Current Medical Therapy for Adenomyosis: From Bench to Bedside

Adenomyosis presents significant challenges in treatment, with current literature primarily focusing on managing abnormal uterine bleeding (AUB) and dysmenorrhea, the main symptoms associated with the condition. Nonsteroidal anti-inflammatory drugs (NSAIDs) and tranexamic acid have limited roles in therapy, mainly providing support for mild symptoms or symptom re-exacerbation during hormone therapy. Progestins such as LNG-IUS (levonorgestrel-releasing intrauterine system) and oral dienogest are commonly used in adenomyosis management, showing promise in improving symptoms and reducing uterine size. However, the lack of guidelines hampers their standardized use. Literature evaluating the medical treatment of adenomyosis-related infertility is very limited. Further research is needed to establish evidence-based guidelines for the medical management of adenomyosis. Additionally, the investigation of new treatment targets, including GnRH antagonists and aromatase inhibitors, holds promise but requires more exploration for their potential in adenomyosis treatment.

It is already known that adenomyosis has adverse obstetric effects such as premature birth, preterm rupture of the membranes, and live birth rate [ 100 ]. Additionally, recent studies have shown that adenomyosis also negatively affects in vitro fertilization outcomes and may cause an increased risk of miscarriage. Anatomical factors such as the global enlargement of the uterus and its anatomical distortion by the presence of intramural adenomyoma can affect utero-gamete and/or the embryo transport or the receptivity of the endometrium [ 101 , 102 ]. Additionally, adenomyosis and endometriosis are highly comorbid conditions. Therefore, adenomyosis should be considered in the diagnosis and management of patients who are undergoing infertility treatment due to endometriosis. While existing research on the medical treatment of adenomyosis focuses on AUB and dysmenorrhea, literature evaluating the medical treatment of adenomyosis-related infertility is very limited. Huang et al. conducted a retrospective study including nine adenomyosis patients with a history of unexplained infertility. All patients received a 6-month GnRH-a treatment following fertility-sparing surgery. They showed that the GnRH-a therapy had a positive effect on dysmenorrhea however the benefit on fertility was still questionable [ 103 ]. In a systematic review conducted by Rocha et al. in 2018, conservative treatments of adenomyosis-associated infertility were evaluated [ 102 ]. The authors reported a higher pooled spontaneous pregnancy rate after the administration of GnRH-as for 24 weeks following conservative surgery for adenomyosis. Cozzolino et al. [ 104 ] conducted a study among women with severe adenomyosis undergoing infertility treatment. They reported that in situations when long-term treatment (≥ 3 months) with depot GnRH-as failed an additional treatment with an AI for 21 days could be beneficial prior to IVF treatment. Intralipid comprises a sterile lipid emulsion composed of polyunsaturated fatty acids derived from soybean oil and egg yolk phospholipids. Lipid emulsions have been comprehensively documented to demonstrate a wide spectrum of immune-modulatory and anti-inflammatory effects, notably encompassing the suppression of natural killer (NK) cell activity [ 105 ]. Given that eutopic endometrium in individuals with adenomyosis often exhibits an inflammatory infiltrate characterized by elevated counts of macrophages and NK cells, the consideration of intralipid administration in the context of adenomyosis has been proposed [ 106 ]. In a retrospective cohort study involving 116 consecutive adenomyosis patients who underwent their initial transfer of a genetically screened euploid embryo, the administration of intralipid as an adjuvant treatment in conjunction with GnRH-a therapy (long downregulation) yielded markedly higher live birth rates (60%) in comparison to GnRH-a therapy alone (40%). This observed difference has been attributed to a twofold increase in the miscarriage rate observed in adenomyosis patients undergoing GnRH-a treatment without the inclusion of intralipid [ 107 ]. Another study from China by Liang et al., evaluated the effect of LNG-IUS on pregnancy rates of women with adenomyosis who were undergoing IVF treatment with a frozen embryo transfer cycle. When these women were treated with LNG-IUS prior to embryo transfer, higher pregnancy rates were reported in comparison with the controls [ 108 ]. However, these results are yet to be validated by randomized controlled trials. Additionally, the benefits of NSAIDs and/or oral contraceptives on the fertility of adenomyosis patients have also not been reported in the literature [ 109 ].

