Long-term oral progestogen therapy effective, well tolerated in endometriosis management

Endometriosis is a chronic disease, which requires interventions that are both effective and well tolerated in the long term. Dr Tak-Keung Sum, Specialist in Obstetrics and Gynaecology in private practice in Hong Kong, reviews clinical and real-world evidence on the long-term efficacy and safety of an oral progestogen, dienogest (Visanne^®, Bayer), and shares his personal experience in managing endometriosis across different patient profiles.

Burden of endometriosis
Endometriosis is a chronic gynae­cological condition characterized by the presence of ectopic endometrial-like tis­sue, which causes pain and may affect fer­tility. It typically requires continuous man­agement until menopause. [Fertil Steril 2014;101:927-935] The type of treatment depends on the individual’s symptoms and preferences, as well as treatment availability, cost, efficacy, and tolerability. [Hum Reprod Open 2022;doi:10.1093/hropen/hoac009]

Chronic pain
Endometriosis causes debilitating chronic pain in the abdominopelvic region and may also manifest as dysmenor­rhoea and dyspareunia. Chronic inflam­mation process involving growth factors and cytokines released by endometriotic implants, active bleeding, and irritation of pelvic floor nerves can sensitize the nervous system and result in a broader spectrum of pain experiences. [Fertil Steril 2014;101:927-935]

Infertility
Endometriosis may severely impact fertility and increase the need for as­sisted reproductive technologies. While surgery may be considered in certain cases, its risks and benefits should be carefully considered, especially in patients desiring fertility preservation. [Lancet 2004;364:1789-1799]

Recurrence after surgery
Postoperative recurrence rates of endometriosis have been estimated to be 21.5 percent at 2 years and up to 50 percent at 5 years. Although surgery may provide immediate pain relief, some clinicians now prefer to delay surgery for as long as possible due to the associat­ed high risk of recurrence. [Nat Rev En­docrinol 2019;15:666-682; Int J Wom­ens Health 2011;3:175-184; Fertil Steril 2015;104:793-801; Hum Reprod Update 2009;15:441-461]

Poor QoL
“The debilitating effects of chronic pain, the threat to reproductive health, as well as the need for repeat surger­ies and long-term interventions to pre­vent or minimize recurrences take a substantial toll on patients with endo­metriosis in terms of their well-being, personal relationships, finances, and work productivity, negatively affecting their quality of life [QoL],” shared Sum. [Int J Womens Health 2011;3:175-184; Lancet 2004;364:1789-1799]

Long-term medical management for endometriosis
Medical treatment with progesto­gens (ie, progestins) such as dienogest or oral contraceptive pills is the first-line therapeutic option for patients with pel­vic pain and no desire for immediate pregnancy. [Fertil Steril 2014;101:927-935; Fertil Steril 2015;104:793-801; Nat Rev Endocrinol 2019;15:666-682]

The European Society of Hu­man Reproduction and Embryology (ESHRE) guidelines strongly recom­mend progestogens for reduction of endometriosis-associated pain, with particular consideration of individu­al agents’ side effect profiles. There is also a strong recommendation for clinicians to offer long-term hormone treatment after surgical management of ovarian endometrioma in women not immediately seeking conception. [Hum Reprod Open 2022;2022:hoac009]

Efficacy and safety data of dienogest
Dienogest, an oral progestin avail­able in 2 mg tablets, is approved for management of endometriosis. [Vis­anne Hong Kong Prescribing Informa­tion] “Robust data support its efficacy and safety in women with endome­triosis in terms of pain reduction and recurrence prevention, including after surgical interventions,” said Sum.

