Dienogest in the treatment of endometriosis

in the treatment ofendometriosis Nicolo Bizzarri, Valentino Remorgida, Umberto Leone Roberti Maggiore, Carolina Scala, Emanuela Tafi, Valentina Ghirardi, Stefano Salvatore,Massimo Candiani, Pier Luigi Venturini & Simone Ferrero† †University of Genoa, IRCCS San Martino Hospital and National Institute for Cancer Research, Pharmacokinetic of DNG Department of Obstetrics and Gynaecology, Genoa, Italy Pharmacodynamic of DNG Introduction: (DNG) is an oral progestin, derivative of 19-nortestos- Mechanism of activity in terone, that has recently been introduced for the treatment of endometriosis.
Areas covered: This review examines the clinical efficacy, safety and tolerabil- Clinical efficacy ity of DNG in the treatment of endometriosis. The material included in the Safety and tolerability current manuscript was searched and obtained via Medline, Pubmed and EMBASE, from inception until February 2014. The term ‘dienogest' was associ-ated with the following search terms: ‘endometriosis', ‘pharmacokinetics', ‘safety' and ‘efficacy'.
Expert opinion: Several trials demonstrated the clinical efficacy, safety andtolerability of DNG. However the use of DNG is associated with some limita-tions. So far, no study investigated the potential of contraceptive effect ofthis treatment and therefore, it should be recommended with other methodsof contraception (e.g., barrier methods). A further limitation of the use ofDNG as daily therapy in the long term is that the cost of the therapy is higherthan other progestins available on the market and combined oral contracep-tives. Therefore, future studies should be designed to compare the efficacyand safety of DNG with other progestins.
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Keywords: dienogest, efficacy, endometriosis, hormonal, pharmacokinetics, progestin, safety (2014) 15(13):1889-1902 Endometriosis is a chronic estrogen-dependent gynecological condition character-ized by the presence of ectopic glands and stroma outside the uterine cavity. Itaffects at least 5 - 10% of women , and it often causes infertility and/or painsymptoms (dysmenorrhea, deep dyspareunia, chronic pelvic pain and dyschezia).
In some patients, pain symptoms are extremely severe and negatively affect qualityof life (QoL), work efficiency and sexual life . The definitive diagnosis is onlyhistological. The role of surgery is both diagnosis and treatment but often, espe-cially in patients with less extensive disease, the first therapeutic approach is med- Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 ical treatment based on the suspicion of the presence of endometriosis achievedthrough a gynecological examination, transvaginal ultrasound and eventually pelvicMRI ].
Several hormonal therapies have been proposed for the treatment of endometriosis-related pain, including oral contraceptive pill and other estropro-gestin formulations (such as the vaginal ring and the transdermal patch), proges-tins (including medroxyprogesterone acetate, norethisterone acetate, desogestreland the levonorgestrel-releasing intrauterine device), gonadotrophin-releasinghormone (GnRH) agonists and hyperandrogenic compounds (such as danazoland gestrinone) . These traditional endocrine therapies for endometriosisinhibit estrogens production in the ovary. However, medical therapy is a purelysymptomatic treatment. In fact, the symptoms usually recur when discontinuing 10.1517/14656566.2014.943734 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted N. Bizzarri et al.
depot) and antiprogestogens (such as gestrinone). NETA Box 1. Drug summary.
allows the achievement of amenorrhea in about two-thirds of the cases , whereas the Lng-IUD causes amenorrhea in one-third of cases reducing bleeding in another third of cases . Therefore, these progestins are particularly useful in patients suffering from mainly dysmenorrhea. Other proges- tins have been used in clinical practice to treat endometriosis Molecular formula (chlormadinone acetate, promegestone and nomegestrol acetate); however, their effectiveness is not supported by scientific studies. Progestins are frequently used as first-line therapy for the treatment of endometriosis. They exhibit anantigonadotropic effect, which inhibits ovarian function to create a hypoestrogenic environment. By directly acting on endometrial progesterone receptors, they induce decidualiza- tion of endometriotic lesion. Lastly, they have been shown to reduce peritoneal inflammation . Progestins have shownresults comparable to surgery in the treatment of dyspareunia Pharmaprojects - copyright to Citeline Drug Intelligence (an Informa associated with endometriosis , are effective in reducing business). Readers are referred to Pipeline pain in patients with intestinal endometriosis , are success- ) and Citeline (.
ful in eradicating symptoms and producing regression ofrecurrent endometriomas ] and have proven effective inthe treatment of rectovaginal endometriosis . However, the therapy. As patients with endometriosis require long- progestins have some adverse effects, including the acne, term therapies, it is important to choose the agents weight gain, headaches and irregular menstrual bleeding.
with the lowest effective dose and with minimal adverse Over the last few years, new therapies have been developed to target pathogenic molecular pathways involved in the GnRH agonists (such as leuprorelin acetate, buserelin process of endometriosis. Among these agents, there are acetate (BA) and triptorelin) are currently considered the aromatase inhibitors, antiangiogenic agents, selective estrogen most effective drugs in relieving pelvic pain associated with receptor modulators, anti-inflammatory agents (such as For personal use only.
endometriosis , but they cause many adverse effects related COX2 inhibitors or pentoxifylline) and statins .
to the hypoestrogenism (hot flushes, osteopenia, mood Dienogest (DNG) is a derivative of 19-nortestosterone that swings, vaginal dryness). These adverse effects may be buff- has recently been introduced for the treatment of endometri- ered by associating GnRH agonist with ‘add-back therapies' osis (This review examines the clinical efficacy, safety (e.g., tibolone or progestins). Hyperandrogenic compounds and tolerability of DNG in the treatment of endometriosis.
cause adverse androgen-like effects (such as acne, seborrhea, The material included in the current manuscript was searched hirsutism, alopecia and weight gain); in addition, they may and obtained via Medline, PubMed and EMBASE, from cause unfavorable changes in the levels of cholesterol in the inception until February 2014. The term ‘dienogest' was blood (higher low density lipoprotein [LDL]-cholesterol and associated with the following search terms: ‘endometriosis', lower high density lipoprotein [HDL]-cholesterol) . The ‘pharmacokinetics', ‘safety' and ‘efficacy'. All pertinent manu- combined oral estrogen-progestin pill (COCs) is currently scripts were carefully evaluated and their reference lists were one of the first choices among symptomatic medical therapies examined in order to find other articles that could be included available for the treatment of endometriosis-associated pain.
in the present manuscript.
