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Cited by 58Endometriosis Research and TreatmentEctopic Pregnancy Diagnosis and ManagementMenstrual Health and Disorders

Oral and depot progestin therapy for endometriosis: towards a personalized medicine

Open access
Buggio, Laura, Somigliana, Edgardo, Barbara, Giussy, Frattaruolo, Maria Pina, Vercellini, Paolo·2017·Expert Opinion on Pharmacotherapy
DOI 10.1080/14656566.2017.1381086
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Abstract

INTRODUCTION: Endometriosis is an estrogen-dependent chronic inflammatory disorder that requires a life-long management plan. Long-term adherence to treatment is pivotal to ensure an effective clinical management. In this optic, one of the cornerstone of endometriosis medical treatment is represented by progestins. Areas covered: This narrative review examines the clinical efficacy, safety and tolerability of oral and depot progestins used in the treatment of endometriosis. The material included in the current manuscript was obtained with a MEDLINE search through PubMed from inception until February 2017. Expert opinion: Progestins are effective in controlling pain symptoms in the majority of women with endometriosis, and their effect seems not inferior to that achieved with other compounds used to treat the disease, such as gonadotropin-releasing hormone agonist. Available progestins include a broad range of both oral and depot compounds, and represent, in most cases, an inexpensive treatment option. In addition, progestins do not increase significantly thrombotic risk and could be adopted in those women with metabolic or cardiovascular contraindication to estrogen-progestins. The choice between the different available compounds should be tailored for every woman with preference to the most cost-effective treatment, depending on the most complained symptom and disease location.

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  • Findingnone given
    § 2.1 NORETHISTERONE ACETATE · p. 9

    No randomized controlled trials assessing effectiveness of DNG compared with combined oral contraceptives or with other progestins have been performed.

    “No randomized controlled trials (RCTs) assessing the effectiveness of DNG compared with combined oral contraceptives or with other progestins have been performed.”
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  • Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 7

    In a patient-preference cohort of women with severe deep dyspareunia, satisfaction rate was significantly higher in progestin (NETA) group than surgery group (59% vs 43%).

    “Satisfaction rate was statistically significantly higher in the progestin group (59% versus 43%).”
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  • Interpretationcitation
    § ABSTRACT · p. 3

    Progestins are effective in controlling pain symptoms in the majority of women with endometriosis.

    “Progestins are effective in controlling pain symptoms in the majority of women with endometriosis”
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  • Premisecitation
    § 1. INTRODUCTION · p. 4

    Women with endometriosis are at increased risk of abdominopelvic chronic pain, dysmenorrhea and deep dyspareunia compared to controls without the disease.

    “Women with endometriosis are at increased risk of abdominopelvic chronic pain, dysmenorrhea and deep dyspareunia compared to controls without the disease [3].”
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  • Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 6

    In that trial, 73% in NETA group were satisfied or very satisfied vs 62% in EP group.

    “Overall, 73% women in the NETA group were satisfied or very satisfied with treatment compared to 62% in the EP group.”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 8

    During DNG 2 mg/d, average estradiol serum levels remain 20-50 pg/ml, which should prevent BMD loss and avoid endometriotic lesion growth.

    “However, during DNG treatment (at a daily dose of 2 mg) the average estradiol (E 2 ) serum levels remain in the range of 20-50 pg/ml; this E 2 serum concentration should, at the same time, prevent bone mineral density (BMD) loss and avoid endometriotic lesions growth [22].”
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    § 2.1 NORETHISTERONE ACETATE · p. 7

    In a pilot study of colorectal endometriosis, NETA 2.5 mg/d for 12 months achieved good satisfaction (60%) and more than half reported improvement in GI symptoms and amelioration of chronic pelvic pain and deep dyspareunia.

    “The satisfaction rate was good (60%), more than half of the patients reported an improvement in gastrointestinal symptoms and an amelioration of chronic pelvic pain and deep dyspareunia.”
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    Premisecitation
    § 1. INTRODUCTION · p. 5

    Progestins can be safely used in women with contraindication to estrogens or who do not tolerate estrogens.

