Prevalence of Hyperandrogenism in Type 1 Diabetes

March 13, 2025 updated by: Manuel Luque Ramírez, Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Prevalence of Hyperandrogenism in Young Women with Type 1 Diabetes and Study of the Underlying Pathophysiological Mechanisms

The investigators aim to estimate the prevalence of functional ovarian hyperandrogenism [idiopathic hyperandrogenism, idiopatic hirsutism, and polycystic ovary syndrome (PCOS)] in adult patients with type 1 diabetes (T1DM) in an observational cross-sectional study. Study population is comprised of premenopausal adult women with a diagnosis of T1DM, consecutively recruited from a Diabetes outpatient clinic at a tertiary hospital in Spain, Europe.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, with an estimated prevalence of 6-15% of the general population worldwide. This heterogeneous syndrome has significant cardio-metabolic, reproductive, and psycho-emotional consequences, and therefore, a prompt recognition and management is of paramount importance for these women. Despite hyperandrogenism is the cornerstone in the pathophysiology of PCOS, this derangement is closely related to insulin resistance, compensatory hyperinsulinemia, and abdominal adiposity. Hyperinsulinemia increases androgen secretion by co-stimulating besides gonadotropins both ovary and adrenal steroidogenesis, which leads to predominant visceral/abdominal fat deposition, and further contributes to insulin resistance and hyperinsulinemia. In addition, PCOS has been classically associated with metabolic alterations such as for overweight/obesity and type 2 diabetes mellitus. However, type 1 diabetes mellitus (T1D) results from autoimmune-mediated destruction of the pancreas, causing a complete insulin lack in most patients. Intensive insulin therapy - a mandatory iatrogenic hyperinsulinism -, while improving chronic glycemic control and prognosis, has led in recent years to the appearance of "new" reproductive consequences in these patients, such as functional hyperandrogenism and menstrual irregularity. This association is expected from the stimulation of ovarian androgen production by exogenous insulin, which reaches the ovary in supraphysiological concentrations. However, these studies present with a high heterogeneity, and prevalence rates significantly vary depending on several variables such as the criteria used for PCOS diagnosis, race/ethnicity, age of the study population, and the prevalence of obesity, among others. In 2016, a systematic review assessing the prevalence of PCOS in T1D was published, including 475 women with T1D from 9 studies. The results showed an overall prevalence of PCOS about 24% in T1D, higher than reported in the general population. Other hyperandrogenic traits such as hirsutism (25%), hyperandrogenaemia (24%), or ovulatory dysfunction (33%) were also common. Although PCOS is one of the most common comorbidities in patients with T1D, there are a limited number of publications in the literature. In summary, PCOS and functional hyperandrogenism remain a condition to be explored thoroughly in these patients.

The investigators hypothesize that the prevalence of functional hyperandrogenism including PCOS in Spanish women with T1D is higher than in women from the general population. Furthermore, signs and symptoms of hyperandrogenism, and hyperandrogenemia may be milder in patients with T1D compared to hyperandrogenic women from the general population. Moreover, the occurrence of PCOS in these women may be influenced by insulin dose, duration of diabetes, and chronic metabolic control.

The main objective of this study is to determine the actual prevalence of PCOS in premenopausal women with T1DM, according to different diagnostic criteria/PCOS phenotypes [classic PCOS (classic NIH criteria), hyperandrogenic PCOS (AES-PCOS criteria), and/or inclusive ESHRE-ASRM/Rotterdam criteria]. As secondary goals, the investigators also aim to describe: i) the hyperandrogenic traits associated with PCOS in women with T1DM; and ii) the metabolic-T1D related parameters in women with or without hyperandrogenism.

Sample size calculation: Sample size analysis used the online sample size and power calculator from the Program of Research in Inflammatory and Cardiovascular Disorders, Institut Municipal d'Investigació Mèdica, Barcelona, Spain (https://www.imim.cat/ofertadeserveis/software-public/granmo/). Considering previous data on prevalence of SOP in adolescents and adult women with T1D according to ESHRE-ASRM/Rotterdam criteria, the investigators concluded that 150 participants would be needed to assume an expected proportion of 40%, with an absolute precision of 5% at both sides of the proportion, and an asymptotic bilateral 95% confidence interval, and with an estimated replacement rate of 10%.