Among the available pills, it is preferable to choose those Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 with a lower content of estrogen in order to decrease the endo- 2. Chemistry of DNG metrial stimulation . Even if COCs are very frequently pre-scribed to alleviate pain symptoms in endometriosis, there is a lack of randomized controlled trials on the efficacy of this is a derivative of 19-nortestosterone , but it differs from treatment and, nowadays, they are not approved for treatment other progestins of the same derivation for the presence of of endometriosis-associated pelvic pain (EAPP) . Among a cyanometilic group in place of an ethynyl group in position progestins, the most widely used are norethindrone acetate 17a. Thus, DNG combines the advantages of 19-nortestos- (NETA, 2.5 mg/day) and the levonorgestrel-medicated intra- terone derivatives (such as the short plasma half-life, the uterine device (Lng-IUD), which after insertion lasts for powerful progestin effect on the endometrium and high 5 years. As we said for COCs, similarly, Lng-IUD is not bioavailability) with the benefits of progesterone derivatives approved for the treatment of endometriosis. Other proges- (such as antiandrogenic activity and a moderate inhibition tins are desogestrel, medroxyprogesterone acetate (oral or of gonadotropin secretion) .
Table 1. Pharmacokinetic of dienogest .
After oral administration of a film-coated tablet of 2 mg dienogest: Bioavailability: 90.5%AUC24 h: 441 ± 92 ng·h/ml;AUC¥: 535 ± 137 ng·h/ml;Cmax: 47.6 ± 8.7 ng/ml;T1/2: 9.4 ± 1.9 h;Tmax: 1.5 h No influence of concomitant food intakeDose-dependent pharmacokinetics in the range of 1 - 8 mg Albumin: 90%SHBG, CBG: 0%Free, unbound: 10% Distribution volume after a single dose of 1 mg: 40 LSteady state: 6 daysNo accumulation of the drug Hydroxylation of double bonds, hydrogenation and aromatization reactions that makes the dienogest to inactivemetabolites that are excreted quickly so DNG is the predominant fraction in plasmaMain enzyme involved: CYP3A4Metabolic sieric clearance (Cl/F): 64 ml/min Urine (free steroids 20 - 30%; ‘glucuronide' fraction 25% and ‘sulfate' fraction 22%)Decrease in serum in two phasesTerminal half-life of distribution: approximately 9 - 10 hThe proportion of metabolites excreted in the urine compared with the fecal is 3:1 after oral administration of0.1 mg/kgHalf-life of urinary excretion of metabolites: 14 hAfter oral administration, 86% of the dose was excreted within 6 days, most within 24 h, primarily in the urine DNG: Dienogest; SHBG: Sex hormone binding globulin.
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3. Pharmacokinetic of DNG a study after administration of 10 mg of DNG transdermallyin healthy male volunteers .
When the DNG is administered orally at a dose of 2 mg, the Ninety percent of DNG binds unspecifically to albumin, bioavailability is high, amounting to 90.5% ) whereas only 10% is present in plasma in the free form The absorption of DNG is fast. By administering a 2 mg tab- DNG does not bind to the sex hormone binding globulin let DNG under fasting, the C (SHBG) or corticoid binding globulin; therefore, the admin- max is about 40.9 ± 11.0 ng/ml with an interval of about 1.75 h (T istration of DNG does not alter the plasma levels of these max) between intake and maximum plasma peak. The half-life time (T proteins. As testosterone is not displaced from the protein 1.7 h. The area under the plasma concentration time curve that binds in plasma, DNG does not increase the levels of (AUC) from time zero to infinity (AUC¥) is about 453 ± serum testosterone and it does not have androgenic effects .
135 ng  h/ml and from time zero to 48 h it is about The apparent distribution volume of DNG is about 40 l 438 ± 123 ng  h/ml .
after single oral dose of 1 mg . In repeated administrations Pharmacokinetic parameters after oral administration of a of oral tablets of DNG 1 mg, steady state is reached within film-coated tablet of 2 mg DNG given as single dose and after 6 days and there is no accumulation of the drug .
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 14 days of dosing are respectively as follows: AUC24 h 441 ± A recent review compared the pharmacokinetic charac- 92 and 547 ± 129 ng·h/ml; AUC¥ 535 ± 137 and 682 ± teristics of DNG with other progestins derivatives of C 19-nortestosterone (such as norethisterone, levonorgestrel, max 47.6 ± 8.7 and 52.2 ± 8.3 ng/ml; 3-keto-desogestrel and gestodene). This comparison showed 1/2 9.4 ± 1.9 and 10.2 ± 1.8 h; Tmax 1.5 and 1.25 h .
In a study of female volunteers who received single oral doses that DNG is the only progestin that does not bind SHBG, of DNG in consecutive menstrual cycles, the mean peak of has no influence on the kinetics of testosterone and has no serum concentrations (Cmax) were 28, 54, 101 and 212 ng/ androgenic effects. Moreover, DNG has the highest free- ml after 1, 2, 4 and 8 mg doses, respectively. The mean areas unbounded fraction in the plasma (about 10%). The high under the serum concentration curve (AUC¥) were 306, 577, circulating levels of free DNG explain the wide penetration 1153 and 2292 ng·h/ml, respectively .
of the molecule in different tissues.
