Undiagnosed Hyperandrogenism in Type 1 Diabetes: Clinical Evidence, Mechanisms, and Screening Implications

Highlights

• Approximately 25% of premenopausal women with Type 1 diabetes (T1D) have undiagnosed androgen excess disorders, with polycystic ovary syndrome (PCOS) affecting one in five.
• Iatrogenic hyperinsulinism, resulting from subcutaneous insulin delivery bypassing portal circulation, acts as a co-gonadotrophin, triggering ovarian androgen secretion in susceptible women.
• Women with a premenarcheal onset of T1D are significantly more predisposed to developing PCOS compared to those with postmenarcheal onset.
• T1D-associated PCOS often presents with milder clinical hirsutism and lower free testosterone levels than non-diabetic PCOS, making biochemical markers like androstenedione and LC-MS/MS testing critical for diagnosis.

Background

For decades, the reproductive health of women with Type 1 diabetes (T1D) was primarily viewed through the lens of pregnancy outcomes and glycemic control. However, emerging evidence suggests a profound intersection between insulin therapy and the endocrine-reproductive axis. In the physiological state, insulin is secreted into the portal vein, allowing the liver to clear a significant portion before it reaches systemic circulation. In T1D, subcutaneous insulin administration leads to systemic hyperinsulinism. Because the ovary remains sensitive to insulin’s stimulatory effects—acting as a co-gonadotrophin alongside luteinizing hormone (LH)—this iatrogenic hyperinsulinemia can stimulate the theca cells to overproduce androgens.

Despite clinical suspicions, the actual prevalence of androgen excess in this population has been historically difficult to quantify due to methodological variances in androgen assays and shifting diagnostic criteria. Recent high-quality studies using mass spectrometry and standardized phenotyping now clarify that androgen excess is not a rare comorbidity but a frequent, often overlooked feature of the T1D clinical landscape.

Key Content

Prevalence and Global Phenotypic Diversity

Recent cross-sectional data provide a robust estimate of the disease burden. Bayona Cebada et al. (2025) demonstrated that hyperandrogenic disorders (including PCOS, idiopathic hyperandrogenism, and idiopathic hirsutism) were present in 26% of premenopausal women with T1D. Specifically, 20% fulfilled the full Rotterdam diagnostic criteria for PCOS. This aligns with earlier findings from various geographic cohorts: a 2023 Mexican study reported a prevalence as high as 39% (Arch Med Res 2023), while a study from India observed a 27% prevalence (Endocrine 2023).

The “classic” phenotype—the combination of hyperandrogenism and ovulatory dysfunction—remains the most common presentation in T1D. However, women with T1D often exhibit milder clinical signs, such as lower Ferriman-Gallwey scores, compared to age- and BMI-matched women with PCOS who do not have diabetes. This subtlety often leads to these disorders remaining undiagnosed during routine diabetes follow-ups.

The Pathophysiological Impact of Insulin and Menarcheal Timing

A critical factor in the development of PCOS in T1D is the timing of diabetes onset. Research consistently shows that women who develop T1D before menarche are at the highest risk. Bayona Cebada et al. found that 73% of T1D women with PCOS had a premenarcheal onset, compared to only 46% in those without PCOS. The hypothesis is that exposure to high systemic insulin levels during the critical maturation of the hypothalamic-pituitary-ovarian (HPO) axis during puberty may irreversibly alter ovarian sensitivity and steroidogenic pathways.

Furthermore, the total daily insulin dose appears to be a biological driver. In several studies, women with T1D and PCOS required significantly higher insulin doses per kilogram of body weight compared to those without PCOS. This suggests a vicious cycle: higher insulin levels drive ovarian androgen production, while the resulting hyperandrogenism may further exacerbate peripheral insulin resistance, requiring even higher doses of exogenous insulin.

Biochemical Profiling and Diagnostic Advances

The diagnosis of hyperandrogenism in T1D has been hampered by the inaccuracy of traditional immunoassays at low testosterone ranges. The adoption of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has revolutionized this field.

Evidence suggests that androstenedione may be a more sensitive biochemical marker than total testosterone for identifying PCOS in T1D populations. A 2018 study (Hum Reprod 2018) highlighted that while free testosterone levels might be only moderately elevated, androstenedione levels effectively differentiated clinical phenotypes. Additionally, anti-Müllerian hormone (AMH) has been identified as a reliable marker of ovarian reserve and polycystic morphology in these patients, though its levels appear to be inversely correlated with total daily insulin dose in some multivariable models.

