Mitigating the economic burden of GnRH agonist therapy for progestogen-resistant endometriosis: why not?

STUDY QUESTION: Is it possible to reduce the cost of GnRH agonist treatment for endometriosis by using non-standard dosing regimens? SUMMARY ANSWER: An extended-interval dosing regimen of a 3.75 mg depot formulation of triptorelin injected every 6 weeks instead of every 4 weeks reduces the cost by one-third without compromising the effect on pain relief. WHAT IS KNOWN ALREADY: Cost constitutes a limit to prolonged GnRH agonists use. Alternative modalities to reduce the economic burden of GnRH agonist treatment have been anecdotally attempted. STUDY DESIGN SIZE DURATION: A systematic review was conducted to evaluate and compare the effect of three alternative modalities for GnRH use in women with endometriosis, i.e. intermittent oestrogen deprivation therapy, reduced drug dosage, and extended-interval dosing regimens of depot formulations. A PubMed and Embase search was initially conducted in October 2022 and updated in January 2023 using the following search strings: (endometriosis OR adenomyosis) AND (GnRH-agonists OR gonadotropin-releasing hormone agonists OR triptorelin OR leuprorelin OR goserelin OR buserelin OR nafarelin). Full-length articles published in English in peer-reviewed journals since 1 January 1980, and reporting original data on GnRH agonist treatment of pain symptoms associated with endometriosis were selected. PARTICIPANTS/MATERIALS SETTING METHODS: Information was extracted on study design, GnRH-agonist used, dosage, total duration of therapy, side effects, treatment adherence, and pelvic pain relief. Reviews, commentaries, conference proceedings, case reports, and letters to the editor were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 1664 records screened, 14 studies regarding clinical outcomes associated with the 3 considered alternative modalities for GnRH agonist use were eventually included (intermittent oestrogen deprivation therapy, n = 2; low-dose or 'draw-back' therapy, n = 8; extended-interval dosing regimen, n = 4). Six studies were randomized controlled trials (RCTs) (double blind, n = 2) and eight adopted a prospective cohort design (non-comparative, n = 6; comparative, n = 2). A total of 776 women with endometriosis were recruited in the above studies (intermittent oestrogen deprivation therapy, n = 77; low-dose or 'draw-back' therapy, n = 528; extended-interval dosing regimen, n = 171). Robust data demonstrating cost saving without detrimental clinical consequences were available for the extended-interval dosing regimen only. In particular, the 3.75 mg triptorelin depot preparation inhibits ovarian function for a longer period compared with the 3.75 mg leuprorelin depot preparation, allowing injections every 6 instead of 4 weeks. Based on the cost indicated by the Italian Medicine Agency for the 3.75 mg triptorelin depot preparation, this would translate in a yearly saving of €744.60 (€2230.15-€1485.55; -33.4%). LIMITATIONS REASONS FOR CAUTION: The quality of the evidence reported in the selected articles was not formally evaluated and a quantitative synthesis could not be performed. Some studies were old and the tested therapeutic approaches were apparently obsolete. Only cost containment associated with GnRH analogue use, and not cost-effectiveness, has been addressed. WIDER IMPLICATIONS OF THE FINDINGS: Consuming less resources without negatively impacting on health outcomes carries ethical and practical implications for individuals and the community, as this approach may result in overall increased healthcare access. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Italian Ministry of Health (Ricerca Corrente 2023, IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano). E.S. discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures. All other authors declare they have no conflict of interest. REGISTRATION NUMBER: N/A.

How to Manage Endometriosis in Adolescence: The Endometriosis Treatment Italian Club Approach.

The evaluation of endometriosis in an adolescent girl is a challenging topic. The initial stage of the disease and the limited diagnostic instrument appropriate for the youth age and for its typical features can reduce the ability of the gynecologist. At the same time, missing a prompt diagnosis can delay the beginning of specific and punctual management of endometriosis, which could avoid a postponed diagnosis from 6 to 12 years, typical of adolescent girls complaining of dysmenorrhea. This article aimed to answer all the potential questions around the diagnosis and management of endometriosis in adolescents starting from a clinical case looking at the possible solution that is easily reproducible in the clinical practice.