The influence of food on absorption is small . DNG is The metabolic pathway of DNG is mainly composed of poorly absorbed through the skin as has been highlighted in hydroxylation of double bonds, but also hydrogenation and N. Bizzarri et al.
aromatization reactions, which transforms DNG in at least pharmacodynamic point of view of the derivatives of 19-nor- nine inactive metabolites . The metabolites have lower testosterone with those of progesterone.
affinity to progesterone receptor compared with DNG .
The strong activity of DNG on endometrial tissue has been CYP 3A4 is the most widely used enzyme in the metabolic demonstrated by investigations in both humans (Kaufmann pathway of DNG . The excretion of DNG takes place assay) and rabbits (McPhail test) . DNG shows strong mainly through the urine after glicuronide and sulfate conju- activity on the endometrium when compared with its activity gation and most of the metabolites are eliminated in the first of inhibiting ovulation. This feature results in a high ratio 24 h. As the metabolites are not hormonally active and are between the dose inhibiting ovulation and the dose that excreted very rapidly, DNG is the predominant fraction in leads to the transformation of the endometrium (uterotropic plasma. A fraction of 20 - 30% of the total excreted in the index), which appears to be the highest among all progestins urine is released as free steroid . The serum clearance of DNG is 64 ml/min . The half-life for excretion of When administered at the dose indicated for the treatment urinary metabolites is 14 h .
of endometriosis (2 mg/day), DNG reduces serum levels of As DNG is metabolized primarily by CYP3A4, coadminis- progesterone to anovulatory levels. The action on the ovary is tration of drugs inducers or inhibitors of this cytochrome alters peripheral rather than central as the serum levels of gonadotro- the concentration at steady state, particularly when DNG is pins (follicle-stimulating hormone and luteinizing hormone administered in association with estradiol valerate. Inducing [LH]) do not undergo significant variations. Studies assessing drugs include rifampin, carbamazepine, phenobarbital and the ultrasound characteristics of the ovaries of patients under phenytoin, whereas erythromycin, ketoconazole, itraconazole, treatment with DNG showed that follicles did not exceed the nefazodone, ciprofloxacin, fluvoxamine and grapefruit juice size of 10 mm maximum diameter . A randomized trial are CYP3A4 inhibitors.
investigated the minimum dose of DNG inhibiting ovulation DNG should not be administered to patients with hepatic by randomizing 102 participants to receive 0.5, 1, 2 or 3 mg/ insufficiency; therefore, acute or chronic diseases of the liver day of DNG; estradiol and progesterone serum levels and the represent a contraindication to the administration of the size of the follicles were evaluated every 3 days. The study drug . Up to now, no study evaluated the pharmacokinetics showed that the lowest dose of DNG capable of inhibiting ovu- of DNG in patients with renal insufficiency . There is no lation was 2 mg/day, both in short-term (1 - 36 days) and difference in the pharmacokinetics of DNG in pre- and post- long-term (36 - 72 days) observation. Another study suggested menopausal women .
the lowest dose able to inhibit ovulation of healthy women offertile age between 20 and 39 years old is 0.6 mg/day when For personal use only.
administered in a single dose during the follicular phase of 4. Pharmacodynamic of DNG the menstrual cycle . The administration of 2 mg DNG2 days before the expected time of ovulation prevents ovulation Synthetic progestins can be divided according to their molecular itself. Whereas when DNG is administered 1 day before ovula- structure and their functional characteristics into two categories: tion (0.5 or 2 mg), ovulation occurs but the LH peak is lower the derivatives of progesterone (such as medroxiprogesterone without anyway alteration in the function of the corpus acetate and megestrol acetate) have a progestogenic and andro- luteum. Furthermore, ovulation and the corpus luteum func- genic activity; the derivatives of 19-nortestosterone, which are tion are not altered by the administration of DNG (both not approved for the treatment of endometriosis, have strong 0.5 and 2 mg) during the peak of LH. The menstrual cycle activity on the endometrium, with mild androgenic, estrogen does not undergo alterations when DNG is administered after and glucocorticoid activity ].
the occurrence of ovulation. These results demonstrate that DNG has pronounced effects on the endometrium that is DNG in a single-dose administration in midcycle can alter the basis of its efficacy in the treatment of endometriosis.
pituitary and ovarian function depending on the time interval Studies in vitro demonstrated that DNG has moderate affinity between administration and the day of LH-surge . More- Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 for progesterone receptors that is 10% of the affinity of over, the anovulatory action ceases when the drug is discontin- natural progesterone . DNG has strong antiandrogenic ued. At a dose of 2 mg/day, the plasma levels of E2 are not activity, whereas it has no glucocorticoid and mineral corti- completely suppressed but remain comparable to those of the coid effects. It also does not activate estrogen receptors, nei- early follicular phase having an important implication from ther a type nor b type .
the clinical point of view, that is, the absence of the occurrence In vivo, DNG has important progestational effects; it of secondary effects caused by hypoestrogenism (such as hot inhibits gonadotropic release, but does not have glucocorti- flushes and bone loss), where instead effects are observed dur- coids, mineral corticoids or significant estrogen-like effects ing treatment of endometriosis with GnRH analogs .
. Despite DNG having low affinity for progesterone When DNG is compared with other progestins (such as receptors, it has a pronounced progestin effect in vivo that NETA, levonorgestrel, gestodene, desogestrel, norgestimate, can be attributed to the high levels of plasma-free molecule cyproterone acetate, chlormadinone acetate), it shows more . Therefore, DNG combines the advantages from the potent progestational effects on the endometrium and weaker actions of suppression of gonadotropins release . DNG 2 mg, E2 levels remain within the ‘therapeutic window' in causes an inhibition of ovulation 3.5 times greater than levo- order to avoid stimulating effects on the lesions and hypoestro- norgestrel in the rabbit and 7 times greater than levonorgestrel genic side effects, such as bone mineral density (BMD) in the rat .