Statistical analysis: Continuous variables will be expressed as mean ± SD with its respective 95% confidence intervals (95%CI). Normality of continuous variables will be checked by the Kolmogorov-Smirnov test, and ensured by applying logarithmic transformations. the investigators will use non-parametric tests to analyse variables that remained skewed even after transformation. The differences in means will be analysed by Student t or Mann-Whitney U tests. Discrete variables will be showed according to their absolute, relative frequency, and 95%CI determined using the Wilson method without continuity correction. The differences between proportions will be estimated using the χ2 or Fisher's exact tests. Correlation analysis will be used to evaluate putative association between continuous variables. Finally, multiple linear an binary logistic regression full and stepwise models (probability for entry ≤0.05, probability for removal ≥0.10) will be performed to ascertain the main determinants of predetermined outcomes. The statistical significance will be set at the P < 0.05 level.

Study Type

Observational

Enrollment (Actual)

150

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Madrid, Spain, 28034
        • Hospital Universitario Ramon y Cajal

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 45 years (Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Premenopausal women with T1DM consecutively recruited from a Diabetes outpatient clinic at a tertiary hospital.

Description

Inclusion Criteria:

  • Age between 18 and 45 years old
  • Type 1 diabetes diagnosed at least 1 year before the inclusion in the study. Diagnosis confirmed by positive autoimmunity (GAD-65 or IA2) and insulin deficiency.
  • Treatment with subcutaneus insulin therapy (multiple dose or continuous subcutaneous insulin infusion).
  • Menarche at least 2 years before the study.

Exclusion Criteria:

  • Honey moon period.
  • Altered thyroid hormone or prolactin levels.
  • Congenital adrenal hyperplasia.
  • Severe chronic disease.
  • Oral contraceptive or glucocorticoid therapy in the previous 3 months.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Cross-Sectional

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Adult premenopausal women with type 1 diabetes mellitus
One-hundred and fifty women aged from 18 to 45 years old consecutively recruited from a type 1 diabetes clinic at a tertiary hospital of Madrid, Spain
Other: Clinical hyperandrogenism assessment
Modified Ferriman-Gallwey scale
Other Names:
  • Hirsutism score
Diagnostic test: Total testosterone (ng/dL)
Circulating total testosterone (LC-MS/MS or IQL-CDC method) at follicular phase
Other Names:
  • Sex steroid profile
Diagnostic test: A1c (%)
High Performance Liquid Chromatography (HPLC)
Other Names:
  • Metabolic control
Diagnostic test: Total cholesterol
Determined by enzymatic methods
Other Names:
  • Lipid profile
Other: Body mass index (BMI) (kg/m2)
Defined as body weight divided by the square of body height, and expressed in kg/m2
Other Names:
  • Anthropometrics and body composition
Diagnostic test: Frequency of chronic vascular complications [n (%)]
Retinopathy, nephropathy, neuropathy, and macrovascular disease.
Diagnostic test: Polycystic ovary morphology
Sonographic assessment
Diagnostic test: Cardiovascular autonomic reflex tests (CARTs)
Cardioautonomic function assessement by Vital scan HW7-HW6T:
Other Names:
  • Cardiovascular function
Diagnostic test: Sex hormone-binding globulin (SHBG) (nmol/L)
Circulating SHBG (IQL) at follicular phase
Other Names:
  • Sex steroid profile
Diagnostic test: Dehydroepiandrosterone-sulphate (IQL) (ng/mL)
Circulating DHEAS (IQL) at follicular phase
Other Names:
  • Sex steroid profile
Other: Waist circumference (cm)
Waist circumference measurement made at the top of the iliac crest
Other Names:
  • Anthropometrics and body composition
Other: Waist-to-hip ratio
Waist circumference divided by hip circumference (measurement should be taken around the widest portion of the buttocks)
Other Names:
  • Anthropometrics and body composition
Other: Body composition
Vital Scan HW7-HW6T
Other Names:
  • Bioimpedanciometry
Diagnostic test: Mean glucose (mg/dL)
Continuous glucose monitoring (GCM) records
Other Names:
  • Metabolic control
Diagnostic test: Time in target range (hours)
Continuous glucose monitoring (GCM) records
Other Names:
  • Metabolic control
Diagnostic test: Time in hyperglycemia (hours)
Continuous glucose monitoring (GCM) records
Other Names:
  • Metabolic control
Other: Insulin dose (UI/Kg)
Daily insulin dose divided by body weight
Other Names:
  • Metabolic control
Other: Insulin sensitivity
Equation that relies on routine clinical measures: A1c, presence of hypertension, and waist circumference
Other Names:
  • Estimated glucose disposal rate (eGDR)
Diagnostic test: High-density lipoprotein (HDL) (mg/dL)
Enzymatic methods after precipitation of serum with phosphotungstic acid and Mg2+
Other Names:
  • HDL-cholesterol
Diagnostic test: Low-density lipoprotein (LDL) (mg/dL)
Estimated by the Friedewald's equation.
Other Names:
  • Lipid profile
Diagnostic test: Triglycerides (mg/dL)
Determined by enzymatic methods
Other Names:
  • Lipid profile

