Uterine adenomyosis is a chronic disease that affects women of childbearing age from years to decades. Conservative surgeries are difficult to perform, and the lesions are prone to recurrence after surgery. They require long-term management. As one of the important issues of long-term management, drug therapy is useful and has effects on controlling symptoms, delaying the progress of the disease, and preventing recurrence. According to the different mechanisms of action, the indications for medication should be understood, used alone or in combination with surgical treatment and integrated traditional Chinese and western medicine. While taking a medication, attention should be paid to the side effects, and evaluate the progress of the adenomyosis. Therefore drug treatment and regular follow-up monitoring are important strategies. In this chapter, the mechanisms and side effects of common drug treatments for adenomyosis are introduced one by one.

10.1 Types and Options of Drug Therapy

10.1.1 Combined Oral Contraceptive (COC)

Combined oral contraceptives (COC) are a combination of steroid hormone preparations containing low doses of estrogen and progesterone. By inhibiting ovulation and endometrial growth, reducing menstrual flow and prostaglandin secretion [1], reducing uterine pressure and uterine spasm, and alleviating dysmenorrhea, COC is the first-line treatment for primary dysmenorrhea, endometriosis-related pain. It also can be used to treat adenomyosis-related pain and heavy menstrual bleeding. Either cyclic or continuous medication can be selected. Although COC is effective in treating endometriosis, the exact effect of dysmenorrhea and menorrhagia induced by adenomyosis has reported by little.

10.1.2 Progestins and Anti-Progestins

10.1.2.1 Levonorgestrel Intrauterine System (LNG-IUS)

Levonorgestrel intrauterine system (LNG-IUS) can continuously and slowly release levonorgestrel locally in the uterine cavity, causing a high-concentration progesterone environment in the uterine cavity, and down-regulating the estrogen and progesterone receptors. As a result, it has a significant inhibitory effect on prostaglandin synthesis in the endometrium, reducing intrauterine pressure and uterine contraction, relieving the severity of pain. LNG-IUS is not only suitable for contraception but also can treat dysmenorrhea and heavy menstruation and prevent recurrence after surgery. An observational study using LNG-IUS [2, 3] in 1100 gynecology patients with heavy bleeding and/or severe dysmenorrhea diagnosed with adenomyosis showed that LNG-IUS significantly reduced adenomyosis-related heavy menstrual periods and dysmenorrhea. The menstrual flow improvement reached a plateau stage after about 6 months and the relief of dysmenorrhea 1 year after placement. These symptom reliefs remained stable after 6 years of follow-up (all p < 0.01). Lin et al. 2018 studied the postoperative use of gonadotropin-releasing hormone analog (GnRH-a) (n = 115) followed with or without LNG-IUS; they showed that LNG-IUS was significantly better than the control group in improving pain and bleeding symptoms [4].

Youm et al. 2014 [5] studied the incidence of spontaneous expulsion of LNG-IUS among 481 women, and identified risk factors for the expulsion. They found that the incidence of expulsion rate was 7.9%, 9.1%, and 9.6% at 1, 2, and 3 years, respectively. The risk factors included adenomyosis, fibroids, heavy periods, dysmenorrhea, and prior treatment with GnRH-a. Li et al. 2016 [6] also studied the unplanned removal and shedding rates of LNG-IUS in patients with adenomyosis, compared with the normal population. The cumulative removal rate and shedding rate of LNG-IUS placed for 60 months were 9% and 16%, respectively. However, the reason for this high discontinued rate of LNG-IUS may be related to the enlargement of the uterine cavity, abnormal uterine contractility, and menorrhagia. Adequate information with the patients about this problem can help to improve collaboration [7]. Empirical treatment shows that for patients with uterine volume > 8 weeks, uterine cavity depth > 10 cm, and heavy menstrual flow causing anemia; GnRH-a can be used for 3–6 months to increase the continuation rate, but randomized controlled trial studies are lacking. Also, for patients with uterine cavity deformation, hysteroscopic-guided or ultrasound-guided placement can be considered, which can reduce the downward movement of LNG-IUS or even the fall off. For endometrial hyperplasia, combined with polyps, or small submucosal fibroids, hysteroscopy can be performed to remove these lesions and obtain the pathology before placing LNG-IUS.