No study evaluated the contraceptive effectiveness of One study investigated the effects of DNG on experi- DNG; therefore, women using this drug are advised to use mental endometriosis. In rats, DNG (0.1, 0.3 or 1 mg/ kg) nonhormonal contraception (such as barrier methods) to pre- causes histological changes in endometriotic implants compa- vent unwanted pregnancies. After cessation of therapy with rable to those observed after danazol administration, but DNG, normal ovarian activity and menstrual cycle recover DNG is less marked than GnRH analog or ovariectomy. All quickly; there have been reports of women conceiving shortly treatments induce a reduction in the volume of the endometri- after the end of treatment, including women with previous otic implants when compared with placebo. On the other history of infertility .
hand, DNG has a lesser effect on BMD when compared with Few studies investigated the influence of DNG on the danazol, buserelin or ovariectomy. Moreover, it was shown breast. A small trial evaluated the ultrasonographic that even the combination of DNG with buserelin had a lower changes induced on the mammary gland by the use of impact on BMD compared with buserelin alone. Furthermore, DNG at high dose (10 mg twice a day [b.i.d.] for 24 weeks), the same study showed that DNG normalizes the activity of demonstrating a reduction of the size of the mammary gland natural killer cells and decreases the release of interleukin-1b and a reduction of the mastopathic lesions that were present by macrophages .
before starting treatment. However, further studies are needed Another recent study demonstrated the potent inhibi- to evaluate the relationship between the use of DNG and tory activity of ectopic endometrial tissue obtained by auto- breast cancer and to compare the effects of DNG on the transplantation of uterine tissue into peritoneal cavity of rats.
breast with other progestogens.
In these rats, DNG was administered at a dosage of 0.3 or The use of DNG (up to 20 mg/day for 24 weeks) does not 1 mg/kg/day for 28 days. At laparotomy, DNG demonstrated cause clinical changes in thyroid function, hemostatic param- a significant reduction of the total endometrial lesion area, thus eters, liver enzymes, metabolism of carbohydrates and lipids confirming the effectiveness of the compound in decreasing the size of endometrial lesions .
5. Mechanism of activity in endometriosis 6. Clinical efficacy For personal use only.
DNG inhibits endometriotic lesions through different mecha- Progestins have been used for many years as medical therapy nisms. In rabbits, it exerts a moderate inhibition of the of endometriosis, although there is limited evidence resulting secretion of gonadotropins, which decreases the endogenous from controlled studies (particularly those against placebo) production of estradiol, thus limiting its trophic action on that supports the effectiveness of many compounds in this the eutopic and ectopic endometrium . It creates a hyper- class. DNG is the only oral progestin that has been specifically progestogenic and hypoestrogenic environment that initially designed for the treatment of endometriosis and its efficacy induces a secretory state and then a decidualization of the has been investigated by several studies with a comprehensive ectopic endometrium and finally its atrophy if the treatment design including randomized, dose-ranging , double-blind is not discontinued . Other studies showed in vitro and comparison with placebo , comparison versus GnRH ago- in vivo on rats an inhibitory action of DNG on the prolifera- nists and finally studies of efficacy and tolerance in long tion of endometrial cells mediated by modulation of the expression of matrix metalloproteinases, which are involved DNG is effective in reducing endometriosis-related pain in the regulation of ectopic endometrial response to estro- symptoms such as dysmenorrhea, premenstrual pelvic pain, gen . Finally, other animal studies have hypothesized the dyspareunia and chronic pelvic pain. Its efficacy is superior Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 inhibition of angiogenesis by the DNG as a further mechanism to placebo and equivalent to GnRH agonists, but with a of action . Because DNG inhibits aromatase and COX-2 better tolerability profile. As pain relief is one of the main expression as well as prostaglandin E2 production in endo- goals of therapy in patients with endometriosis, it should be metriotic stromal cells in experimental in vitro study, these considered an indicator of treatment success .
pharmacological features might contribute to the therapeuticeffect of DNG on endometriosis, thus demonstrating the 6.1 Dosage comparison important anti-inflammatory effect of DNG that is relevant The optimal dose that guarantees the resolution of symptoms in reducing the size of the endometriotic lesions . The during treatment with DNG was assessed in a 24-week, average serum concentrations of E2 remain in the range of randomized, open-label study including 68 women with endo- 20 - 50 pg/ml when DNG is administered at a dose of 2 mg/ metriosis stages I, II and III accordingly to the revised American day, thus showing only moderate estrogen suppression .
Fertility Society (rAFS) classification ]. Women were ran- Therefore, when DNG is administered at the dose of domized to receive DNG once daily at the doses of 1, 2 or N. Bizzarri et al.
DNG 2 mg/day
VAS (mm, mean ± SEM) 10
Weeks of treatment
Figure 1. Superiority of DNG 2 mg/day versus placebo for 12 weeks (p < 0.0001).
Reproduced with permission from .
DNG: Dienogest; SEM: Standard error of the mean; VAS: Visual analog scale.
