Maximizing the medical treatment of endometriosis, the double progestin system (DPS) for difficult endometriosis

(DE) in women with pain symptoms

condition;
Effective drugs with no side effects just do not exist;
Medications for chronic disorders are, by definition, symptomatic.
Rapid symptom recurrence at drug discontinuation is expected
“Inefficacy,” is defined as lack of symptom relief during treatment and not after treatment

surgical treatment of endometriosis has been based mainly on a straightforward oncologic principle, i.e. radical removal of lesions.
Endometriotic deep lesions are benign and usually not progressive (Fedele L, 2004)
The outcome and complications of surgical treatment for DE are difficult to assess, because they are influenced by numerous variables including severity of the disease, number and location of endometriotic nodules, degree of infiltration of the bowel or the urinary tract and overall experience of the surgical team
There are no specific guidelines from any society regarding the indication and surgical approach for bladder and bowel DE. (Kho, RM ., 2018)
Currently, the general recommendation by ACOG, ESHRE, and SOGC for the definitive treatment of pain associated with DE is still hysterectomy with or without bilateral salpingo-oophorectomy in women with no desire for future fertility, associated intractable pelvic pain, adnexal masses, or multiple previous conservative surgical procedures
(G.A.J. Dunselman, 2014; American College of Obstetricians and Gynecologists, 2010; N. Leyland, 2010)

remedy for severely symptomatic endometriosis patients.

Weir et al. (2005) analysed the clinical records of 53 385 hospital admissions for the treatment of endometriosis in the province of Ontario, Canada, from 1994 to 2002.
The records of 7993 patients with 15 years of age or older, with no prior hospital admission for endometriosis in the preceding 2 years, who underwent ‘minor’ or ‘intermediate’ conservative surgery for early disease, constituted the base for a 4 year longitudinal study.
During the observation period, the likelihood of hospital re-admission for additional surgical treatment was 27% and that of having a hysterectomy was 12%.
However, in spite of a substantial risk of re-operation, operative laparoscopy is increasingly performed for treating symptomatic endometriosis.
On the basis of large epidemiologic databases, it has been estimated that ∼1 in 400 North American women aged 15–45 years is hospitalized for surgical treatment of endometriosis each year (Weir et al., 2005).

from primary surgery because of recurrence of pain was reported in about one in five women (19%) who underwent bowel resection (C. De Cicco,2011)
The 24 month cumulative probability of moderate or severe dysmenorrhoea recurrence was 20% in the former group and 25% in the latter, without statistically significant differences. Crosignani et al. (1996)
A similar rate of pain recurrence (22%), 2 years after laparoscopic surgery for stage III–IV disease, was reported by Busacca et al. (1999) in a group of 141 patients.
Abbott et al. (2003) investigated the outcomes of laparoscopic excision of endometriosis up to 5 years after surgery in 176 women with severe pain symptoms, the 5 year cumulative probability of requiring further surgery was 36%.
Vignali et al. (2005) evaluated the risk of pain and disease recurrence after conservative surgery for endometriosis in a series of 115 women with deep lesions. After a minimum follow-up of 12 months, recurrence of pain was observed in 28 patients (24%) and recurrence of lesions in 15 (13%). Twelve subjects (10%) underwent repetitive surgery. Multivariate analysis demonstrated that only age was a significant predictor of pain recurrence, enhancing the risk in younger patients. Recurrence of lesions was predicted by obliteration of the Douglas pouch and re-operation was predicted by non-radical first-line surgery.

rate of recurrence of endometriosis, affecting long-term quality of life for many women, improvement in long-term control of the condition was felt by the Committee to be clinically very important.
The Committee were aware of the high rate of reoperation for endometriosis with associated risks of surgery and, as there was strong evidence to support this, considered that avoidance of repeat surgery by the use of long -term medical therapy would be beneficial.

cohort study

The incidence of subsequent gynaecological surgery was significantly higher in women with endometriosis (n = 11 052; 62%) when compared with women with no evidence of endometriosis at laparoscopy (n = 42 136; 50.6%), women who had undergone laparoscopic sterilisation (n = 58 704; 36%) and age‐matched women from the general population (n = 2907; 16.3%).
The median (IQR) time for a second surgical procedure (after the initial diagnostic operation) for the endometriosis group was less than 2 years [1.8 (0.8, 4.6)], which was significantly shorter than the corresponding period in women in the three unexposed groups. Half of all women with endometriosis had undergone repeat surgery within 5.5 years.