    “can be safely used in those women with contraindication to estrogens [11] or in those who do not tolerate estrogens [12].”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 8

    NETA is as effective as DNG for pain relief, psychological status, sexual functioning and health-related quality of life.

    “NETA has been shown to be as effective as DNG for pain relief, psychological status, sexual functioning and health-related quality of life (QoL).”
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    § 2.1 NORETHISTERONE ACETATE · p. 6

    Lower NETA dosage increases tolerability, reducing weight gain and androgenic side effects, and limits negative impact on serum cholesterol.

    “The lower dosage increases the tolerability, reducing weight gain and androgenic side effects, and limits the negative impact on serum cholesterol values [13].”
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    Premisecitation
    § 1. INTRODUCTION · p. 4

    Endometriosis is a chronic inflammatory gynecological disorder associated with pelvic pain symptoms and infertility.

    “Endometriosis is a chronic inflammatory gynecological disorder associated with pelvic pain symptoms and infertility [1].”
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    § 2.1 NORETHISTERONE ACETATE · p. 8

    DNG at 2 mg/d inhibits gonadotropin production with decrease in endogenous estradiol, establishing a hypoestrogenic and hyperprogestinic environment that stimulates initial decidualization and subsequent atrophy of endometriotic lesions.

    “When administered at the dosage indicated for the management of endometriosis (2 mg/d), DNG inhibits the production of gonadotropin with a decrease in the endogenous release of estradiol, with the establishment of a hypoestrogenic and hyperprogestinic environment that stimulates initial decidualization and subsequent atrophy of endometriotic lesions [22].”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 7

    At 1-year follow-up, NETA performed better than surgery in women without deep lesions, whereas in those with rectovaginal endometriosis, the two treatments showed comparable efficacy.

    “At 1-year follow-up, NETA performed better than surgery in women without deep lesions, whereas in those with rectovaginal endometriosis, the two treatments showed comparable efficacy [15].”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 6

    NETA is partly metabolized to estrogens, with positive effects on bone metabolism.

    “In addition, NETA is partly metabolized to estrogens [17,18], with subsequent positive effects on bone metabolism.”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 10

    In a prospective study of 30 patients with deep infiltrating endometriosis, after one year of DNG treatment there was significant improvement in all pain symptoms including deep dyspareunia, without reduction in volume of endometriotic lesions at transvaginal sonography.

    “After one year of treatment there was a significant improvement in all pain symptoms, including deep dyspareunia, without a reduction in the volume of endometriotic lesions at transvaginal sonography.”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 12

    In an open-label prospective study of 12 women with stage IV endometriosis, DSG-POP plus letrozole treatment was associated with significant improvement of dyspareunia and chronic pelvic pain, but none completed 6-month protocol due to functional ovarian cysts.

    “Unfortunately, none of the patients completed the 6months treatment protocol, due to the development of functional ovarian cysts, with a median length of treatment of 84 days (range 56-112).”
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      “During treatment, all the patients reported a significant improvement of dyspareunia and an amelioration of chronic pelvic pain.”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 10

    In a multicenter Japanese study of 135 patients with endometriosis, long-term DNG 2 mg/d for 52 weeks was safe and effective; most common adverse effects were menorrhagia (71.9%), headache (18.5%), and constipation (10.4%).

    “The most common adverse effects observed during treatment were menorrhagia (71.9%), headache (18.5%), and constipation (10.4%).”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 11

    In a study of 40 women with laparoscopically confirmed mild endometriosis, continuous DSG-POP (75 μg) and COC (EE 20 μg + DSG 150 μg) both significantly improved pelvic pain after 6 months without between-group differences.

    “After 6 months of treatments, a significant improvement of pelvic pain was observed in both study groups, without between-group differences.”
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    Premisecitation
    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 15

    Prolonged DMPA use is associated with decrease in BMD and increased risk of fracture due to estrogen deficiency.