Association of endometriosis and adenomyosis with pregnancy and infertility.

We performed a comprehensive narrative synthesis of systematic reviews with meta-analysis published in the last 5 years on the association of endometriosis and adenomyosis with reproductive and obstetric outcomes. This review aimed to define the information on which to base preconceptional counseling and clarify whether and in which cases pregnant women with endometriosis and adenomyosis should be referred to tertiary care centers and followed as high-risk obstetric patients. Reduced pregnancy and live birth rates and an increased miscarriage rate were observed in women with endometriosis and adenomyosis. The effect was larger in women with adenomyosis than in those with endometriosis. Women with superficial peritoneal and ovarian endometriosis do not appear to be at considerably increased risk of major obstetric and neonatal complications, whereas women with severe endometriosis, whether operated or not, are at several-fold increased risk of placenta previa. Moreover, deep infiltrating endometriosis is a risk factor for spontaneous hemoperitoneum in pregnancy and is associated with surgical complications at cesarean section. Overall, women with adenomyosis are at increased risk of various adverse obstetric outcomes, including preeclampsia, preterm delivery, fetal malpresentation, postpartum hemorrhage, low birth weight, and small for gestational age. Most studies included in the considered systematic reviews are characterized by substantial qualitative and quantitative heterogeneity. This makes a reliable assessment of the available evidence difficult, and caution should be exercised when attempting to derive clinical indications. Nevertheless, women with deep infiltrating endometriosis and severe adenomyosis should be considered at high obstetric risk and can benefit from referral to tertiary care centers where they can be safely followed through pregnancy and delivery. Whether the same should apply also to pregnant women with minimal endometriosis and adenomyosis forms is currently uncertain. Emerging evidence suggests that some adverse reproductive and obstetric outcomes observed in women with endometriosis are, in fact, associated with coexisting adenomyosis.

Advances in the medical management of bowel endometriosis.

Endometriosis infiltrating the bowel can be treated medically in accurately selected women not seeking conception and without overt obstructive symptomatology. When the rectosigmoid junction is involved, the probabilities of intestinal symptoms relief, undergoing surgery after treatment failure, and developing bowel obstruction during hormonal treatment are around 70%, 10%, and 1-2%, respectively. When the lesion infiltrates exclusively the mid-rectum, thus in cases of true rectovaginal endometriosis, the probabilities of intestinal symptoms relief and undergoing surgery are about 80% and 3%, respectively. Endometriotic obstructions of the rectal ampulla have not been reported. A rectosigmoidoscopy or colonoscopy should be performed systematically before starting medical therapies, also to rule out malignant tumours arising from the intestinal mucosa. Progestogens are safe, generally effective, well-tolerated, inexpensive, and should be considered as first-line medications for bowel endometriosis. Independently of symptom relief, intestinal lesions should be checked periodically to exclude nodule progression during hormonal treatment.

The impact of IVF on deep invasive endometriosis.

OBJECTIVE: Ovarian hyper-stimulation during IVF is associated with a significant raise in serum estrogens and one may expect detrimental effects on estrogen-dependent diseases such as endometriosis. However, available evidence from large case series of affected women performing IVF is generally reassuring with the possible exception of women carrying deep invasive lesions. On this basis we deemed important investigating more in depth whether women with deep invasive endometriosis could be a subgroup at higher risk of recurrence or disease progression during IVF. STUDY DESIGN: Women with endometriosis who underwent IVF and who had a second evaluation after 3-6 months from a failed cycle were retrospectively reviewed. The main inclusion criteria were the presence of deep invasive endometriosis and/or a history of surgery for this form of the disease. The primary aim of the study was to determine the frequency of endometriosis-related complications in the interval between the two evaluations. Secondary aims were pain symptoms and lesion size modifications. RESULTS: Eighty-four women were ultimately selected: baseline ultrasound documented deep invasive lesions in 60 of them. One case of possible endometriosis-related complication was recorded, corresponding to a rate of 1.2% (95%: 0.05%-5.5%) for the whole cohort and 1.7% (95%CI: 0.08-7.6%) for the subgroup of women with ultrasound detected lesions. This rate appears similar to the reported frequency of endometriosis progression in women not receiving IVF. No significant modifications in pain symptoms or lesions size occurred. CONCLUSIONS: Women with deep invasive endometriosis who underwent IVF do not seem to be exposed to a substantially increased risk of recurrence/disease progression. Larger evidence from independent groups is however required for a definitive conclusion.

