Adenomyosis with abnormal uterine bleeding complicated by venous thrombosis: a case series and literature review

Abstract

Background:

Adenomyosis is a benign disease characterized by the invasion of endometrial glands and stroma into the uterine myometrium, commonly presenting with abnormal uterine bleeding.

Methods:

This paper retrospectively analyzes three cases of adenomyosis complicated by venous thromboembolism (VTE) in patients hospitalized at our hospital from 2023 to 2025, and discusses its high-risk factors and treatment strategies in combination with the literature review. Inclusion criteria: patients diagnosed with adenomyosis and having a history of menorrhagia complicated by venous thromboembolism. Exclusion criteria: VTE caused by other diseases; patients in menopause.

Result:

Case 1 involved a 47-year-old female who developed thrombosis in the right basilic vein after laparoscopic total hysterectomy. Case 2 was a 47-year-old female who experienced lower extremity venous thrombosis following treatment with gonadotropin-releasing hormone agonists (GnRH-a) combined with a levonorgestrel-releasing intrauterine system. Case 3 was a 49-year-old female who developed portal vein, splenic vein, and superior mesenteric vein thrombosis after long-term norethisterone therapy. Clinical experience indicates that GnRH-a combined with dienogest (DNG) can effectively control symptoms and preserve the uterus, but thrombotic risks require vigilance. Through case analysis and literature review, this article emphasizes the importance of individualized treatment plans.

Conclusion:

Patients with adenomyosis presenting with an enlarged uterus and menorrhagia are prone to developing VTE. When VTE occurs, total hysterectomy is often selected as the treatment. We attempted a combined regimen of GnRH-a, DNG, and anticoagulant therapy, which was effective in one case.

Background:

Adenomyosis^[1] is a common gynecological disorder characterized by the invasion of endometrial glands and stroma into the uterine myometrium, leading to uterine enlargement, dysmenorrhea, and menstrual abnormalities. Thrombotic events in adenomyosis patients frequently occur during menstruation or abnormal uterine bleeding (AUB) episodes^[2], often accompanied by elevated CA-125, CA-199, and D-dimer levels, and a uterine volume ≥100 cm³. Clinicians must prioritize thromboprophylaxis and management during menstruation, including anticoagulation or hormonal interventions, to reduce the risk of thrombotic events. However, the specific association between adenomyosis and thrombotic diseases, as well as optimal therapeutic strategies, remains inadequately studied.

HIGHLIGHTS

• These three case reports highlight an elevated perioperative thrombotic risk in adenomyosis patients with large uteri, underscoring the need for enhanced venous thromboembolism management.

• While surgical intervention remains the conventional approach for adenomyosis complicated by thrombotic events, this case series presents the first documented successful uterine-preserving treatment using combined GnRH-a and dienogest therapy – a previously unreported strategy.

Current treatments for adenomyosis with AUB and thrombotic diseases include medical therapies (progestins, GnRH-a, DNG) and surgical interventions [endometrial ablation, uterine artery embolization (UAE), total hysterectomy]. Long-term use of progestins (e.g., norethisterone, conjugated estrogens) may increase thrombotic risks, particularly at high doses or with prolonged duration^[3]. While GnRH-a and levonorgestrel intrauterine systems (LNG-IUS) are effective, their roles in thromboprophylaxis and management require further investigation, especially in patients with severe AUB.

This article reports three cases of adenomyosis complicated by thrombotic diseases, explores potential associations, and evaluates the efficacy and safety of different treatment strategies. Through this article, we aim to alert gynecologists that, for patients with adenomyosis presenting with AUB, clinicians should remain vigilant for the occurrence of VTE during treatment. It is advisable to avoid the use of high-dose estrogen or progesterone therapies whenever possible, and postoperative VTE prophylaxis should be prioritized. For female VTE patients comorbid with adenomyosis, particular caution should be exercised in anticoagulant therapy, and management requires multidisciplinary collaborative approaches. The treatment of adenomyosis complicated by venous thromboembolic disease and AUB presents significant therapeutic challenges, with no prior reports on GnRH-a combined with DNG therapy. In this study, we administered GnRH-a combined with DNG to severe cases who developed venous thrombosis alongside AUB while desiring uterine preservation. Our research aims to provide clinicians with more comprehensive therapeutic references and offer new directions for future investigations.