    “One of major sources of concerns regarding prolonged use of DMPA is the decrease of BMD and the increase risk of fracture, due to estrogen deficiency accompanying its use.”
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    • cites [55] Berenson AB, 2001, Obstet Gynecol

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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 12

    In a patient preference trial of symptomatic rectovaginal endometriosis, satisfaction rate was higher with DSG-POP than vaginal ring (61.7% vs 36.1%), and gastrointestinal symptoms, chronic pelvic pain and deep dyspareunia improved more in DSG-POP group.

    “At the end of the study, the rate of satisfied women was higher in the group treated with DSG-POP (61.7% vs. 36.1%).”
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      “Gastrointestinal symptoms, chronic pelvic pain and deep dyspareunia were improved more in the DSG-POP group.”
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    Premisecitation
    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 15

    In a RCT of 30 patients after conservative surgery for endometriosis, intramuscular DMPA and LNG-IUS were both effective in management of pain symptoms through three years; no recurrences of lesions detected at transvaginal ultrasound in both groups.

    “Both treatments were effective in the management of pain symptoms through the study period.”
    • Also stated in: § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 15 · plain
      “No recurrences of lesions were detected at transvaginal ultrasound in both therapeutic groups.”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 12

    In a patient preference trial of symptomatic rectovaginal endometriosis and migraine without aura, satisfaction rate was higher with DSG-POP than COC (61.2% vs 37.8%), and severity and number of migraine attacks significantly improved in POP group but not COC group.

    “Satisfaction rate was higher in POP group (61.2% versus 37.8%), a significant improvement in QoL, both in terms of mental and physical components, was demonstrated with DSG treatment.”
    • Also stated in: § 2.1 NORETHISTERONE ACETATE · p. 12 · plain
      “In addition, the severity and number of migraine attacks were significantly different between baseline and 6-month treatment in POP group ( P < 0.001) but not in COC group ( P = 0.078).”
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    Premisecitation
    § 2.4 CYPROTERONE ACETATE · p. 13

    In a RCT of 90 patients with recurrent moderate or severe pelvic pain after conservative surgery for endometriosis, low-dose cyproterone acetate (12.5 mg/d) and COC were equally effective in reducing pain symptoms and enhancing QoL and sexual satisfaction.

    “Both treatments were equally effective in reducing pain symptoms and enhancing QoL and sexual satisfaction.”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 10

    In a pooled analysis of four randomized controlled European trials, DNG's most common adverse reactions were headache (9%), breast discomfort (5.4%), depressed mood (5.1%), and acne (5.1%); bleeding pattern was well-tolerated and only 0.6% reported bleeding events as main cause for premature discontinuation.

    “In a pooled analysis of four randomized, controlled, European trials [38] the most common adverse reactions were headache (9%), breast discomfort (5.4%) depressed mood (5.1%), and acne (5.1%).”
    • Also stated in: § 2.1 NORETHISTERONE ACETATE · p. 10 · plain
      “The bleeding pattern was well-tolerated, and only the 0.6% of the enrolled women reported bleeding events as the main cause for premature discontinuation.”
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    Premisecitation
    § 2.1 NORETHISTERONE ACETATE · p. 9

    DNG 2 mg/d is significantly better than placebo in relieving pelvic pain and dysmenorrhea related to endometriosis and as effective as GnRH agonist therapy in relieving pain.

    “Overall, a daily dose of 2 mg DNG has been significantly better than placebo in relieving pelvic pain and dysmenorrhea related to endometriosis and as effective as GnRH agonist therapy in relieving pain [33].”
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    § 2.1 NORETHISTERONE ACETATE · p. 10

    In a pilot study of six patients with bladder endometriosis treated with DNG 2 mg/d for 12 months, pain symptoms improved in all, urinary symptoms disappeared, and bladder nodule size significantly decreased at 3 and 12 months.

    “A recent pilot study [35] on six patients treated for 12 months with DNG 2 mg/d showed an improvement of pain symptoms in all patients.”
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      “In particular, urinary symptoms disappeared and at transvaginal ultrasound a significant decrease of bladder nodule size at 3- and 12-months evaluation was described.”
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    § 2.1 NORETHISTERONE ACETATE · p. 8

    DNG exerts strong antiandrogenic properties and has no glucocorticoid or mineralocorticoid effects.