L Saraswat D Ayansina KG Cooper S Bhattacharya AW Horne S Bhattacharya 2017 BJOG

the severe complication rate (i.e., Clavien-Dindo IIIB) was 3% (n = 4). (Jayot, Aude, 2020)
A recent systematic review revealed a 6.3% rate of major complications following bowel endometriosis resection, including:
Transient urinary retention: The most frequently reported post-operative difficulty is urinary retention, probably due to damage to the parasympathetic plexus resulting in temporary bladder denervation. This problem is associated with, but it is not exclusive to, colorectal resection (Dubernard et al., 2008).
Fistula: with a reported risk as high as 10% even in expert hands (Darai et al., 2005; Dubernard et al., 2006).
Anastomotic leakage (0.8% of cases).
Anastomotic stricture (6.3%) of a total of 1643 patients who underwent laparoscopic rectosigmoid resection. Protective ileostomy is the sole modifiable factor related to anastomotic stenosis (Bertocchi, E, 2019).
Many women prefer to live with residual dyschezia than to risk a fecaloid fistula or a derivative colostomy.

A, Koninckx P. Bowel resection for deep endometriosis: a systematic review. BJOG 2011;118:285–91. b-Berlanda N, Vercellini P, Carmignani L, Aimi G, Amicarelli F, Fedele L. Ureteral and vesical endometriosis. Two different clinical entities sharing the same pathogenesis. Obstet Gynecol Surv 2009;64:830–42.

decide on whether they opt for surgical treatment of lower bowel endometriosis?

Until we have robust data, it is difficult to provide women with accurate information about the surgical risk.
Based on the larger studies in the review by De Cicco et al., we can advise that the chances of having a major surgical complication are probably around 10%.
The case series of Kondo et al. suggests that the major complication rate is likely to be lower in women undergoing a mucosal skimming procedure relative to those having a segmental resection.
Women also need to be advised that the complication rate may be higher in units that have relatively little experience of this surgery and, as recommended by the Royal College of Obstetricians and Gynaecologists (RCOG), the surgeon should quote his/her own complication rate.

De Cicco C, 2011; Kondo W, 2011; Royal College of Obstetricians and Gynaecologists. 2008

from medical records of 238 women with recto-sigmoid endometriosis.
Results: Over the course of follow-up, 143 (60.1%) women remained in medical treatment while 95 (39.9%) presented with worsening of pain symptoms or intestinal lesion growth (failure of medical treatment group), with surgical resection performed in 54 cases.
Conclusion: Patients with recto-sigmoid endometriosis who failed to respond to medical treatment were younger and had larger intestinal lesions. Hormonal therapy was equally efficient in improving pain symptoms other than dyspareunia compared to surgery, and was associated with lower complication rates in women with recto-sigmoid endometriosis.
Medical treatment should be offered as a first-line therapy for patients with bowel endometriosis. Surgical treatment should be reserved for patients with pain symptoms unresponsive to hormonal therapy, lesion growth or suspected intestinal subocclusion.

treatment

symptoms
Size of the lesions
Pain symptoms unresponsive to hormonal therapy,
Lesion growth or suspected intestinal subocclusion.
Age of the patient- younger patients seems to have more recurrence
BMI- high BMI is associated with recurrence
Feasibility of surgery

progressed in only one third of women- may be better candidates for treatment with OCs rather than with progestogen monotherapies.
b.Medium-risk lesions: Ovarian endometriomas-low association with malignancy, typically less than 0.8%- asymptomatic endometriomas do not require intervention for infertility-  low-dose OCs, used cyclically or continuously.
High-risk lesions: Deep fibrotic nodules- Progestogens, instead of OCs, should generally be considered the first-line medical treatment- two-thirds of patients with deep endometriosis respond favorably to progestogen treatment

P. Vercellini, 2016

(1) “all treatments led to a clinically significant reduction in pain on the VAS when compared to placebo. The magnitude of this treatment effect was similar for all treatments, suggesting that there was little difference between them in their capacity to reduce pain. No other significant differences were found between the hormonal treatments”; and
(2) “it is known that there are a cluster of extremely cheap hormonal treatments (including the combined oral contraceptive pill) and a cluster of extremely high-cost treatments including dienogest and GnRHas”