Methods

This paper retrospectively analyzes three cases of adenomyosis complicated by venous thromboembolism (VTE) in patients hospitalized at our hospital from 2023 to 2025, and discusses clinical data, treatment, and prognosis.

Inclusion criteria: Patients diagnosed with adenomyosis and having a history of menorrhagia complicated by venous thromboembolism.

Exclusion criteria: VTE caused by other diseases; patients in menopause.

The work has been reported in line with the PROCESS criteria^[4].

Results

Case 1. A 47-year-old female with a high school education, currently unemployed, who has given birth to one son. She presented with “increased menstrual flow accompanied by dysmenorrhea for 5 years” to People’s Hospital of Putuo District on September 14, 2024, with AUB for half a month. No significant abnormalities were noted in her past medical history. Ultrasound (US) revealed an anteverted uterus with irregular enlargement (anteroposterior diameter: 98 mm) and multiple hypoechoic lesions in the anterior and posterior walls, with the largest measuring 62 × 44 mm. Laboratory tests showed hemoglobin (HGB) 75 g/L, CA125: 64.7 U/mL; normal coagulation function, and D-dimer: 46 ng/mL. The patient opted for surgical treatment and underwent laparoscopic total hysterectomy under general anesthesia on 20 September 2024. Postoperative pathology confirmed adenomyosis and multiple uterine leiomyomas. On postoperative day 2, D-dimer levels significantly increased to 2940 ng/mL, prompting immediate subcutaneous injection of low-molecular-weight heparin (LMWH) 5000 IU. On day 3, the patient reported localized pain in the right forearm. US confirmed thrombosis in the right basilic vein. LMWH 5000 IU once daily was continued, and rivaroxaban 10 mg once daily was prescribed post-discharge. By September 28, 2024, D-dimer decreased to 862 ng/mL, and the patient was discharged on September 29 with alleviated forearm pain.

Case 2. A 47-year-old female with a junior high school education, working as a hotel staff member, has given birth to one son. She had a history of thyroid surgery (currently on levothyroxine sodium 50 μg/day), presented with recurrent menorrhagia and dysmenorrhea for 12 years. GnRH-a therapy was initiated in September 2023 (subcutaneous injection every 28 days for three doses), followed by LNG-IUS placement in November 2023. Menorrhagia recurred in January 2024. An US on February 27, 2024, revealed a markedly enlarged uterus (119 × 115 × 125 mm) with thickened myometrium and multiple small hypoechoic areas. CA125 on March 19, 2024, was 415.47 U/mL. The patient experienced one month of AUB, followed by the detection of thrombosis in the right popliteal vein, posterior tibial vein, and intramuscular veins via ultrasonography on March 22, 2022. LMWH 5000 IU once daily was carried out. The thrombus resolved after anticoagulant therapy. The patient was admitted to People’s Hospital of Putuo District on April 5, 2024, for “vaginal bleeding for 1 month, aggravated for 3 days.” Medications at admission included rivaroxaban 20 mg once daily and atorvastatin calcium 20 mg nightly. Gynecological examination revealed a markedly enlarged uterus. Laboratory tests showed HGB: 51 g/L; D-dimer: 1.88 mg/L. US showed significant uterine enlargement consistent with adenomyosis and a displaced LNG-IUS. Admission diagnosis: adenomyosis with severe anemia. A diagnostic curettage was performed on April 7. Pathology findings showed secretory endometrial glands with stromal decidualization and fibrinoid necrosis. Total hysterectomy on April 11 confirmed adenomyosis and endometrial polyps. No thrombotic recurrence was observed during follow-up.