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prevalence of PCOS in T1DM
Time Frame: 2020-2022
Prevalence of PCOS in women with T1DM according to ESHRE-ASRM/Rotterdam criteria
2020-2022
Prevalence of classic PCOS in T1DM
Time Frame: 2020-2022
Prevalence of PCOS in women with T1DM according to classic NIH criteria
2020-2022
Prevalence of hyperandrogenic PCOS in T1DM
Time Frame: 2020-2022
Prevalence of PCOS in women with T1DM according to AES-PCOS criteria
2020-2022

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prevalence of related traits in women with T1D
Time Frame: 2020-2022
Prevalence of related hyperandrogenic traits (idiopatic hirsutism, hyperandrogenemia, oligomenorrhea and isolated polycytic ovarian morphology) in women with T1DM
2020-2022
Influence fo the onset of type 1 diabetes on hyperandrogenism
Time Frame: 2020-2022
To assess the influence of the timing of diagnosis of type 1 diabetes in the appearance of hyperandrogenism, and also the possible effect of duration of diabetes.
2020-2022
Influence of Insulin Requirements on hyperandrogenism
Time Frame: 2020-2022
To describe daily insulin requirements and their influence on functional hyperandrogenism occurrence. We also aim to determine the effect of the chronic metabolic control in PCOS appearance.
2020-2022
Influence of metabolic control on hyperandrogenism
Time Frame: 2020-2022
To describe the influence of metabolic control (A1c) on functional hyperandrogenism occurrence. We also aim to determine the effect of the chronic metabolic control in PCOS appearance.
2020-2022
Influence of body composition on hyperandrogenism
Time Frame: 2020-2022
To evaluate the influence of risk factors body composition in the occurrence of ovarian hyperandrogenism and PCOS in women with type 1 diabetes.
2020-2022
Influence of hyperandrogenism on insulin requirements
Time Frame: 2020-2022
To describe the influence of hyperandrogenism on metabolic control.
2020-2022
Influence of hyperandrogenism on A1c
Time Frame: 2020-2022
To describe the influence of hyperandrogenism on metabolic control.
2020-2022
Influence of hyperandrogenism on mean glucose (GCM)
Time Frame: 2020-2022
To describe the influence of hyperandrogenism on metabolic control.
2020-2022
Influence of hyperandrogenism on time in range (GCM)
Time Frame: 2020-2022
To describe the influence of hyperandrogenism on metabolic control.
2020-2022
Influence of hyperandrogenism on chronic complications
Time Frame: 2020-2022
To describe the influence of hyperandrogenism on the frequency of chronic complications related to type 1 diabetes mellitus
2020-2022

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Collaborators

University of Alcala
Hospital Universitario Ramon y Cajal
Instituto de Salud Carlos III
Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders

Investigators

  • Study Director: Manuel Luque-Ramírez, PhD, MD, MBA, CIBERDEM, Instituto de Salud Carlos III
  • Study Chair: Héctor F Escobar-Morreale, PhD, MD, University of Alcala

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 9, 2020

Primary Completion (Actual)

December 30, 2024

Study Completion (Actual)

December 30, 2024

Study Registration Dates

First Submitted

July 7, 2021

First Submitted That Met QC Criteria

July 16, 2021

First Posted (Actual)

July 28, 2021

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

March 13, 2025

Last Verified

March 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DM1PCOS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

IPD Sharing Time Frame

Since study ending with no time limit restriction

IPD Sharing Access Criteria

Reasonable request

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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