Individualized conservative therapeutic strategies for adenomyosis with the aim of preserving fertility

Lei Han, Han L, Yanni Liu, Liu Y, Kaixue Lao, Lao K, Jiang J, Jianxi Jiang, Zhang C, Caiying Zhang, Wang Y, Yanlin Wang
Frontiers in medicine · 2023 · vol. 10 , pp. 1133042 · doi:10.3389/fmed.2023.1133042 · PMID:37064035 · PMC10098355 · W4361271385
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This paper discusses individualized conservative therapeutic strategies for adenomyosis to preserve fertility, aiming to improve assisted reproduction and long-term management by preserving the uterus.

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This paper reviews and synthesizes individualized conservative therapeutic strategies for adenomyosis, emphasizing fertility preservation in reproductive-age women, and discusses the disease’s proposed pathogenesis and major imaging diagnostic criteria using transvaginal ultrasound (FIGO 2018 features) and MRI, with surgery/biopsy noted as the gold standard. It finds that because etiology and mechanisms remain incompletely understood and there are no unified diagnostic criteria, management often focuses on long-term symptom control and reduction/avoidance of recurrence while tailoring treatment to age, ovarian reserve, severity, prior therapies, symptoms, and fertility goals. Across medication classes, it reports that NSAIDs can relieve pain but do not prevent progression and have relapse after withdrawal, while combined oral contraceptives and androgen derivatives reduce menstrual symptoms but carry cautions such as thromboembolic risk or recurrence and androgen-like adverse effects. The paper also describes progesterone-based approaches (including dienogest and dydrogesterone) as mechanisms for lowering endometrial proliferation and lesion expansion, with noted safety considerations and adverse effects, and it highlights that long-term mifepristone safety needs further verification. This paper is centrally about adenomyosis — it specifically focuses on individualized conservative therapeutic strategies aimed at preserving fertility.

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Abstract

Adenomyosis is a diffuse or localized organic disease caused by benign invasion of endometrial glands and stroma into the myometrium. It is a common disease that seriously affects reproductive health of women in childbearing age. Due to the unknown etiology and pathophysiological mechanism, and the lack of unified diagnostic criteria and effective treatment methods, total or subtotal hysterectomy has become a radical treatment for adenomyosis, which will lead to the complete loss of fertility. With the continuous exploration of the treatment to adenomyotic patients who have infertility or fertility intentions, new drugs, surgical methods and treating concepts appears. Adopt individualized conservative therapeutic strategies for patients with different conditions, preserve the uterus as much as possible and protect the patient's fertility, which will play an important role on the follow-up assisted reproductive treatment and long-term management of adenomyosis.
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High

High intensity focused ultrasound (HIFU) is a kind of physical therapy, which has the advantages of no operation, no bleeding, no ionizing radiation and repeatability ( 38 ). It is a more accurate treatment for localized adenomyosis with good effect, and preserves the integrity of the uterus. It is suitable for patients who have fertility planning and desire to conserve the uterus. The principle of HIFU ablation is to focus the ultrasound on the target tissue through the instrument. The thermal effect, cavitation effect and other physical effects of the ultrasound instantly raise the temperature of the target tissue to 65°C ~ 100°C, and cause tissue protein denaturation, coagulative necrosis. The tissue finally is dissolved, absorbed, calcified or fibrotic ( 41 ). With the continuous improvement of technology, the popularity and indications of HIFU treatment are gradually expanding, but it is easy to recur. In most cases it needs to be used in combination with other methods ( 45 ).