    “Moreover, DNG exerts strong antiandrogenic properties, whereas it has no glucocorticoid nor mineral corticoid effects [22,23].”
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    § 2.4 CYPROTERONE ACETATE · p. 13

    In a pilot study of seven women with laparoscopically confirmed endometriosis, a 6-month cyclical cyproterone acetate regimen improved dysmenorrhea in all subjects and second-look laparoscopy showed amelioration of endometriosis stage.

    “Dysmenorrhea improved in all study subjects.”
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      “At the end of the treatment, a secondlook laparoscopy showed an amelioration of the endometriosis stage.”
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    • cites [46] Moran C, 1996, Preliminary Report. Arch Med Res

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    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 15

    In those trials, DMPA-SC group showed significantly less BMD loss than leuprolide at month 6, and BMD returned to pretreatment levels at 12 months in DMPA-SC group but not leuprolide group.

    “Patients in the DMPA-SC group showed significantly less BMD loss than did leuprolide patients at month 6.”
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      “In addition, BMD levels return to pretreatment levels at 12 months' follow-up in the DMPA-SC group but not in the leuprolide group.”
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    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 14

    In a RCT of 80 women with endometriosis, intramuscular DMPA (150 mg/3 months) and cyclic COC plus low-dose oral danazol (50 mg/d) both significantly decreased all symptom scores without significant between-group differences.

    “A significant decrease was demonstrated in all symptoms scores in both study groups without significant between-group differences.”
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    Interpretationcitation
    § 2.1 NORETHISTERONE ACETATE · p. 10

    Overall, DNG is a well-tolerated drug with a rate of discontinuation related to adverse reactions <5%.

    “Overall, DNG is a well-tolerated drug with a rate of discontinuation related to adverse reactions &lt;5% [22].”
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    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 19

    In 50 symptomatic women with surgically confirmed endometriosis, the ENG subdermal implant improved pain severity and had a high satisfaction rate (80%).

    “In 2005, Ponpuckdee et al . [96] evaluated the efficacy of ENG-subdermal implant in the treatment of fifty symptomatic women with surgically confirmed endometriosis, with an improvement of pain severity and a high satisfaction rate (80%).”
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    • cites [96] Ponpuckdee J, 2005, J Med Assoc Thai

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    Study design and conductcitation
    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 19

    Few data are available on the use of the ENG implant for treatment of endometriosis, and the majority came from case reports and case series.

    “Few data are available on the use of this device for the treatment of endometriosis and the majority came from case reports and case series [93-95].”
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    Premisecitation
    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 16

    According to ACOG and WHO recommendations, the benefits of DMPA use surpass the risks.

    “according to the American College of Obstetricians and Gynecologists (ACOG) [48] and WHO recommendations [72] the benefits of DMPA use surpasses the risks.”
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    Interpretationcitation
    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 16

    The plausible mechanisms of LNG-IUS use in endometriosis include induction of endometrial glandular atrophy, extensive decidual transformation of the stroma, downregulation of endometrial cell proliferation, and intensification of apoptotic activities.

    “The plausible mechanisms at the basis of LNG-IUS use in endometriosis field comprehend the induction of endometrial glandular atrophy, an extensive decidual transformation of the stroma, the downregulation of endometrial cell proliferation, and the intensification in apoptotic activities [74].”
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    • cites [74] Viganò P, 2007, Womens Health

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    Study design and conductcitation
    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 17

    In the RCT of Wong et al., the sample size was small (n=15) and the number of patients who continued throughout the whole follow-up period was even smaller (n=13).

    “In the RCT of Wong et al. [52] no recurrences were identified; however, the sample size was small ( n =15) and the number of patients that continued the study throughout the whole followup period was even minor ( n = 13).”
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    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 19

    The follow-up in Ponpuckdee et al. lasted only 12 weeks.

    “The follow-up lasted only 12 weeks, and 30% of the patients reported spotting and breakthrough bleeding.”
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    • cites [96] Ponpuckdee J, 2005, J Med Assoc Thai

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    Premisecitation
    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 19

    The frequency of migration of radiopaque implant is 1.3 per million inserted devices.

