Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy Stefano Lello

Home , Etynodiol, Gestonorone caproate, Hormone therapy, Lynestrenol, Nomegestrol, Nomegestrol acetate

Drugs 2010; 70 (5): 541-559 REVIEW ARTICLE 0012-6667/10/0005-0541/$55.55/0

Endocrinological Gynecology, Pathophysiology of Menopause and Osteoporosis Unit, IRCCS-Istituto Dermopatico dell’Immacolata, Rome, Italy

Contents

Abstract...... 541 1. Overview of Classification of Progestogens ...... 543 2. Pharmacodynamics of Nomegestrol Acetate...... 544 3. Pharmacokinetic Properties ...... 544 4. Therapeutic Effectiveness ...... 547 4.1 In Gynaecology ...... 547 4.2 In Menopause ...... 548 4.3 Single-Agent Contraception...... 549 5. Safety Profile ...... 549 5.1 Risk of Thromboembolism ...... 549 5.1.1 Differential Effects of Progestogens on Nitric Oxide in Endothelial Cells ...... 549 5.1.2 Implications of the ESTHER Study ...... 550 5.2 Endometrial Hyperplasia ...... 551 5.3 Cardiovascular Risk ...... 551 5.3.1 Epidemiology ...... 551 5.3.2 Effects on Surrogate Markers of Cardiovascular Risk ...... 552 5.4 Breast Cancer Risk ...... 553 5.4.1 Epidemiology ...... 553 5.4.2 Biology...... 553 5.5 Effects on Bone Turnover ...... 555 6. Tolerability and Acceptability...... 555 7. Potential Role in Combination Oral Estrogen/Progestogen Contraception...... 556 8. Conclusions ...... 556

Abstract This review summarizes the pharmacology, safety and clinical efficacy of nomegestrol acetate, based on the available published literature, and assesses the pharmacological characteristics that underlie a role in different gynaecological disorders and hormone replacement therapy (HRT), and a potential role in combination estrogen/progestogen oral contraception. Nomegestrol acetate is a potent, orally active progestogen with a favourable tolerability profile and neutral metabolic characteristics. Unlike the majority of older progestogens, which were 19-nortestosterone derivatives synthesized pri- marily for their antigonadotropic activity as a component of hormonal contraception in combination with an estrogen, nomegestrol acetate is a 19-norprogesterone derivative designed to bind specifically to the progesterone 542 Lello

receptor, and is relatively lacking in affinity for other steroid receptors. Nome- gestrol acetate exerts strong antiestrogenic effects at the level of the endometrium and has potent antigonadotropic activity, but without any residual androgenic or glucocorticoid properties. At a dosage of 1.25 mg/day, nomegestrol acetate inhibits ovulation while permitting follicle growth, whereas at dosages of 2.5 or 5 mg/day, both ovulation and follicle development are suppressed. The antigonadotropic action of nomegestrol acetate is mediated, like other progestins, at the hypothalamic and pituitary level. Moreover, nomegestrol acetate has partial antiandrogenic activity. Absorption of nomegestrol acetate is rapid after oral administration, reaching a peak serum concentration within 4 hours, with a terminal half-life of approximately 50 hours. Nomegestrol acetate has been used successfully for the treatment of some gynaecological disorders (menstrual disturbances, dysmenorrhoea, premenstrual syndrome) and as a component of HRT in combination with estradiol for the relief of menopausal symptoms; it has been approved in Europe as monotherapy for the treatment of the menopausal syndrome, uterine diseases and menorrhagia, and in combination with an estrogen for the treatment of menopausal symptoms. In vitro data suggest that nomegestrol acetate preserves the beneficial haemostatic effects of estrogen; furthermore, nomegestrol acetate has a neutral or beneficial effect on lipid profiles, and does not adversely affect glucose metabolism or bodyweight. Nomeges- trol acetate has shown a lack of profilerative activity in normal and cancerous breast tissue, and does not have a deleterious effect on bone remodelling. These potent antigonadotropic properties, and other beneficial metabolic and pharmacological characteristics, suggest that nomegestrol acetate can be an effective progestogen for use in combination with an estrogen in oral estrogen/progestogen contraceptive treatment and in HRT, while it also provides some non-contraceptive benefits for women’s health.

Several ‘generations’ of synthetic progestogens gesterone receptor, with little interaction with derived either from testosterone (19-nortestosterone other steroid receptors, and are thus more speci- derivatives) or from progesterone (17a-hydroxy fically progestational with little or no androgenic, progesterone derivatives and 19-norprogesterone estrogenic or glucocorticoid activity.[1-3] The derivatives) have been developed for use as hor- neutral effect of these ‘pure’ progestational mo- monal therapy for contraception and in meno- lecules on metabolic factors potentially confers pausal regimens. Most of the progestogens in the the advantage of greater tolerability, with neutral first three generations were derived from testo- or favourable effects on lipid profiles and other sterone and designed mainly for use in contra- surrogate markers of cardiovascular risk, includ- ception.[1,2] These first progestogens included ing glucose, high-sensitivity C-reactive protein noretynodrel (norethinodrel), norethisterone and homocysteine levels, without unfavourable acetate, norgestrel, levonorgestrel, desogestrel, effects on haemostatic factors. The available gestodene and norgestimate. More recent pro- progestogens have differences in their pharmaco- gestogens include dienogest, drospirenone, and logical characteristics according to their structure the 19-norprogesterone derivatives, trimeges- or metabolites, bioavailability and metabolism, tone, elcometrine and nomegestrol acetate. which may contribute to differences in clinical The 19-norprogesterone derivatives have been properties. However, few direct comparative trials designed to bind almost exclusively to the pro- of progestogens have been undertaken.