10.1.3 Dienogest

The new progestogen (dienogest) has achieved good results in the treatment of endometriosis [8], inhibits ovulation, inhibits the growth of ectopic endometrium, alleviate dysmenorrhea, and reduce menstrual flow. A Phase III, randomized, double-blind, multicenter, placebo-controlled study on dienogest was completed in Japan in 2017 [9]. The study included 67 patients with dienogest treatment for 16 weeks. The pain in the treated group was significantly reduced compared with the placebo group and before treatment (p < 0.01). So far, in the study, patients had been taking continuous medication for more than 6 years and even after menopause as a long-term treatment. However, uterine bleeding is common during medication. About 20% of patients discontinued treatment, and the overall effect might be slightly worse than that of endometriosis treatment [10]. A study of 130 patients with adenomyosis [11] confirmed that the 2 mg/day dose of dienogest is effective and safe in treating adenomyosis.

10.1.4 Mifepristone

Mifepristone is an anti-progestin drug at the receptor level, without progesterone, estrogen, androgen, and anti-estrogen activities. Mifepristone has been approved for the treatment of uterine fibroids in China. The treatment of endometriosis and adenomyosis has not been approved by the China Food and Drug Administration (CFDA) and many countries. However, there have been many reports that mifepristone is safe and effective for treating adenomyosis for 3 months. Because mifepristone can cause estrogen to stimulate the endometrium continuously, the safety of long-term mifepristone treatment for more than 3 months on the endometrium has yet to be confirmed. Che et al. 2020 [12] found that mifepristone may effectively reduce the uterine volume and reduce the CA125 concentration by inhibiting the expression of CDK1 and CDK2, leaving the cells in a resting state and inducing apoptosis of endometrial epithelial cells.

10.2 Anti-Estrogen Drug

10.2.1 GnRH-a

GnRHa (Gonadotropin-releasing hormone agonist) is a class of synthetic GnRH derivatives that can compete with GnRH for the GnRH receptor. Continuous administration can down-regulate and change the effect of the GnRH receptor. It can inhibit the synthesis and release of LH (Luteinizing hormone) and FSH (follicle-stimulating hormone), thereby further inhibiting the synthesis of estrogen and progesterone in the ovaries, thus causing amenorrhea or to significantly reduce bleeding, relieve pain, and reduce uterine volume [13]. The dosage and precautions are the same as those for the treatment of endometriosis. The side effects are mainly perimenopausal symptoms caused by low estrogen levels, including bone calcium loss, etc., which can be treated by add-back [14]. There are flare-up effects after about 2 weeks of medication, some patients may have increased pain and excessive bleeding, etc., and they gradually disappear with the continuation of the drug. GnRH-a can reduce nitric oxide synthase levels to reduce endometrial free radical production, increase endometrial NK (natural killer) cell levels, and decrease interleukins 12, 15, and 18 [15]. Theoretically, GnRH-a pretreatment applied for 3–6 months before the assisted reproduction technique or the natural conception, can increase the chance of conception. GnRH-a is not only effective alone but is also often used as a preoperative pretreatment and postoperative consolidation treatment for patients with a large uterus or with anemia.

10.2.2 Aromatase Inhibitor

Aromatase (AR) is a complex enzyme of microsomal cytochrome P450. It composes of hemoglobin P450arom and reduced form of coenzyme NADPH and is widely expressed in the ovary. It is a key enzyme and rate-limiting enzyme that catalyzes the conversion of androgens to estrogen in the body. Aromatase inhibitor (AI) can specifically cause AR inactivation and inhibit estrogen production. Badawy et al. [16] performed a small randomized controlled clinical trial for the treatment of adenomyosis. It was found that letrozole (2.5 mg/d) was similar to goserelin in both symptom relief and uterine volume reduction, yet two patients were pregnant during a letrozole treatment. Besides, AIs have not been approved by the CFDA for the treatment of endometriosis and adenomyosis.