Pain relief and QoL improvement
“The efficacy of dienogest in pro­viding pain relief for patients with en­dometriosis has been demonstrated in several clinical studies, including in Asian populations, as reflected in our patients’ experience,” Sum noted. (Cases 1 and 2)

A randomized, double-blind, placebo-controlled phase III study assessed dienogest 2 mg QD in 255 Chinese women aged 18–45 years with laparoscopically diagnosed en­dometriosis. After 24 weeks of treat­ment, the difference between the di­enogest and placebo arms for mean reduction in endometriosis-associated pelvic pain (EAPP) was statistical­ly significant in favour of dienogest (-24.54 mm; p<0.0001). Dienogest was well tolerated, with minimal ad­verse events (AEs) and no impact on bone mineral density after 24 weeks of treatment. [J Womens Health (Larchmt) 2018;27:148-155]

The multicentre, prospective ENVI­SIOeN study demonstrated that dien­ogest significantly improved the QoL of Asian women with endometriosis. Results showed decreased Endo­metriosis Health Profile-30 (EHP-30) scores across all domains, indicating improvement in health-related QoL. The pain domain was improved in 78.4 percent of patients, with a mean pain score decrease of 4.5 points. At the same time, 31.5 percent of patients experienced treatment-emergent AEs, where amenorrhoea (5.9 percent) and metrorrhagia (5.1 percent) were the most common events. [BMC Womens Health 2019;19:68]

Other clinical studies have demon­strated consistent efficacy results in favour of dienogest in relieving EAPP vs placebo, as well as compara­ble efficacy but better tolerability vs gonadotropin-releasing hormone ag­onists. [Eur J Obstet Gynecol Reprod Biol 2010;151:193-198; Hum Reprod 2010;25:633-641; Gynecol Endocrinol 2021;37:930-933]

Fertility preservation
Endometriomas, which are com­mon in endometriosis, can adversely affect fertility, but its surgical remov­al may decrease ovarian reserve. A retrospective study of 116 women found that dienogest-based therapy significantly reduced endometrioma volume after 12 months vs controls (p<0.0001), with a notable decrease in cyst size and higher rates of cyst disappearance in those receiving dienogest alone vs dienogest plus ethinylestradiol. [Gynecol Endocrinol 2020;36:545-549]

Similarly, an observational study involving 157 patients indicated that long-term dienogest use (up to 9 years) reduced endometrioma size from a mean of 33.2 mm to 7 mm, while also alleviating various pain symptoms in patients with chronic EAPP. However, prolonged use was linked to increased AEs, including menstrual changes and osteopenia, necessitating care­ful monitoring. [Arch Gynecol Obstet 2024;309:589-597]

“These results suggest that dienogest-based therapy effectively controls endometrioma growth and may reduce need for surgery, which may be important in preserving fer­tility for patients with endometriosis, such as the patient described in Case 2,” said Sum. [Gynecol Endocrinol 2020;36:545-549; Arch Gynecol Ob­stet 2024;309:589-597]

For women with endometrio­sis who wish to get pregnant after achieving sufficient pain relief, current evidence indicates that the menstru­al cycle returns to normal within 2 months after stopping dienogest. This suggests that dienogest is an effec­tive option for managing endometrio­mas while preserving fertility potential in affected women, as demonstrat­ed in Case 2. [Int J Womens Health 2011;3:175-184; Jpn Pharmacol Ther 2007;35:769-783; J Obstet Gynaecol Res 2009;35:1069-1076; Arch Gynecol Obstet 2012;285:167-173; Visanne Hong Kong Prescribing Information]

Prevention of postoperative recurrence
A retrospective study with approx­imately 2.5 years of follow-up included 126 patients with deep infiltrating endo­metriosis who underwent laparoscopic resection of uterosacral ligaments, fol­lowed by postoperative administration of dienogest or no medication. At 5 years, the prevalence of postoperative recurrence of endometriomas was lower with dienogest vs no medication (0.531 vs 0.077; p<0.05), as was the preva­lence of postoperative endometriosis-related symptoms (0.726 vs 0.133; p<0.01). (Figure 1) [Eur J Obstet Gynecol Reprod Biol 2017;216:51-55]