Metabolic and Inflammatory Synergies

T1D and PCOS both contribute to a pro-inflammatory state. However, recent exploratory studies (Sci Rep 2025) suggest that obesity and metabolic syndrome components are more dominant drivers of inflammation (elevated IL-6 and CRP) than the PCOS diagnosis itself within the T1D cohort.

From a vascular perspective, while both T1D and PCOS are independent risk factors for premature atherosclerosis, current data (Pol Arch Intern Med 2017) suggest that the presence of PCOS does not significantly increase subclinical vascular disease (measured via CIMT or FMD) beyond the risk already conferred by T1D in young, normal-weight women. Nevertheless, the long-term cumulative risk of the two conditions remains a subject of ongoing longitudinal investigation.

Therapeutic Class Evidence: Metformin and Life-Style Interventions

While insulin is the primary treatment for T1D, adjunctive therapies for hyperandrogenism have been explored. Randomized controlled trials in T1D adolescents (Horm Res Paediatr 2013) have shown that metformin can significantly decrease serum androgens, including testosterone and androstenedione. However, these biochemical improvements do not always translate to significant clinical changes in hirsutism or ovulation rates within short-term study periods.

Obesity remains the most significant modifiable risk factor. Population-based longitudinal studies (Clin Endocrinol 2020) have demonstrated that obesity confers a 4-fold increased risk of PCOS in women with T1D. Therefore, weight management is not merely a cardiovascular goal but a primary reproductive health intervention in this population.

Expert Commentary

The realization that 25% of women with T1D have undiagnosed androgen excess represents a significant gap in current clinical practice. Most diabetes guidelines focus heavily on the prevention of microvascular and macrovascular complications, often relegating reproductive health to preconception counseling.

Clinicians must recognize that “PCOS in T1D” may be a distinct clinical entity, sometimes referred to as “Type 1.5 Diabetes” phenotype when it includes features of insulin resistance and dyslipidemia. The diagnostic challenge is real: because these women are already on intensive insulin therapy, the traditional metabolic markers of PCOS (like HOMA-IR) are less useful. Diagnosis must rely on a high index of suspicion for menstrual irregularity and subtle skin signs, followed by high-quality biochemical testing.

One area of controversy remains the causality of iatrogenic hyperinsulinism. While the co-gonadotrophin theory is strong, the fact that not all T1D women develop PCOS suggests a genetic predisposition. Future research should focus on identifying genetic variants that make certain women more sensitive to the ovarian effects of systemic insulin. Furthermore, the role of modern insulin delivery systems (like closed-loop pumps) in potentially reducing systemic hyperinsulinism and its impact on PCOS prevalence is an exciting frontier for translational research.

Conclusion

Androgen excess disorders are a major, yet largely hidden, comorbid burden in the T1D population. With one in four premenopausal women affected, routine screening for menstrual cycle irregularities and clinical signs of hyperandrogenism should be integrated into standard T1D care. Early detection is particularly crucial for those with premenarcheal disease onset and those struggling with obesity. By addressing these reproductive disorders, clinicians can mitigate the long-term risks of infertility, chronic anovulation, and metabolic deterioration, ultimately improving the holistic health and quality of life for women living with Type 1 diabetes.

References

• Bayona Cebada A, 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. PMID: 40747135.
• Nattero-Chávez L, et al. Hirsutism and Polycystic Ovarian Morphology are the Most Frequent Components of Polycystic Ovary Syndrome in Women with Type 1 Diabetes. Arch Med Res. 2023;54(7):102895. PMID: 37866088.
• Suman V, et al. Prevalence of polycystic ovary syndrome and its clinical and hormonal profile in young females with type 1 diabetes mellitus. Endocrine. 2023;82(2):303-310. PMID: 37615813.
• Thong EP, et al. Obesity, menstrual irregularity and polycystic ovary syndrome in young women with type 1 diabetes: A population-based study. Clin Endocrinol (Oxf). 2020;93(5):564-571. PMID: 32640055.
• Codner E, et al. Metformin for the treatment of hyperandrogenism in adolescents with type 1 diabetes mellitus. Horm Res Paediatr. 2013;80(5):343-9. PMID: 24280743.
• O’Reilly MW, et al. Measurement of selected androgens using liquid chromatography-tandem mass spectrometry in reproductive-age women with Type 1 diabetes. Hum Reprod. 2018;33(9):1727-1734. PMID: 30020477.