Management of Endometriosis: Toward Value-Based, Cost-Effective, Affordable Care.

Endometriosis management seems to be influenced by outcome-independent biomedical, pharmacological, and technological developments. The propensity towards doing more affects several aspects of care, sometimes translating into proposals that are not based on sound epidemiological principles and robust evidence. Different stakeholders share the interest for doing more testing and using novel and costly drugs or devices in patients with endometriosis. Although some women may benefit from such an approach, the majority do not, and some may be harmed. Moreover, an uncontrolled increase in expenditures for endometriosis management without demonstrated and proportional health benefits would waste the finite resources of national health care services and would risk cost-related non-adherence. Cost-effectiveness analyses should be systematically pre-planned in future trials on endometriosis, and the concept of "value" of medical interventions should guide investigators and health care policymakers. Reducing low-value care, financial toxicity, and the burden of treatment is respectful not only of endometriosis patients, but also of the entire society. Whenever possible, long-term therapeutic strategies should be tailored to each woman's needs, and high-value tests and treatments should be chosen based on her priorities and preferences. Moreover, listening to patients, understanding their concerns, avoiding disease labelling, explaining plainly what is known and what is unknown, and giving constant reassurance and encouragement may be exceedingly important for the successful management of endometriosis and may change the patient's perception of her clinical condition. Physician empathy has no untoward effects, does not cause harms, and may determine whether a woman successfully copes or desperately struggles with her disease during reproductive life.

Creation of a Neovagina by Laparoscopic Modified Davydov Vaginoplasty in Patients with Partial Androgen Insensitivity Syndrome.

STUDY OBJECTIVE: To evaluate the feasibility, safety, and outcome of laparoscopic modified Davydov vaginoplasty in subjects with partial androgen insensitivity syndrome (PAIS). DESIGN: A retrospective cohort study (Canadian Task Force classification III). SETTING: A tertiary referral center. PATIENTS: Ten continuous patients operated on between October 2008 and May 2014. INTERVENTIONS: Laparoscopic modified Davydov vaginoplasty. The surgical technique was tailored on PAIS subjects who presented a male pelvic anatomy and, frequently, anomalies of the external genitalia. MEASUREMENTS AND MAIN RESULTS: Anatomic success was defined as a neovaginal width allowing the insertion of 2 fingers and a neovaginal length of at least 5 cm. Functional success was defined as the presence of regular sexual intercourse. Laparoscopic modified Davydov vaginoplasty was successfully performed in all patients without surgical complications. At hospital discharge, anatomic success was achieved in all patients. At the 12-month follow-up, anatomic success was achieved in 9 patients and functional success in 7 patients. Two patients with anatomic success did not start any sexual activity by personal choice. One patient had an anatomic failure with a neovaginal length of 2 cm. This patient had not complied with the postoperative use of vaginal dilators. CONCLUSION: This is the first study reporting the outcomes of laparoscopic modified Davydov vaginoplasty in subjects with PAIS. Postoperative long-term outcomes were comparable with those achieved in women with Rokitansky syndrome. The laparoscopic modified Davydov operation may represent the procedure of choice for the creation of a neovagina and the concomitant correction of anomalies of the external genitalia in subjects with PAIS.

"Per vaginam" topical use of hormonal drugs in women with symptomatic deep endometriosis: a narrative literature review.

