Correspondence from de Zegher and Ibáñez: “Uncommon LMNA Variation Contributes to the Development of Polycystic Ovary Syndrome in Two Distinct Cohorts”
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By
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Francis de Zegher
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Lourdes Ibáñez
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January 2, 2025
Clinical Scorecard: Uncommon LMNA Variation Contributes to the Development of Polycystic Ovary Syndrome in Two Distinct Cohorts
At a Glance
| Category | Detail |
|---|---|
| Condition | Polycystic Ovary Syndrome (PCOS) associated with LMNA gene variations |
| Key Mechanisms | Loss-of-function LMNA mutations cause partial lipodystrophy with altered adipose tissue distribution and insulin resistance, leading to PCOS development via impaired adipogenesis and ectopic fat accumulation |
| Target Population | Women with PCOS, particularly those without obesity and carrying LMNA variants |
| Care Setting | Endocrinology and gynecology outpatient clinics managing PCOS |
Key Highlights
- Rare LMNA gene variants contribute to PCOS pathogenesis, especially in non-obese women.
- PCOS variants linked to reduced adipogenesis (e.g., laminopathies) tend to occur without obesity, contrasting with obesity-associated PCOS driven by augmented lipogenesis.
- Therapeutic implications suggest adipogenesis-enhancing treatments like pioglitazone may benefit PCOS patients with LMNA variants and without obesity.
Guideline-Based Recommendations
Diagnosis
- Assess insulin sensitivity and adipose tissue topography in PCOS patients.
- Consider genetic testing for LMNA variants in PCOS patients, especially those without obesity.
- Use body composition analysis (e.g., dual X-ray absorptiometry) and imaging (MRI) to evaluate ectopic fat distribution when possible.
Management
- Avoid one-size-fits-all treatment; tailor therapy based on obesity status and underlying pathophysiology.
- Use combined contraceptive pills as first-line treatment broadly, but recognize limitations in non-obese PCOS with LMNA variants.
- Consider adipogenesis-enhancing agents such as pioglitazone for PCOS patients with LMNA-related lipodystrophy and limited lipid storage capacity.
- Glucagon-like peptide-1 receptor agonists may be helpful in obese PCOS patients.
Monitoring & Follow-up
- Monitor insulin sensitivity and fat distribution changes during treatment.
- Evaluate therapeutic response to adipogenesis-enhancing agents in non-obese PCOS patients.
Risks
- Risk of misclassification and suboptimal treatment if LMNA-related PCOS is not identified.
- Potential adverse effects of pioglitazone and other medications should be considered.
Patient & Prescribing Data
Women with PCOS, stratified by obesity status and presence of LMNA variants
Non-obese PCOS patients with LMNA variants may respond better to adipogenesis-enhancing treatments like pioglitazone rather than conventional therapies targeting gonadotropic axis or appetite suppression.
Clinical Best Practices
- Incorporate genetic and phenotypic assessments to identify LMNA-related PCOS variants.
- Differentiate PCOS subtypes based on adipogenesis capacity and obesity status to guide personalized therapy.
- Use advanced imaging and body composition tools to assess ectopic fat and adipose tissue distribution.
- Consider adipogenesis-enhancing medications for PCOS patients with lipodystrophy features and limited subcutaneous fat.
References
- Bauer et al. Study on LMNA variants in PCOS
- Gambineri et al. 2008 on LMNA-related PCOS
- de Zegher and Ibáñez correspondence letter
Based on findings from:
Letter to the Editor From de Zegher and Ibáñez: “Rare Variation in LMNA Underlies Polycystic Ovary Syndrome Pathogenesis in 2 Independent Cohorts”
Francis de Zegher, Lourdes Ibáñez. The Journal Of Clinical Endocrinology & Metabolism, 2025.
https://academic.oup.com/jcem/article/110/5/e1709/7941445
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