10.3 Androgenic Derivatives

Danazol and gestrinone are effective in treating endometriosis and can also relieve dysmenorrhea for adenomyosis. There were also reports of using danazol-containing IUDs to treat adenomyosis with significant results. Because of androgenic adverse reactions, danazol has been discontinued in China. However, it has been reported in the early years that the use of low-dose danazol at 100–200 mg/day can relieve dysmenorrhea of ​​endometriosis or adenomyosis. Therefore, danazol has not been completely abandoned [17]. Gestrinone is an artificially synthesized triene 19-norsteroidal compound, which is an androgen derivative. It has strong anti-progestin and anti-estrogen activities and also has very weak estrogen and androgenic activities. By inhibiting the release of FSH and LH, it can directly act on eutopic and ectopic endometrial receptors, exert anti-progestin and anti-estrogen effects, increase free testosterone levels in the body, and reduce levels of sex hormone-binding globulin. It inhibits the growth of the endometrium and is used for the treatment of endometriosis and adenomyosis. The postoperative use of gestrinone in adenomyosis has a significant difference in menstrual volume, endometrial thickness, and dysmenorrhea score. However, irregular bleeding occurs during use, and the liver mainly metabolizes the drug so that long-term application may affect liver function [18].

10.4 Anti-Prostaglandin Drugs

There are currently no specific studies on non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of adenomyosis. The Cochrane systematic review (including 18 randomized controlled trials) reported that NSAIDs could reduce menstrual bleeding in 30% of patients, which was better than the placebo. Therefore NSAIDs can be used as a first-line drug for treating menstruation and relieve menstrual cramps. However, in about 18% of patients with dysmenorrhea, treatment with NSAIDs is ineffective [19]. To increase the effect of NSAIDs, they may be combined with COC. NSAIDs inhibit cyclooxygenase and reduce prostaglandin synthesis at the endometrial level, thereby alleviating dysmenorrhea and reducing menstrual bleeding (approximately 30%). There is no statistically significant difference in the efficacy of different types of NSAIDs while controlling menstrual-related anemia and pain without affecting fibroids or uterine size. Although NSAIDs can reduce uterine bleeding, they are less effective than other treatments, such as tranexamic acid or danazol and LNG-IUS. Patients with adenomyosis can use symptomatic treatment with NSAIDs when planning a pregnancy. NSAIDs commonly used in clinical practice include salicylic acid, paracetamol, indomethacin, ibuprofen, and mefenamic acid. All have fewer and mild adverse reactions and easily accepted by patients.

10.5 Hemostatic Drugs and Iron Supplements

Tranexamic acid is effective in treating heavy menstruation and may apply to adenomyosis with menorrhagia. However, there is no RCT study on its use to treat adenomyosis combined with menorrhagia. The usage is either oral or intravenous infusion. The patient should be monitored to reduce the possibility of thrombotic complications when using this product. For those with a tendency to thrombosis and myocardial infarction, it should be used with caution. For iron deficiency anemia, iron should be used at the same time to stop the bleeding, and vitamin C can increase the iron absorption rate.

10.6 Chinese Medicine and Herbs

Traditional Chinese medicine (TCM) is a great treasure of traditional medicine in China. It has its unique features in the understanding and treatment of adenomyosis. It is an understanding of Chinese medicine that the adenomyosis is related to “blood stasis.” Its pathogenesis is due to external evil invasion, emotional trauma, physical factors, or surgical injury. The “menstrual blood” is due to retrograde blood stasis in the lower abdomen, which blocks the cells and causes disease. The treatment is based on promoting blood circulation and removing blood stasis, clearing away heat and removing toxic substances, and does not inhibit ovulation. There are many prescriptions of TCM for adenomyosis. Commonly used oral Chinese herbs include Sanjie analgesic capsules, Guizhi Fuling capsules, and Shaofu Zhuyu decoction.