PURPOSE: We aim to provide a comprehensive overview of the role of the vagina as a route for drug delivery and absorption, with a particular focus on the use of vaginal hormonal compounds for the treatment of deep infiltrating symptomatic endometriosis. METHODS: A MEDLINE search through PubMed was performed to identify all published studies in English language on vaginal hormonal treatments for symptomatic endometriosis. RESULTS: Main advantages of the vaginal route include avoidance of the hepatic-first pass metabolic effect, the possibility of using lower therapeutic dosages, and the reduction of side effects compared with the oral administration. Studies on endometriosis treatment mainly focused on the use of vaginal danazol (n = 6) and the contraceptive vaginal ring (n = 2). One pilot study evaluated the efficacy of vaginal anastrozole in women with rectovaginal endometriosis. Most investigations evaluated the vaginal use of hormonal agents in women with deep infiltrating endometriosis/rectovaginal endometriosis. Overall, a substantial amelioration of pelvic pain symptoms associated with endometriosis was observed, particularly of dysmenorrhea. A significant reduction in rectovaginal endometriotic nodule dimensions measured at ultrasound examination was detected by some but not all authors. CONCLUSIONS: The vaginal route represents a scarcely explored modality for drug administration. High local hormonal concentrations might achieve a greater effect on endometriotic lesions compared with alternative routes. Future studies should focus on the use of the vagina for delivering target therapies particularly in patients with deeply infiltrating rectovaginal lesions.

What Is Known and Unknown About the Association Between Endometriosis and Sexual Functioning: A Systematic Review of the Literature.

It is well known that endometriosis is associated with an increase in the risk of deep dyspareunia, with potential negative effects on global female sexual functioning and couple relationship. The aims of this study were to review the literature on the impact of endometriosis on female sexual functioning and to suggest new avenues for future research and treatment strategies. An electronic database research was performed to identify all the studies on the relation between endometriosis and sexual functioning published in the period 2000 to 2016. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. After the screening process, a total of 9 studies investigating the relation between endometriosis and female sexual functioning were considered. Overall, these studies indicated that around two thirds of women with endometriosis have some form of sexual dysfunction not limited to deep dyspareunia. These findings suggest that the global sexual impact of endometriosis requires further investigation, focusing not only on pain during intercourse but also on psychological and relational dimensions, including partner's sexual functioning. Because sexual functioning is a complex, multidimensional phenomenon, the ideal treatment for endometriosis-related sexual dysfunctions should be conducted by a multidisciplinary team composed of gynecologists, sexologists, and psychologists/psychotherapists.

'Money for nothing'. The role of robotic-assisted laparoscopy for the treatment of endometriosis.

Despite higher costs for robotic-assisted laparoscopy (RAL) than standard laparoscopy (SL), RAL treatment of endometriosis is performed without established indications. PubMed/MEDLINE was searched for 'robotic surgery' and 'endometriosis' or 'gynaecological benign disease' from January 2000 to December 2016. Full-length studies in English reporting original data were considered. Among 178 articles retrieved, 17 were eligible: 11 non-comparative (RAL only) and six comparative (RAL versus SL). Non-comparative studies included 445 patients. Mean operating time, blood loss and hospital stay were 226 min, 168 ml and 4 days. Major complications and laparotomy conversions were 3.1% and 1.3%. Eight studies reported pain improvement at 15-month follow-up. Comparative studies were all retrospective; 749 women underwent RAL and 705 SL. Operating time was longer for RAL in five studies. Major complications and laparotomy conversions for RAL and SL were 1.5% versus 0.3% and 0.3% versus 0.5%. One study reported pain reduction for RAL at 6-month follow-up. RAL treatment of endometriosis did not provide benefits over SL, overall and among subgroups of women with severe endometriosis, peritoneal endometriosis and obesity. Available evidence is low-quality, and data regarding long-term pain relief and pregnancy rates are lacking. RAL treatment of endometriosis should be performed only within controlled studies.

Self-management and psychological-sexological interventions in patients with endometriosis: strategies, outcomes, and integration into clinical care.

Endometriosis has a multifactorial etiology. The onset and progression of the disease are believed to be related to different pathogenic mechanisms. Among them, the environment and lifestyle may play significant roles. Diet, dietary supplements, physical exercise, osteopathy, massage, acupuncture, transcutaneous electrical nerve stimulation, and Chinese herbal medicine may represent a complementary and feasible approach in the treatment of symptoms related to the disease. In this narrative review, we aimed to examine the most updated evidence on these alternative approaches implicated in the self-management of the disease. In addition, several studies have demonstrated that endometriosis may negatively impact mental health and quality of life, suggesting that affected women may have an increased risk of developing psychological suffering as well as sexual problems due to the presence of pain. In light of these findings, we discuss the importance of integrating psychological interventions (including psychotherapy) and sexual therapy in endometriosis treatment.