4 mg. Randomization in group with 1 mg was stopped due the women with endometriosis . The patients had laparoscopi- unsatisfactory control of the cycle, with irregular menstrual cally confirmed endometriosis (stages I- IV according to bleeding. DNG at the dose of 2 and 4 mg daily caused improve- the classification rASRM), with laparoscopy performed within ment of symptoms in a large number of women. The prevalence 12 months before the study and baseline EAPP score > 30 mm of dyspareunia decreased from 51.7% (baseline) to 6.9% at on the visual analog scale (VAS). Approximately 70% of 24 weeks in the 2 mg group and from 57.1 to 5.7% in the the patients included in the study had endometriosis at stages 4 mg. Similar results were also achieved for other symptoms III- IV. The average VAS scores decreased by 27.4 mm in the such as diffuse pelvic pain. Regarding the pain reported by the DNG group and 15.1 mm in the placebo group during For personal use only.
woman during the clinical examination, this was reduced by the 12 weeks of the study, resulting in a difference between 75.9% (baseline) to 44.8% in the 2 mg group and by 73.2% the two groups of 12.3 mm, which was statistically significant (baseline) to 21.4% in the group of 4 mg. Therefore, based on in favor of DNG (IC 95%: 6.4 - 18.1, p < 0.0001) the results of this study, the dosage of 2 mg/day of DNG was A secondary efficacy end point in the placebo-controlled chosen for the treatment of endometriosis.
study was the score Biberoglu and Behrman (B & B).
Another study of dosage comparison was made by a This score confirmed the results of the primary end point, Japanese group that compared DNG administered at a demonstrating a greater reduction in signs and symptoms in dose of 1, 2 and 4 mg/day for 24 weeks divided into two daily the DNG group compared with the placebo group. The doses. The study included 187 patients. The study concluded scale ‘Clinical Global Impression' was used as parameter that there was an improvement in symptoms with the three of the improvement of the general state. The rate of different dosages but the comparison between these dosages ‘improvement' was 52.9% for DNG and 22.9% for the was not statistically significant. Instead, there was a statistically placebo. The changes in QoL were assessed by using SF-36 significant difference (p < 0.001) in the comparison of dosage Health Survey Questionnaire demonstrating a significant as regards the level of plasmatic E2. Mean serum estradiol improvement of pain in the DNG group compared with the Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 concentrations at between 8 weeks and the end of treatment placebo group. The sum of the scores related to mental and in this study were 84.5, 37.4 and 26.2 pg/ml for DNG doses psychological aspects improved in a similar manner with min- of 1, 2 and 4 mg/day, respectively. On the basis of the reduc- imal differences between the two groups. The study concluded tion in plasma E2, the 2 mg/day dose was considered to be that DNG was superior to placebo in the improvement of the optimal dosage in Japan. A serum estradiol concentration pain symptoms.
in the range of 30 - 50 pg/ml is considered sufficient to inhibit Subsequently, the 168 women who had participated in the endometriotic lesion growth and it is adequate to prevent 12-week placebo-controlled study by Strowitzki et al. were hypoestrogenic side effects such as bone mineral loss .
recruited for a study of long-term extension for the evaluationof pain control while using DNG to 2 mg/day for 53 weeks, 6.2 Double-blind comparison with placebo for a total of 65 weeks adding the two studies . The average DNG (2 mg/day) was compared with placebo in a 12-week, VAS score in this population decreased progressively through- randomized, double-blind study including 188 premenopausal out the treatment period, from 56.9 mm (baseline placebo-

Leuprolide acetate VAS (mm, mean ± SEM) 10
Weeks of treatment
Figure 2. Noninferiority of DNG 2 mg/day versus leuprolide acetate for 24 weeks (p < 0.0001).
Reproduced with permission from .
DNG: Dienogest; SEM: Standard error of the mean; VAS: Visual analog scale.
controlled study) to 34.1 mm (baseline of the extension study More recently, the same authors proposed a subsequent long term), up to 11.5 mm at the end of treatment.
analysis of previous study to analyze the secondary efficacy A 52-week, noncomparative, multicenter study was and safety outcomes comparing DNG and LA in patients performed in Japan to test the long-term efficacy of DNG with endometriosis . Study methods were the same of the (2 mg/day) to define the safety evaluation of drug adverse reac- previous trial. This study evaluated QoL, safety and tolerabil- tion as primary end point. The study included 135 women and ity. This evaluation was made through study of pain relief evaluated five subjective symptoms during nonmenstruation seen as reduction in VAS scales, B & B scores, impairment (lower abdominal pain, lumbago, dyschezia, dyspareunia and in daily activities, incidence of hypoestrogenic effects, irregu- pain on vaginal examination) and two objective findings (indu- lar bleeding and impact on standard laboratory parameters.
ration involving the pouch of Douglas and limited uterine The conclusion of the study was that DNG was as effective For personal use only.
mobility). The incidence of drug adverse reactions in studied as LA in treating the symptoms of endometriosis with QoL population was 88.9% (120/135 cases). The primary reactions benefits and a favorable safety profile.
consisted of metrorrhagia (71.9%), headaches (18.5%) and A Japanese randomized, double-blind, double dummy, constipation (10.4%). Metrorrhagia was the most frequently multicenter, controlled study compared the administration found symptom, but it is seen that with the continuation of DNG (1 mg b.i.d., 128 women) and intranasal BA spray therapy there was a decrease in the intensity of the bleeding (300 mcg three times a day, 125 women) for 24 weeks .
and the number of days of bleeding. In all the women in the The results of this study were a reduction of the symptoms study, bleeding was resolved with the end of treatment. They and signs in the two subgroups at baseline and after 24 weeks concluded that the long-term effect on BMD was small, of treatment. Symptoms evaluated were low abdominal pain, whereas the effectiveness increased cumulatively .
lumbago, dyschezia, dyspareunia and pain on internal exami-nation. Objective findings evaluated were induration in the 6.3 Comparisons with GnRH-agonists pouch of Douglas and limited uterine mobility. The differ- DNG at a dose of 2 mg/day was compared with leuprolide ace- ence between two groups was not statistically significant tate (leuprolide acetate [LA], a GnRH analog administered at a except for the reduction in the score for the induration of Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 dose of 3.75 mg intramuscularly every 4 weeks) in a random- the pouch of Douglas. Compared with BA, DNG was associ- ized Phase III noninferiority trial. This study included ated with irregular genital bleeding more frequently (95% in 252 women with endometriosis confirmed by laparoscopy .