Nomegestrol acetate, a 19-norprogesterone Table I. Classification of progestogens (reproduced from Schindler derivative, is a potent and clinically useful syn- et al.,[3] with permission from Elsevier) thetic progestogen. Nomegestrol acetate was Progestogen Example developed by the Monaco-based company, Progesterone Natural progesterone The´ramex S.A.M. It has been approved in Europe Retroprogesterone Dydrogesterone as monotherapy (nomegestrol acetate 5 mg) for Progesterone derivative Medrogestone the treatment of uterine disorders and menor- 17a-Hydroxyprogesterone Medroxyprogesterone acetate, rhagia, or at a dose of 3.75 mg in combination derivatives (pregnanes) megestrol acetate, chlormadinone with an estrogen (estradiol 1.5 mg) for the treat- acetate, cyproterone acetate 19-Norprogesterone Gestonorone caproate, nomegestrol ment of menopausal symptoms. derivatives (norpregnanes) acetate, demegestone, The objective of this article is to review the promegestone, elcometrine, pharmacology, safety and clinical efficacy of nom- trimegestone egestrol acetate in its current therapeutic indica- 19-Nortestosterone Norethisterone (norethindrone), tions, and to summarize the antigonadotropic derivatives (estranes) norethisterone acetate, lynestrenol, etynodiol acetate, noretynodrel properties and other beneficial metabolic and 19-Nortestosterone Norgestrel, levonorgestrel, pharmacological characteristics that underlie a derivatives (gonanes) desogestrel, etenogestrel, potential role in combination with an estrogen in gestodene, norgestimate, dienogest combined oral contraceptives. Medical literature Spironolactone derivative Drospirenone (any language) on the clinical effectiveness and safety/tolerability of nomegestrol acetate was identified using the MEDLINE and EMBASE ception, most of the older progestogens still bind to databases. Additional references were identified the androgen receptor to some extent and retain from the reference lists of published articles, and some level of undesirable androgenic adverse from bibliographical information, including con- effects. More recently, newer progestogens have tributory unpublished data, requested from the been designed in an effort to create a more ideal company responsible for developing the drug. progestogen, exerting strong antiestrogenic actions on the endometrium, in conjunction with potent antigonadotropic activity, to provide the benefits 1. Overview of Classification of of progesterone without androgenic or glucocorti- Progestogens coid effects, such as acne, hirsutism, bloating and fluid retention, and unfavourable effects on lipid Progestogens share a basic progestogenic effect profiles.[5] Furthermore, the incorporation of anti- on the estrogen-primed endometrium. However, androgenic properties into some progestogens may there are large differences between progestogens have the additional beneficial effect of reducing in the range and extent of their other biological endogenous androgen action.[5] Newer progesto- effects.[3] In addition to natural progesterone, gens,whichhavebeendesignedtobindvery progestogens derived either from testosterone (19- specifically to the progesterone receptor and are rela- nortestosterone derivatives) or from progesterone tively lacking in affinity for other steroid receptors, (17a-hydroxyprogesterone derivatives and 19-nor- include trimegestone, elcometrine and nomegestrol progesterone derivatives) have been synthesized acetate (19-norprogesterone derivatives), dienogest for contraception and menopausal hormone (a non-ethinylated 19-nortestosterone derivative) therapy use.[3-5] Uniquely, drospirenone is a pro- and drospirenone (a spironalactone derivative that gestogen derived from spironolactone.[3-5] The has anti-mineralocorticoid properties).[1,3] classification of progestogens is summarized in The relative binding affinities of selected table I. Most of the first progestogens were progestogens with human steroid receptors are 19-nortestosterone derivatives, and were synthesized summarized in table II, and the biological activ- with antigonadotropic action as a primary design ities of natural progesterone and synthetic pro- target. Currently the basis of hormonal contra- gestogens are presented in table III.

Table II. Relative binding affinities of selected progestogens with human steroid receptors and serum binding proteinsa (reprinted from Pasqualini,[6] by permission of the publisher [Taylor & Francis Group, http://www.informaworld.com]) Progestogen Receptors progesterone androgen estrogen glucocorticoid mineralocorticoid sex hormone- corticosteroid- binding globulin binding globulin Progesterone 50 0 0 10 100 0 36 Dydrogesterone 75 0 -- - - - Chlormadinone 67 5 0 8 0 0 0 Cyproterone 90 6 0 6 8 0 0 Medroxyprogesterone 115 5 0 29 160 0 0 Megesterol 65 5 0 30 0 0 0 Nomegestrol 125 6 0 6 0 0 0 Promegestone 100 0 0 5 53 0 0 Drospirenone 35 65 0 6 230 0 0 Norethisterone 75 15 0 0 0 16 0 Levonorgestrel 150 45 0 1 75 50 0 Norgestimate 15 0 0 1 0 0 0 Etonogestrel 150 20 0 14 0 15 0 Gestodene 90 85 0 27 290 40 0 Dienogest 5 10 0 1 0 0 0 a Progesterone is considered as 100% affinity. - indicates no data.

2. Pharmacodynamics of Nomegestrol doses,[9] whereas medroxyprogesterone acetate was Acetate androgenic, even if only at high doses.[10] In contrast, nomegestrol acetate has an antiandrogenic This section provides a brief overview of the effect, although the effect was 20 times lower than key pharmacodynamic properties of nomegestrol that of cyproterone acetate.[9] There is no (or very acetate. Nomegestrol acetate is a 19-norproges- little) binding of nomegestrol acetate to estrogen, terone-derived progesterone receptor agonist glucocorticoid and mineralocorticoid receptors (17a-acetoxy-6-methyl-19-nor-pregna-4,6-diene-3, (table II). Nomegestrol has a potent antigonado- 20-dione) with an oral route of administration. tropic action, effectively inhibiting ovulation in It possesses progestogenic, antiandrogenic and women at an oral dosage of 1.25 mg/day, and sup- antiestrogenic properties. pressing both ovulation and follicle development Small structural changes to the progesterone at higher doses.[11] The antigonadotropic effect of molecule may account for considerable differences nomegestrol acetate is mediated at the hypotha- in the effects of progestogens. The addition of a lamic and pituitary levels,[12] and is not mediated double bond between C-6 and C-7 of the hydroxy- by means of the androgen receptor, unlike some progesterone skeleton and the deletion of the CH3 other progestogens.[13] The progestational and radical at C-19 confers a higher progestational antiovulatory potencies of nomegestrol acetate potency to nomegestrol acetate than that of and other progestogens are presented in figure 2. medroxyprogesterone acetate, a 17a-hydroxyprogesterone derivative (figure 1).[8] Nomegestrol acetate lacks androgenic or estrogenic activity. 3. Pharmacokinetic Properties When evaluated in animal experiments investi- gating the effects of progestogens on testosterone- The pharmacokinetics of nomegestrol acetate stimulated prostate growth, nomegestrol acetate were studied in ten clinical trials in approximately had no androgenic effect, even at very high 70 healthy pre- and postmenopausal women.[14] In

00Ai aaIfrainB.Alrgt reserved. rights All BV. Information Data Adis 2010 Table III. Biological activities of natural progesterone and synthetic progestogens (reproduced from Schindler et al., with permission from Elsevier, with additional data from Kumar et al.[7] ) Progestogen Progestogenic Anti-gonadotropic Anti-estrogenic Estrogenic Androgenic Anti-androgenic Glucocorticoid Anti-mineralocorticoid Progesterone ++ + --–++

Dydrogesterone +- + --–-–

Medrogestone ++ + --–--

17a-Hydroxyprogesterone derivatives

Chlormadinone acetate ++ + --++-

Cyproterone acetate ++ + --+++-

Megestrol acetate ++ + -–++-

Medroxyprogesterone acetate ++ + -–-+-

19-Norprogesterone derivatives

Elcometrine ++ + -----

Nomegestrol acetate ++ + --–--

Promegestone ++ + -----

Trimegestone ++ + --–-–

Spironalactone derivatives

Drospirenone ++ + --+-+

19-Nortestosterone derivatives

Norethisterone ++ + ++---

Lynestrenol ++ + ++---

Noretynodrel –+ – +–---

Levonorgestrel ++ + -+---

Norgestimate ++ + -+--- rg 00 0(5) 70 2010; Drugs Etonogestrel ++ + -+---

Gestodene ++ + -+-++

++ – –-+--

Dienogest 545 ++ indicates strong activity; + indicates activity; – indicates weak activity; - indicates no activity. 546 Lello

