Prevalence of Hyperandrogenism in Type 1 Diabetes

NCT ID: NCT04979377

Last Updated: 2025-03-17

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

150 participants

Study Classification

OBSERVATIONAL

Study Start Date

2020-03-09

Study Completion Date

2024-12-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Type 1 Diabetes Polycystic Ovary Syndrome Hyperandrogenism Hirsutism Oligomenorrhea Ovulation Disorder

Study Design

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Observational Model Type

COHORT

Study Time Perspective

CROSS_SECTIONAL

Study Groups

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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

Clinical hyperandrogenism assessment

Intervention Type OTHER

Modified Ferriman-Gallwey scale

Total testosterone (ng/dL)

Intervention Type DIAGNOSTIC_TEST

Circulating total testosterone (LC-MS/MS or IQL-CDC method) at follicular phase

A1c (%)

Intervention Type DIAGNOSTIC_TEST

High Performance Liquid Chromatography (HPLC)

Total cholesterol

Intervention Type DIAGNOSTIC_TEST

Determined by enzymatic methods

Body mass index (BMI) (kg/m2)

Intervention Type OTHER

Defined as body weight divided by the square of body height, and expressed in kg/m2

Frequency of chronic vascular complications [n (%)]

Intervention Type DIAGNOSTIC_TEST

Retinopathy, nephropathy, neuropathy, and macrovascular disease.

Polycystic ovary morphology

Intervention Type DIAGNOSTIC_TEST

Sonographic assessment

Cardiovascular autonomic reflex tests (CARTs)

Intervention Type DIAGNOSTIC_TEST

Cardioautonomic function assessement by Vital scan HW7-HW6T:

Sex hormone-binding globulin (SHBG) (nmol/L)

Intervention Type DIAGNOSTIC_TEST

Circulating SHBG (IQL) at follicular phase

Dehydroepiandrosterone-sulphate (IQL) (ng/mL)

Intervention Type DIAGNOSTIC_TEST

Circulating DHEAS (IQL) at follicular phase

Waist circumference (cm)

Intervention Type OTHER

Waist circumference measurement made at the top of the iliac crest

Waist-to-hip ratio

Intervention Type OTHER

Waist circumference divided by hip circumference (measurement should be taken around the widest portion of the buttocks)

Body composition

Intervention Type OTHER

Vital Scan HW7-HW6T

Mean glucose (mg/dL)

Intervention Type DIAGNOSTIC_TEST

Continuous glucose monitoring (GCM) records

Time in target range (hours)

Intervention Type DIAGNOSTIC_TEST

Continuous glucose monitoring (GCM) records

Time in hyperglycemia (hours)

Intervention Type DIAGNOSTIC_TEST

Continuous glucose monitoring (GCM) records

Insulin dose (UI/Kg)

Intervention Type OTHER

Daily insulin dose divided by body weight

Insulin sensitivity

Intervention Type OTHER

Equation that relies on routine clinical measures: A1c, presence of hypertension, and waist circumference

High-density lipoprotein (HDL) (mg/dL)

Intervention Type DIAGNOSTIC_TEST

Enzymatic methods after precipitation of serum with phosphotungstic acid and Mg2+

Low-density lipoprotein (LDL) (mg/dL)

Intervention Type DIAGNOSTIC_TEST

Estimated by the Friedewald's equation.

Triglycerides (mg/dL)

Intervention Type DIAGNOSTIC_TEST

Determined by enzymatic methods

Interventions

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Clinical hyperandrogenism assessment

Modified Ferriman-Gallwey scale

Intervention Type OTHER

Total testosterone (ng/dL)

Circulating total testosterone (LC-MS/MS or IQL-CDC method) at follicular phase

Intervention Type DIAGNOSTIC_TEST

A1c (%)

High Performance Liquid Chromatography (HPLC)

Intervention Type DIAGNOSTIC_TEST

Total cholesterol

Determined by enzymatic methods

Intervention Type DIAGNOSTIC_TEST

Body mass index (BMI) (kg/m2)

Defined as body weight divided by the square of body height, and expressed in kg/m2

Intervention Type OTHER

Frequency of chronic vascular complications [n (%)]

Retinopathy, nephropathy, neuropathy, and macrovascular disease.