DNG group vs 67% in BA group) and with fewer hot flushes DNG and LA led to a continuous and comparable reduction of (50% in DNG group vs 67% in BA group). The reduction in pelvic pain as measured by VAS. However, at the end of the BMD during DNG treatment was significantly lower than 24 weeks, the reduction in the average VAS score was that during BA treatment (p = 0.0030).
47.5 mm for the DNG group and 46 mm for the LA group A randomized, open-label, multicenter trial compared (95% CI: - 9.26, 6.25). Therefore, the noninferiority of DNG (1 mg b.i.d. for 16 weeks) with triptorelin (3.75 mg DNG compared with LA was demonstrated (p < 0.0001) intramuscularly every 4 weeks for 16 weeks) as consolidation (A similar improvement was also achieved by using therapy after laparoscopic surgery in 120 women with the score B & B as a parameter for assessing the severity of endometriosis . In this trial, patients underwent a fist lapa- symptoms and signs.
roscopy, which had a diagnostic, staging and therapeutic N. Bizzarri et al.
purpose. Endometriosis was staged according to the rAFS and The observation of a reduction of the lesions after use of FOATI classifications both before and after this first laparos- DNG may suggest that this is not only a symptomatic drug.
copy. Subsequently, patients received DNG or triptorelin for One of the first studies showed a reduction of the lesions 16 weeks and when medical therapies were discontinued they observed with second laparoscopy in 57 patients diagnosed underwent a second laparoscopy with the aim of scoring with endometriosis who received DNG 1 mg b.i.d. for endometriotic lesions according to rAFS and FOATI classifi- 24 weeks . The second laparoscopy showed the disappear- cations. The difference between the changes in the implants ance of endometriotic lesions in 66.7% of women. Among the score observed at second laparoscopy between the two groups patients who still had endometrial lesions despite the therapy, after 4 months of treatment was not statistically significant a marked improvement was seen in 80.4% of women and no change in only 19.6%. Similar results were obtained in a sub- A recent meta-analysis included two studies that sequent study . The study ‘dose-finding' by Kohler et al.
compared the efficacy and safety profile of DNG and also assessed the lesions reduction by the rAFS score.
GnRH analogs, one performed in Europe and the other in a They showed that DNG at 2 mg and 4 mg/day results in a Japanese population. The conclusion was that women in reduction of lesions after 24 weeks of treatment. The average Europe and Japan respond in a similar manner in terms of rAFS score changed from 11.4 to 3.6 (p = 0.0003) in the 2 mg pain relief after treatment with either DNG or GnRH ana- group and from 9.7 to 3.9 (p < 0.0001) in the 4 mg group.
logs. DNG also showed equivalent effects on pain in both The severity of endometriosis according to the rAFS score populations. However, there was heterogeneity in the changes decreased in both study groups. A multicenter, randomized trial including 142 women with stage II to IV endometriosiscomparing DNG (1 mg b.i.d.) and triptorelin acetate(3.75 mg IM/month) for 16 weeks confirmed a reduction in 6.4 Use of DNG following GnRH-agonists the extent of endometriotic lesions. The rAFS score was ini- Regarding the use of DNG as maintenance therapy after tially 38 in both groups at baseline and dropped to 4 in GnRH agonist to treat pelvic pain associated with endometri- both groups after 16 weeks . Subsequently, another multi- osis, we found only one study in the literature carried out in center randomized trial comparing doses of 1, 2 or 4 mg 2011 by Kitawaki et al. This prospective, nonrandomized DNG per day in two doses in 187 women diagnosed with clinical trial arises from the need to discontinue therapy with endometriosis showed a decrease in the size of endometriotic GnRH agonist because of the known side effects of prolonged cysts (p < 0.05) .
treatment (maximum 6 months). Thus, the authors examined A very recent study clarified the impact of DNG on local whether long-term administration of DNG following GnRH For personal use only.
histological events in humans that explain its therapeutic agonist therapy would prolong the relief of pelvic pain while effect on endometriosis. The aim of this study was to evaluate reducing the amount of irregular uterine bleeding. Group G the in vivo effect of DNG on endometriosis tissue. Endome- (n = 38) received GnRH agonist (leuprolide acetate or BA trioma tissues from patients treated with DNG (n = 7) or for 4 - 6 months and then DNG (1 mg/day) for 12 months).
not treated (n = 11, controls) were collected. This study dem- The dose of DNG was increased to 1.5 or 2 mg/day when the onstrates that endometrioma taken from patients treated with patient had uncontrollable uterine bleeding. Group D DNG show remarkable histological features such as reduction (n = 33) received only DNG (2 mg/day) for 12 months.
of proliferation measured with Ki67 (p < 0.05), aromatase Pelvic pain was assessed using a VAS. Uterine bleeding was expression (p < 0.05) and angiogenesis (p = 0.20), and semiquantified using a pictorial blood loss assessment chart increase of apoptosis (p < 0.05) .