Wang et al. 2018 [20] and others searched 302 cases of adenomyosis treated with Chinese medicine in the literature and used the software “Traditional Chinese Medicine Assistance Platform” to enter 56 prescriptions for the treatment of adenomyosis. The highest frequency of herbs being used is the Angelica sinensis. This herb has actions to activate blood circulation, remove stagnation, and relieve pain; it corresponds to the core pathogenesis of dysmenorrhea and “blood stasis” in patients with adenomyosis. Besides, the use of enema to deliver Chinese herbal medicine is also practiced. As the female uterus is close to the rectum, it is the belief that the Chinese herbs can reach it, while avoiding the bitter taste aversion caused by oral herbs. Thus the Chinese patient is happy to accept. Jin et al. 2019 [21] treated 130 patients with adenomyosis with herbal enema and showed that the effective rate is 92.31%, which was higher than that of the mifepristone treatment group (76.92%), and the relapse rate and adverse reaction rate were low. In addition to oral and enema, acupuncture treatment can promote the operation of “qi” and the blood. Local warming and moxibustion can warm the meridians and reconcile “qi” and the blood.

Liu et al. 2018 [22] treated 30 adenomyosis patients with acupuncture combined with Chinese medicine. The main points of acupuncture are the uterus, Qihai, Zhongji, Hachiman, Shenshu, etc., once daily from 7 days before menstruation to the end of the menstruation, at the same time taking Yiqi analgesic decoction, 1 dose daily, for three consecutive menstrual cycles; the reported effective rate can reach 86.7%. The practice of Chinese medicine should not be just the use of Chinese herbs or a combination of herbs and western drugs. It should be the study of how to maximize the role of TCM and its combination of treatment to make the treatment of adenomyosis more effective, which are worthy of exploring. For the time being, there is still a long way to go before Chinese medicine can truly achieve both the symptoms of relief and the cure.

10.7 Combination of Treatments

10.7.1 The Combined Use of Drugs

The combined use of drugs includes the simultaneous use of two or more drugs, as well as the sequential use of several medications. Common drug combinations for adenomyosis include GnRH-a supplemented with OC (oral contraceptive)/LNG-IUS as a long-term treatment that can reduce the effects of a long-term low level of estrogen and consistent with health economics. The combined use of drugs helps to increase the continuation rate of LNG-IUS by reducing the uterine size and reduces the expulsion rate of the IUD (intra-uterine device). Also, the combination of TCM and western medicine is important combined drug therapy. Xuefu Zhuyu Capsule combined with LNG-IUS, Guizhi Fuling capsule combined with gestrinone, levonorgestrel combined with Sanjie analgesic capsule, etc. have been reported, with effects better than any single medication. However, attention must be paid to monitor the side effects and incompatibility of drugs when using different drugs together at the same time.