1- National Institute for Health and Care Excellence, 2017

women with peritoneal and ovarian endometriosis, stepping up to continuous use with tailored cycling only in those women with persistent dysmenorrhea despite cyclic OC use.
In case of inefficacy on pain during OC use, patients should step up to a low-cost progestogen such as NETA.
Starting directly with a low-cost progestogen should be considered in patients with deep lesions or with deep dyspareunia as their main complaint.
In case of inefficacy of or intolerance to progestogens, patients may step up to GnRH-agonists or antagonists

should always be absence of pain; if this end point is not achieved with oral contraceptives, the patient should be offered more definitive therapy. Many patients fail to adequately respond to oral contraceptives while others develop progestin resistance with disease progression despite using a progestin based therapy […] The realization that all therapies have different efficacy and the availability of new endometriosis drugs will allow more rapid progression to definitive therapy”

H.S. Taylor, 2017

illness: Women with severely symptomatic endometriosis, in addition to pain, usually experience major worsening in health-related quality of life, psychological status, sexual functioning and marital relationship, social life, and school or work productivity.
The burden of treatment: endometriosis, includes taking medications, managing side effects, attending gynecologic visits, performing imaging investigations and repeated blood tests, undergoing surgical procedures, self-monitoring, lifestyle changes, administrative task to access and coordinate care, full or partial payment of treatments, and other hidden costs.

G. Spencer-Bonilla, 2017

RCT conducted in women with symptomatic endometriosis, a low-dose oral contraceptive (OC) substantially improved not only dysmenorrhea but also other pain symptoms including nonmenstrual pain and deep dyspareunia (1).
However, Casper suggested that progestogens should be preferred to OCs as a first-line treatment, based on the consideration that estrogen and progesteron receptors would be, respectively, over- and underexpressed in ectopic endometrial implants- potential risk of lesion progression (2).
The currently available epidemiological data do not support a pathogenic role of OCs in the development of endometriosis (3)
OCs when chosen as a modality to manage endometriosis, combinations with the lowest possible estrogen dose should be chosen, such as those with only 15–20 μg of EE or 1.5 mg of 17 β-oestradiol (E2)

1- T. Harada, 2017. 2- R.F. Casper, 2017. 3- P. Vercellini, 2011

statistically significant differences were observed between the two treatment schedules in other pain symptoms as well as in postoperative ovarian endometrioma recurrence rate (1).
Using OC continuously increases the likelihood of erratic bleeding that, if not promptly dealt with by tailored cycling (2), may cause prolonged pain (3) 
Cyclic OC use may increase therapeutic compliance in patients (amenorrhea).
Continuous and tricycling (where three packets are taken in a row, followed by a pill free interval) may be the best approach (4) 

1- L. Muzii, 2014. 2- T. Harada, 2017. 3- P. Vercellini, 2013.
4- National Institute for Health and Care Excellence,2017

Literature data, 2003–2015

(NETA), levonorgestrel (LNG), and nomegestrol acetate (NOMAC).
Dienogest (DNG) is the only high-cost progestogen currently licensed for the treatment of endometriosis.

hence, we need to explore which progestin suites each woman”
Al-Jefout Moamar

these drugs explains their efficacy in terms of pelvic pain relief and, at the same time, their limited tolerability and safety.
The combination of GnRH agonists with add-back therapy (generally, a bone-sparing progestogen such as NETA or an estrogen–progestogen hormone replacement therapy) limits vasomotor side effects and prevents bone resorption, but further increases costs

or 400 mg was tested against a placebo.
At 3-month evaluation- a clinical response with respect to dysmenorrhea were 43–46% and 72–76% in the lower- and the higher-dose elagolix group, respectively,
At the end of the 6-month study period, the percentage of participants experiencing amenorrhea in the high-dose elagolix group in the two trials varied from 47% to 66%.
Hot flushes - reported by 42–48% of women in the high-dose elagolix group.
The mean percent bone mineral density (BMD) reduction at the lumbar spine observed at 6-month follow-up in women in the high-dose elagolix group varied from −2.49 to −2.61.
Therefore, unless GnRH antagonists will be marketed at a price lower than that of GnRH agonists, the advantages of the former compounds over the latter ones may reveal smaller than expected.
 Unplanned pregnancy rate in women who used elagolix was over 1% (6/497)