O CH3 O CH3 C C H3C H3C O COCH3

H3C H3C

H 6 O O

CH3

Progesterone Medroxyprogesterone acetate

O CH O CH 3 3 O C C H3C H3C O C CH3 O COCH3 CH2 H 19

10 H 6 O O

CH3

Nomegestrol acetate Elcometrine

Fig. 1. Chemical structures of nomegestrol acetate and elcometrine, two 19-norprogesterone derivates, compared with the structures of native progesterone and medroxyprogesterone acetate, which is a 17a-hydroxyprogesterone derivative. summary, serum nomegestrol acetate concentra- CYP3A4 and CYP2A6. Excretion is via urine tions increase rapidly after oral administration, and faeces.[14] m / reaching peak plasma concentration (Cmax)within In a representative study, Cmax of 7.21 g L 2–3 hours, regardless of dose. There is a linear was reached in 3.33 hours after oral administra- correlation between nomegestrol acetate dose and tion of a single dose of nomegestrol acetate [14] / Cmax and area under the concentration-time curve 3.75 mg. The AUC24h was 62.4 ngÁh mL, and (AUC) at daily doses ranging from 5 to 100 mg. AUC¥ was 150.0 ngÁh/mL. Total body clearance The absolute bioavailability is approximately 63% was 289.9 L/h and the elimination half-life was and individual variability in pharmacokinetic 36.2 hours. In contrast, the terminal half-life is parameters is low.[14] Nomegestrol acetate circu- 7–8 hours for norethisterone, up to 26 hours for lates in the blood approximately 97.5–98% levonorgestrel and approximately 48 hours for bound to albumin. Binding to transcortin and sex cyproterone acetate.[15,16] Little accumulation hormone-binding globulin is negligible for concen- occurs after repeated administration of nome- trations between 0.1 and 100 ng/mL (the range gestrol acetate and the steady state is reached in encompassing therapeutic concentrations).[14] The 5 days.[14] apparent volume of distribution is large (approxi- In pharmacokinetic studies of nomegestrol mately 1200–1300 L), indicating that protein acetate 3.75 mg in combination with estradiol binding is not a limiting factor in the distribution 1.5 mg, combined administration did not lead to of the molecule.[14] any significant interaction with single or repeated Nomegestrol acetate is metabolized in the liver dosing.[14] Nor did food intake produce any via cytochrome P450 (CYP) system; hydroxyla- clinically significant changes in nomegestrol tion to six main metabolites with no or minimal acetate pharmacokinetics. Because progestogen progestational activity is dependent on CYP3A3, metabolism is dependent on CYP3A4, there is a

MPA menorrhoea and menorrhagia of fibromas. A

TMG NOM total of 1825 women with various gynaecological DRS disorders (menorrhagia, bleeding and spotting, McPhail irregular cycle duration, clotting, dysmenor- index NES 100 > LNG 10 > PRG 1 rhoea) were treated in a multicentre study with Ovulation NES 100 > LNG 50 > PRG 1 inhibition nomegestrol acetate 5 mg for 10–20 days until day 25 of their cycle for 3 consecutive cycles. TMG DRS Cycle disturbances were resolved or improved in 81.3% of subjects.[17] The efficacy of nomegestrol DNG acetate in the treatment of menstrual cycle disorders and dysfunctional uterine bleeding was also Fig. 2. Progestogenic and antiovulatory potencies of nomegestrol acetate (NOM), trimegestone (TMG), elcometrine (NES), dienogest shown in a study of 66 women treated by three (DNG) and drospirenone (DRS) compared with the older progesto- hospital departments in France (table IV).[18] gens, levonorgestrel (LNG) and medroxyprogesterone acetate – (MPA), and the physiological hormone progesterone (PRG). Pro- In 56 women aged 22 50 years with menstrual gestogenic activity was assessed using the McPhail index, which disorders or premenstrual syndrome, nomeges- measures the dose of progestin required to transform the endo- trol acetate 5 mg/day administered for 10 days metrium to a secretory state. Antiovulatory activity was evaluated by assessing the progestin dose required to inhibit spontaneous from day 16 of the cycle for 3 consecutive cycles ovulation (reproduced from Sitruk-Ware,[2] with permission from reduced menstrual loss from as early as the first Adis, a Wolters Kluwer business [ª Adis Data Information BV 2004. % All rights reserved]). cycle of therapy. Approximately 50 of nomegestrol acetate recipients had normal cycles after 1 cycle, whereas normalization was not observed potential for clinically significant interactions until the third cycle with dydrogesterone 10 mg between nomegestrol acetate and inducers or twice daily. Four weeks after the end of treat- inhibitors of CYP3A4 such as rifampicin or ment, 80.0% of nomegestrol acetate and 54.5% of [14] ketoconazole, respectively. dydrogesterone recipients had normal menstrual flow.[19] There are indications from a small, prospec- 4. Therapeutic Effectiveness tive study that nomegestrol acetate is effective in treating haemorrhages related to fibromyoma. 4.1 In Gynaecology Stabilization or improvement of functional symp- Nomegestrol acetate has been evaluated as a tomatology, volume or presence of fibromyomas, single agent in the treatment of symptoms asso- and uterine volume was seen in 88%,85% and 86% ciated with progesterone deficiency, specifically of patients, respectively, in 18 women (mean age 44 menstrual irregularities, premenstrual syndrome, years) treated with 3–9 cycles of nomegestrol mastodynia, functional uterine bleedings, dys- acetate 5 mg/day for 11 days per cycle.[14] Finally,

Table IV. Effect of four consecutive cycles of nomegestrol acetate 5 mg/day from days 16 to 25 of the cycle in 66a women with menstrual cycle disorders and dysfunctional uterine bleedings[18] Effect Menorrhagia Spotting and metrorrhagia Cycle duration disorders prolonged bleeding heavy bleeding (n = 8) prolonged short irregular (n = 24) (n = 25) (n = 11) (n = 11) (n = 21) Normalized 11 15 6 5 5 16 Improved 7 2 0 0 0 0 No change 2 2 1 1 1 1 Worsened 1 0 0 0 0 0 Incomplete data 3 6 1 5 5 4 a Patient numbers do not total 66 because some women had more than one gynaecological disorder. Data were incomplete for patients who did not complete 4 cycles of treatment.