Intervention Type DIAGNOSTIC_TEST

Polycystic ovary morphology

Sonographic assessment

Intervention Type DIAGNOSTIC_TEST

Cardiovascular autonomic reflex tests (CARTs)

Cardioautonomic function assessement by Vital scan HW7-HW6T:

Intervention Type DIAGNOSTIC_TEST

Sex hormone-binding globulin (SHBG) (nmol/L)

Circulating SHBG (IQL) at follicular phase

Intervention Type DIAGNOSTIC_TEST

Dehydroepiandrosterone-sulphate (IQL) (ng/mL)

Circulating DHEAS (IQL) at follicular phase

Intervention Type DIAGNOSTIC_TEST

Waist circumference (cm)

Waist circumference measurement made at the top of the iliac crest

Intervention Type OTHER

Waist-to-hip ratio

Waist circumference divided by hip circumference (measurement should be taken around the widest portion of the buttocks)

Intervention Type OTHER

Body composition

Vital Scan HW7-HW6T

Intervention Type OTHER

Mean glucose (mg/dL)

Continuous glucose monitoring (GCM) records

Intervention Type DIAGNOSTIC_TEST

Time in target range (hours)

Continuous glucose monitoring (GCM) records

Intervention Type DIAGNOSTIC_TEST

Time in hyperglycemia (hours)

Continuous glucose monitoring (GCM) records

Intervention Type DIAGNOSTIC_TEST

Insulin dose (UI/Kg)

Daily insulin dose divided by body weight

Intervention Type OTHER

Insulin sensitivity

Equation that relies on routine clinical measures: A1c, presence of hypertension, and waist circumference

Intervention Type OTHER

High-density lipoprotein (HDL) (mg/dL)

Enzymatic methods after precipitation of serum with phosphotungstic acid and Mg2+

Intervention Type DIAGNOSTIC_TEST

Low-density lipoprotein (LDL) (mg/dL)

Estimated by the Friedewald's equation.

Intervention Type DIAGNOSTIC_TEST

Triglycerides (mg/dL)

Determined by enzymatic methods

Intervention Type DIAGNOSTIC_TEST

Other Intervention Names

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Hirsutism score Sex steroid profile Metabolic control Lipid profile Anthropometrics and body composition Cardiovascular function Sex steroid profile Sex steroid profile Anthropometrics and body composition Anthropometrics and body composition Bioimpedanciometry Metabolic control Metabolic control Metabolic control Metabolic control Estimated glucose disposal rate (eGDR) HDL-cholesterol Lipid profile Lipid profile

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

45 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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Hospital Universitario Ramon y Cajal

OTHER

Sponsor Role collaborator

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders

OTHER

Sponsor Role collaborator

University of Alcala

OTHER

Sponsor Role collaborator

Instituto de Salud Carlos III

OTHER_GOV

Sponsor Role collaborator

Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

OTHER

Sponsor Role lead

Responsible Party

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Manuel Luque Ramírez

Co-Principal investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Manuel Luque-Ramírez, PhD, MD, MBA

Role: STUDY_DIRECTOR

CIBERDEM, Instituto de Salud Carlos III

Héctor F Escobar-Morreale, PhD, MD

Role: STUDY_CHAIR

University of Alcalá

Locations

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Hospital Universitario Ramón y Cajal

Madrid, Madrid, Spain

Site Status

Countries

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Spain

References

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Escobar-Morreale HF, Roldan B, Barrio R, Alonso M, Sancho J, de la Calle H, Garcia-Robles R. High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2000 Nov;85(11):4182-7. doi: 10.1210/jcem.85.11.6931.

Reference Type BACKGROUND
PMID: 11095451 (View on PubMed)

Roldan B, Escobar-Morreale HF, Barrio R, de La Calle H, Alonso M, Garcia-Robles R, Sancho J. Identification of the source of androgen excess in hyperandrogenic type 1 diabetic patients. Diabetes Care. 2001 Jul;24(7):1297-9. doi: 10.2337/diacare.24.7.1297. No abstract available.