H.S. Taylor, 2017

subdermal implant for severe and persistent endometriosis-associated pelvic pain: An effective new therapy.
Cecilia Hoi Man Ng (PhD), Anthony James Marren (FRANZCOG), Ian Stewart Fraser (MD, DSc), Angela Pardey (MBBS), John Pardey (MBBS) and Moamar Ibrahim Al-Jefout (MD, PhD)

of simultaneous use of dual progestogen-delivery systems (DPS) with the LNG-IUS and etonogestrel subdermal implant (ESI) as a new combination therapy for severe, refractory endometriosis-associated pelvic pain

the woman wishes to conceive or not.
The American Society for Reproductive Medicine (ASRM), the European Society of Human Reproduction and Embryology (ESHRE) and the World Endometriosis Society (WES) have developed comprehensive consensus statements for the management of chronic pelvic pain and endometriosis. Other organizations have also developed detailed evidence-based reviews of management (e.g. Cochrane Collaboration).
These have all tried to offer sound, evidence-based recommendations from randomized trials on large numbers of women.
However, little attention has been given specifically to that small group of women with refractory symptoms who have responded poorly to more conventional therapies.

gradual move towards greater use of local delivery of progestogen via LNG-IUS; Mirena®, which delivers levonorgestrel into the uterine cavity at a steady rate of 20 mg/day from the time of insertion.
It has been demonstrated to be an effective therapy in the prevention of recurrence of endometriosis following laparoscopic treatment, as well as moderately effective in control of pain symptoms in many women with endometriosis.
There has also been occasional use of a systemic but constant delivery of progestogen through the etonogestrel subdermal implant (ESI; Implanon®, which delivers etonogestrel at a steady initial rate of 60 – 70 mg/day into the systemic circulation.
It has been reported that the ESI may be effective in improving primary dysmenorrhea and also pelvic pain associated with endometriosis.

of progestogens is maintained that should offer simultaneous dual targeting of local uterine and more distant lesions, as well as preventing new lesions from forming.
A constant local and systemic combined delivery of progestogen offered by the LNG-IUS and ESI should offer a logical extension of conventional hormonal treatment of “difficult” endometriosis.
Simultaneous use of the LNG-IUS and the ESI for a case of debilitating adolescent endometriosis was first reported by Al-Jefout, et al. 2009.
The case study of a 13-year-old female with pelvic pain secondary to endometriosis, refractory to a series of conventional medical and conservative surgical therapies and whose life was completely dominated by the persistent pain of endometriosis.
In this case a combination of LNG-IUS and ESI proved to be a highly effective dual therapy, allowing her to return to school studies and a completely normal lifestyle.

was approved by the Ethics Review Committees from Royal Prince Alfred Hospital, Sydney and the University of Sydney.
The patients, and where relevant, their parents, gave informed consent to undertake this off-label therapy
Prior to the insertion of the DPS, all women had undergone a series of attempts at various medical and/or surgical treatments, without satisfactory control of symptoms

systems (DPS) with the LNG-IUS and etonogestrel subdermal implant (ESI) as a new combination therapy for severe, refractory endometriosis-associated pelvic pain.
Methods: This report details the very successful simultaneous use of LNG-IUS and ESI for debilitating and refractory endometriosis in 40 women with refractory pelvic pain secondary to endometriosis.

(range 9 – 98) months.
The mean age at first review was 25.2 (range 13 – 50) years. The mean duration of symptomatology was 7.9 (range 0.5 – 30) years – 39/40 recorded dysmenorrhea; 16/19 deep dyspareunia; 12/40 dyschezia; and 4/40 dysuria; 16/40 recorded additional symptoms (e.g. heavy menstrual bleeding, erratic pelvic pain, and painful abdominal bloating).
A small proportion of the teenagers (n = 4; 10% of the total) could be classified as “dramatic” improvement, defined as the development of amenorrhea with no pelvic pain. “Marked” improvement, as defined by the major resolution of most symptomatology was reported in 26/40 (65%).
Three had a “borderline” initial response (i.e. some improvement in symptoms) but then obtained marked and ongoing improvement after short-term supplementation with an oral progestogen or 3 months of a GnRH analogue.
Persistent borderline benefit was reported in 5/40 (13%).

option in management of refractory endometriosis-associated pelvic pain. This DPS is a promising, sustained-release approach for severe, persistent endometriosis pain, especially in young women.