Clinical trial NCT04979377: Prevalence of Hyperandrogenism in Type 1 Diabetes
Official title: Prevalence of Hyperandrogenism in Young Women With Type 1 Diabetes and Study of the Underlying Pathophysiological Mechanisms
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Type 1 Diabetes
Polycystic Ovary Syndrome
Hyperandrogenism
Hirsutism
Oligomenorrhea
Ovulation Disorder
Keywords: Polycystic ovary syndrome
Hyperandrogenism
Type 1 diabetes
Prevalence
Hirsutism
Ovulatory dysfunction
Testosterone
Insulin
Lead sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
Sponsor class: OTHER
Collaborators: name: Hospital Universitario Ramon y Cajal
name: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders
name: University of Alcala
name: Instituto de Salud Carlos III
First posted: 2021-07-28
Enrollment: 150
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Premenopausal women with T1DM consecutively recruited from a Diabetes outpatient clinic at a tertiary hospital.

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Prevalence of PCOS in T1DM
timeFrame: 2020-2022
measure: Prevalence of classic PCOS in T1DM
timeFrame: 2020-2022
measure: Prevalence of hyperandrogenic PCOS in T1DM
timeFrame: 2020-2022
Secondary outcomes:
measure: Prevalence of related traits in women with T1D
timeFrame: 2020-2022
measure: Influence fo the onset of type 1 diabetes on hyperandrogenism
timeFrame: 2020-2022
measure: Influence of Insulin Requirements on hyperandrogenism
timeFrame: 2020-2022
measure: Influence of metabolic control on hyperandrogenism
timeFrame: 2020-2022
measure: Influence of body composition on hyperandrogenism
timeFrame: 2020-2022
measure: Influence of hyperandrogenism on insulin requirements
timeFrame: 2020-2022
measure: Influence of hyperandrogenism on A1c
timeFrame: 2020-2022
measure: Influence of hyperandrogenism on mean glucose (GCM)
timeFrame: 2020-2022
measure: Influence of hyperandrogenism on time in range (GCM)
timeFrame: 2020-2022
measure: Influence of hyperandrogenism on chronic complications
timeFrame: 2020-2022
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
Study officials:
affiliation: CIBERDEM, Instituto de Salud Carlos III
name: Manuel Luque-Ramírez, PhD, MD, MBA
role: STUDY_DIRECTOR
affiliation: University of Alcalá
name: Héctor F Escobar-Morreale, PhD, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.