in a small, placebo-controlled study, 4 cycles of Nomegestrol acetate for 12 days per month in nomegestrol acetate 5 mg/day for 20 days per cycle combination with continuous estrogen implant reduced spontaneous breast pain in 42 pre- therapy induced a regular withdrawal bleed menopausal women aged 21–49 years with symp- (defined as that commencing £15 days after toms of benign breast disease, characterized by discontinuing nomegestrol acetate) each month mastodynia and structural modification of the in all 36 postmenopausal women enrolled in breast, such as solid nodules or mastosis plaques. another double-blind, randomized study.[21] Do- At the start of treatment, 62% of women had sages of nomegestrol acetate were 0.5, 1.0 and moderate to severe breast pain. This had reduced 2.5 mg/day. The regimens were evaluated over to 16% after 4 months of treatment.[14] At the end 4 cycles. The mean day of onset of withdrawal of the study, 85% of women receiving nomegestrol bleeding was day 15 (i.e. 3 days after the last dose acetate had minimal or no breast pain. Nomeges- of nomegestrol acetate) for the nomegestrol trol acetate also reduced the feeling of breast acetate 0.5 mg/day group, and days 16 and 18, swelling (p < 0.001 vs placebo), as determined by respectively, for the 1.0 and 2.5 mg/day groups. the reduction of thoracic perimeter (p < 0.05).[14] Morphological and biochemical analysis did not demonstrate a clear dose-response relationship, 4.2 In Menopause suggesting that all doses were adequate. Nome- gestrol acetate 5 mg/day was added to continuous Progestogens are commonly combined with transdermal estradiol therapy (50 mg/day) in a estrogens in hormone replacement therapy prospective, randomized study in 34 postmeno- (HRT) to counteract the risk of estrogen-related pausal women. The progestogen was adminis- endometrial hyperplasia. However, progestogens tered for 10 days per month (days 12–21) or with residual androgenic or glucocorticoid activ- bimonthly (for 15 days every 2 months) for ity may decrease the beneficial effects of estrogen 1 year.[22] Both protocols gave good control of on metabolic parameters. Several studies have the menstrual cycle, without increasing the risk of shown nomegestrol acetate, which does not have endometrial pathology. There were no significant androgenic or glucocorticoid effects, to be sui- differences in the mean onset of bleeding after the table for use in HRT. Nomegestrol acetate was last dose of nomegestrol acetate or in the dura- studied as a component of an HRT regimen tion of bleeding. Compliance was good in both consisting of nomegestrol acetate 1.5 or 3.75 mg treatment groups. in combination with estradiol 1.0 or 2.5 mg for 3 There was a significantly higher rate of regular consecutive cycles in a double-blind, randomized, progestogen-associated withdrawal bleeding on prospective study in 57 nonhysterectomized wo- days 14–25 of each 28-day cycle in healthy post- men.[20] Both doses significantly reduced meno- menopausal women receiving nomegestrol acet- pausal complaints, and improved plasma lipid ate 5 mg/day in combination with transdermal profiles without unfavourable effects on other estradiol 50 mg/day, compared with estradiol in metabolic or haemostatic factors. There was a combination with medroxyprogesterone acetate, rapid decrease in the frequency and severity of dydrogesterone or natural progesterone.[23] hot flushes, which was statistically significant A total of 100 women were enrolled in the from the first cycle of treatment. The frequency 12-month, open-label, randomized study. Reg- of hot flushes was reduced from 3.9 to 0 per day ular bleeding (defined as any bleeding occurring in the nomegestrol acetate 2.5 mg/day group, towards the end of, or immediately after, pro- and from 4.0 to 0.3 in the nomegestrol acetate gestogen administration; all other types were 3.75 mg/day group (both p < 0.001 vs placebo). defined as irregular) occurred in 81.6% of cycles The intensity of hot flushes and a global score in the nomegestrol acetate group, compared with for climacteric symptoms were both significantly 64.4% and 71.8%, respectively, with natural reduced by treatment (p < 0.01 and p < 0.05, progesterone and medroxyprogesterone acetate respectively). (p < 0.01 vs nomegestrol acetate), and with 75.2%

in the women who received estradiol in combi- 5. Safety Profile nation with dydrogesterone (p < 0.05 vs natural progesterone). Irregular bleeding was recorded in 5.1 Risk of Thromboembolism 5.7% of the cycles of women receiving nomeges- Studies to date have suggested that, as proges- trol acetate and in 12.0% (p < 0.05 vs nomegestrol togen-only therapy, nomegestrol acetate does not acetate), 8.4% and 7.5% of the cycles of women increase the risk of venous thromboembolism receiving progesterone, medroxyprogesterone (VTE). In a study by Basdevant et al.,[27] treatment acetate or dydrogesterone, respectively. with nomegestrol acetate had no significant effect Further discussion of the role of nomegestrol on plasminogen and fibrinogen levels. However, acetate in combination HRT is discussed in the there was a significant increase in antithrombin III safety section (section 5). of between 5% and 7% during treatment (p < 0.01 vs baseline).[27] The clinical significance of this 4.3 Single-Agent Contraception finding is unclear, although a deficiency in antithrombin III, an inhibitor of coagulation, is asso- A study to assess the impact of nomegestrol ciated with some venous thromboses. acetate on the human cervix found a loss of However, although the absolute risk is very low, spinability, an absence of ferning pattern and a there is evidence from clinical studies of a doubling strong tightening of the glycoprotein meshwork of relative risk of VTE or fatal pulmonary embo- in midcycle mucus, rendering the cervical canal lism associated with estrogen/progestogen contra- non-permeable to spermatozoa and bacteria, ceptive and combination HRT.[28-31] Although thus indicating that nomegestrol acetate pos- initially attributed to the estrogen component [24] sesses contraceptive potential. (ethinylestradiol in this instance), it now appears Nomegestrol acetate 1.25, 2.5 or 5 mg once a that greater risk is associated with formulations day from day 5 to 25 inhibited ovulation, and containing progestogens such as gestodene or deso- uniformly depressed luteinizing hormone and pro- gestrel in combination with a low-dose estrogen, gesterone levels in 13 normally menstruating compared with levonorgestrel in combination with [11] women. At the 1.25 mg/day dosage, ovulation low-dose estrogen.[32-34] was inhibited while follicle growth was permitted, whereas dosages of 2.5 or 5 mg/day suppressed 5.1.1 Differential Effects of Progestogens on Nitric both ovulation and follicle development. The re- Oxide in Endothelial Cells sults indicate that nomegestrol acetate exerts a Differences in the relative risk of thrombo- useful antigonadotropic activity via hypothalamic- embolic events in women taking an estrogen pituitary effects and ovarian action. In another combined with different progestogens may in study, nomegestrol acetate 5 mg/day for 21 days per part be explained by differential effects on bene- cycle showed a strong antigonadotropic activity in ficial estrogen-induced endothelial formation of normally cycling women.[12] Ovulation was sup- nitric oxide, a potent vasoprotective and antit- pressed in all women, and plasma luteinizing hor- hrombotic factor. The effect of progestogens on mone levels, luteinizing hormone pulse frequency the expression of endothelial nitric oxide synthase and luteinizing hormone response to exogenous (eNOS) and the formation of nitric oxide in hu- gonadotropin-releasing hormone were all signifi- man endothelial cells was investigated in a recent cantly decreased. Luteinizing hormone and follicle- study.[35] It was demonstrated that medroxy- stimulating hormone secretory patterns in normally progesterone acetate and progesterone markedly cycling women receiving nomegestrol acetate downregulated the expression of eNOS, as evi- 5mg/day for 21 days per cycle are shown in figure 3. denced by decreased eNOS messenger RNA and A subdermal implant containing 55 mg (10%) protein levels. This was associated with decreased of nomegestrol acetate has been shown to be ef- nitric oxide formation, which can lead to a fective in the prevention of ovulation with a single reduced ability of endothelial cells to prevent implant used over 1 year.[25,26] platelet aggregation. This downregulation of the