    “The frequency of migration of radiopaque implant is 1.3/every millions of inserted devices [101].”
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    • cites [101] Agenzia Italiana del Farmaco AIFA, Nota Informativa Importante su Nexplanon (impianto contenente etonogestrel) (10/11/2016). cited 2017 Feb 6Available from: http://www.aifa.gov.it/sites/default/files/DHPC_letter_Nexplanon_10.11.2016.pdf

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    Interpretationnone given
    § 4. CONCLUSIONS · p. 22

    The efficacy of drugs for endometriosis seems similar among drugs, but the effectiveness may radically differ.

    “In addition, the efficacy (i.e., which one works better under ideal and highly controlled conditions, such as in an RCT) on the disease seems to be similar among drugs but the effectiveness (i.e., whether one drug works better than the other in real life, that is, under non-ideal circumstances) may radically differ.”
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    § ARTICLE HIGHLIGHTS · p. 24

    Progestins act through inhibition of inflammatory pathways and responses, provoking apoptosis in endometriotic cells.

    “Progestins act through the inhibition of inflammatory pathways and responses, provoking apoptosis in endometriotic cells.”
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    Study design and conductnone given
    § 4. CONCLUSIONS · p. 22

    RCTs do not provide information on adherence.

    “RCTs are obviously outstanding evidence, but they do not provide information on adherence.”
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    § ARTICLE HIGHLIGHTS · p. 24

    Progestins stimulate atrophy or regression of endometrial lesions, induce anovulation, inhibit angiogenesis, and decrease expression of matrix metalloproteinases, thus diminishing invasiveness of endometriotic implants.

    “Moreover, this class of drug stimulate atrophy or regression of endometrial lesions, induce anovulation, inhibit angiogenesis, and decrease expression of matrix metalloproteinases, thus diminishing the invasiveness of endometriotic implants.”
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    Interpretationreasoning
    § 4. CONCLUSIONS · p. 21

    Abandoning medical treatment exposes women to recurrences and possible demanding and risky subsequent surgeries.

    “Definitely abandoning medical treatment is the real failure because it exposes women to recurrences and possible demanding and risky subsequent surgeries.”
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    § ARTICLE HIGHLIGHTS · p. 24

    Long-term adherence to treatment is pivotal to ensure effective clinical management of endometriosis.

    “Long-term adherence to treatment is pivotal to ensure an effective clinical management.”
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    Premisecitation
    § 3.1 DEPOT MEDROXYPROGESTERONE ACETATE (DMPA) · p. 19

    In March 2016, the FDA published a warning regarding the risk of migration of the ENG implant within the arm from the insertion site, due to deep insertion.

    “In March 2016, the FDA published a warning regarding the risk of migration of the implant within the arm from the insertion site, due to deep insertion of the implant [100].”
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    • cites [100] Food and Drugs Administration (FDA). 2016. Implanon (etonogestrel) implants. Detailed view: safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER) cited 2017 Feb 5 Available from: https://www.fda.gov/safety/medwatch/safetyinformation/ucm400440.htm

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    § 4. CONCLUSIONS · p. 22

    In endometriosis, the vagina represents a scarcely explored route for drug delivery, and the majority of available evidence came from studies on danazol and the estrogen-progestin contraceptive vaginal ring.

    “In endometriosis field, the vagina represents a scarcely explored route for drug delivery, and the majority of available evidence came from studies on danazol and the estrogenprogestin contraceptive vaginal ring.”
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    Premisenone given
    § 4. CONCLUSIONS · p. 21

    Available progestins used in the treatment of endometriosis include a broad range of both oral and depot compounds, and represent, in most cases, an inexpensive alternative treatment option.

    “Available progestins used in the treatment of endometriosis include a broad range of both oral and depot compounds, and represent, in most cases, an inexpensive alternative treatment option.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § ARTICLE HIGHLIGHTS · p. 24

    Endometriosis is an estrogen-dependent chronic inflammatory disorder of fertile age that requires chronic treatment.

