ORIGINAL ARTICLE

Selectivity and minimal androgenicity of norgestimate in monophasic and triphasic oral contraceptives FREEDOLPH D. ANDERSON,M.D. From t h e Eastern Virginia Medical School, Norfolk, Virginia

Aria Ohstet Gynecol Scand 1992; Vol 71, Suppl 156: 15-21

The contraceptive progestin norgestimate (NGM) has a high affinity for uterine progestin receptors and a lack of affinity for androgen receptors similar to that of natural progesterone. NGM’s selectivity results in excellent efficacy, cycle control, and minimal androgenicity when it is combined with ethinyl estradiol (EE). Clinical studies of a monophasic regimen of NGMlEE indicate a positive impact on lipid metabolism, revealing an increase in serum levels of high-density lipoprotein cholesterol with a concomitant and significant decrease in the low-density lipoprotein/high-density lipoprotein cholesterol ratio. Little impact on carbohydrate metabolism was noted. Serum levels of sex hormone binding globulin, an indicator of androgen-estrogen balance, also increased significantly with NGMlEE in accordance with its low androgenic activity. A significant betweenregimen difference in SHBG was seen in a comparison study of NGMlEE and LNG/EE triphasic formulations (a mean rise of 68.6% with NGMlEE vs a decrease of 6.1% with LNG/EE). NGM’s lack of estrogenicity was evidenced by unchanged prolactin levels and absence of effect on the coagulation system. In a large study of the monophasic formulation in 59.701 women, some improvement in acne was reported as well as minimal weight gain. An overview of clinical data is provided from United States and European trials as well as some preclinical data relevant to NGM’s selectivity. Key words: Norgestimate triphasic. androgenicity, selectivity

introduction The low-dose combined oral contraceptive (OC) agents are remarkably effective; studies of low-dose OCs show them to be as effective as the earlier, high-dose preparations (1,2). It is their potential, noncontraceptive, adverse effects that remain of concern. In recent years, research has focused on reducing the androgenic activity of the progestin component. The 19-nortestosterone derivatives used as progestins in OCs commonly have residual androgenic and anabolic actions that may be associated with problems of acne, weight gain and, occasionally, hirsutism. T h e long-term consequences of alterations in lipid metabolism are also of interest (3,4).

A goal of contraceptive research has been to improve selectivity of the progestin component (ie. to increase the desired pharmacologic properties associated with progestational agents while minimizing extraneous androgenic actions). The new progestin, norgestimate (NGM), has been identified as a promising agent in studies demonstrating its highly selective progestational activity. Because steroids may exert their pharmacologic activity through active metabolites, some studies have compared the NGM parent compound (Fig. 1) with its principal metabolite, 17-deacetyl N G M to determine whether it possesses a similar androgen-free profile. An overview of important preclinical and clinical studies relevant to the selectivity of NGM is given here. Actu Ohstet Gynecol Scand Suppl 156 (1992)

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gina is inhibited by oral and SC administration of NGM (6). In contrast to its antiestrogenic properties, NGM has proved to be virtually inactive in a series of estrogenic test systems (8). Thus, the antiestrogenic properties are a progestin-mediated action, as opposed to direct interference with the interaction of estrogen and its receptor. The degree to which progestational effects are maximized and androgenic effects minimized is a measure of progestin selectivity. An ideal progestin should achieve a progestational response when given at a low concentration and elicit an androgenic response only at a high concentration. In androgen Fig. 1. Norgestimate [( +)-13-ethyl-17-acetoxy-18,19-direceptor binding assays, only very high concentranor- I7u-pregn-4-en-20-yn-3-one oxime] tions of NGM (764 nM) displaced 50% (ICs,,) of radiolabeled (3H-testosterone) dihydrotestosterone, Preclinical studies: progestational vs the androgen standard (Fig. 2) (9). In progestin receptor binding assays, NGM's IC,,, was 3.5 nM, a androgenic activity relative binding affinity of 1.24 (Fig. 3). Its androThe highly progestational and minimally androgenic gen-to-progestin (NP) receptor binding ratio was responses of NGM have been demonstrated in a 219, indicating a highly selective progestational renumber of experimental models. In vitro, NGM sponse. Fig. 4 compares the AIP ratios of NGM and binds to cytosolic progestin receptors with an affinity its primary metabolite, 17-deacetyl NGM, with similar to that of progesterone (P) (5). Another pa- other progestins (9). The descending order of selecrameter used to characterize typical progestin phar- tivity was NGM > P > gestodene (GES) > LNG. macology is ovulation suppression. In rabbits, oral The estrogen component of an OC induces elevadoses of NGM have been shown to inhibit ovulation tions in sex hormone binding globulin (SHBG), a by blocking the preovulatory surge of luteinizing protein that binds testosterone (T), effectively rehormone (LH) (6). In addition, NGM replacement ducing the amount of bioactive agent and decreasing enahles pregnancy to continue despite the absence its potential androgenic activity. A strongly androof endogenous P in ovariectomized rats. In estrogen- genic progestin can inhibit this action by competprimed immature rabbits, endometrial stimulation itively displacing T from SHBG and allowing more follows both oral and subcutaneous (SC) adminis- free active T to produce its active androgenic effects tration. In this test, the potency of NGM is main- ( l O , l l ) , as well as by blocking the estrogen-induced tained after SC administration, indicating that its rise in SHBG (discussed later in this article). progestational activity does not depend on first-pass In in vitro studies of human SHBG, both NGM oral metabolism (5,7). and 17-deacetyl NGM showed little affinity for Inhibition of estrogenic activity by NGM has also SHBG, being unable to displace T from SHBG even been demonstrated experimentally. In ovariecto- at concentrations >10,000 nM (12). The more anmizcd rats, estrone-induced cornification of the va- drogenic progestins GES and LNG displaced T at