Control cycle NOM

10 9

8 7

6 5

4 LH (IU/L) LH (IU/L) 3 2

0 1 04080120 160 200 240 04080120 160 200 240 Time (min) Time (min)

5 7.5

4 6.5

FSH (IU/L) 3 FSH (IU/L) 5.5

2 4.5 04080120 160 200 240 04080120 160 200 240 Time (min) Time (min)

Fig. 3. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretory patterns in two representative, normally cycling women on day 11 of the control cycle and on day 11 of nomegestrol acetate (NOM) 5 mg/day administration. Arrows indicate LH pulses (reproduced from Couzinet et al.,[12] with permission). expression of eNOS was shown to be mediated thrombotic response to thrombin and decreased via activation of the glucocorticoid receptors and endothelial formation of nitric oxide associated not the progesterone receptor. However, neither with medroxyprogesterone acetate and proges- nomegestrol acetate nor levonorgestrel affected terone might partly explain the increase in the eNOS expression, and the lack of glucocorticoid relative risk of thromboembolic events in women receptor activity of these progestogens was taking combined low-dose oral contraceptives confirmed.[35] containing a progestogen with partial gluco- A follow-on study provided additional clar- corticoid activity, compared with those taking ification of the role of progestogens in modifying levonorgestrel in combination with estrogen at a beneficial estrogen-induced formation of nitric similar dose.[32-34] Although neither levonorges- oxide. Although all progestogens investigated trel nor nomegestrol acetate have glucocorticoid (medroxyprogesterone acetate, progesterone, activity, clinical studies are necessary to confirm levonorgestrel and nomegestrol acetate) sig- the relationship of nomegestrol acetate to nificantly blunted the estradiol-stimulated ex- thromboembolic risk. pression of eNOS in human endothelial cells, estradiol-induced formation of nitric oxide was 5.1.2 Implications of the ESTHER Study also reduced by medroxyprogesterone acetate The ESTHER (Estrogen and Thromboembo- and progesterone.[36] However, formation of lism Risk) case-control study found that oral nitric oxide was preserved by levonorgestrel and but not transdermal estrogen is associated with nomegestrol acetate, allowing the beneficial increased risk of VTE.[37] Additional analysis effect of estrogen to persist. The increased pro- of data from ESTHER also suggested that

19-norprogesterone derivatives (norpregnanes) are carcinoma associated with unopposed estrogen associated with increased risk of VTE, compared use in non-hysterectomized women.[42,43] Proges- with natural progesterone or hydroxyprogesterone terone or a progestogen prevents the over- derivatives (pregnanes).[38] However, these findings proliferation of the endometrial tissue, with the donotappeartobeinaccordwithexistingdata degree to which this effect is achieved dependent regarding nomegestrol acetate and haemostasis[27] on the antiestrogenic properties of the progestin, and, furthermore, it may not be possible to extra- and the dose and duration of treatment. Nom- polate these data obtained in menopausal women egestrol acetate prevents the estrogen-dependent to younger premenopausal women. proliferation of the endometrium when used in The primary focus of the ESTHER study was combination with estrogens.[44] In the study by to examine the effect of the route of estrogen Fraser et al.[21] on the addition of nomegestrol administration on VTE risk in postmenopausal acetate to estrogen therapy in postmenopausal women.[37] As an observational study, ESTHER women, nomegestrol acetate 0.5, 1.0 or 2.5 mg/day was potentially more subject to selection bias than induced consistent changes in the endometrium. an appropriately designed prospective trial. The With the exception of one patient, who showed a authors acknowledge that 19-norprogesterone de- small area of co-existing, non-secretory endo- rivatives are more likely to be prescribed to women metrium, uniform secretory transformation was with hyperestrogenic symptoms, a risk factor for seen in all samples. No mitotic activity was ob- VTE,anddescribesuchprescriptionbiasasastudy served in any patient, and there was no evidence of limitation that could explain in part the high VTE cystic or atypical hyperplasia. Overall, assess- risk among women using transdermal estrogen in ments using light microscopy, transmission elec- combination with a norpregnane.[38] Indeed, nom- tron microscopy and endometrial biochemical egestrol acetate is frequently prescribed for analysis confirmed that nomegestrol acetate in- women with marked hyperestrogenic symptoms duced uniform secretory transformation in the because of its antigonadotropic and antiestrogenic endometrium, which is consistent with the provi- activity. The small number of patients within pro- sion of endometrial protection. Secretory trans- gestogen subgroups is also acknowledged as a formation also occurred in the majority of study limitation; of the 259 cases and 603 controls postmenopausal women at the end of 1 year of in the analysis, the finding that suggested an in- nomegestrol acetate-containing HRT in the study creased risk of VTE was based on 40 cases who by De Leo et al.[22] No subjects developed received 19-norprogesterone derivatives (22 nom- endometrial hyperplasia and treatment with egestrol acetate and 18 promegestone). Of these nomegestrol acetate did not increase the risk of 40 cases, 12 were receiving oral estrogen and other endometrial pathologies. 28 were receiving transdermal estrogen.[39] Finally, the ESTHER authors noted that, since a number 5.3 Cardiovascular Risk of other studies of oral estrogens in combination with progestogens, including nomegestrol acetate, 5.3.1 Epidemiology have not found an increased risk of prothrombotic The effect of combined HRT on cardiovas- effects with 19-norprogesterone derivatives,[20,40,41] cular risk is controversial. Although it is accepted further investigation into whether or not 19-nor- that estrogen use in women after menopause progesterone derivatives have prothrombotic theoretically may reduce cardiovascular morbid- effectsisrequired.[38] ity and mortality, there are concerns that some progestogens may partially oppose the beneficial 5.2 Endometrial Hyperplasia effects of estrogen. Many of the progestogens used in HRT and contraceptives are testosterone The addition of progestogens to estrogen derived, and can have adverse effects relating to replacement therapy is necessary to prevent an their androgenic and/or glucocorticoid proper- increased risk of endometrial hyperplasia and ties. Conversely, estrogen has beneficial effects