Case 3. A 49-year-old female with a bachelor’s degree, working as a medical professional, nulliparous, with a history of long-standing adenomyosis. She has experienced recurrent AUB since November 2021, requiring multiple blood transfusions and hormonal therapies (oral progesterone or norethisterone). On May 5, 2022, hysteroscopic endometrial polyp resection was performed, with pathology showing endometrial polyps with localized infarction. Recurrent bleeding persisted, and leuprolide acetate (3.75 mg) was administered subcutaneously starting May 10, 2022. During treatment, recurrent heavy bleeding occurred, managed with Yasmin (ethinylestradiol + drospirenone) or norethisterone. After four doses, menstrual flow decreased. By August 27, 2022, US showed an enlarged uterus (144 × 103 × 133 mm) with multiple hypoechoic lesions, the largest measuring 39 × 35 mm. There was no recurrence of menorrhagia or AUB in 2023. In January 2024, heavy bleeding recurred, and norethisterone (8 tablets three times daily) was prescribed. On January 28, 2024, the patient developed epigastric pain. Abdominal CT on February 12, 2024, revealed extensive thrombosis in the portal, splenic, and superior mesenteric veins. Physical examination: The patient’s uterus was significantly enlarged, with the uterine fundus at the level of the umbilicus. Admission diagnosis: Portal vein thrombosis; Superior mesenteric vein thrombosis; Adenomyosis; Moderate anemia. Treatment included dalteparin 2500 IU twice daily for 3 days, followed by once daily, alongside discontinuation of norethisterone. The patient strongly desired uterine preservation. GnRH-a therapy (goserelin 3.6 mg) was initiated on March 2, 2024, alongside continued anticoagulation. The patient received injections every 28 days. During treatment, AUB persisted, and oral DNG 2 mg once daily was initiated, with dose adjustments based on the amount of vaginal bleeding. By the fourth injection, vaginal bleeding decreased, and the DNG dose was reduced to 1 mg once daily. By the eighth injection, vaginal bleeding ceased, and DNG was discontinued. As of January 2025, the patient had received 10 injections, and the uterus has returned to a size approximately equivalent to that at 8 weeks’ gestation (Table 1). Follow-up CT scan 2 months after discharge demonstrated improvement in thromboses of the portal vein, splenic vein, superior mesenteric vein and their branches compared with the previous study.

Table 1.

Clinical details of the three patients with venous thromboembolism

Patient	Demographic features	Clinical presentation	Size of uterus	CA-125 (U/ml)	D-Dimer (mg/L)	Type of VTE	Treatment	Prognosis
Case 1	A 47-year-old female, of Han ethnicity, with a high school education, currently unemployed. She was born and currently resides in Zhoushan, Zhejiang Province, China. She is married and has one son, with a history of two induced abortions. Her spouse is healthy. Her father, mother, and one brother have all passed away due to illnesses, while her five other siblings are healthy.	History of adenomyosis for 5 years, two days after undergoing a hysterectomy, the patient developed right upper limb pain, with ultrasound imaging demonstrating thrombosis in the right basilic vein	The anteroposterior diameter measures 98 mm.	64.7	12.1	Right basilic vein	Anticoagulation therapy	No thrombus recurrence without anticoagulation therapy.
Case 2	A 47-year-old female, of Han ethnicity, with a junior high school education, employed as a hotel staff with an annual income of approximately 100,000 RMB. She was born and currently resides in Zhoushan, Zhejiang Province, China. She is married and has one son. Her spouse is healthy. Her father, mother, and one elder sister are all healthy.	History of adenomyosis for 12 years, abnormal uterine bleeding lasting onemonth with severe anemia.	119*115*125 mm	415.47	3.56	Right popliteal vein, posterior tibial vein, and intramuscular veins	After successful anticoagulation therapy leading to thrombosis resolution, total hysterectomy was conducted.	No thrombus recurrence without anticoagulation therapy.
Case 3	A 49-year-old female, of Han ethnicity, with a bachelor’s degree, working as a physician with an annual income of approximately 150,000 RMB. She was born and currently resides in Zhoushan, Zhejiang Province, China. She is divorced, has no children, and has a history of one induced abortion. Her father has a long-term history of hypertension, and her mother passed away due to liver cancer. She has one younger brother who is healthy.	History of adenomyosis for many years,treated with oral norethisterone tabletsfor two weeks following recurrent menorrhagia.	144X103X133mm	199.82	14.09	Portal, splenic, and superior mesenteric veins	GnRH-a combined with dienogest	The uterus has returned to a size approximately equivalent to that at 8 weeks’ gestation

