesterol, and triglyceride and phospholipidplasma levels. Treatment with norethindrone, a 19-nortes-tosterone derivative, reduced body weight gain and de-creased all plasma lipid parameters. In contrast, nomeges-trol acetate, like progesterone, did not alter lipid or glucosemetabolism [25].

Human breast cancer T47-D cells grown in an estrogenicenvironment contain a large number of progesterone recep-tors. Nomegestrol acetate was equally as effective as otherprogestogens, such as progesterone, medroxyprogesteroneacetate, and norethindrone acetate, in inhibiting cell divi-sion. This antiproliferative effect on human breast cancercells grown in estrogenic conditions is believed to be due tonomegestrol acetate’s selective estrogen enzyme modula-tion [26,27].

Because of their use with estrogens in hormone replace-ment therapy, there has been concern about the effects ofprogestogens on the beneficial effects of estrogens on cor-onary artery disease. In two models of coronary vascularreactivity in cynomolgus and rhesus monkeys, orally ad-ministered nomegestrol acetate did not have a negatingeffect on the beneficial effects of estradiol [28,29].

There is no approved NDA for nomegestrol acetate in theUS, thus data on safety studies conducted in animals are notavailable. There are no published studies on the toxicologyof nomegestrol acetate. However, based on the similarity ofthe structure of nomegestrol acetate to other contraceptive

progestogens and the absence of reported adverse effects inhumans, it would be reasonable to assume that the animaltoxicology data for nomegestrol are similar to the data fromthe other progestogens.

Uniplant use for 1 year was studied in 1803 healthywomen. Cumulative discontinuation rate at 12 months was15.7%, primarily menstrual related [30]. Nomegestrol ace-tate implants had no significant effect on serum cholesterol,lipoproteins, and triglycerides in normal women after 12months of use [31]. A total of 18 normal women received asubdermal implant of nomegestrol acetate for 2 years. At theend of the 2-year period, there was an increase in bodyweight and a slight increase in systolic and diastolic bloodpressure at 12 but not at 24 months. Insulin, HbA1c, LDL-C,HDL-C, and gamma-glutamyl transpeptidase remained un-changed during the 2 years of Uniplant use. There weresignificant changes in several clinical chemistry parametersduring the 24-month period, but none were outside thenormal range. Thus, no clinical effects on lipoproteins,carbohydrate metabolism, insulin levels, and on hepaticfunction were observed in women using Uniplant for 2years [32].

6. Discussion

There has been extensive nonclinical safety testing forthe implantable progestogens levonorgestrel and nestorone.The results from the animal studies for etonogestrel andnomegestrol acetate are not available for review. Availablestudies show that levonorgestrel has undergone the mostthorough toxicological evaluation. Early studies using theoral route of administration to support safety as an oralcontraceptive were supplemented with additional studiesusing the parenteral route of administration. No unusualtoxicity was noted in studies in rodents, dogs, and monkeys.Levonorgestrel was not genotoxic in in vitro and in vivotests and did not induce tumors that have not been seenbefore with other contraceptive progestogens in long-termcarcinogenicity studies. Seven-year studies in beagles dem-onstrated that a high dose of levonorgestrel could elicit asignificant tumorigenic response. However, results fromhigh-dose carcinogenicity studies in dogs probably have norelevance to humans [33]. Levonorgestrel had no adverseeffects on fetal development despite its known androgenic-ity. As of this writing, etonogestrel (3-keto-desogestrel) hasnot been approved in the US and thus much of the publish-able toxicological information is derived from the prodrug,desogestrel. Similar to levonorgestrel, desogestrel was thor-oughly examined for toxicity by the oral route of adminis-tration. The data from toxicology, genotoxicity, carcinoge-nicity, and fetal development studies demonstrated overallsafety, and desogestrel is widely marketed as an oral con-traceptive. Results from the toxicology and long-term car-cinogenicity studies with etonogestrel are necessary beforeany final determination of safety can be made. Nestorone

7A. Jordan / Contraception 65 (2002) 3–8

has not been approved in the US, but the US PopulationCouncil generously allowed reference in this article to thedata submitted to the FDA. Nestorone has been thoroughlyexamined for toxicity in rats and monkeys, for genotoxicityin vitro and in vivo, and for effects on reproduction in ratsand rabbits. The results amply demonstrate the safety of thissteroid. Nestorone is currently being tested for carcinoge-nicity in a long-term study in rats and in a 6-month study intransgenic mice. Nomegestrol acetate is not approved in theUS, and no publishable toxicological data are available.Published studies on the mechanism of action of the steroid,binding data, and the similarity of the structure of nomeges-trol acetate to other contraceptive steroids give some assur-ance of safety. To date, there are no data available fromanimal carcinogenicity studies of nomegestrol acetate.

In general, the available published and unpublished datademonstrate that the implantable steroids are similar in theirtoxicity profiles in animals to the approved oral contracep-tive progestogens and provide sufficient safety informationto support human use. For the two progestogens etono-gestrel and nomegestrol acetate, information from safetytesting in animals is not available, and a final judgment onsafety in animals await the results of the long-term toxicol-ogy and carcinogenicity studies.

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