To date, there is no approved medical therapy for adenomyosis, and the evidence for deciding which medical treatment is preferred is severely limited, partly because of the complexity of diagnosis, partly because of the prevalence of concomitant gynecological conditions, such as endometriosis and uterine leiomyomas, which often may influence the response to medical therapy, sometimes necessitating recourse to surgical approach. The concomitant prevalence of endometriosis in patients with adenomyosis is well-documented, with a significant number of individuals exhibiting both conditions simultaneously [ 110 ]. This overlapping occurrence poses challenges in the management of symptoms and treatment decisions. However, it has been observed that medical therapies targeting adenomyosis can also provide beneficial effects on symptoms related to endometriosis. Currently, the available literature focuses mainly on the treatment of AUB, dysmenorrhea, and the attempt to restore the original volume of the enlarged uterus in cases of adenomyosis. Data evaluating fertility outcomes and the impact the disease may play on sex life and QoL in general after treatment are scarce and not supported by robust evidence. Nevertheless, scientific research evaluating new drugs for adenomyosis is active, as evidenced by the various ongoing trials in this field (Table 2 ). Table 2 Ongoing trials on medical therapies for the treatment of adenomyosis NCT number Conditions Study design Interventions Outcome measures NCT05151016 Patients with adenomyosis Randomized interventional study Study Group: mifepristone 10 mg oral tablets, daily for 24 weeks Change from baseline in pain on the visual analogue scale at week 24 Control Group: Triptorelin Acetate 3.75 mg subcutaneous injection, every 28 days for 24 weeks Pictorial blood loss assessment chart Change from baseline in uterine size at week 24 Change from baseline in hemoglobin at week 24 Change from baseline in CA125 at week 24 NCT03654144 Patients with adenomyosis Randomized interventional study Study Group: Dienogest oral tablet Mean pain score Control Group: Combined Oral Contraceptive NCT03421639 Patients with adenomyosis Patients who underwent recurrent implantation failure Randomized interventional study Study group: oral anastrazole 1 mg/day oral tablet plus leuprolide 3.75 mg/monthly for 12 weeks Pregnancy after embryo transfer Uterine volume reduction Control Group: leuprolide acetate 3.75 mg subcutaneous injection, every 28 days for 12 weeks NCT03037944 Patients with adenomyosis Randomized interventional study Group A: LNG- IUS 60 mg Measurement of pain by an appropriate pain measurement score Group B: ethinyl estradiol 0.03 mg plus drospirenone 3 mg oral tablets, daily for 24 weeks. Number of bleeding days NCT02556411 Patients with adenomyosis Randomized interventional study Study group: LNG 0.10 mg plus ethinylestradiol 0.02 mg oral tablets, daily Change of pelvic pain as measured by visual analogue scale Quality of sexual life Control group: LNG-IUS 13.5 mg. LNG-IUS levonorgestrel intrauterine system Ongoing trials on medical therapies for the treatment of adenomyosis Patients with adenomyosis Patients who underwent recurrent implantation failure Pregnancy after embryo transfer Uterine volume reduction Change of pelvic pain as measured by visual analogue scale Quality of sexual life LNG-IUS levonorgestrel intrauterine system Therapy with NSAIDs may only be useful as a support in the case of mild symptoms or re-exacerbation of symptoms during hormone therapy; however, if these drugs are effective in treating menstrual pain, no data are present related to the superiority of one NSAID in comparison with another; additionally, NSAIDs seems to be less effective than hormonal treatment or tranexamic acid on treating AUB associated to adenomyosis [ 20 , 21 ]. LNG-IUS appears to be an effective first-line therapy for treating adenomyosis, which succeeds in improving symptoms and in decreasing the uterine size of patients affected [ 31 – 33 ]. The low incidence of adverse effects and the long duration of action, once this progestin-releasing device is inserted into the uterine cavity, make it one of the treatments of choice in cases of adenomyosis, reducing the need for surgical interventions. Several studies have investigated the efficacy of DNG in the treatment of adenomyosis and have reported promising results [ 42 ], with efficacy levels comparable to those of LNG-IUS, according to some authors [ 26 ]. Unfortunately, both in the case of LNG-IUS and particularly in the case of DNG, the limited number of studies available prevents us from attaining a high level of scientific evidence to provide definitive treatment recommendations in this context. By reducing estrogen levels, danazol helps alleviate symptoms associated with adenomyosis such as pelvic pain and AUB. However, the use of danazol in adenomyosis therapy is limited due to its androgenic side effects, including weight gain, acne, and voice changes. These side effects can significantly impact patients’ quality