Laparoscopic repair of a symptomatic post-cesarean section isthmocele: a video case report.

OBJECTIVE: To describe our technique for laparoscopic management of post-cesarean section isthmocele. DESIGN: Surgical video article. Local Institutional Review Board approval for the video reproduction has been obtained. SETTING: University hospital. PATIENT(S): A 36-year-old patient with a history of two previous cesarean deliveries. She complained of persistent postmenstrual spotting and chronic pelvic pain. At transvaginal ultrasound examination, a cesarean scar defect of 20.0 × 15.6 mm was identified, with a residual myometrial thickness over the defect of 2.6 mm. MAIN OUTCOME MEASURE(S): Repair of isthmocele and relief of pain. INTERVENTION(S): Isthmocele excision and myometrial repair was performed laparoscopically. The first step of the procedure was the cautious mobilization of the bladder from its adhesions with the site of the previous cesarean scar. Subsequently, the isthmocele site was identified with the aid of intraoperative transrectal ultrasonography. Transrectal ultrasonographic assistance is particularly important when a bulge of the cesarean scar is not laparoscopically visible. Once identified, the isthmocele pouch was incised and its pitchy content drained. Then the cesarean scar was excised with cold scissors, avoiding cauterization to reduce the risk of tissue necrosis. This step is considered completed when the whitish scar tissue of the isthmocele site margins are no longer present and reddish healthy myometrium is visualized. Before suturing the defect, a Hegar dilator was placed into the cervix with the aim of maintaining the continuity between the cervical canal and the uterine cavity. Then, the myometrial repair was performed with the use of a single layer of interrupted 2-0 Vycril sutures. To limit tissue ischemia, we prefer not to add a second layer of sutures. Finally, the visceral peritoneum defect was closed, with the aim of restoring the physiologic uterine anatomy. In this case, multiple peritoneal endometriotic implants were also identified and excised. RESULT(S): Operating time was 70 minutes. The postoperative course was uneventful and the patient was discharged on postoperative day 2. At 40-day postoperative follow-up, transvaginal and transabdominal ultrasonography showed complete anatomic repair of the uterine defect. At 3-month follow-up, the patient reported resolution of postmenstrual spotting and chronic pelvic pain. CONCLUSION(S): Good reproductive outcomes have been reported after hysteroscopic treatment of uterine isthmocele. However, laparoscopy has the advantage over hysteroscopy of allowing thorough repair of the uterine defect, thus restoring a normal myometrial thickness. Therefore, as demonstrated in this case, a laparoscopic approach might be considered to be the procedure of choice for the repair of a large uterine isthmocele with extreme thinning of the residual myometrium.

Management of Endometriosis in the Infertile Patient.

The management of endometriosis-related infertility remains debated. However, in recent years, the role of in vitro fertilization (IVF) has progressively grown. Reasons to explain this change include (1) the improvement of the effectiveness and safety of IVF, (2) the raised awareness of the modest effectiveness of surgery, (3) the inherent risks of surgery including in particular the damage to the ovarian reserve when ovarian endometriomas have to be removed, (4) the ineffectiveness of intrauterine insemination and the possible risks of endometriosis progression associated with the use of this technique. However, IVF is not able to overcome all the potential detrimental effects of endometriosis and can actually fail. Future efforts should aim at improving the effectiveness and safety of both surgery and IVF. Fertility preservation techniques may play a role in the future, but data are currently too scanty to support its recommendation.

Surgery versus hormonal therapy for deep endometriosis: is it a choice of the physician?