VTE, venous thromboembolism

Discussion

Xiaolong Zong et al^[2] found that both arterial and VTE may occur in adenomyosis patients. Among these cases, multiple cerebral infarctions were the most common (54.5%), while 38.9% exhibited systemic embolism resembling Trousseau’s syndrome in cancer patients. Adenomyosis patients may have an elevated risk of VTE, particularly during menstruation or AUB episodes. Potential mechanisms include:

Inflammation and coagulation activation

Ectopic endometrial lesions in adenomyosis release inflammatory mediators (e.g., interleukin-6, tumor necrosis factor-α, C-reactive protein), which promote local inflammation and activate the coagulation system, leading to a hypercoagulable state^[5]. Chronic inflammation damages vascular endothelial cells, enhances platelet aggregation, and increases fibrin deposition^[6]. Menstrual shedding of the endometrium further exacerbates inflammation and coagulation abnormalities by releasing tissue factor (TF), which activates the extrinsic coagulation pathway. Xishi Liu et al^[7] demonstrated elevated TF expression in ectopic endometrium compared to normal endometrium, suggesting TF as a potential therapeutic target for symptomatic adenomyosis.

Some scholars propose that benign tumors producing mucins and TF may induce hypercoagulability^[8]. TF, involved in coagulation, is linked to menorrhagia and dysmenorrhea. CA125, a glycoprotein in the mucin family, has been implicated in thrombogenesis^[9]. Nishioka et al^[10] reported a case of cerebral venous thrombosis associated with massive adenomyosis, attributing thrombus formation to elevated CA125 and iron-deficiency anemia. A retrospective study found significantly higher DVT and PE risks in adenomyosis patients during menstruation compared to nonmenstrual periods^[2]. Studies indicate elevated serum CA125 and D-dimer levels in adenomyosis patients during menstruation, correlating with ischemic stroke episodes. These markers normalize post-hysterectomy^[11]. CA-125 and CA-199 promote thrombosis via neutrophil and platelet signaling. Most cerebral infarctions in these patients occur during menstruation, when fibrinogen and prothrombin levels rise alongside reduced fibrinolysis, further increasing thrombotic risk^[9]. In all three patients presented in this series, CA125 levels were markedly elevated.

Uterine volume and anemia

Uterine adenomyosis with a volume ≥100 cm³ is associated with coagulation activation. Elevated soluble fibrin and D-dimer levels in these patients may signal thrombotic predisposition. Enlarged uteri, particularly in extensive adenomyosis, carry risks of infarction and thrombosis, exacerbated by menstrual coagulation and fibrinolytic activation, worsening menorrhagia^[12]. Chronic blood loss from menorrhagia may induce anemia, further aggravating hypercoagulability. Anemia disrupts endothelial adhesion molecule genes, promotes thrombosis via inflammatory stimuli during bleeding, and may drive menstrual thrombogenesis in adenomyosis patients^[13]. Both Case 2 and Case 3 demonstrated significant uterine enlargement.

Hormonal fluctuations and hormonal therapy

Fluctuations in hormone levels play a significant role in thrombotic diseases complicated by adenomyosis. Cyclic variations in estrogen and progesterone not only influence endometrial growth and shedding but also affect coagulation by modulating the expression of clotting factors and anticoagulants. For example, high-dose estrogen increases levels of clotting factors VII, VIII, and fibrinogen while reducing the activity of antithrombin III and protein S, thereby promoting thrombosis^[14]. In contrast, low-dose or physiological doses of estrogen enhance the production of nitric oxide and prostacyclin, mitigate oxidative damage to endothelial cells, protect vascular endothelial function, induce vasodilation, inhibit platelet aggregation, improve lipid metabolism, and exert anti-inflammatory effects that reduce vascular inflammation, consequently lowering thrombotic risk^[15,16].

Progestin medications (e.g., medroxyprogesterone acetate, norethisterone) may elevate thrombotic risk^[3]. These agents, commonly used to treat gynecological conditions such as endometriosis and uterine fibroids by modulating hormonal levels^[17], can influence coagulation, increase blood viscosity, or alter endothelial function, thereby promoting thrombosis. Long-term progestin use significantly enhances the activity of clotting factors II, VII, and X while reducing antithrombin III activity, leading to a hypercoagulable state and a marked increase in VTE risk. Rajesh Rajput et al^[18] reported a case of central venous sinus thrombosis in a patient receiving norethisterone for dysfunctional uterine bleeding, which resolved after treatment with low-molecular-weight heparin and warfarin. In Case 3, a patient developed abdominal pain 2 weeks after oral norethisterone therapy for hemostasis during severe bleeding, followed by portal, splenic, and mesenteric vein thrombosis. This may be attributed to hormonal fluctuations during menstruation, hemoconcentration, and thrombogenic effects of norethisterone.

