Subarachnoid haemorrhage during premenopausal dienogest therapy in a patient with multiple risk factors.

A woman in her 40s (gravida 1 para 0; height, 162 cm; weight, 51 kg; body mass index, 19.4) was diagnosed with adenomyosis and endometriosis approximately 3 years ago. She had a family history of SAH (second-degree relative) and a personal history of smoking 15 cigarettes per day for 30 years (22.5 pack-years). She had no history of hypertension, headaches, head trauma or alcohol consumption. DNG therapy was initiated at 1 mg/day but was increased to 2 mg/day 3 months later owing to persistent breakthrough bleeding. Her blood pressure, laboratory test results and body weight remained stable for 10 months after increasing the dose. Three weeks after her last outpatient visit, the patient experienced a sudden severe headache and was transported to the emergency department for evaluation.

The patient recovered and was discharged on postoperative day 16 with no complications noted at her follow-up visit on day 50. The patient recovered without any neurological deficits and resumed normal daily activities. Imaging to evaluate the status of the aneurysm was planned for several months postoperative. The patient remains under neurosurgical observation, and at this time, no recurrence of symptoms has been reported.

The patient was transferred to the emergency room of the tertiary care centre, where she underwent endovascular treatment with Woven EndoBridge (WEB) placement for the ruptured aneurysm. During the WEB placement, she received intravenous aspirin and clopidogrel as part of the perioperative antiplatelet regimen. Postoperatively, only oral aspirin (100 mg/day) was continued for maintenance therapy. DNG therapy was discontinued immediately following the patient’s diagnosis.

Dienogest (DNG) therapy is prescribed to approximately 600 000 patients in Japan for the treatment of endometriosis and adenomyosis. It is also approved in 106 countries and regions worldwide, with substantial clinical use across Europe, North America and the Asia-Pacific region. Only two cases of subarachnoid haemorrhage (SAH) during DNG therapy have been reported thus far in Japan, with no international reports. SAH has traditionally been considered an incidental complication of DNG therapy; however, epidemiological data have shown that menopausal and premenopausal women have a significantly increased risk of SAH. Experimental studies have confirmed that oestrogen deficiency contributes to aneurysm formation and rupture. Given that DNG induces a hypooestrogenic state, we investigated whether this therapy increased the risk of developing SAH through vascular changes.