10.7.2 The Combined Use of Drugs and Surgery

In 2018, Rocha et al. [23] published a review that summarized a total of 16 studies in the past 7 years. The overall spontaneous pregnancy rate after conservative surgery was 18.2%. When supplemented with GnRH-a after surgery, the pregnancy rate can reach 40.7%, compared with only 15% of patients treated with supplements as a control group. However, there were also reports that the live birth rate of the combined drug and surgery group is not higher than that of the surgery only group. In a large-scale prospective study in 2009, Wang et al. [24] reported that for 114 patients with adenomyosis, GnRH-a was used for 6 months after conservative surgery. At 2 years follow up, there were 32 live births. However, this live birth rate was not higher than that of patients who underwent surgery alone. Some scholars conducted a follow-up study of 148 patients recurring laparotomy versus laparoscopy for severe diffuse adenomyosis for up to 6 years [25]. Regardless of the open surgery group or the laparoscopic surgery group, the postoperative GnRH-a + LNG-IUS/OC recurrence rate of symptoms was significantly lower than that of the single GnRH-a treatment group. Therefore, it is recommended for patients with conservative surgery to use GnRH-a for 4–6 months, which can inhibit the growth of residual lesions while waiting for the uterine incision to heal; it can also reduce the recurrence rate of pain. After that, those who have fertility demand should try to get pregnant, and those who have infertility problems should seek assisted reproductive technology, such as IVF (In vitro fertilization). For young patients without fertility requirements, contraceptive pills can be use instead, or LNG-IUS can be considered. Besides, preoperative GnRH-a can also increase hemoglobin concentration, reduce the size of the uterus, reduce the difficulty of surgical operation, and reduce anemia.

10.7.3 High-Intensity Focused Ultrasound (HIFU) and Drug Combination

The long-term management of HIFU treatment for adenomyosis in recent years has also been widely recognized. At present, the long-term management method commonly used after high-intensity focused ultrasound (HIFU) treatment of adenomyosis is mainly drug therapy, and related studies have confirmed that the long-term efficacy of HIFU combined with drugs for adenomyosis has significantly improved.

Guo et al. 2018 [26] retrospectively analyzed 78 patients with adenomyosis treated with HIFU, of which 45 patients were treated with HIFU only, 15 patients were treated with HIFU + LNG-IUS, and 18 patients were treated with HIFU + GnRH-a. At a 6-month and 12-month follow-up, the HIFU combined with GnRH-a and LNG-IUS groups improved significantly in terms of dysmenorrhea score, menstrual volume score, uterine size, and lesion size compared with the HIFU-treated group alone. Also, Ye et al. 2016 [27] retrospectively analyzed the efficacy of HIFU ablation alone, HIFU combined with GnRH-a or with LNG-IUS or with GnRH-a + LNG-IUS in the treatment of dysmenorrhea in adenomyosis; the combination therapy had significantly better relief than HIFU alone. Also, the recurrence rate was significantly reduced (P < 0.008).

There is no existing consensus for the indications and methods of combination therapy. From their clinical experience, Ye and Xu 2019 [28] summarized their recommended treatments for adenomyosis patients as follows: (a) If the patient’s symptoms are mainly dysmenorrhea and the uterus size is <2 months of pregnancy, with no fertility demand, then the use of LNG-IUS on the first day after the end of the menstruation can be recommended; (b) For patients with uterine enlargement ≥2 months of pregnancy or increased menstrual flow and no fertility demand, GnRH-a is recommended for 4–6 months after HIFU treatment. Given the rapid recovery of uterine volume after GnRH-a, LNG-IUS was placed at 1 or 2 months before discontinuation of GnRH-a; (c) For patients with the significantly enlarged uterus and fertility demand, HIFU should be associated with GnRH-a treatment; then try to get pregnant as soon as possible after GnRH-a treatment, and if necessary, a short-term oral contraceptive before pregnancy can be used to control the recurrence.

To summarize, pharmacotherapy of adenomyosis is mainly applied to temporarily relieve pain, reduce bleeding, or reduce the size of lesions and the uterus. It is used for patients with mild to moderate symptoms or consolidates treatment to prevent a recurrence. Given the adverse reactions of drugs to varying degrees, they should be fully informed before treatment, and work out a treatment plan with the patient. During the medical treatment, patients should be monitored and followed up closely. For patients starting drug treatment, they should be followed up for 1–3 months to understand the occurrence of adverse reactions and deal with them accordingly. During the maintenance process, follow up every 3–6 months to understand the improvement of symptoms, such as bleeding, pain, and drug effects on the liver and kidney. For symptoms that do not improve or even progress, other treatments, such as surgery, should be considered.