Reference Type BACKGROUND
PMID: 11423519 (View on PubMed)

Codner E, Escobar-Morreale HF. Clinical review: Hyperandrogenism and polycystic ovary syndrome in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2007 Apr;92(4):1209-16. doi: 10.1210/jc.2006-2641. Epub 2007 Feb 6.

Reference Type BACKGROUND
PMID: 17284617 (View on PubMed)

Escobar-Morreale HF, Roldan-Martin MB. Type 1 Diabetes and Polycystic Ovary Syndrome: Systematic Review and Meta-analysis. Diabetes Care. 2016 Apr;39(4):639-48. doi: 10.2337/dc15-2577.

Reference Type BACKGROUND
PMID: 27208367 (View on PubMed)

Codner E, Soto N, Lopez P, Trejo L, Avila A, Eyzaguirre FC, Iniguez G, Cassorla F. Diagnostic criteria for polycystic ovary syndrome and ovarian morphology in women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2006 Jun;91(6):2250-6. doi: 10.1210/jc.2006-0108. Epub 2006 Mar 28.

Reference Type BACKGROUND
PMID: 16569737 (View on PubMed)

Codner E, Iniguez G, Villarroel C, Lopez P, Soto N, Sir-Petermann T, Cassorla F, Rey RA. Hormonal profile in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus. J Clin Endocrinol Metab. 2007 Dec;92(12):4742-6. doi: 10.1210/jc.2007-1252. Epub 2007 Sep 25.

Reference Type BACKGROUND
PMID: 17895317 (View on PubMed)

Gaete X, Vivanco M, Eyzaguirre FC, Lopez P, Rhumie HK, Unanue N, Codner E. Menstrual cycle irregularities and their relationship with HbA1c and insulin dose in adolescents with type 1 diabetes mellitus. Fertil Steril. 2010 Oct;94(5):1822-6. doi: 10.1016/j.fertnstert.2009.08.039. Epub 2009 Sep 30.

Reference Type BACKGROUND
PMID: 19796762 (View on PubMed)

Codner E, Merino PM, Tena-Sempere M. Female reproduction and type 1 diabetes: from mechanisms to clinical findings. Hum Reprod Update. 2012 Sep-Oct;18(5):568-85. doi: 10.1093/humupd/dms024. Epub 2012 Jun 17.

Reference Type BACKGROUND
PMID: 22709979 (View on PubMed)

Nattero-Chavez L, Alonso Diaz S, Jimenez-Mendiguchia L, Garcia-Cano A, Fernandez-Duran E, Dorado Avendano B, Escobar-Morreale HF, Luque-Ramirez M. Sexual Dimorphism and Sex Steroids Influence Cardiovascular Autonomic Neuropathy in Patients With Type 1 Diabetes. Diabetes Care. 2019 Nov;42(11):e175-e178. doi: 10.2337/dc19-1375. Epub 2019 Sep 17. No abstract available.

Reference Type BACKGROUND
PMID: 31530659 (View on PubMed)

Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018 Sep 1;33(9):1602-1618. doi: 10.1093/humrep/dey256.

Reference Type BACKGROUND
PMID: 30052961 (View on PubMed)

Escobar-Morreale HF, Carmina E, Dewailly D, Gambineri A, Kelestimur F, Moghetti P, Pugeat M, Qiao J, Wijeyaratne CN, Witchel SF, Norman RJ. Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2012 Mar-Apr;18(2):146-70. doi: 10.1093/humupd/dmr042. Epub 2011 Nov 6.

Reference Type BACKGROUND
PMID: 22064667 (View on PubMed)

Escobar-Morreale HF, Bayona A, Nattero-Chavez L, Luque-Ramirez M. Type 1 diabetes mellitus and polycystic ovary syndrome. Nat Rev Endocrinol. 2021 Dec;17(12):701-702. doi: 10.1038/s41574-021-00576-0. No abstract available.

Reference Type BACKGROUND
PMID: 34561669 (View on PubMed)

Other Identifiers

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DM1PCOS

Identifier Type: -

Identifier Source: org_study_id

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