(PBAC). There was no significant difference in pain reductionbetween group G and group D: dysmenorrhea (p < 0.001), 7. Safety and tolerability nonmenstrual pelvic pain (p < 0.01) and dyspareunia(p < 0.05). The PBAC score during the first 6 months on The most frequent adverse effects seen during long treatment DNG was significantly smaller in group G than in group D Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 (52 weeks) with DNG at 2 mg/day in 135 women were head- (p < 0.01). Therefore, the authors concluded that DNG ache (18.5%), constipation (10.4%), nausea (9.6%), hot flushes long-term therapy maintains the relief of pelvic pain obtained (8.9%), weight gain (8.1%), dizziness (5.9%) and breast tender- with GnRH agonist and this regimen reduces the amount of ness (5.9%) . In an analysis of four clinical trials that irregular uterine bleeding that often occurs during the early collected 332 cases, the most commonly reported adverse events phase of DNG therapy.
in women treated with DNG 2 mg/day were headache (9.0%),breast discomfort (5.4%), depressed mood (5.1%) and acne 6.5 Efficacy in reduction of the lesions Although pain relief is considered the primary efficacy mea- The most common side effect is abnormal uterine bleeding, sure in studies on endometriosis, some investigations assessed which is more frequent during the first few weeks of DNG the changes in the size of the endometriotic lesions at laparos- use and decreases with continued treatment [,. In the copy after treatment with DNG.
long-term use of DNG (52 weeks at 2 mg/day), 97/135 patients For personal use only.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 N. Bizzarri et al.
Table 3. Bleeding patterns in women treated with DNG 2 mg/day .
Bleeding patterns First 90 days of treatment Fourth 90 days of treatment (total number = 290).
(total number = 149).
Infrequent bleeding Frequent bleeding Irregular bleeding Prolonged bleeding Data are presented as number of patients and percentage.
Adapted from Visanne Product Monograph .
DNG: Dienogest.
(71.9%) reported metrorrhagia, but in 96 of these cases the when compared with GnRH analogs. Twenty-four weeks of symptom disappeared during treatment or 2 months after end treatment with DNG (2 mg/day orally) decrease mean of treatment with a median number of days of genital bleeding E2 levels by only 6.4 pmol/l compared with 240.5 pmol/l in per 28 days of treatment period of 21 days at 5 - 8 weeks, 9 days patients treated with LA (3.75 mg, depot intramuscolar injec- at 21 - 24 weeks and 2 days at 49 - 52 weeks of treatment, indi- tion, every 4 weeks) at the end of treatment () . In a cating a decrease in abnormal bleeding as the treatment period 12-week placebo-controlled study, E2 decreased by 70 ± was extended. The abnormal bleeding during therapy with 282 pmol/l ; the mean E2 levels showed minimal changes DNG is caused by endometrial regression (breakthrough bleed- during continuous treatment with DNG for 53 weeks .
ing) due to a continuous duty, which results in different bleed- In agreement with these observations, DNG does not cause ing pattern ranging from spotting to irregular bleeding. In significant hypoestrogenic adverse effects such as reduction patients treated with 2 mg/day of DNG up to 52 weeks of BMD, vaginal dryness, hot flashes, decreased libido and (Phase III trials), in the first 90 days of therapy the bleeding pat- sleep disturbances . In particular, in the patients treated tern was prolonged bleeding (38%), irregular bleeding (35%) with DNG, hot flushes occur with a mean of 0.89 days per and infrequent bleeding (27%), frequent bleeding (13%) and week of treatment, whereas in patients treated with LA they For personal use only.
amenorrhea (2%). In the fourth 90-day therapy, the bleeding occur for an average of 23.4 days per week. Furthermore, pattern were changed as follows: amenorrhea (28%), infrequent the frequency of this symptom remains low during treatment bleeding (24%), frequent bleeding (3%), irregular bleeding with DNG, whereas it tends to increase during treatment with (22%) and prolonged bleeding (4%) (,].
LA. A further study comparing DNG (1 mg b.i.d.) and trip- The period chosen was 90 days in accordance with the reference torelin acetate (3.75 mg/month intramuscularly) for 16 weeks range proposed by the WHO ].
showed a significantly lower incidence of hot flashes in the As already shown in preclinical studies, DNG has low DNG group (9.6 vs 61.2%) .
activity for androgen receptors and it has also some antiandro- Twenty four weeks of treatment with DNG do not signif- genic activity , which explains the limited androgen-like icantly change BMD, whereas LA causes a significant reduc- adverse effects like weight gain, acne, alopecia and hirsutism.
tion in BMD at the lumbar spine . This observation is One of the features that makes DNG so effective in the confirmed by the changes of bone reabsorption markers (mea- treatment of endometriosis is the fact that it creates a hypoes- sured with urine calcium levels and urinary Cross-Laps levels) trogenic climate at the level of endometrial tissue without, in patients treated with LA group versus no significant change however, excessively decreasing plasma E2 concentration, in those treated with DNG.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 which tends to stabilize at the lower limit of the normal range DNG does not have adverse effects on lipid metabolism.
of concentration . Klipping et al. assessed the minimum This was also confirmed by a study that analyzed the safety dose of DNG inhibiting ovulation by randomizing 102 partic- of DNG at high dose (20 mg/day) for 24 weeks . In the ipants to receive 0.5, 1, 2 or 3 mg/day of DNG. The results of study comparing DNG and placebo for 12 weeks, the levels this study showed that complete ovulation inhibition was of plasma lipids (such as LDL, HDL and triglyceride) showed observed at DNG doses ‡ 2 mg/day and was rapidly reversed little change in both groups . When compared with LA for after treatment cessation. Besides they showed that 2 mg a 24-week treatment, no clinically relevant change in lipids DNG achieves a decrease in E2 concentration sufficient to levels was observed in both treatment groups .
reduce estrogen-dependent disease, combined with a systemic DNG does not appear to have significant effects on carbo- E2 exposure that minimizes hypoestrogenic side effects and hydrate metabolism. In the dose-finding study of 24 weeks, likelihood of bone loss. This is an important advantage in there was no significant change in blood glucose in any terms of adverse effects from hypoestrogenism, especially patient . The treatment with progestins may facilitate

Leuprolide acetate Estradiol level (pmol/l)
Weeks of treatment
Figure 3. Sieric estradiol levels by using DNG 2 mg/day or leuprolide acetate for 24 weeks.