GnRH-a, which suppress pituitary gonadotropin release and lower estrogen levels, are widely used to treat hormone-dependent tumors (e.g., breast cancer, prostate cancer) and endometriosis. However, hypoestrogenic states may induce endothelial dysfunction and coagulation imbalances, increasing thrombotic susceptibility. Barry A. Ripps et al^[19] documented a case of superior mesenteric and portal vein thrombosis in a patient after 3 months of GnRH-a therapy, with thrombus resolution following 6 weeks of anticoagulation. Clinical observations indicate elevated rates of deep vein thrombosis (DVT) and pulmonary embolism (PE) in GnRH-a users. Guo Z et al^[20] conducted a systematic review and meta-analysis on androgen deprivation therapy (ADT) and thromboembolic events in prostate cancer patients. Results showed that GnRH-a monotherapy, GnRH-a combi-ned with oral anti-androgens, and androgen monotherapy significantly increased DVT risk, while GnRH-a alone and orchiectomy elevated PE risk. Tony G. Zreik et al^[21] reported a fatal PE case associated with GnRH-a therapy and intravenous estrogen treatment for severe bleeding. A 52-year-old woman with uterine fibroids received GnRH-a and add-back therapy but experienced persistent menorrhagia. After intravenous conjugated estrogen administration, she developed fatal PE on the second day, suggesting that GnRH-a combined with high-dose estrogen exacerbates thrombotic risk.

Surgery

Surgical interventions, such as hysterectomy, may increase VTE risk due to postoperative immobility. Despite advancements in surgical techniques and perioperative care, hysterectomy remains associated with a postoperative VTE incidence of approximately 1%, as reported in the journal of Obstet Gynecol^[22]. Prolonged bedrest impairs lower limb muscle pump function, causing venous stasis, while surgical trauma induces inflammation and hypercoagulability, synergistically promoting thrombosis. Adenomyosis patients often exhibit preexisting VTE risk factors, such as chronic pelvic pain and menorrhagia-related activity restriction. Additionally, enlarged uteri increase surgical complexity and intraoperative blood loss, further elevating postoperative thrombotic risk. Chen et al^[23] described a case of ovarian vein thrombosis 6 days posthysterectomy in an adenomyosis patient, detected via CT due to abdominal pain. D-dimer levels were markedly elevated, but the thrombus resolved spontaneously without anticoagulation. In Case 1, thrombosis occurred 2 days posthysterectomy, likely linked to disease-related inflammation and hypercoagulability, which responded to anticoagulation.

Even in the absence of hyperlipidemia or hereditary thrombophilia, patients with adenomyosis often present with menorrhagia or AUB, and are typically treated with tranexamic acid or hormonal medications for hemostasis. Elevated CA-125, CA19-9 levels, hypercoagulable states, and the postoperative recovery period may collectively contribute to the development of thromboembolic diseases. These factors represent high-risk indicators for thromboembolic events in adenomyosis patients. Consequently, when managing severe adenomyosis cases with markedly elevated CA-125, CA19-9, and D-dimer levels, accompanied by significant uterine enlargement and menorrhagia/AUB, special attention should be given to thromboprophylaxis during medical treatment or within 1–2 weeks postoperatively to prevent thromboembolic complications.