on vascular walls, increasing the release of nitric ciated with an increased risk of ischaemic or oxide and leading to relaxation of smooth muscle haemorrhagic stroke.[48] cells and vasodilation, with an inhibition of the development of atherosclerosis.[2] In animal 5.3.2 Effects on Surrogate Markers of models, the beneficial effect of estrogen on the Cardiovascular Risk coronary artery dilator response is inhibited by Dyslipidaemia is an accepted risk factor for 50% when medroxyprogesterone acetate (a pro- cardiovascular disease.[49] Studies of estrogen re- gestogen with some androgenic properties) is placement therapy in postmenopausal women added to estrogen therapy.[45] However, nome- have shown beneficial effects on lipid profiles, gestrol acetate did not inhibit the estrogen- with a reduction in low-density lipoprotein induced dilator responses on coronary arteries (LDL) cholesterol levels and an increase of in a primate cardiovascular model in which 10–15% in high-density lipoprotein (HDL) cho- ovariectomized monkeys were fed a moderately lesterol levels.[50] The estrogen-induced increase atherogenic diet while receiving estradiol, estra- in HDL cholesterol was partially reversed by the diol plus nomegestrol acetate or no hormone addition of medroxyprogesterone acetate to oral replacement.[46] Although nomegestrol acetate estrogens in women receiving combined HRT.[50] had the desired effect of counteracting the typical Improvements in HDL cholesterol levels were estrogen-like effects on the endometrium (in- not effected by the addition of natural proges- creased proliferation and increased hormone terone. Nor was the increase in HDL cholesterol receptor expression), it did not affect estrogen- in women in another study who were receiving induced reductions in constrictor responses of estradiol valerate opposed by nomegestrol acet- epicardial coronary arteries to acetylcholine ate 5 mg/day, although it was partially reversed challenge. This suggests that, unlike medroxypro- by norethisterone acetate (a progestogen with gesterone acetate, nomegestrol acetate did not residual androgenic properties) 5 mg/day.[51] reduce the beneficial effects of estrogen on coro- Total and LDL cholesterol decreased significantly nary vascular reactivity.[46] after 1 year of treatment with nomegestrol Data from large outcome trials on the effects acetate-containing HRT in 34 postmenopausal of nomegestrol acetate or other norpregnanes women.[22] In this study, the LDL to HDL ratio fell on cardiovascular risk are lacking. The WHI by 10% at 1 year (p < 0.01). However, the clinical (Women’s Health Initiative) study tested a single relevance of these changes in lipid parameters is HRT drug regimen comprising the pregnane me- unclear. In another study, in 36 premenopausal droxyprogesterone acetate in combination with women, 6 cycles of nomegestrol acetate 5 mg/day conjugated equine estrogens in 16 608 post- from day 7 to 25 of the cycle did not significantly menopausal women who were followed up for a affect total, HDL or LDL cholesterol, or apoli- mean of 5.2 years.[47] In this study, the overall poprotein B levels.[27] There was a significant health risks of HRT were greater than the benefits, decrease in apolipoprotein A1 levels (p < 0.01 vs without an effect on all-cause mortality. Rates of baseline) and a transient decrease in triglycerides overall cardiovascular disease, coronary heart dis- in the third cycle. Thus, overall, nomegestrol ease (especially non-fatal myocardial infarction), acetate had a neutral effect on lipid metabolism in stroke and VTE were higher in women receiving these studies. estrogen plus progestogen therapy compared with In 20 premenopausal women, treatment with estrogen plus placebo.[47] However, the relevance 6 cycles of nomegestrol acetate 5 mg/day for of these findings to HRT comprising other oral 20 days per cycle did not lead to any significant and/or transdermal formulations of estrogens and changes in plasma glucose or insulin values progestogens, such as the norpregnane nomeges- during the oral glucose tolerance test, or in glycosy- trol acetate, is unclear. Of interest, a recent lated haemoglobin levels, suggesting that nome- meta-analysis of observational studies found that gestrol acetate does not adversely affect glucose progestogen-only contraception use was not asso- tolerance after 6 months of treatment.[52]

Additionally, glucose tolerance did not deterior- medroxyprogesterone acetate 2.5 mg, or placebo, ate in two women with impaired glucose toler- for a mean of 5.2 years from 1993 to 2002. An ance at baseline. Bodyweight, fasting blood interim analysis showed an increased risk of glucose and insulin levels were also unchanged in breast cancer (hazard ratio 1.26; 95% CI 1.0, another study of nomegestrol acetate 5 mg/day in 1.59) and, surprisingly, an increase in coronary 36 premenopausal women.[27] As glucose intol- heart disease risk (hazard ratio 1.29; 95% CI 1.02, erance and hyperinsulinaemia are established risk 1.63).[47] The Million Women Study found that factors for cardiovascular disease, these findings current, but not past, use of combined HRT was are noteworthy. associated with an increased risk of breast cancer Nomegestrol acetate has also been shown to compared with never having used (risk ratio 2.0; reduce high-sensitivity C-reactive protein, a mar- 95% CI 1.88, 2.12).[54] The combination HRT ker of cardiovascular risk. In a 6-month, pro- regimens used by women in the Million Women spective, randomized, placebo-controlled study, Study consisted of equine estrogen or estradiol 84 healthy postmenopausal women received daily in combination with the older progestogens oral conjugated equine estrogen 0.625 mg, con- medroxyprogesterone acetate, norethisterone, jugated equine estrogen 0.625 mg plus medroxy- norgestrel or levonorgestrel, and the extension progesterone acetate 2.5 mg, conjugated equine of these findings to all HRT regimens is con- estrogen 0.625 mg plus nomegestrol acetate 5 mg, troversial. As has been discussed, progestogens or placebo. Serum high-sensitivity C-reactive pro- available for HRT and contraception are not all tein increased significantly in the estrogen alone the same, and other progestogens may have more and estrogen plus medroxyprogesterone acetate favourable effects on breast cancer risk. How- groups (20% and 59%, respectively; p = 0.03 and ever, data on HRT regimens based on newer p = 0.006, respectively), whereas estrogen plus no- progestogens are lacking. Furthermore, the early megestrol acetate decreased serum high-sensitivity increase in breast cancer risk identified in the C-reactive protein by 25% (p = 0.01). Serum homo- Million Women Study suggests that HRT may be cysteine levels were significantly reduced in all promoting the diagnosis of pre-existing tumours active treatment groups compared with baseline rather than causing breast cancer.[55] Currently, and placebo (p < 0.05).[53] However, it should be treatment decisions on appropriate combinations emphasized that the clinical significance of these and dosages of HRT should be short term and effects on surrogate markers of cardiovascular reviewed annually as further information be- disease has not been confirmed in appropriate comes available. outcome studies. 5.4.2 Biology 5.4 Breast Cancer Risk The breast is a particularly hormone- responsive organ, with estrogen and progesterone 5.4.1 Epidemiology in conjunction playing major roles in mammary The effects of progestogens used in oral con- gland biology. Data from experimental studies traceptives and HRT on breast tissue are con- suggest that all progestogens do not have the troversial; suggestions range from an increased same effects on breast cells, and this prevents the risk of breast cancer, to a significant decrease or extrapolation of findings obtained with one to no difference in risk. The effect of progesto- combination to other combinations. Although gens can also be a function of their combination the respective roles of estrogen and progesterone with estrogens. The WHI study[47] and the on the proliferative activity of the breast are not Million Women Study[54] raised concerns over the completely understood, it seems to be clear that effect of progestogens on breast cancer risk. In the most active estrogen, estradiol, is implicated the WHI study, 16 608 postmenopausal women in all stages of breast cancer.[56] Furthermore, received a continuous HRT regimen consisting mammary cancer tissue contains all the enzymes of conjugated equine estrogens 0.625 mg plus responsible for the local biosynthesis of estradiol