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Fig. 2. Relative receptor binding affinities (RBA) of NGM, its primary metabolite 17-deacetylated NGM and other progestins for the androgen frat prostate) receptor. (Adapted from Upmalis D. Phillips A: Receptor binding and' in vivo activities of the new progestins. Journal SOGC 1991:13: 35. by permission of Ribosome Communications).

Selectivity of norgestimate Fig. 3. Relative receptor binding affinities of NGM, its primary metabolite 17-deacetylated N G M and other progestins for the progestin (rabbit uterus) receptor. (Adapted from Upmalis D, Phillips A: Receptor binding and in vivo activities of the new progestins. Journal SOGC 1991; 13: 35, by permission o f Ribosome Communications).

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RBA relatively low doses, showing IC,,, at concentrations of 23.1 nM and 53.4 nM, respectively (Fig. 5) (12).

Clinical studies The known clinical effects of androgenicity in a n OC progestin include adverse changes in lipid and carbohydrate metabolism, abnormal body weight gain, and exacerbation of acne and hirsutism in susceptible subjects.

Lipid metabolism Favorable changes in the serum lipid levels of women using NGM/EE were demonstrated in a 2year multicenter study comparing monophasic preparations of N G W E E and N G l E E (Lo/Ovral@) in 1,261 subjects. Chapdelaine et a1 reported that serum levels of H D L were increased significantly from baseline values in the NGM/EE group but were decreased significantly in the norgestrel (NG)/EE group

(13). Increases in L D L levels were moderate in the NGM/EE group but were pronounced in the NGlEE group, resulting in a significant between-regimen difference in the LDWHDL ratio (Fig. 6) (13).

Carbohydrate metabolism In two U.S. multicenter trials comparing NGM/EE and NG/EE monophasic regimens, a nonsignificant change from baseline in mean fasting blood glucose was seen in the NGM/EE group; an increase of 2.3% at cycle 24, compared with a significant increase of 4.6% in those using NG/EE. In the 3-hour glucose tolerance test performed in one of the trials, the mean profiles at baseline were similar to cycle 12 in both groups and elevated only slightly at cycle 24 (14). In a 6-cycle study conducted by Kaiser in Germany and reported by Becker (15), 21 subjects using NGM/EE showed no significant changes in fasting blood glucose values. Clinically insignificant in-

Norgestimate Progesterone Fig. 4. Progestin selectivity as expressed by the ratio of the lC,,, concentration for androgen binding divided by the ICs,, concentration for progestin binding. (Modified from Upmalis D, Phillips A: Receptor binding and in vivo activities of the new progestins. Journal SOGC 1991; 13: 35, by permission of Ribosome Communications).

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Fig. 5 . Displacement of ['Hltestosterone from human 5ex hormone hinding globulin in vitro. Relatively low IC,,, values (in parenthcses) with gestodene (GSD) and levonorgestrel (LNG) indicate high potential f o r androgenicity. Littlc if any ['Hltestosterone was displaced by either NGM or i t s 17-deacetyl metabolite. T=testosterone; (From Phillips (12).)