Only two other reports of SAH during DNG therapy have been documented in Japan, and no international cases have been identified. As DNG does not significantly affect coagulation pathways, SAH has traditionally been considered an incidental complication; however, epidemiological data indicate that the incidence of SAH is doubled in postmenopausal women. 1 Other studies have suggested that a shorter reproductive lifespan and surgically induced menopause are associated with an increased risk of SAH. 2 As shown in table 1 , oestrogen deficiency contributes to vascular fragility through mechanisms such as neutrophil extracellular trap formation (NETosis), 3 effects on the function and growth of endothelial cells, 4 increased interleukin-17A and decreased E-cadherin expression, 5 impaired nitric oxide production due to reduced activation of endothelial nitric oxide synthase via oestrogen receptor beta signalling 6 and diminished clearance of reactive oxygen species. 7 Furthermore, recent animal and cellular studies have demonstrated that oestrogen deficiency may lead to increased matrix metalloproteinase-9 activity and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing protein-3 inflammasome activation, contributing to extracellular matrix degradation and vascular inflammation, 8 both of which can weaken the vessel walls and increase the risk of aneurysm rupture. These findings suggest that DNG-induced oestrogen suppression poses a risk to patients with underlying vascular vulnerabilities. DNG induces a hypooestrogenic state, lowering serum oestradiol levels to approximately 30 pg/mL, which is below the average of 71 pg/mL observed among premenopausal women under 50 years of age with SAH, as shown in figure 7 . 9 In contrast, the mean oestradiol level among the non-SAH control group was 230 pg/mL (p<0.001). This hormonal profile resembles the postmenopausal physiology and may promote the formation and rupture of aneurysms. The known risk factors for cerebral aneurysms include genetic predisposition, oestrogen deficiency, hypertension, smoking, alcohol consumption and head trauma. 10 Numerous epidemiological studies have established cigarette smoking as one of the strongest independent risk factors for aneurysmal SAH. An international case–control study demonstrated a clear dose-dependent association between current active smoking and the risk of SAH, whereas neither past smoking nor passive smoking was associated with increased risk. 11 Furthermore, a study using the prospective UK Biobank cohort, which included 246 771 women and 210 085 men with a median follow-up of 12 years, identified older age, a family history of stroke and current smoking as independent predictors of SAH in women. 12 A nationwide observational study also reported that smoking increased the risk of aneurysmal SAH twofold between the ages of 30 and 60 and that smokers tended to present with SAH at younger ages. 13 In addition, Mendelian randomisation analysis has shown that genetically determined smoking behaviour is causally associated with non-traumatic SAH, minimising the influence of confounding factors. 14 In the present case, both a family history of SAH and long-term smoking likely contributed to aneurysm formation and rupture risk. It is also plausible that an unrecognised aneurysm had already been present before the initiation of DNG therapy. However, smoking alone does not fully explain the temporal association between starting DNG and the onset of SAH, suggesting that drug-induced hypooestrogenism during the 14-month treatment period may have accelerated the timing of aneurysmal rupture, a possibility that cannot be excluded. To contextualise the present case, we reviewed two previously reported cases of SAH during DNG therapy in Japan ( table 2 ). In case 1, the patient received a gonadotropin-releasing hormone antagonist for 6 months followed by 3 months of DNG, resulting in a sustained hypooestrogenic state for a total of 9 months. In case 2, the patient had been taking DNG for 10 years, during which prolonged hypooestrogenism may have contributed to cerebral arterial fragility; the subsequent head trauma was presumed to have triggered the rupture of a traumatic aneurysm. Taken together, these observations suggest that a persistent hypooestrogenic state during DNG therapy, compounded by additional risk factors—trauma in case 2 and smoking plus a family history of SAH in case 3—may increase the likelihood of aneurysm rupture and subsequent SAH. DNG, dienogest; SAH, subarachnoid haemorrhage. We have implemented a structured screening protocol for patients receiving DNG therapy at our institution, as shown in box 1 , with the aim of preventing SAH in patients with underlying vascular vulnerabilities, as illustrated by the present case. During the initial interview, we assess the presence of SAH-related risk factors, including a history of cerebral aneurysm, family history of SAH, hypertension, recurrent headaches, smoking, alcohol use and prior head trauma. Based on this assessment, patients are categorised into two high-risk groups as outlined in table 3 , while the majority of patients fall outside these categories and are considered low risk. Patients with a known cerebral aneurysm or a history of SAH are contraindicated for DNG therapy and referred to neurosurgery for further evaluation. Patients with relative risk factors, such as a family history of SAH, hypertension, headaches, smoking, alcohol use or head trauma, are evaluated using brain MRI and magnetic resonance angiography (MRA) before initiating DNG therapy. During the first 2 months of implementation, we screened 120 patients, of whom 10 had a family history of SAH and subsequently underwent MRA according to the protocol. Of the 10 patients evaluated with MRA, one had a 2-mm unruptured aneurysm in the left internal carotid artery, as shown in figure 8 . DNG therapy was discontinued, and the patient is currently undergoing neurosurgical observation. If future evidence demonstrates that DNG does not increase the risk of developing SAH, our screening protocol may be discontinued. History of cerebral aneurysm. Family history of subarachnoid haemorrhage. Hypertension. Recurrent headaches. Smoking history. Alcohol consumption. History of head trauma. DNG, dienogest; SAH, subarachnoid haemorrhage. The aforementioned findings underscore the importance of evaluating the risk of cerebral aneurysm before initiating DNG therapy. A structured screening approach may help prevent serious complications and support the need for individualised risk assessment. DNG is widely prescribed in Japan for the treatment of endometriosis and adenomyosis, with >600 000 patients receiving this therapy nationwide. Despite its clinical benefits, the long-term safety profile of DNG warrants further investigation, particularly regarding its cerebrovascular risk. Although DNG is not associated with coagulation abnormalities, its oestrogen-suppressive effects may have systemic consequences beyond gynaecological indications. This case highlights the importance of interdisciplinary collaboration between gynaecology and neurosurgery. The patient presented with multiple risk factors, including a personal history of smoking, a family history of SAH and a prolonged hypooestrogenic state, all of which may have contributed synergistically to the aneurysm rupture. Given the increasing use of DNG among reproductive-aged women for the management of endometriosis, clinicians should consider cerebrovascular screening in high-risk patients—such as those with a history of smoking, hypertension, headaches or a family history of cerebrovascular disease—before initiating this therapy. Although rare, SAH during DNG therapy may be a preventable adverse event if appropriate screening and risk stratification are performed. Future research should focus on the nationwide surveillance of cerebrovascular events during DNG therapy as well as prospective studies evaluating the relationship between oestrogen suppression and aneurysm pathogenesis. Safety assessments in gynaecology should adopt a comprehensive approach that includes the evaluation of systemic risks and promotes interdisciplinary cooperation. Patients considered for or currently receiving dienogest therapy should be screened for cerebrovascular risk factors, including family history of subarachnoid haemorrhage (SAH), smoking, hypertension, headache, alcohol use and head trauma. Dienogest should be contraindicated in patients with known cerebral aneurysms or prior SAH. Brain MRI and magnetic resonance angiography should be considered prior to initiating dienogest in high-risk individuals, given the potential for dienogest-induced hypooestrogenic states to increase SAH risk. Protocols for neurosurgical referral and cerebrovascular imaging should be established to ensure safe administration of dienogest in clinical practice.

The initial differential diagnoses considered in this case included migraine, hypertensive crisis and intracerebral haemorrhage. However, the sudden onset and severity of the patient’s headache, combined with the aforementioned CT findings, led to the confirmed diagnosis of SAH. The absence of trauma, hypertension or coagulopathy supported the spontaneous rupture of a cerebral aneurysm.

As shown in figures1 6 , CT of the head revealed an SAH (Hunt and Hess grade 2, World Federation of Neurosurgical Societies grade 1 and Fisher group grade 3), while CT and digital subtraction angiography confirmed the presence of a ruptured aneurysm in the anterior communicating artery. No other vascular abnormalities were observed, nor were any abnormalities detected on routine laboratory tests, aside from the expected oestradiol suppression from the DNG, which is not typically assessed in the neurosurgical setting.