Intro

Adenomyosis is a benign invasion of endometrial glands and stroma into the myometrium, causing myofibrillar connective tissue hypertrophy and hyperplasia, and forming diffuse or localized lesions of the uterus ( 1 ). Its main clinical manifestations are progressive dysmenorrhea, uterine enlargement, abnormal uterine bleeding (including increased menstrual volume and prolonged menstrual cycle) and infertility ( 2 ). Its occurrence in the infertility population can reach to more than 30%, and it seriously affects the patients’ quality of life. As adenomyosis is more common in women of childbearing age, it has gradually become one of the important clinical problems impairing human fertility, and its incidence rate range from 5 to 70% ( 3 ). Severe adenomyosis may be associated with adverse pregnancy and delivery outcomes ( 4 ). The pathogenesis of adenomyosis is an important basis for treatment, but it has not been fully clarified. There are two main hypotheses about the pathogenesis of adenomyosis ( 5 ). One is the endometrial metaplastic hypothesis: adenomyosis lesions are generated directly by the differentiation of ectopic Mullerian tube residual cells, especially pluripotent stem cells with embryonic pluripotent ( 6 ). This hypothesis can partly explain the reason why many unmarried young women without pregnancy suffer from adenomyosis. The other is the endometrial metastatic hypothesis, which believes that the enhancement and disorder of endometrial peristaltic waves, intrauterine infection (including Mycobacterium tuberculosis) or surgical procedures lead to the damage of endometrial-myometrial interface, namely the endometrial myometrium junction zone (JZ); then the glandular cells and stromal cells in the endometrium pass through the endometrial basal layer at the damaged site and invade the myometrium ( 7 , 8 ). Endometrial stem cells may be recruited and self-repairing mechanism may be initiated in the local lesion. At the same time, the lesion can induce immune imbalance and aseptic inflammation, with increasing proglandin E2 (PGE2), proglandin H2 (PGH2), cyclooxygenase-2 (COX-2) and transforming growth factor β1 (TGF-β1), vascular endothelial growth factor (VEGF) and other factors ( 5 ). The increased aromatase activity promotes the synthesis of estradiol, which will up-regulate oxytocin and its receptor, as well as enhance peristalsis and damage of the endometrium ( 9 ). In this way, a vicious circle will be created, which eventually caused the cracking of the myometrium, endometrial basal cells invading into the myometrium, and the formation of adenomyosis lesions locally. This hypothesis can explain the clinical manifestations of elevated estrogen, menstrual abdominal pain, and increased menstruation in patients with adenomyosis ( 5 ). In addition, there are other hypotheses, such as the hypothesis of retrograde menstruation, mesothelial metaplasia, etc. ( 6 , 10 ). So far, no single hypothesis can fully explain all the pathological mechanisms and clinical manifestations of adenomyosis. Recently, investigations on the relationship between colors of human iris and hair and the characteristics of endometriosis may provide new inroads into the molecular aspects of the pathological mechanisms of these complex diseases ( 11 ). At present, there is no consensus on the diagnostic criteria of adenomyosis by imaging methods. The criteria for the diagnosis of adenomyosis based on transvaginal ultrasonography (TVUS) images developed by the Federation International of Gynecology and Obstetrics (FIGO) in 2018 included eight ultrasound features ( 12 , 13 ): asymmetric thickening of the myometrium, cystic lesions of the myometrium, island hyperechoic signals, fan-shaped shadows, linear or punctate echoes of the endometrium, streaked blood flow signals passing through the lesions, irregular shape and discontinuous JZ. If there are 2 or more of the above signs, the diagnosis can be made in combination with the patient’s clinical manifestations. MRI features of adenomyosis are of great significance for diagnosis ( 13 , 14 ). On T2-weighted imaging, localized adenomyosis showed ovoid, irregular or quasi-circular mass in the myometrium, with unclear boundary, low signal similar to the JZ, and scattered dotted or flaky high signal in the lesion, showing cystic expansion or hemorrhage in the lesion. Diffuse adenomyosis showed equal signal on T1-weighted image (T1WI), and dotted high signal in some lesions of T2WI showed that JZ was damaged, showing diffuse thickening. When the thickness of JZ > 12 mm, adenomyosis was highly suspected. If the thickness of JZ is 8–12 mm, combined with high signal spots or irregular boundary, it is proposed to be diagnosed as adenomyosis. Of course, pathological examination through surgery or biopsy is the gold standard for the diagnosis of adenomyosis.

Author

LH and YL determined the topic and write the manuscript. KL and JJ retrieved literatures. CZ made the table. CZ and YW analyzed data and revised the manuscript. All authors contributed to the article and approved the submitted version.

Disclaimer

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Conclusions

Adenomyosis is a disease that tends to occur in childbearing aged women. The treatments are diverse but lack specificity. The basic treating principles for the adenomyosis patients with fertility requirements should include protecting physical and mental health, preserving reproductive organs and functions. It is crucial to allow patients the full advantages of each method and choose an individualized strategy according to the grading and needs of each patient. Follow up should be insisted, and combined or continuous therapy should be used to relieve symptoms and prevent disease progression if necessary.