    “Endometriosis is an estrogen-dependent chronic inflammatory disorder of fertile age that requires a chronic treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4. CONCLUSIONS · p. 22

    Vaginal administration has several advantages, such as reduction of daily dosages, continuity of drug release, avoidance of hepatic first-pass effect, and possibility of extending the interval between doses.

    “However, advantages of the vaginal administration are several, such as the reduction of daily dosages, the continuity of drug release, the avoidance of the hepatic first-pass effect, and the possibility of extending the interval between doses, all factors that”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given
    § 4. CONCLUSIONS · p. 20

    Progestin therapies for endometriosis appear effective in managing pain symptoms but differ considerably in cost and side-effects profile.

    “Progestins therapies adopted for the treatment of endometriosis include a wide range of therapeutic options (Table 4), that appear effective in the management of pain symptoms associated with the disease but differ considerably regarding their cost and side-effects profile.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Premisecitation
    § REFERENCES · p. 41

    DNG 2 mg/day improves pain symptoms in women with symptomatic endometriosis.

    “Improvement of pain symptoms, sexual function, QoL and satisfaction with DNG”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Morotti et al., 2014 [32]

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation
    § REFERENCES · p. 41

    DNG 2 mg/day causes more alopecia than MPA 30-60 mg/day in women with symptomatic endometriosis.

    “Higher pain relief with DNG. More bleeding, alopecia, and headache with DNG. More weight gain, depression and breast”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Oh et al., 2015 [31]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § REFERENCES · p. 43

    LNG-IUS and expectant management after laparoscopic treatment of endometriotic lesions provide similar dyspareunia relief in women with symptomatic endometriosis.

    “Greater pain relief (dysmenorrhea and chronic pelvic pain) with LNG-IUS. Similar dyspareunia relief. Lower recurrence rate of dysmenorrhea in LNG-IUS group. Improvement in QoL in women treated with LNG-IUS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tanmahasamut et al ., 2012 [83]

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation
    § REFERENCES · p. 41

    DNG 2 mg/day improves sexual function in women with symptomatic endometriosis.

    “Improvement of pain symptoms, sexual function, QoL and satisfaction with DNG”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Morotti et al., 2014 [32]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Premisecitation
    § REFERENCES · p. 41

    MPA 30-60 mg/day causes more weight gain than DNG 2 mg/day in women with symptomatic endometriosis.

    “Higher pain relief with DNG. More bleeding, alopecia, and headache with DNG. More weight gain, depression and breast”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Oh et al., 2015 [31]

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation
    § REFERENCES · p. 42

    DNG 2 mg/day has a higher discontinuation rate than NETA 2.5 mg/day due to drug cost in women with symptomatic endometriosis.

    “Similar satisfaction with treatment, frequency of irregular bleeding and pain relief. Comparable improvements in QoL and sexual functioning. Better tolerability with dienogest. Higher discontinuation rate with DNG (owing to drug”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vercellini et al ., 2016 [21]

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation
    § REFERENCES · p. 41

    DNG 2 mg/day improves QoL in women with symptomatic endometriosis.

    “Improvement of pain symptoms, sexual function, QoL and satisfaction with DNG”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Morotti et al., 2014 [32]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § REFERENCES · p. 43

    LNG-IUS causes more bleeding than goserelin 3.6 mg depot s.c. injections/28 days in women with symptomatic endometriosis.

    “Similar pain relief at 1,3 and 6 months' follow-up; at 1 year follow-up patients treated with GnRHa had lower pain score compared with those treated with LNG-IUS. Higher patient satisfaction rate with GnRHa. More bleeding with LNG-IUS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bayoglu Tekin et al. , 2012 [82]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Premisecitation
    § REFERENCES · p. 41

    MPA 30-60 mg/day causes more depression than DNG 2 mg/day in women with symptomatic endometriosis.

    “Higher pain relief with DNG. More bleeding, alopecia, and headache with DNG. More weight gain, depression and breast”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Oh et al., 2015 [31]

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation
    § REFERENCES · p. 41

    DNG 2 mg/day improves satisfaction in women with symptomatic endometriosis.