Managing adenomyosis with concurrent AUB/menorrhagia and thrombosis poses therapeutic dilemmas, as anticoagulation exacerbates bleeding while hemostatic agents or high-dose progestins are contraindicated. (Table 2) George A. Vilos and colleagues^[24] reported their clinical experience in managing such patients, where the LNG-IUS effectively reduced menstrual bleeding or induced amenorrhea in most cases. However, some patients experienced severe hemorrhage requiring uterine artery embolization. Years later, partial expulsion of the LNG-IUS occurred in a subset of patients, ultimately leading to hysterectomy with pathological confirmation of adenomyosis. These findings suggest that LNG-IUS may serve as a first-line option for patients with AUB requiring anticoagulant therapy. Nevertheless, in adenomyosis patients with an enlarged uterus and heavy menstrual bleeding, the risk of LNG-IUS expulsion may increase, necessitating close monitoring and individualized management. In Case 2, LNG-IUS displacement occurred three months post-insertion, accompanied by recurrent menorrhagia and lower extremity venous thrombosis, ultimately necessitating hysterectomy. Thus, LNG-IUS efficacy is limited in significantly enlarged uteri.

Table 2.

Cases of adenomyosis complicated by abnormal uterine bleeding and venous thromboembolic disease

First Author	Ref.#	inducement	Type of thrombus	Treatment	Curative effect and subsequent treatment
George A. Vilos	24	Unknown	DVT/PE?	LNG-IUS	The LNG-IUS was expelled after 2 years, followed by hysterectomy.
Eliane Yuting Hong	35	Menorrhagia treated with tranexamic acid	Bilateral PE, left lower limb DVT	Warfarin GnRH-a	Ineffective, followed by total hysterectomy
		Menorrhagia treated with tranexamic acid	PE	Rivaroxaban. GnRH-a and UAE	Ineffective, followed by total hysterectomy
		Had two previous episodes of PE and was on lifelong warfarin.	PE	Warfarin and GnRH-a	Ineffective, followed by total hysterectomy
		COCP	PE	Warfarin and GnRH-a	loss to follow-up
		Menorrhagia over the past year	Bilateral PE, left lower limb DVT	Thrombolytic therapy, warfarin, IVC filter, GnRH-a.	Ineffective, followed by total hysterectomy
Akira S	32	GnRH-a,hypermenorrhea	DVT	Low-dose GnRH-a	Effective
Zaiqiang Yu	46	Pseudo-menopause therapy	PE	UAE	Ineffective, followed by total hysterectomy
Frank Nawroth	42	Hereditary hyperhomocysteinemia	Occlusion of the left femoral vein	Endometrium ablation and gestagene	Ineffective, followed by supracervical hysterectomy.

DVT, deep vein thrombosis; PE: pulmonary embolism; UAE, uterine artery embolization; HEA, hysteroscopic endometrial ablation; COCP: Combined oral contraceptive pill; GnRH-a, gonadotropin-releasing hormone agonists.

DNG is an orally administered synthetic progestin with potent progestogenic activity and partial anti-androgenic effects. It reduces menstrual bleeding and alleviates dysmenorrhea by inhibiting endometrial hyperplasia, decreasing local inflammatory responses, partially suppressing ovarian estrogen secretion, and diminishing estrogen-induced endometrial stimulation^[25,26]. Additionally, it effectively reduces uterine artery blood flow and decreases uterine volume^[27]. As a progestin, DNG may theoretically elevate thrombotic risk, but its associated thrombosis risk is lower than that of oral contraceptives^[28]. For patients at low thrombotic risk, DNG may serve as a therapeutic option. A study^[28] conducted between 2009 and 2013 on dysmenorrhea treatments in women aged 10–59 years revealed that ethinylestradiol-containing medications (e.g., norethindrone, drospirenone) had venous and arterial thromboembolism rates of 2.38 and 0.63 cases per 10 000 person-years, respectively, with an overall rate of 3.17 cases. In contrast, DNG users showed no similar increase in thrombotic risk, suggesting its relatively lower thrombogenic potential. However, DNG may cause breakthrough bleeding. Ihssane Merimi et al^[29]reported a case of severe hemorrhage and PE in a patient with adenomyosis who developed these complications 1 month after initiating DNG 2 mg daily. The patient underwent emergency hysterectomy followed by anticoagulant therapy. This highlights the need for vigilance regarding breakthrough bleeding risks with DNG monotherapy. To date, there are no reported cases of DNG use in adenomyosis patients with concurrent thrombotic disorders. For such patients, DNG should be used under close monitoring, balancing therapeutic benefits against potential risks. Combination with anticoagulant therapy may be warranted when necessary.