Conservative

The uterus is not only a reproductive organ, but also plays a role in maintaining the normal anatomical structure of the pelvic floor as well as the blood supply of pelvic organs, especially ovary. Radical surgery, including total hysterectomy or subtotal hysterectomy, is the most thorough and effective method to treat adenomyosis, but it will deprive the fertility and have adverse effects on patients’ pelvic floor function, ovarian function, sexual life quality and self-cognition ( 46 ). Therefore, more and more attention has been paid to the conservative surgery. Uterine artery embolization (UAE) and laparoscopic uterine artery occlusion on patients with adenomyosis both aim to block the blood supply of the lesion, but may lead to obstruction of ovarian blood supply or endometrial necrosis, resulting to secondary infertility ( 47 ). Transcervical endometrial resection (TCER) can lessen the symptoms of adenomyosis but cannot interfere with its progress. TCER removes the material basis of embryo implantation, so it cannot be used for patients with fertility requirements ( 48 ). Resection of uterine lesion (RUL) is a very complex and challenging operation, and to achieve a balance between removing adenomyosis and retaining normal myometrium and the integrity of the uterus ( 49 ). RUL is often applied to adenomyosis patients with fertility requirements or young age. Therefore, there is no completely rigid surgical procedure, and flexible operations should be carried out according to factors such as the shape of the uterus, the size and location of the lesions. Common operational methods include wedge resection, asymmetric resection, and partial resection of muscle wall lesions ( 50 ). The repair of uterine myometrium and the reconstruction of uterine body are crucial for the uterus to withstand pregnancy, including H-shaped and, U-shaped suture, muscle overlapping-flap suture and triple-flap suture proposed by Osada, etc. ( 51 , 52 ). In recent years, Xiao et al. have created the major uterine wall resection and reconstruction of the uterus (MURU) on the basis of RUL, which provides a new surgical method for patients with severe adenomyosis to preserve the uterus ( 42 ). MURU destroys the structure of the uterus, and the uterine scar is large with the high risk of uterine rupture during pregnancy. Therefore we are modifying the procedures to meet the fertility requirements of patients after operation. Of course, multi-center clinical research and more verification are needed before large-scale promotion of MURU. However, the recurrence, low natural pregnancy rate and the risk of uterine rupture during pregnancy are the main problems after conservative surgery ( 53 ). It is very important to treat as early as possible and develop an individual combined therapy to preserve the uterus according to the degree of adenomyosis.

Coi Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Individualized

Different therapies for adenomyosis have their own advantages and disadvantages, which causes great confusions for doctors and patients and probably leads to insufficient or excessive treatments ( Table 1 ). Xiao et al. proposed a personalized therapeutic strategy based on the concept of grading, which provides a new option for patients with adenomyosis who wish to preserve fertility ( 41 , 42 ). It divides adenomyosis into three grades according to the LR: mild (LR ≤ 30 mm), medium (LR between 30-40 mm) and severe (LR ≥ 40 mm). The corresponding processing methods for each grade are as follows: The characteristics and application of individualized fertility preserving treatments for adenomyosis. (1) For patients of mild grade, the long-term management by LNG-US is the main method. If there are still symptoms such as dysmenorrhea after that, NSAIDs, progesterone and COC should be given. Remove LNG-US before receiving assisted reproductive therapy. (2) For patients of moderate grade, GnRH-a can be used for 3–6 months firstly. If LR reduces to ≤30 mm, the patients should be treated according to the principle of mild grade. If LR does not reduce obviously, HIFU can be used for to reduce LR as combined treatment. (3) For patients of severe grade, GnRH-a should also be used for 3–6 months firstly. RUL or modified MURU should be performed after GnRH-a, and LNG-US is placed into the uterine cavity during the surgery. Remove LNG-US before receiving assisted reproductive therapy. This grading of adenomyosis is mainly based on the LR in imaging, which lacks evaluation of clinical symptoms of patients, and needs further development to be widely used in practice. Anyway, this grading strategy is a great promotion to the treatment of adenomyosis.

Funding Information

This work was supported by the Scientific Research Fund of Binzhou Medical University (BY2021KYQD34); Scientific Research Initiation Fund of Affiliated Hospital of Binzhou Medical University Hospital (2021-03); Science and Technology Plan Project of Honghuagang District in Zunyi City (Zun Hong Ke He She[2020] No. 07); Science and Technology Plan Project of Zunyi City (Zun Yi Ke He HZ[2020] No. 271).

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