Highlights
High Prevalence of Undiagnosed Disorders
One in every four women with Type 1 diabetes (T1D) suffers from an undiagnosed androgen excess disorder, with Polycystic Ovary Syndrome (PCOS) being the most frequent manifestation.
Impact of Disease Onset
Women who develop T1D before the onset of menarche (premenarcheal onset) are significantly more susceptible to developing these disorders.
Mechanistic Drivers
Systemic iatrogenic hyperinsulinism, a necessary result of subcutaneous insulin therapy, appears to act as a co-gonadotrophin, stimulating ovarian androgen production.
Screening Recommendations
The high prevalence and clinical impact of these conditions warrant routine screening for hyperandrogenism and ovulatory dysfunction in all premenopausal women with T1D.
Background and Clinical Context
The intersection of metabolic and reproductive health has long been a subject of intense clinical scrutiny. For women with Type 1 diabetes (T1D), the management of glycemic control is frequently complicated by systemic iatrogenic hyperinsulinism. Unlike physiological insulin secretion, which is directed into the portal circulation, therapeutic insulin is administered subcutaneously. This leads to high systemic concentrations that bypass the liver’s first-pass metabolism.Critically, insulin functions as a co-gonadotrophin at the level of the ovary. In predisposed individuals, these high systemic levels can trigger excessive androgen secretion. While previous research has suggested an increased prevalence of androgen excess in this population, many studies have been limited by small sample sizes or outdated diagnostic methodologies. This new evidence provides a clearer, more rigorous assessment of the disease burden in women with T1D.
Study Design and Methodology
Between January 2020 and March 2024, researchers conducted a cross-sectional study at an academic hospital in Madrid, Spain. The study included 149 consecutive premenopausal women with T1D. To provide a comparative framework, the researchers also analyzed 295 typical patients with PCOS who did not have T1D.The methodology employed was notably robust. Serum androgens were measured using state-of-the-art liquid chromatography-tandem mass spectrometry (LC-MS/MS), and free testosterone was determined via equilibrium dialysis—the gold standard for such measurements. Patients were phenotyped according to the latest international guidelines, ensuring that the diagnostic criteria for PCOS and other androgen disorders were applied with high precision.
Key Findings: The Prevalence of Androgen Excess
The results indicate a substantial and largely unrecognized burden of disease. Hyperandrogenic disorders—including PCOS, idiopathic hyperandrogenism, and idiopathic hirsutism—were present in 26% (39 of 149) of the women with T1D.
The PCOS Phenotype in T1D
Among those with androgen excess, 30 women (20% of the total T1D cohort) met the full diagnostic criteria for PCOS. The most common presentation was the classic phenotype, characterized by the combination of clinical or biochemical hyperandrogenism and ovulatory dysfunction.When comparing women with T1D who had PCOS to those who did not, several significant differences emerged:
Age and Onset
Women with T1D and PCOS were significantly younger than their counterparts without PCOS (mean age 25 vs. 31 years). Furthermore, the timing of T1D onset was a critical factor: 73% of the women with PCOS had a premenarcheal onset of diabetes, compared to only 46% of those without the disorder.
Biochemical Characteristics
Interestingly, when compared to the 295 ‘typical’ PCOS patients (those without T1D), women with both T1D and PCOS exhibited milder hyperandrogenic signs. Their free testosterone concentrations were significantly lower (13 pM vs. 21 pM) than those of typical PCOS patients. This suggests that while the hyperandrogenism in T1D is prevalent, its biochemical expression may be subtler than in the general PCOS population, potentially contributing to its frequent underdiagnosis.
Mechanistic Insights and Biological Plausibility
The association between T1D and androgen excess is rooted in the physiological role of insulin in the reproductive axis. In the ovary, insulin enhances the response of theca cells to luteinizing hormone (LH), thereby increasing the synthesis of androgens. In T1D, the loss of the portal-to-systemic insulin gradient means the ovaries are exposed to much higher insulin concentrations than would occur naturally.The study’s finding that premenarcheal onset of T1D increases risk suggests that the exposure of the hypothalamic-pituitary-ovarian axis to iatrogenic hyperinsulinism during the critical developmental window of puberty may permanently alter reproductive function, predisposing these women to PCOS.
Expert Commentary and Clinical Implications
The implications of this study are profound for the clinical management of women with T1D. The finding that one in four women remains undiagnosed suggests a significant gap in current care models.
Limitations and Cautions
The researchers acknowledge certain limitations, including the cross-sectional nature of the study, which prevents the establishment of a direct causal link between insulin therapy and the development of PCOS. Additionally, because women previously diagnosed with PCOS were excluded from the recruitment, the 26% prevalence rate may actually be an underestimation of the true burden.
A Call for Routine Screening
Given the long-term health risks associated with PCOS—including infertility, metabolic syndrome, and endometrial hyperplasia—routine screening is essential. Clinicians managing T1D should incorporate assessments of menstrual regularity and clinical signs of hyperandrogenism (such as hirsutism or persistent acne) into their standard reviews. This is particularly vital for women who were diagnosed with T1D before their first menstrual period.
Conclusion
This research clarifies a long-standing clinical suspicion: androgen excess is a major, yet frequently overlooked, comorbidity in women with Type 1 diabetes. The prevalence of 26% highlights the need for multidisciplinary care involving both endocrinologists and gynecologists. By identifying these disorders early, healthcare providers can implement preventive measures and treatments that safeguard the reproductive and general health of women living with T1D.
Funding and Clinical Data
This work was supported by grants PIE18/01122 and PI21/00116 from the Instituto de Salud Carlos III and co-funded by the European Union. A.B.C. received a Río Hortega grant (CM19/00138). The authors reported no competing interests.
References
1. Bayona Cebada A, Nattero-Chávez L, De la Calle De la Villa E, et al. Androgen excess disorders remain undiagnosed in one of every four premenopausal women with Type 1 diabetes. Hum Reprod Open. 2025;2025(3):hoaf048. doi:10.1093/hropen/hoaf048.2. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19-25.3. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270-284.