GnRH-a, a mainstay for adenomyosis and endometriosis, induces hypoestrogenism via pituitary suppression, reducing menstrual flow, pain, inflammation, and lesion activity^[30]. Some patients receiving GnRH-a therapy have achieved uterine size normalization and successful childbirth^[31]. A patient with adenomyosis-related cerebral venous sinus thrombosis underwent low-dose GnRH-a therapy (leuprolide acetate 1.88 mg subcutaneously every 4 weeks for 2.5 years), effectively controlling symptoms. After switching to buserelin nasal spray (900 µg/day initially, tapered to 600 µg/day), estradiol levels were maintained at 20–50 pg/mL^[32]. Akira et al^[33] reported a case where GnRH-a was used for the treatment of adenomyosis complicated by deep venous thrombosis. The patient developed lower extremity venous thrombosis after four cycles of injections. As she desired uterine preservation, low-dose intranasal administration of buserelin acetate (450 μg/day) was initiated (standard dose: 900 μg/day), which proved effective. Improvements were observed in anemia, chronic pelvic pain, and venous thrombosis. This suggests that low-dose GnRH-a may represent a viable treatment option for adenomyosis patients with concurrent DVT, potentially offering reduced thrombotic risk compared to conventional dosing regimens. Low-dose GnRH-a may reduce thrombotic risk.

Zhang et al^[34] compared DNG monotherapy versus GnRH-a sequential DNG for adenomyosis. Both groups showed reduced dysmenorrhea VAS scores, CA125/CA19-9 levels, and improved hemoglobin (all P<0.001). The GnRH-a + DNG group achieved greater uterine volume reduction at 15–24 months (P < 0.05), with higher amenorrhea rates and fewer bleeding episodes. Neither regimen adversely affected hepatic/renal function or coagulation, supporting GnRH-a sequential DNG for hemorrhage control and uterine shrinkage.

Treating concurrent bleeding and thrombosis is challenging. Antifibrinolytics and hormonal therapies are contraindicated during active thrombosis. Anti-thrombus medication exacerbates the uterine hyperbleeding and should be eschewed for patients with AUB.

GnRH-a can induce amenorrhea to control menorrhagia, though immediate hemostasis is unreliable. Multiple case reports have indicated that in patients with adenomyosis complicated by AUB and thrombotic disease, GnRH-a therapy proves ineffective. Persistent heavy bleeding despite treatment ultimately necessitates hysterectomy^[35,36]. Reports describe adenomyosis patients developing PE on rivaroxaban, with persistent menorrhagia despite GnRH-a and UAE, ultimately requiring hysterectomy^[35]. Thus, GnRH-a may fail to control bleeding during anticoagulation, necessitating cautious decision-making. Uterine preservation further complicates balancing hemostasis and thrombosis management.

For patients desiring uterine preservation with refractory bleeding on GnRH-a, adding DNG may be effective. In our case, on the basis of anticoagulation therapy, the patient adopted treatment with GnRH-a combined with DNG, which stabilized the thrombotic state, reduced uterine volume, and avoided the need for hysterectomy. However, thrombotic risks persist, necessitating monitoring, and long-term safety needs further study. Anticoagulation may mitigate thrombosis but increase bleeding. Takamura Masashi et al^[37]reported a 45-year-old with type I adenomyosis and PE history on warfarin/aspirin. After 6 months of GnRH-a and 9 months of DNG, hemorrhagic shock occurred despite transfusion and anticoagulant reversal, requiring emergency hysterectomy. Thus, DNG may delay surgery but mandates vigilance in anticoagulated patients.

In adenomyosis with thrombosis, menstrual or severe vaginal bleeding requires balanced hemostasis and thromboprophylaxis. Medical therapy is first-line, though risks exist. For life-threatening or refractory bleeding, surgery is indicated.