of life and may lead to noncompliance with treatment. However, if administered vaginally [ 55 ] or trans-cervically [ 56 ], it would seem to be able to guarantee good results in terms of remission of symptoms and restoration of uterine size. Furthermore, the availability of other hormonal options, such as progestins, with better tolerability profiles has led to a decrease in the use of danazol in adenomyosis therapy. At the best of our knowledge, no specific trials have been developed on the role of other progestins, such as desogestrel [DSG] and etonogestrel [ETG]-subdermal implant, for treating patients with adenomyosis; however, it could be argued that these drugs could exert a similar benefit on pain symptoms owing to suppression of the hypothalamic–pituitary–ovarian axis and a less hypoestrogenic effect. In general, a potential disadvantage of progestins in women desiring contraception is that only few of them (DSG, ETG-subdermal implant and LNG-IUS) are approved as contraceptives. COCs can be offered to young patients who do not desire to place LNG-IUS, and who do not tolerate the (often common) side effects occurring under oral progestin therapy, or who also requires contraception. Although successful in controlling dysmenorrhea and AUB due to adenomyosis, patients should be made aware of the possibility that treatment with COCs may be less effective than treatment with progestins, as previously reported [ 36 ]. GnRH-as have demonstrated effectiveness in managing symptoms related to adenomyosis, although at the moment they should be considered as second-line therapy for patients with adenomyosis. In fact, the use of GnRH-as is limited by its hypogonadal effects, and adherence to treatment without clear guidelines on add-back therapy is challenging for many women [ 65 ]. Nevertheless, the use of GnRH-as has been also employed prior to fertility treatments to improve the chances of pregnancy in infertile women with adenomyosis [ 111 ]. After being studied for the treatment of endometriosis [ 112 , 113 ], new research is demanding to study the effectiveness and safety of GnRH-ants for treating adenomyosis. The principal purported advantages of GnRH-ants in the context of these hormonal-dependent diseases encompass dose-dependent estrogen suppression, spanning from partial suppression at lower doses to near-complete suppression at higher doses. However, GnRH-ants could maintain sufficient circulating estrogen levels for limiting vasomotor symptoms, vaginal atrophy, and loss of bone mineral density; additionally, they are characterized by immediate suppression of gonadotropins, circumventing the flare-up effect and by swift reversibility, with a return to normal hormone secretion following the cessation of treatment; lastly, they have oral administration for enhanced convenience. However, it is important to note that customizing the extent of hypoestrogenism may correlate with the degree of clinical response. In other words, reducing side effects may be linked to an incomplete alleviation of pain. Existing data suggests that lower dosages of GnRH-ants, particularly those tailored to maintain favorable estrogen levels to preserve bone density, may not provide comprehensive pain relief for individuals with endometriosis. It is worth noting that a similar scenario could also apply to adenomyosis, especially considering that in the majority of trials observing adenomyosis, there is a significant coexistence of endometriosis and adenomyosis in the enrolled patients [ 70 , 71 ]. Nevertheless, more evidence is needed for drawing a conclusion on the role of GnRH-ants for treating adenomyosis, in particular, investigating the impact of a long-term regimen and the concomitant necessity of adopting an add-back therapy. In light of the limited findings on the role of medical options for infertility and adenomyosis, the use of GnRH-as or progestins (oral or LNG-IUS) for 3 to 6 months prior to embryo transfer could be an option for patients who are undergoing IVF treatment with a frozen embryo transfer cycle. Additionally, considering the recent advancements in GnRH-ants, characterized by different dosages and biological activities, these agents might become increasingly significant in the treatment of adenomyosis-related infertility in the future. The important point being made is that relying solely on GnRH-as or -ants to suppress ovarian estrogen production may not be sufficient to completely quiesce adenomyosis because of this local estrogen production by aromatase in the adenomyotic tissue itself [ 84 ]. To address this issue, the use of AIs has been investigated, showing efficacy for the improvement of AUB and pelvic pain associated with adenomyosis [ 64 ]. Nevertheless, the role of AIs in the management of adenomyosis requires further research, as previous data on their use consists in small nonrandomized trials. Additionally, the potential risk of endometrial cancer associated with AI use warrants careful consideration and requires clarification through additional investigations [ 88 ]. AIs could