Deep endometriosis, occurring approximately in 1% of women of reproductive age, represents the most severe form of endometriosis. It causes severe pain in the vast majority of affected women and it can affect the bowel and the urinary tract. Hormonal treatment of deep endometriosis with progestins, such as norethindrone acetate or dienogest, or estroprogestins is effective in relieving pain in more than 90% of women at one year follow up. Progestins and estroprogestins can be safely administered in the long-term, may be not expensive and are usually well tolerated. Therefore, they should represent the first-line treatment of deep endometriosis associated pain in women not seeking natural conception. However, hormonal treatment is ineffective or not tolerated in about 30% of women, the most common side effects being erratic bleeding, weight gain, decreased libido and headache. Surgical excision of deep endometriosis is mandatory in presence of symptomatic bowel stenosis, ureteral stenosis with secondary hydronephrosis, and when hormonal treatments fail. Surgical treatment is similarly effective as compared to hormonal treatment in relieving dismenorhea, dyspareunia and dyschezia at one year follow up in more than 90% of women with deep endometriosis. Surgical removal of the nodules may require resection of the bowel, ureter or bladder, with possible severe complications such as rectovaginal or ureterovaginal fistula and anastomotic leakage. A thorough counsel with the patient is necessary in order to pursue a therapeutic plan centered not on the endometriotic lesions, but on the patient's symptoms, priorities and expectations.

When love hurts. A systematic review on the effects of surgical and pharmacological treatments for endometriosis on female sexual functioning.

INTRODUCTION: Endometriosis is associated with an increased risk of dyspareunia, therefore this chronic gynecologic disease should be considered as a major cause of sexual dysfunctions. The aims of this study were to review the literature on the effects of surgical and pharmacological treatments for endometriosis on female sexual functioning, and to provide suggestions for future treatment strategies. MATERIAL AND METHODS: We followed the PRISMA guidelines to conduct this systematic review, which involved an electronic database search of studies on the association between endometriosis and sexuality published between 2000 and 2016. RESULTS: As a result of the screening process, 22 studies were included in this systematic review. The 22 studies included were divided into two categories: (a) surgical intervention studies (n = 17), examining postoperative sexual outcomes of surgery for endometriosis; (b) pharmacological intervention studies (n = 5), evaluating the effects of pharmacological endometriosis treatments on sexual functioning. The studies considered showed that overall surgical and pharmacological interventions for endometriosis can lead to medium-/long-term improvement, but not necessarily to a definitive resolution of female sexual dysfunctions due to endometriosis. CONCLUSIONS: Sexual functioning is a multidimensional phenomenon and the ideal treatment for endometriosis-related sexual dysfunctions should be conducted by a multidisciplinary team that involves not only gynecologists, but also sexologists and psychologists/psychotherapists. Improving global sexual functioning, and not just reducing pain at intercourse, should be considered as a major clinical goal of endometriosis treatment.

Estrogen-progestins and progestins for the management of endometriosis.

Endometriosis is characterized by frequent recurrences of symptoms and lesions even after extirpative surgery. Because medical therapies control but do not cure the disease, long periods of pharmacologic management may be needed until pregnancy desire or, sometimes, physiologic menopause. Hormonal drugs suppress ovulation and menstruation and have similar beneficial effects against pain. However, only estrogen-progestins and progestins have safety/tolerability/cost profiles that allow long-term use. These compounds induce atrophy of eutopic and ectopic endometrium, have antiinflammatory and proapoptotic properties, and can be delivered via different modalities, including oral, transdermal, subcutaneous, intramuscular, vaginal, and intrauterine routes. At least two-thirds of symptomatic women are relieved from pain and achieve appreciable improvements in health-related quality of life. Progesterone resistance may cause nonresponse in the remaining one-third. When using estrogen-progestins continuously, individualized, tailored cycling should be explained to improve compliance. All combinations demonstrated a similar effect on dysmenorrhea, independently from progestin type. Estrogen-progestins with the lowest possible estrogen dose should be chosen to combine optimal lesion suppression and thrombotic risk limitation. Progestins should be suggested in women who do not respond or manifest intolerance to estrogen-progestins and in those with dyspareunia and/or deep lesions. Progestins do not increase significantly the thrombotic risk and generally may be used when estrogens are contraindicated. Estrogen-progestins and progestins reduce the incidence of postoperative endometrioma recurrence and show a protective effect against endometriosis-associated epithelial ovarian cancer risk.

Adenomyosis: What the Patient Needs.

A panel of experts in the field of endometriosis expressed their opinions on management options in a 28-year-old patient, attempting pregnancy for 1 year, with severe cyclic pelvic pain and with clinical examination and imaging techniques suggestive of adenomyosis. Many questions this paradigmatic patient may pose to the clinician are addressed, and all clinical scenarios are discussed. A decision algorithm derived from this discussion is also proposed.