Reproduced with permission from .
DNG: Dienogest.
weight gain. No significant change in weight has been due to adverse effects < 5%. The most common adverse effects reported in patients treated with DNG 2 mg/day for 12 weeks were abnormal uterine bleeding, headache, breast discomfort, when compared with placebo . The long-term study depressed mood and acne, while not going to significantly showed that only a minimal change in body weight change body weight, BMD and lipid profile in the blood of (+0.58 kg) occurred after 1 year of treatment with DNG.
women. Abnormal bleeding, generally well tolerated bywomen, tends to decrease with continued treatment.
9. Expert opinion DNG combines the advantages of 19-nortestosterone deriva-tives with the benefits of progesterone derivatives. DNG has Although the European Society of Human Reproduction and For personal use only.
a good pharmacokinetic profile with an absorption of Embryology (ESHRE) explains that the cure of symptomatic 90.5% when taken by mouth, half-life that is suitable for endometriosis can involve analgesics, hormones, surgery, the dosage of one administration per day and a limited influ- assisted reproduction or a combination of approaches, ence from the food on the absorption. The marked tropism of endometriosis treatment today is mostly made up of empiric DNG in vivo against the endometrial tissue explains its effec- therapy with analgesics and hormonal therapy based on a tiveness in the treatment of endometriosis. The mechanism of diagnosis of suspicion . The treatment should be effica- action in endometriosis arises from the fact that the DNG cious, but it should also be the least expensive and with inhibits the secretion of gonadotropins with decrease in the minimal risks. Hormonal therapies (GnRH agonists, danazol, endogenous release of estradiol (which, however, stabilizes at gestrinone, combined oral contraceptives and medroxyproges- levels that do not induce adverse effects of estrogen defi- terone) have similar efficacy, but differ in their adverse effects ciency), thus creating a hypoestrogenic and hyperprogestinic and costs. GnRH agonists (such as leuprorelin acetate, BA endocrine environment that induces initial decidualization and triptorelin) are currently considered the most effective and subsequent atrophy of endometriotic lesions. In addition, drugs in relieving pelvic pain associated with endometriosis , DNG has strong antiandrogenic activity, whereas it has no but they cause many adverse effects related to the hypoestro- Expert Opin. Pharmacother. Downloaded from informahealthcare.com by ACT Health (The Canberra Hospital) on 08/20/14 glucocorticoid and mineral corticoid effects. The efficacy of genism (hot flushes, bone mineral depletion, mood swings, DNG was also demonstrated by the clinical point of view vaginal dryness). Therefore, GnRH agonists are not recom- with a trial that has shown the superiority of DNG compared mended for continuous use for a period of time that exceeds with placebo in reducing the pain associated with endometri- 6 months of treatment because of the potential depletion of osis. Furthermore, DNG was compared with the reference the bone mass. The use of an add-back therapy, which adds treatment for endometriosis represented by GnRH agonists an estrogen, progestin or estrogen- progestin combination, demonstrating noninferiority of DNG compared with these allows to reduce the adverse effects of estrogen deficiency compounds with a lower incidence of adverse effects (espe- and to extend the duration of the treatment, but this leads cially hypoestrogenic effects), both as regards the improve- to an increase in costs. Hyperandrogenic compounds cause ment of the symptom pain and as regards the reduction of adverse androgen-like effects (acne, seborrhea, hirsutism, endometriotic lesions diagnosed at laparoscopy. DNG is a alopecia and weight gain) in addition to make an unfavorable well-tolerated drug with a rate of treatment discontinuation change in the levels of cholesterol in the blood (increased N. Bizzarri et al.
LDL-cholesterol and decrease HDL-cholesterol) . System- are needed to confirm its good clinical efficacy and tolerabil- atic reviews of the literature have shown limited evidence in ity. However, some issues remain unsolved. In fact, as DNG favor of the efficacy of low-dose combined oral contraceptives causes inhibition of ovulation, it does not solve the problem in relation to the pelvic pain associated with endometri- of infertility associated with endometriosis. Moreover, this is osis , although some trials have demonstrated their still an open issue as currently there are no hormonal therapies superiority over placebo . They have also been shown to ensuring an improvement in infertility associated with be effective as GnRH analogs . However, hormonal contra- endometriosis. On the other hand, no study investigated the ceptives are widely used for their advantages, including some potential of contraceptive effect of DNG; therefore, this ther- contraceptive protection, long-term safety, low cost and apy should be associated with other methods of contraception control of menstrual cycle. Progestins are used today as one (e.g., barrier methods). Finally, a further limitation of the use of the options for treatment of endometriosis. Among these of DNG as daily therapy in the long term is that the cost of agents, the most widely used are NETA 2.5 - 5.0 mg/day the therapy is higher than other progestins available on the and the Lng-IUD. They allow a long-term treatment of endo- market and combined oral contraceptives. Future studies metriosis, although they may cause some adverse effects such should compare the efficacy and safety of DNG with other as headaches, weight gain, androgenic effects (especially for derivatives of 19-nortestosterone) and reduced BMD.
Thanks to these features that combine excellent efficacy in Declaration of interest reducing pain and symptoms associated with endometriosisand in reducing the size of endometrial lesions with good tol- S Stefano has had financial relationships (lecturer or member erability of the product in the long term, the DNG has been of advisory board) with Pfizer and Astellas. The authors have proposed as the progestin in the reference treatment of no other relevant affiliations or financial involvement with endometriosis. In addition, DNG long-term therapy has any organization or entity with a financial interest in or finan- also proven effective in maintenance therapy after use of cial conflict with the subject matter or materials discussed in GnRH agonists . Further studies with large sample size the manuscript apart from those disclosed.
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