    “Improvement of pain symptoms, sexual function, QoL and satisfaction with DNG”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Morotti et al., 2014 [32]

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation
    § REFERENCES · p. 41

    DNG 2 mg/day causes more headache than MPA 30-60 mg/day in women with symptomatic endometriosis.

    “Higher pain relief with DNG. More bleeding, alopecia, and headache with DNG. More weight gain, depression and breast”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Oh et al., 2015 [31]

      Not checked in the free run.

56 of 56

  • The paper relies on this without support.

    Long-term adherence to treatment is pivotal to ensure effective clinical management.

    “Long-term adherence to treatment is pivotal to ensure an effective clinical management.”

  • The paper relies on this without support.

    In Italy, the annual cost of DNG 2 mg/d is about 770 US$.

    “In fact, in Italy, the annual cost of treatment with 2 mg/d of DNG is about 770 US $.”

  • The paper relies on this without support.

    The ENG subdermal implant contains 68 mg of ENG and is FDA-approved for three years of use.

    “The etonogestrel (ENG) subdermal contraceptive implant is a device containing 68 mg of ENG and is currently approved by the FDA for three years of use.”

  • The paper relies on this without support.

    There have been post-marketing reports of ENG implants migrating within the vessels of the arm and the pulmonary artery, requiring an endovascular or surgical procedure for removal.

    “In addition, there have also been post-marketing reports of implants migrated within the vessels of the arm and the pulmonary artery, which request an endovascular or surgical procedure for the removal.”

  • The paper relies on this without support.

    The main obstacle to research in endometriosis is ignorance of the real causes of the disease.

    “The main obstacle to research in this field is our ignorance of the real causes of the disease.”

  • The paper relies on this without support.

    The economic burden is the main obstacle to widespread dienogest diffusion.

    “the economic burden represents the main obstacle to the widespread of dienogest diffusion, in spite of the good outcomes in terms of pain management.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Ferreira study arms account for 43 of 44 enrolled patients

    Minor

    Table 3 lists 44 patients enrolled, but the two reported groups contain 22 and 21 patients, totaling 43. The table does not account for the remaining patient.

    Reported 44 · recomputed 43

  • One-year result exceeds the stated 36-week follow-up

    Minor

    The Bayoglu Tekin row gives a follow-up period of 36 weeks but also reports a result at one year, which falls beyond that stated period.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. Gezer A, 2015, Womens Health, 11, 643
  2. Muneyyirci-Delale O, 1998, Int J Fertil Womens Med, 43, 24
  3. Moran C, 1996, Preliminary Report. Arch Med Res, 27, 535
  4. Berenson AB, 2001, Obstet Gynecol, 98, 475
  5. Viganò P, 2007, Womens Health, 3, 207
  6. Ponpuckdee J, 2005, J Med Assoc Thai, 88, S7
  7. Brown J, 2014, Cochrane Database Syst Rev, 3, CD009590

Cited by

Sorted by citations

Related

Authors
Buggio, L., Somigliana, E., Barbara, G., Frattaruolo, M. P., & Vercellini, P.
Affiliations
  • University of Milan (IT)
  • Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Corresponding author
Somigliana, Edgardo
ORCID
Venue
Expert Opinion on Pharmacotherapy
Publisher
Informa UK Limited
Published
2017-09-24
Volume
18
Issue
15
Pages
1569-1581
ISSN
  • 1465-6566 (ISSN-L)
  • 1744-7666
DOI
10.1080/14656566.2017.1381086
OpenAlex
W2755238760
Cited by
58
References
100
Citations by year
2026: 2 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 12 · 2021: 8 · 2020: 13 · 2019: 3 · 2018: 3
FWCI
0.85
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Expert Opinion on Pharmacotherapy (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ectopic Pregnancy Diagnosis and Management
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Menstrual Health and Disorders
Keywords
endometriosis, progestins, oral progestogens, depot progestin, personalized medicine, treatment efficacy and safety, GnRH agonist, thrombosis risk, cost-effectiveness, medication adherence
MeSH terms
Administration, Oral, Clinical Trials as Topic, Delayed-Action Preparations, Endometriosis, Female, Humans, Pain, Progestins, Treatment Outcome, Precision Medicine

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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