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creases were seen at 1 hour after glucose loading. Insulin values were increased slightly at cycle 3 and decreased at cycle 6, returning to pretreatment levels during the follow-up period. Values for the HbA,,. subunit of hemoglobin, which reflect longterm changes in glucose metabolism (3 to 4 months), were in the normal range, unchanged by treatment with NGM/EE (15). Sex hormone binding globulin

Serum levels of SHBG are an established parameter of androgen-estrogen balance, varying inversely with androgenic activity. During use of combined OCs, the serum levels of SHBG rise under estro-

genic stimulation unless this rise is prevented by an androgenic progestin. Thus, high levcls of SHBG equate with low androgenicity in a combined OC (16,17). In a comparison study of 40 women, serum levels of SHBG were increased significantly in the NGM/EE group, by 161.1% at cycle 4. Increases were not statistically significant in the NG/EE group (Fig. 7) (13). The between-regimen difference was significant (p=0.0007). A 6-month efficacy study was performed in 4,234 healthy women aged 16 to 41 years to compare triphasic NGWEE (Ortho Tri-Cycleno, Tri-CilestB) with LNG/EE (Triphasilo) (18). SHBG values measured in a subset of 45 women increased 68.6% with

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triphasic NGM/EE but decreased 6.1 Yo with triphasic LNGIEE. This between-regimen difference was significant at the 5 % level. In the noncomparative German study in 21 subjects (15), SHBG values rose threefold from control levels to approximately 5.0 ng/dL at cycle 6 ( p < 0.01), whereas free T fell to approximately 0.4 ng/dL ( p < 0.01). Levels of dehydroepiandrosterone sulfate decreased during the treatment period, reflecting the ability of NGM/EE to inhibit adrenal androgen synthesis (15). Body weight changes In the clinical trials of NGM/EE, analysis of the data

on body weight changes did not reveal any trend suggesting an androgenic effect. In multicenter studies conducted in Europe (19), 59,701 women were

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treated with monophasic NGM/EE (Cilest'y), 42,022 of them through 6 menstrual cycles, with report forms completed for each cycle and visits after cycles 3 and 6. The average age of the subjccts was 24 years. Approximately half of the subjects had not used contraceptive agents previously. Contraceptive efficacy, calculated for the total subjects enrolled was excellent, with a Pearl index of 0.25 for 342,348 cycles of use. The mean body weight of the subjects, which was 61.2 k 9.0 kg at the start o f the study, increased only O.6YO at cycle 6. In the U.S. multicenter trials, Corson noted that treatment was discontinued by relatively few subjects because of weight gain: 7 of 736 (l.OYo) with NGMlEE vs 10 of 737 (1.4%) with NG/EE (14). Chagdelaine et al reported in their study of 1,261 women that the withdrawal rates for weight gain were 0.84% in the NGM/EE group, compared with 1.54% in the NG/EE group (13). Acne

In more than 40,000 women participating in the European multicenter trial (19), only 1% reported either the first appearance of acne or worsening of existing acne over the 6-cycle study. Of the women with acne at the beginning of the study, 38% (1,940 of 5,086) reported improvement (Fig. 8). In the Chapdelaine studies, acne was cited as the reason for withdrawal by 0.84% of subjects using NGM/EE, compared with 1.20% of those using NG/EE. Hirsutism was not reported among the 1,261 subjects (13). In a study of 224 women treated with NGM/EE over 6 cycles, Mall-Haefeli et al reported no product failures, relatively constant mean body weight, and abatement of acne in about onefourth to one-third of cases (2).

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Estrogenicity NGM's lack of estrogenicity was demonstrated in clinical laboratory tests on 21 women who used NGM/EE through 6 menstrual cycles (15). Basal levels of prolactin and levels of prolactin following stimulation by metoclopramide were unchanged during treatment, indicating balanced activity without estrogenicity (15). Clinically significant effects on coagulation, a barometer of estrogenicity, have not been reported in tests conducted during trials of NGM/EE. In Anger's study of NGM/EE in 19 subjects, fibrinopeptide A, a sensitive marker of coagulation system activation, was unchanged during the six treatment cycles ( 1 5 ) . Nor were there any clinically relevant alterations in factors that promote coagulation: fibrinogen, factor VII, or factor VIII. The anticoagulant factors, antithrombin 111 and protein C , remained in the normal range during the study.

Comment The pharmacologic activity of NGM results from the actions of both N G M and its 17-deacetylated metabolite, neither of which has a significantly androgenrelated pharmacology. Both have potent progestational effects. The selectivity of NGM has been demonstrated preclinically in a variety of models and clinically in a combined O C . In women using NGMcontaining OCs, ovulation is suppressed without unfavorable effects on serum lipids, carbohydrate metabolism, or blood coagulation. Recommendations for NGM/EE use are consistent with the view toward utilizing OC agents that provide effective contraception with a large margin of safety (1).

