Atrial flutter under enclomiphene: what risk after mitral surgery?

Clinical context and therapeutic challenge

The management of macroreentrant atrial tachycardias in patients with a complex anatomical substrate constitutes a major clinical challenge. This clinical case reports the situation of a 46-year-old man, with a history of mitral valve repair and chronic immune thrombocytopenic purpura (ITP), admitted for symptomatic atrial flutter. The arrhythmia was documented shortly after a dosage escalation of enclomiphene, increased from 25 mg to 50 mg per day. Upon admission, the patient presented a testosterone level of 1400 ng/dL (normal: 265-923 ng/dL) and severe thrombocytopenia (36 × 10⁹/L), creating a therapeutic impasse for the initiation of anticoagulation essential for rhythm control.

Study objectives and hypotheses

The objective of this case study is to analyse the potential causality between enclomiphene-induced endogenous testosterone increase and the onset of arrhythmia in a pre-disposed heart. The study examines how to weigh the role of this hormonal modulator against an established post-surgical scar substrate. The main hypothesis is that enclomiphene may have acted as a secondary triggering factor on a remodelled atrium. Finally, the article details the multidisciplinary strategy adopted to increase the platelet count to allow for safe anticoagulation and transoesophageal echocardiography-guided cardioversion.

Clinical management and therapeutic protocol

This case report details the multidisciplinary strategy adopted for a 46-year-old patient presenting with complex atrial flutter. The investigation protocol was triggered following the onset of exertional dyspnea, coinciding with an increase in the enclomiphene dose from 25 mg to 50 mg per day. The clinical challenge relied on the simultaneous management of a post-surgical arrhythmogenic substrate (mitral repair 20 years earlier) and chronic immune thrombocytopenic purpura (ITP).

• Initial assessment: The analysis combined an ECG (2:1 flutter, 137 bpm), a transthoracic echocardiography and a complete biological work-up. Key markers included a testosterone level of 1400 ng/dL and severe thrombocytopenia at 36 × 10⁹/L (compared to 43 × 10⁹/L one month prior).
• ITP Treatment: To secure anticoagulation, corticosteroid therapy with prednisone (100 mg/d) was initiated, accompanied by a tapering withdrawal schedule of 10 mg per week over a 10-week period.
• Ventricular response control: Pharmacological management combined metoprolol tartrate (50 mg twice daily) and diltiazem (240 mg daily).
• Decision criteria: The initiation of anticoagulation and the performance of TEE-guided cardioversion were conditional upon reaching a platelet threshold of 50 × 10⁹/L.

The differential diagnosis excluded through imaging (CT angiography) and biology (troponin, thyroid function) any embolic, ischemic, or metabolic cause, in order to analyze the interaction between the pre-existing anatomical substrate and the suspected hormonal trigger.

Clinical and biological results

The 46-year-old patient presented with progressive exertional dyspnea that appeared shortly after doubling his enclomiphene dose (from 25 mg to 50 mg per day). The initial clinical examination and complementary tests revealed the following data:

Electrographic and hemodynamic data

• Rhythm: Atrial flutter with 2:1 atrioventricular conduction.
• Ventricular rate: 137 beats per minute.
• Stability: Hemodynamically stable patient, with no signs of respiratory distress or pathological heart sounds (murmurs, gallops).

Biological and hormonal analyses

The biological assessment revealed a marked elevation in testosterone and pre-existing severe thrombocytopenia, complicating the therapeutic strategy.

Imaging observations

Transthoracic echocardiography revealed chronic structural remodeling, constituting a potential arrhythmogenic substrate:

• Ventricular function: Preserved left ventricular ejection fraction (LVEF), but slightly reduced right ventricular systolic function.
• Morphology: Mild asymmetric left ventricular hypertrophy and mild left atrial dilatation.
• Valvulopathies: Mild regurgitation on the four cardiac valves.
• Exclusion of comorbidities: The CT pulmonary angiogram excluded a pulmonary embolism and the chest X-ray was normal.

Management strategy

Due to the bleeding risk associated with ITP (Immune Thrombocytopenic Purpura), the anticoagulation required for cardioversion was deferred. Corticosteroid therapy with prednisone (100 mg/day) was initiated to reach a target platelet threshold of > 50 × 10⁹/L. Rate control was initiated with metoprolol tartrate (50 mg twice daily) and diltiazem (240 mg per day).