theoretically complement GnRH-as or GnRH-ants by further reducing the available estrogen, not only from the ovaries but also from the local enzymatic activity within the adenomyotic tissue. Although the combination of AIs and GnRH-as has been extensively investigated as adjuvant hormonal therapy for breast cancer [ 114 ], no data on adenomyosis are present in the current literature. SPRMs have a controversial role in the management of adenomyosis, as data evaluating their role in this setting are limited. UPA has been evaluated in a few studies, reporting comprehensive data on symptom control [ 78 ]. However, there are international alerts suggesting a risk of serious liver problems associated with its use. Mifepristone, with its anti-inflammatory effect, may reduce symptoms and disease progression [ 79 ]; however, evidence related to this drug is very limited and larger patient numbers are needed to determine its actual efficacy. Similar to endometriosis [ 115 ], the development, maintenance, and progression of adenomyosis are due to a variety of altered mechanisms including cell proliferation, immune function, apoptosis, invasion capacity, and angiogenesis. The growing knowledge of different molecular pathways involved in endometriosis development paved the way for the investigation of new drugs. Among them, in the future, modulation of prolactin [ 90 , 91 ] and studies on the epigenetics of adenomyosis [ 92 ] could provide new nonsteroidal therapeutic options for the treatment of adenomyosis. A significant factor contributing to the failure of numerous nonhormonal drug research, nonreaching late stage of scientific investigation in humans, is the lack of comprehension of the natural progression of ectopic endometrium, which is implied in the pathogenesis of adenomyosis and endometriosis [ 116 , 117 ]. This often arises from the utilization of animal models that inadequately replicate the essential characteristics of human conditions. In conclusion, adenomyosis remains a challenging condition to manage due to the lack of approved medical therapies and limited high-quality evidence supporting treatment decisions. The available literature primarily focuses on addressing symptoms such as AUB and dysmenorrhea, as well as reducing the size of the enlarged uterus. Future research should aim to elucidate the optimal therapeutic strategies for adenomyosis, explore novel nonsteroidal treatment options, and expand our understanding of the disease’s impact on fertility and quality of life.

Adenomyosis is a common benign condition affecting women and is characterized by dysmenorrhea, menorrhagia, abnormal uterine bleeding (AUB), infertility, and chronic pelvic pain. This disease occurs when the endometrium invades the myometrium, resulting in a diffuse uterine enlargement. Microscopic examination reveals non-neoplastic ectopic endometrial glands and stroma surrounded by hypertrophic and hyperplastic myometrium [ 1 , 2 ]. The disruption of the normal junction between the basal endometrium and myometrium is hypothesized to be the primary event leading to the development of adenomyosis [ 3 , 4 ]. Although the exact cause of this junction disruption is not fully understood, it has been suggested that forceful and uncoordinated myometrial contractions, often seen in women with heavy menstrual flow [ 5 ] may contribute to the pathogenesis of adenomyosis. Additionally, the disease onset may be favored by disruption of the endometrial–myometrial border due to spontaneous, induced abortion or uterine dilatation and curettage, although the pathogenic action of these factors is controversial [ 6 , 7 ]. Adenomyosis is frequently associated with endometriosis [ 8 , 9 ]. While they share similarities, adenomyosis is considered a distinct entity from endometriosis, and there are clinical and pathological features that differentiate them [ 8 , 10 , 11 ]. Adenomyosis can also coexist with uterine leiomyomas [ 12 ] or congenital uterine anomalies [ 13 ], making their differentiation challenging on ultrasound examination [ 14 ]. In some cases, these associations may require surgical intervention rather than medical treatment alone. Furthermore, depending on a woman’s age, desire for fertility, and reported symptoms, adenomyosis may necessitate long-term medical therapy that extends until menopause [ 15 ]. Currently, there are no established guidelines for the treatment of adenomyosis. However, like endometriosis, which is also a hormone-dependent inflammatory condition, various hormonal and nonhormonal treatments are being used off-label to manage adenomyosis (Fig. 1 ). While these treatments can effectively control symptoms in many cases [ 16 – 18 ], their efficacy may vary. The aim of the current narrative review is to give an overview of the main drugs employed or under investigation for treating adenomyosis. Fig. 1 The biological targets of the main drug classes available for treating symptoms related to adenomyosis The biological targets of the main drug classes available for treating symptoms related to adenomyosis