Estradiol cell lines, converting estrone to the biologically Sulfotransferase inactive estrone sulfate with a strong stimulating effect at low doses and a weak effect at high 17β-HSD concentrations (figure 6).[59] The strong anti- Estrone-sulfate Estradiol-sulfate sulfatase activity of nomegestrol acetate in the bio-

Sulfatase Estrone-sulfate synthesis of estradiol via the sulfatase pathway in estrogen-dependent breast cancer, as well as the Sulfotransferase stimulatory effect on the formation of the in- Estrone active estrone sulfate, suggests a possible antiproliferative effect for nomegestrol acetate in Aromatase breast tissue. Furthermore, in growth assays using MCF-7 and T47-D human breast cancer Androgens cell lines, nomegestrol acetate did not stimulate proliferation, whereas estradiol, norgestrel and Fig. 4. Enzymatic mechanism involved in the formation and transformation of estrogens in human breast cancer (reprinted from Pasqualini,[6] gestodene stimulated breast cancer cell growth by permission of the publisher [Taylor & Francis Group, http:// via activation of the estrogen receptor.[60-62] = www.informaworld.com]). HSD hydroxysteroid dehydrogenase. However, while indicating that various progestogens have different effects on breast cells, the from circulating precursors.[56] The synthesis of clinical implications of such in vitro data are un- estradiol occurs via two main pathways: the clear, and the results of appropriately controlled ‘sulfatase pathway’, whereby estrogen sulfatase clinical trials would be required to confirm these transforms estrone sulfates into estrone, which is interesting data. then converted into the biologically active estradiol by 17b-hydroxysteroid dehydrogenase 1; and MCF-7 the ‘aromatase pathway’, in which aromatase T47-D transforms androgens into estrogens, but to a far 100 lesser extent than the sulftase pathway (figure 4). 90 It is also well established that estrogen sulfo- transferases present in breast tissue are involved 80 in the conversion of estrogens into their biologi- 70 cally inactive sulfates.[56] In vitro studies have shown that nomegestrol 60 acetate blocks the conversion of estrone sulfate to 50 estradiol in MCF-7 and T47-D hormone-dependent breast cancer cell lines (figure 5),[57] and in 40 normal or cancerous breast tissue.[58] At a con- 30 centration of 5 · 10-5 mol/L, nomegestrol acetate

Inhibition of sulfatase activity (%) 20 inhibited conversion of estrone sulfate to estradiol by 40.8% in normal breast tissue and by 10 % 49.2 in cancerous tissue, where sulfatase activ- 0 ity was more intense.[58] Nomegestrol acetate also 0.5 μmol/L 5 μmol/L 50 μmol/L inhibits the conversion of estrone to estradiol via Fig. 5. Inhibitory effects of nomegestrol acetate on sulfatase activity 17b-hydroxysteroid dehydrogenase 1 in MCF-7 (conversion of estrone sulfate to estradiol) in MCF-7 and T47-D human and T47-D cell lines, with stronger effects in hormone-dependent breast cancer cells. Preconfluent cells were incubated for 24 hours at 37C with estrone sulfate alone (control) or in the progesterone receptor-rich T47-D cell line the presence of indicated concentrations of nomegestrol acetate. Re- compared with the MCF-7 cell line.[57] Nome- sults (pmol of estradiol formed per mg of DNA from estrone sulfate) are expressed as the percentage of control value, which is considered as gestrol acetate also has a stimulatory effect on 0% inhibition (data from Chetrite et al.[57]) [reproduced from Shields- sulfotransferase activity in MCF-7 and T47-D Botella et al.,[56] with permission from Elsevier].

MCF-7 the estradiol group (p < 0.001). The results sug- T47-D gest that nomegestrol acetate may have a bene- 90 ficial effect on bone, with the marked decrease in 80 bone alkaline phosphatase versus total alkaline phosphatase a surrogate marker for the lack of 70 deleterious effect on bone remodelling of estra- 60 diol plus nomegestrol acetate. However, data on the clinical impact of nomegestrol acetate on 50 bone densitometry or fracture risk are lacking.

40 6. Tolerability and Acceptability 30 Nomegestrol acetate has generally been very well 20 tolerated during clinical studies. The most com-

Stimulation of sulfotransferase activity (%) 10 monly reported adverse events have been non- specific or the same as those that have been reported 0 for other newer progestogen molecules. For nome- μ μ μ 50 nmol/L 0.5 mol/L 5 mol/L 50 mol/L gestrol acetate, the most frequently and consis- Fig. 6. Stimulatory effects of nomegestrol acetate on the conver- tently reported adverse events in a relatively small sion of estradiol to estrogen sulfates in MCF-7 and T47-D human series of clinical trials assessing nomegestrol acetate hormone-dependent breast cancer cells. Preconfluent cells were [13,20-23,27,63] incubated for 24 hours at 37C with a physiological concentra- as part of combination HRT, or as tion (5 nmol/L) of 3H-estrone alone (control) or in the presence of monotherapy,[64] were abnormal bleeding/spotting nomegestrol acetate at the indicated concentrations (data from Chetrite et al.[59]) [reproduced from Shields-Botella et al.,[56] with (12.5–29.3% of patients), headache (approximately permission from Elsevier]. 10% of patients) and hot flushes (1.7%). Breast pain or tenderness was reported in 32.8% of estradiol/ [63] 5.5 Effects on Bone Turnover nomegestrol acetate recipients in a single study, although this adverse event was specifically mon- Compared with placebo, adding nomegestrol itored for but not observed in any patient in another acetate 3.75 mg/day to estradiol 1.5 mg/day sig- study.[13] In some studies, 4–10% of women with- nificantly reduced levels of biochemical markers drew from treatment because of adverse events, of bone turnover in a 12-week study in 176 post- which were most commonly nausea, headache, menopausal women (p < 0.001). There was a de- breast tenderness or irregular bleeding.[14,20,22,63] crease in the levels of four biochemical markers of Several studies reported no relevant drug-related bone turnover, total serum alkaline phosphatase, adverse events for up to 12 months of nomegestrol bone alkaline phosphatase, serum osteocalcin acetate treatment.[21,23] In placebo-controlled, and urinary type-I collagen peptides, as early as phase III registration trials for estradiol/nom- 6 weeks after treatment commenced, with mean egestrol acetate HRT (n = 257), the frequency of decreases of approximately 6%,5%,12% and adverse events was similar between active treatment 32%, respectively.[63] Bone alkaline phosphatase, and placebo.[14] In general, bodyweight and osteocalcin and type-I collagen peptides also de- blood pressure were unchanged during nomeges- creased in the estradiol group (by approximately trol acetate-containing therapy.[13,20,21,63] The most 0.4%,9% and 34.7%, respectively). However, comprehensive reporting of adverse events was in serum alkaline phosphatase increased by 4.1% the study by Nguyen-Pascal et al.[63] in a total of compared with a decrease of 6.2% in the estradiol 176 postmenopausal patients treated for 12 weeks plus nomegestrol acetate group (p < 0.001). Fur- with one of the following three regimens: placebo; thermore, the percentage increase in bone alka- estradiol 1.5 mg/day; or estradiol 1.5 mg/day plus line phosphatase was significantly higher in the nomegestrol acetate 3.75 mg/day. A total of 304 estradiol plus nomegestrol acetate group than in adverse events (not necessarily related to treatment)