Synergy between surgical substrate and hormonal modulation

This clinical case highlights the potential role of enclomiphene as a trigger for macro-reentrant atrial tachycardia in a previously operated heart. While the mitral valve surgery, performed 20 years earlier, created a durable arrhythmogenic substrate through scars and suture lines, the therapeutic escalation of enclomiphene appears to have acted here as a secondary modulator. The transition from a dose of 25 mg to 50 mg per day coincided with an elevation of testosterone to 1400 ng/dL, reinforcing the hypothesis of a hormonal contribution to atrial electrophysiology, consistent with population data associating high testosterone with arrhythmias.

Diagnostic limits and uncertainties

The study highlights several gray areas: the lack of prior monitoring prevents precise dating of the flutter onset, making it difficult to distinguish between de novo arrhythmia and the exacerbation of a subclinical process. Furthermore, without electroanatomical mapping, the exact circuit (isthmus-dependent or related to the atrial scar) remains hypothetical. The absence of follow-up data after hospital discharge also limits the interpretation of direct causality and clinical outcome following hormonal adjustment.

Implications for clinical management

Therapeutic management was complicated by severe immune thrombocytopenia (ITP) (36 × 10⁹/L). The impossibility of initiating immediate anticoagulation illustrates the clinical challenge of rhythm control in a haemorrhagic setting. The authors adopted a pragmatic strategy: corticosteroid therapy (prednisone 100 mg/d) to cross the threshold of 50 × 10⁹/L platelets, a condition deemed necessary to allow safe anticoagulation before a scheduled cardioversion under transoesophageal ultrasound guidance.

Summary of results

This clinical case reports the onset of atrial flutter in a 46-year-old patient shortly after doubling his dose of enclomiphene (50 mg/day), resulting in supratherapeutic testosterone levels of 1400 ng/dL. Management was complicated by chronic immune thrombocytopenia (36 × 10⁹/L) requiring corticosteroid therapy (prednisone 100 mg/day) to reach a safe platelet threshold of 50 × 10⁹/L before initiating the anticoagulation required for cardioversion.

In concrete terms, for the practitioner:

• Hormonal vigilance: Monitor heart rate during any dosage escalation of enclomifene or clomiphene, as these molecules can act as pro-arrhythmic electrophysiological modulators, especially on a scarred cardiac substrate (e.g., former mitral surgery).
• Critical platelet threshold: In cases of ITP requiring rate control, aim for a minimum platelet count of 50 × 10⁹/L before starting anticoagulation to balance bleeding and thromboembolic risks.
• Multifactorial analysis: In the presence of de novo arrhythmia, do not overlook the impact of recent pro-androgenic treatment, even if the patient already presents predisposing structural cardiac abnormalities.

Technical lexicon of the study

Enclomiphene citrate: Trans-isomer of clomiphene citrate, acting as a non-steroidal estrogen receptor antagonist. It stimulates the release of gonadotropins to increase endogenous testosterone production in the context of secondary hypogonadism.

Atrial macro-reentrant tachycardia: Organized arrhythmia around fixed conduction barriers (atriotomy scars, surgical sutures), frequent after mitral valve surgery, and constituting here the anatomical substrate of atrial flutter.

Immune thrombocytopenic purpura (ITP): Hematological disorder characterized by chronic thrombocytopenia. In this case, platelet counts ranged between 36 and 43 × 10&sup9;/L, requiring a safety threshold of 50 × 10&sup9;/L for the initiation of anticoagulation.

TOE-guided cardioversion: Procedure for restoring sinus rhythm via transoesophageal echocardiography, necessary to exclude an atrial thrombus when anticoagulation cannot be immediately initiated due to a high risk of bleeding.

Secondary hypogonadism: Testosterone deficiency resulting from a failure of the hypothalamic-pituitary axis, treated in this case with a daily dose of enclomiphene inadvertently increased from 25 mg to 50 mg.

Arrhythmogenic substrate: Set of atrial structural modifications (left atrial dilatation, left ventricular hypertrophy, post-operative scarring) predisposing to the development of arrhythmias during hormonal or drug stimulation.

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