Conclusion High contraceptive efficacy with minimal androgenicity has been demonstrated with monophasic and triphasic NGM/EE preparations. Noncontraceptive metabolic effects involving carbohydrate and thrombosis parameters are limited to changes within the normal range. Favorable changes in serum lipid levels were demonstrated.

References 1. Speroff L. Glass RH, Kase NG. Steroid contraception. In: Speroff L. Glass RH. Kase NG, (eds). Clinical Gyncologic Endocrinology and Infertility. 4th ed. Baltimore, Williams & Wilkins, 1989: 461-98. 2. Mall-Haefeli M, Werner-Zodrow I. Huber PR. BioAcra Obsret Gynecol S c u d Suppl156 (1992)

chemical and clinical results with the new micropill Cilest. In: Keller PJ (ed). Aktuelle Aspekte der Hormonalen Kontrazeption. Basel, Karger, 1990: 1-12. 3. Wahl P, Walden C, Knopp R, et al. Effect of estrogen/ progestin potency on lipid/lipoprotein cholesterol. N Engl J Med 1983; 308: 862-67. 4. Bradley DD, Wingerd J, Petitti DB, et al. Serum highdensity lipoprotein cholesterol in women using oral contraceptives. estrogens and progestins. N Engl J Med 1978; 299: 17-20. 5. Phillips A. The selectivity of a new progestin. Acta Obstet Gynecol Scand Suppl 1990; 1.52: 21-24. 6. Phillips A, Hahn DW, Klimek S. McGuire JL. A coniparison of the potencies and activities of progestogens used in contraceptives. Contraception 1987; 36: 181-92. 7. McGuire JL, Phillips A , Hahn DW, et al. Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites. Am J Obstet Gynecol 1990; 163: 2127-31. 8 Phillips A, Hahn DW, McGuire JL. Prcclinical evaluation of norgestimate, a progestin with minimal androgenic activity. Am J Obstet Gynecol 1991; 165: 1611. 9 Phillips A , Demarest K. Hahn DW, Wong F, McGuire JL. Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins. Contraception 1990; 41 (4): 399410. 10 Anderson DC. Sex-hormone-binding globulin. Clin Endocrinol 1974; 3: 69-96. 11 Victor A. Weiner E, Johansson EDB. Sex hormone binding globulin: the carrier protein for d-norgestrel. J Clin Endocrinol Metab 1976: 43: 24447. IL. Phillips A, Hahn DW, McGuire JL. Relative binding affinity of norgestimate and other progestins for human sex hormone-binding globulin. Steroids 1990; 5.5: 373-5. 13. Chapdelaine A, Desmarais J-L, Derman RJ. Clinical evidence of the minimal androgenic activity of norgcstimate. Int J Fertil 1989; 34: 3477.52. 14. Corson SL. Efficacy and clinical profile of a new oral contraceptive containing norgestimate. U.S. clinical trials. Acta Obstet Gynccol Scand Suppl 1990; 1.52: 25-31. 15. Becker H. Supportive Europcan data on a new oral contraceptive containing norgestimate. Acta Obstct Gynecol Scand Suppl 1990; 152: 33-9. 16. Larsson-Cohn U , Fahraeus L, Wallentin L, Zador G. Lipoprotein changes may be minimized by propcr composition of a combined oral contraceptive. Fcrtil Stcril 1981; 35: 172-9. 17. El Makhzangy MN, Wynn V, Lawrence DM. Sex hormone binding globulin capacity as an index of oestrogenicity or androgenicity in women on oral contraceptive steroids. Clin Endocrinol 1979; 10: 39-45. 18. London RS. Chapdelaine A, Upmalis D. et al. Comparative contraceptive efficacy and mechanism of action of the norgestimate-containing triphasic oral contraceptive. Acta Obstet Gynecol S a n d Suppl 1992; 71: 9;14. 19. Grunwald K, Rabe T. Runnebaum B. Clinical tolerance of a low-dose norgestimate-containing combina4-

Selectivity of norgestimate tion oral contraceptive (Cilest) in a West German multicenter study (Heidelberg Multicenter Oral Contraceptive Study). In: Keller PJ (ed). Aktuelle Aspekte der Hormonalen Kontraception. Karger Basel, 1991: 67-78,

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Address for correspondence:

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