were reported by 133 patients; 70.7% in the placebo in this review, suggest its suitability for use with group, 75.9% in the estradiol group and 82.9% an estrogen in combined oral estrogen/progesto- in the estradiol/nomegestrol acetate group. There gen formulations. Nomegestrol acetate lacks un- was no statistically significant difference between desirable androgenic or estrogenic actions, and groups in the overall incidence of adverse events. demonstrates similar activity to the physiological Mastalgia, the most commonly reported event, was hormone progesterone. Furthermore, the initial reported by 6.9%,24.1% and 32.8% in the placebo, indications of beneficial effects on bone remodel- estradiol and combination groups, respectively. ling and preclinical data suggesting possible Abnormal bleeding occurred in 3.4%,10.3% and antiproliferative or, at the very least, a lack of 29.3%, respectively, and hot flushes were reported proliferative effect in normal and cancerous in 12.1%,1.7% and 1.7% of patients. Ten percent of breast tissue make nomegestrol acetate an inter- patients, evenly distributed across the three groups, esting progestogen to consider for combination reported experiencing headaches. Systolic and with an estrogen. However, the final effect of diastolic blood pressure did not change over the nomegestrol acetate-containing oral contra- 12 weeks in any treatment group. In general, in the ception will also depend on the type and dose of absence of direct comparative studies, the safety the associated estrogen, and demonstration in a profile of nomegestrol acetate appears to be similar clinical setting of its promising properties re- to that of other, newer progestogens. garding metabolic and vascular profile. In the single published study of nomegestrol Recruitment was completed in May 2007 for acetate 5 mg/day monotherapy for which adverse two pivotal, phase IIIa clinical trials of a novel event data were presented, tolerability was clas- oral contraceptive containing nomegestrol acet- sified as ‘good’.[64] Adverse events were rare or ate 2.5 mg and estradiol 1.5 mg (NOMAC/E2).[65] reported in a single patient, and included asthenia The randomized, comparative, multicentre trials in one patient, hot flushes, bloating, nausea and in over 180 centres in 24 countries were designed pelvic pain. There were no significant changes in to assess the contraceptive efficacy, cycle control bodyweight or blood pressure. Most adverse and general safety and acceptability, and to events were classified as ‘unlikely to be’ or ‘pos- evaluate the effects of the nomegestrol acetate/ sibly related to’ nomegestrol acetate. Metror- estradiol monophasic combination oral contra- rhagia occurred in 9.4% of cycles (and resulted in ceptive on ovarian function in a large group of withdrawal from treatment in 7.6% of patients). healthy women aged 18–50 years. Over 4000 Spotting was reported in 25.8% of cycles. women were enrolled for the trials. A drospir- Data from registration studies and postmarket- enone plus ethinyl estradiol monophasic oral ing surveillance show nomegestrol acetate to be contraceptive formulation was the comparator in well tolerated. In registration studies, the most fre- both trials. The trials (NCT00413062[66] and quently reported adverse events were headache NCT00511433[67]) are listed as having been (5.5%), mastodynia (1.5%) and insomnia (1.2%).[14] completed on the ClinicalTrials.gov database, With the exception of spotting, most adverse events and results are awaited. A regulatory application were of similar nature and frequency in placebo and was filed for NOMAC/E2 in contraception in the nomegestrol acetate recipients. Postmarketing European Union in October 2009. pharmacovigilance monitoring >100 million menstrual cycles identified an incidence of nomegestrol 8. Conclusions acetate-related adverse effects of 0.0006%.[14] Nomegestrol acetate is a potent and versatile 7. Potential Role in Combination Oral progestogen molecule with an established role in Estrogen/Progestogen Contraception menopause and the treatment of menstrual cycle disturbances, and demonstrated efficacy as a The antigonadotropic activity and metabolic single antigonadotropic agent. The specificity of characteristics of nomegestrol acetate, as detailed binding to the progesterone receptor and a lack

of binding to other steroid receptors results in 11. Bazin B, Thevenot R, Bursaux C, et al. Effect of nomegestrol strong antiestrogenic effects with potent anti- acetate, a new 19-nor-progesterone derivative, on pituitary- ovarian function in women. Br J Obstet Gynaecol 1987 gonadotropic activity, but without androgenic or Dec; 94 (12): 1199-204 glucocorticoid properties. In addition to its role 12. Couzinet B, Young J, Kujas M, et al. The antigonadotropic in the treatment of gynaecological disorders and activity of a 19-nor-progesterone derivative is exerted both its combined role with estradiol in HRT, nom- at the hypothalamic and pituitary levels in women. J Clin Endocrinol Metab 1999 Nov; 84 (11): 4191-6 egestrol acetate has a favourable tolerability pro- 13. Couzinet B, Young J, Brailly S, et al. The antigonadotropic file, neutral metabolic characteristics and a lack activity of progestins (19-nortestosterone and 19-norpro- of proliferative activity in breast tissue, which gesterone derivatives) is not mediated through the andro- suggests that it could be an effective progestogen gen receptor. J Clin Endocrinol Metab 1996 Dec; 81 (12): / 4218-23 for use in combination estrogen progestogen 14. Data on file, Theramex S.p.A., 2002 contraceptive therapy and capable of providing 15. Ezan E, Benech H, Bucourt R, et al. Enzyme immunoassay some non-contraceptive benefits for women’s for nomegestrol acetate in human plasma. J Steroid Bio- health. chem Mol Biol 1993 Oct; 46 (4): 507-14 16. Dusterberg B, Humpel M, Speck U. Terminal half-lives in plasma and bioavailability of norethisterone, levonorgestrel, cyproterone acetate and gestodene in rats, beagles and Acknowledgements rhesus monkeys. Contraception 1981 Dec; 24 (6): 673-83 17. Cohen A. 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