Emerging treatments

Aromatase inhibitors

Aromatase inhibitors (e.g., letrozole) may be considered by a specialist for use in the treatment of adenomyosis. The use of aromatase inhibitors is recommended by the European Society of Human Reproduction and Embryology (ESHRE) in conjunction with oral contraceptives, progestins, or gonadotropin-releasing hormone (GnRH) agonists for patients with pain associated with drug-resistant and surgery-resistant rectovaginal endometriosis.[154] The rationale for using aromatase inhibitors in the treatment of adenomyosis and endometriosis is based on the abnormal expression of aromatase cytochrome P450 in both diseases.[20][155] However, there is no robust evidence regarding the use of aromatase inhibitors for adenomyosis management.[156] One small randomized controlled trial involving 32 patients with adenomyosis compared the effectiveness of letrozole to the GnRH agonist goserelin over a period of 12 weeks; both groups showed a reduction in total adenomyoma volume at 12 weeks (40.9% for letrozole vs. 49.1% for goserelin) with no significant difference found between the two groups.[114]

GnRH antagonists

GnRH antagonists induce a dose-dependent suppression of the pituitary-gonadal axis and have an established role in the context of endometriosis and uterine leiomyomas. The data to support the use of GnRH antagonists in adenomyosis are limited, but case reports and pilot studies of GnRH antagonists for adenomyosis have shown promising results, with reduction of lesion size and improved patient quality of life. However, a rapid return to baseline uterine volume and bleeding patterns was observed within 12 weeks of discontinuation.[109][157][158][159] Large-scale studies are required.

Selective progesterone receptor modulators

Selective progesterone receptor modulators (e.g., ulipristal, mifepristone) have been shown to reduce heavy menstrual bleeding and improve quality of life in women with symptomatic fibroids.[157][160] Available data suggest that selective progesterone receptor modulators may have a beneficial role in treating patients with abnormal uterine bleeding due to adenomyosis, while the evidence regarding pelvic pain and dysmenorrhea is conflicting.[161] In one retrospective cohort study, the efficacy of ulipristal was compared between patients with both leiomyomas and adenomyosis (cases) versus patients with leiomyomas alone (controls). The results showed that 90.2% of cases achieved optimal bleeding control compared with 73.8% in the control group (P = 0.028). Improvement in reported visual analog scale scores was also noted in patients treated with ulipristal.[162] Similar results have been reported using mifepristone in patients with adenomyosis, with improvement in pain as reported by visual analog scale scores.[163] In one randomized controlled trial investigating the use of ulipristal in patients with adenomyosis, significant improvements in bleeding, amenorrhea, and pain scores were reported. However, no difference was observed after 3 months of stopping the treatment, and there was no improvement in quality of life or anemia after 6 months.[164] Contradictory results were reported in a few case series and reports, where worsening of pelvic pain and radiologic findings were observed after 3 months of ulipristal treatment, not only in the extent of the disease but also in the size and number of lesions.[157][165] Note that ulipristal has significant adverse effects, including weight gain, fatigue, and abdominal discomfort.[166] Safety concerns, including reports of liver injury requiring transplantation, have led to the withdrawal of ulipristal for the treatment of fibroids in some countries.[167]

High-intensity focused ultrasound (HIFU)

HIFU is a minimally invasive thermal ablation procedure that has shown promise for management of adenomyosis.[2] This is a conservative alternative to surgery that employs focused ultrasound waves to heat targeted tissue, resulting in coagulative necrosis and cell death without damage to surrounding tissues.[168] The procedure is typically monitored with magnetic resonance imaging (MRI) or ultrasound, and does not require incisions.[168] Severe adverse effects have been found to be rare.[169][170] HIFU has been found to significantly reduce uterine size in patients with adenomyosis, ranging from 12.7% at 6 months to 54.0% at 12 months in various studies.[168][169] It also shows promise in reducing heavy menstrual bleeding, with a 25% to 66% reduction at 12 months reported in studies using MRI-guided focused ultrasound and 48% to 65% reduction in studies using ultrasound-guided focused ultrasound.[171][172] HIFU may also improve dysmenorrhea associated with adenomyosis, with reported improvement in menstrual pain scores ranging from 25% to 83%.[173] A desire for future fertility is considered to be a relative but not absolute contraindication to HIFU.[126] However, the data to counsel patients regarding timing, risks, efficacy, and fertility outcomes are still lacking. Combining medical treatment such as GnRH agonists or the levonorgestrel intrauterine device (IUD) with HIFU may also be beneficial.[174][175]

Uterine-sparing excision surgery (for diffuse adenomyosis)

Uterine-sparing excision surgery (adenomyomectomy) may be considered as a last resort for diffuse adenomyosis in patients who wish to preserve fertility. It must be performed by highly skilled and experienced surgeons in specialized centers. The surgical procedure for resection of diffuse disease is significantly more challenging than for focal disease, and carries considerable perioperative risks. It typically requires advanced techniques performed primarily via laparotomy, although minimally invasive approaches have also been reported.[141][176] Careful counseling is essential regarding the uncertain impact on fertility and pregnancy outcomes and the increased risk of serious complications in any subsequent pregnancy.[2] The risk of uterine rupture is increased with a greater extent of excision and associated larger size of myometrial defect.[2] Many experts recommend prelabor cesarean delivery.[126] According to one meta-analysis, the rupture rate after surgery for diffuse adenomyosis was found to be 6.8%; however, only 44 cases were included in this analysis.[177] Subsequent retrospective studies have shown no cases of uterine rupture following diffuse excisional surgery, based on 75 pregnancy outcomes across two studies.[178][179]

Hysteroscopic excision

Hysteroscopic resection of adenomyosis has been described in the literature, but data on its safety, efficacy, and impact on fertility are scarce.[126] One case series of 51 patients who underwent hysteroscopic resection of adenomyotic cysts under transabdominal ultrasound guidance found that bleeding symptoms improved in 65%, with partial or complete relief.[180] At 2-year follow-up, clinical effectiveness was reported in 84.6% of patients, and over 93% of women reported improvement in dysmenorrhea.[180] No fertility outcomes were reported.

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