Endometrial ablation^[38], suitable for nonfertile patients with normal-sized uteri, reduces menstrual flow via thermal, cryo-, or radiofrequency techniques. Increasingly used for menorrhagia/AUB, it offers minimal invasiveness and rapid recovery. Indications include: (1) benign menorrhagia impairing quality of life; (2) absence of significant uterine abnormalities or submucosal fibroids <3 cm; (3) exclusion of malignancy; (4) failed medical therapy or surgical contraindications; (5) uterine depth <10 cm. Contraindications: malignancy, active infection, uterine anomalies, submucosal fibroids, or uterine depth >11 cm^[39]. George A. Vilo et al^[24] reported a case where endometrial ablation reduced bleeding in a warfarin-treated VTE patient unresponsive to LNG-IUS. Short-term efficacy is superior to medications^[40], but long-term failure rates (5%–20% at 2–5 years) necessitate reintervention for recurrent symptoms, particularly in adenomyosis or enlarged uteri^[41]. If endometrium ablation fails, a hysterectomy is required. Frank Nawroth et al^[42] described a 37-year-old female with hereditary hyperhomocysteinemia who presented with recurrent thromboembolic events and refractory menorrhagia. After failure of endometrium ablation and progesterone therapy, definitive management with supracervical hysterectomy was performed. Cases 1–3 had uteri >11 cm, precluding ablation. For eligible patients without fertility goals, small uteri, or refractory AUB/thrombosis, ablation may be attempted with close follow-up.

Uterine artery embolization (UAE)^[43,44] reduces uterine blood flow, inducing ischemic necrosis of ectopic endometrium, shrinking uterine volume, alleviating pain, and controlling bleeding. Indicated for medically refractory adenomyosis with severe symptoms, UAE is contraindicated in pregnancy, active infection, coagulopathy, malignancy, renal insufficiency, contrast allergy, or large uteri (>12-week gestation size). A systematic review noted 74% long-term (>12 months) symptom improvement post-UAE. A 7-year follow-up showed 82% sustained symptom control without hysterectomy^[45]. However, comparative studies with other therapies are lacking. Zaiqiang Yu et al^[46] described a patient with adenomyosis and PE who underwent UAE for anticoagulation-exacerbated bleeding, but uterine swelling worsened iliac vein compression, necessitating hysterectomy. UAE may be suitable for acute bleeding in small uteri. UAE may exacerbate thrombotic conditions due to immobilization or a hypercoagulable state, and thus it is not recommended for use during the acute phase of thrombotic diseases.

Hysterectomy^[47], definitive for refractory cases or comorbid conditions (e.g., fibroids), eliminates bleeding but requires perioperative anticoagulation^[48]. Multiple case reports have demonstrated the efficacy of total hysterectomy in patients with failed medical therapy, UAE or endometrium ablation, showing no thrombotic recurrence postoperatively even in the absence of anticoagulant treatment^{[35,36,42,46]}. Cases 1 and 2 underwent hysterectomy after failed medical therapy, with postoperative thrombosis in Case 1 resolving via anticoagulation. Case 2 had recurrent menorrhagia and DVT preoperatively but no post-hysterectomy recurrence. Laparoscopic or robotic hysterectomy is preferred for minimal invasiveness. Postoperative D-dimer monitoring and early anticoagulation are advised for thromboprophylaxis. Prompt evaluation of unexplained pain is critical to avoid missed diagnoses.

Conclusion

Adenomyosis with thrombotic complications requires individualized, multidisciplinary management. Pretreatment VTE risk assessment is crucial for high-risk patients, avoiding thrombogenic agents (e.g., high-dose estrogen, norethisterone) and favoring nonhormonal or anticoagulant-combined therapies. Early postoperative mobilization and mechanical/pharmacologic prophylaxis are recommended. For concurrent bleeding and thrombosis, GnRH-a combined with DNG may balance symptom control and thrombotic risk, though long-term safety needs further study. Refractory cases warrant surgery (ablation, UAE, or hysterectomy) with perioperative anticoagulation. Future research should optimize therapies and explore novel hemostatic agents or minimally invasive techniques.

Ethical approval

Not applicable.

Consent

Written consent for publication was obtained from the patient. We declare that the patient has been informed and agrees to publish identifiable information in open access journals.

Sources of funding

Not applicable.

Author contributions

Y.C. and H.L. collected data. H.Z. wrote the paper. H.L. analyzed the data. H.Z. reviewed and verified all the raw data. All authors read and approved the final manuscript.

Conflicts of interest disclosure

The authors declare no conflicts of interest.

Guarantor

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Research Registration Unique Identifying Number (UIN)

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Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The datasets used or analyzed during the current study are available from the corresponding author upon reasonable request.