Subclinical Hypothyroidism and Chronic Inflammation in PCOS

The Influence of Subclinical Hypothyroidism on Chronic Inflammation Activity in Women With Different PCOS Phenotypes

Chronic inflammation in polycystic ovary syndrome (PCOS) may be the result of dysregulation of cytokine production (due to insulin resistance, excess visceral fat and hyperandrogenemia), i.e., overproduction of pro-inflammatory factors (e.g. TNF, IL-1, IL-6) in relation to anti-inflammatory ones (IL-10). This condition may be an important link between obesity and insulin resistance, which is crucial in the etiopathogenesis of the syndrome. However, it is not known whether it results from the tendency to accumulate adipose tissue or is a feature of the syndrome itself. Concomitant endocrinopathies, i.e. obesity, dyslipidemia, insulin resistance, diabetes and thyroid diseases, may additionally influence the activity of chronic inflammation. There is no data indicating the relationship between chronic inflammation and PCOS phenotypes, the severity of metabolic disorders, ovarian reserve and the influence of thyroid function on its activity in PCOS.

Study Overview

• Status: Recruiting
• Conditions: Subclinical hypothyroïdism; PCOS (Polycystic Ovary Syndrome) of Bilateral Ovaries; Hypothalamic-Pituitary-Gonadal Axis Dysfunction
• Intervention / Treatment: Diagnostic test: Measurement and comparison of leucocytosis and concentrations of CRP, procalcitonin, fibrinogen, ferritin, IL-1, IL-6, IL-10, TNF-alpha in both study arms; Diagnostic test: Evaluation of the impact of subclinical hypothyroidism, with present/ absent antithyroid antibodies, on the balance between anti- and pro-inflammatory factors in women in both study arms; Diagnostic test: Assessment of the impact of imbalance between anti- and pro-inflammatory factors in women with different PCOS and HPOD phenotypes on ovarian reserve indices

Detailed Description

The aim of the study is:

i) to assess and compare serum concentrations of selected inflammatory markers (leucocytosis, CRP, procalcitonin, fibrinogen, ferritin, IL-1, IL-6, IL-10, TNF-alpha) in women with different phenotypes PCOS and hypothalamic-pituitary-ovarian axis dysfunction (HPOD) (control), ii) to evaluate the impact of subclinical hypothyroidism (defined as TSH>2.5 uIU/ml, fT3 3,1-6,80 pmol/l, fT4 12,0-22,0 pmol/l), with the presence and absence of circulating antithyroid antibodies (a-TPO and a-TG), on the balance between anti- and pro-inflammatory factors in women with different PCOS and HPOD phenotypes, iii) to assess the impact of imbalance between anti- and pro-inflammatory factors in women with different PCOS and HPOD phenotypes on ovarian reserve indices, expressed as FSH and AMH concentrations.

The study population will be characterized in terms of demographic (age, BMI), gynecological (age of first and last menstrual period, cycle length, history of reproductive organ surgeries, ultrasound measurements of endometrial width, ovarian volume) and obstetrics (pregnancies, childbirth, miscarriages) data. PCOS syndrome (and its phenotypes) will be recognized by the Rotterdam criteria. HPOD will be diagnosed according to WHO criteria. During hospitalization, blood samples will be collected for scheduled analyzes (30 ml of blood in total).

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Iwona M. Gawron, Ph.D.; Phone Number: +48 12 4248570; Email: iwona.gawron@uj.edu.pl
• Study Contact Backup: Name: Robert Jach, Prof., Ph.D.; Phone Number: +48 12 4248571; Email: robert.jach@uj.edu.pl

Study Locations

• Poland
  • Krakow, Poland, 31-501
    • Recruiting
    • Jagiellonian University Medical College, Department of Gynecology and Obstetrics
    • Contact: Iwona Gawron, Ph.D.; Phone Number: +48 124248570; Email: iwona.gawron@uj.edu.pl
    • Contact: Jach Robert, Prof., Ph.D.; Phone Number: +48124248571; Email: jach@cm-uj.krakow.pl
  • Kraków, Poland, 31-501
    • Recruiting
    • Jagiellonian University Medical College, Department of Gynecology and Obstetrics
    • Principal Investigator: Iwona M. Gawron, Ph.D.
    • Contact: Iwona M. Gawron, Ph.D.; Phone Number: +48 12 4248570; Email: iwona.gawron@uj.edu.pl
    • Contact: Robert Jach, Prof.; Phone Number: +48 12 4248571; Email: robert.jach@uj.edu.pl
    • Sub-Investigator: Krzysztof Skotniczny, Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• age 18-45 years,
• cycle length <21 days or > 35 days,
• unsuccessful attempts to conceive for at least 12 months of regular intercourse with sonographically confirmed anovulation with excluded male, tubal and uterine infertility factors.

Exclusion Criteria:

• absence of at least one ovary,
• previously diagnosed thyroid disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Polycystic ovary syndrome (PCOS); Women meeting the Rotterdam-ESHRE-ASRM criteria for a diagnosis of PCOS	Diagnostic test: Measurement and comparison of leucocytosis and concentrations of CRP, procalcitonin, fibrinogen, ferritin, IL-1, IL-6, IL-10, TNF-alpha in both study arms; A venous blood sample of approximately 10 ml will be collected in the morning after 8 hours of fasting to determine and compare the above parameters of peripheral blood in both arms of the study; Diagnostic test: Evaluation of the impact of subclinical hypothyroidism, with present/ absent antithyroid antibodies, on the balance between anti- and pro-inflammatory factors in women in both study arms; A venous blood sample of approximately 10 ml will be collected in the morning after 8 hours of fasting to determine and compare blood levels of leukocytosis, CRP, procalcitonin, fibrinogen, ferritin, IL-1, IL-6, IL-10, TNF-alpha depending on the blood concentrations of TSH, a-TPO and a-TG in women in both study arms; Diagnostic test: Assessment of the impact of imbalance between anti- and pro-inflammatory factors in women with different PCOS and HPOD phenotypes on ovarian reserve indices; A venous blood sample of approximately 10 ml will be collected in the morning after 8 hours of fasting to determine and compare blood levels of leukocytosis, CRP, procalcitonin, fibrinogen, ferritin, IL-1, IL-6, IL-10, TNF-alpha and AMH, FSH in women in both study arms
Active Comparator: Hypothalamic-Pituitary-Ovarian Axis Dysfunction (HPOD); Women meeting the WHO criteria for a diagnosis of HPOD	Diagnostic test: Measurement and comparison of leucocytosis and concentrations of CRP, procalcitonin, fibrinogen, ferritin, IL-1, IL-6, IL-10, TNF-alpha in both study arms; A venous blood sample of approximately 10 ml will be collected in the morning after 8 hours of fasting to determine and compare the above parameters of peripheral blood in both arms of the study; Diagnostic test: Evaluation of the impact of subclinical hypothyroidism, with present/ absent antithyroid antibodies, on the balance between anti- and pro-inflammatory factors in women in both study arms; A venous blood sample of approximately 10 ml will be collected in the morning after 8 hours of fasting to determine and compare blood levels of leukocytosis, CRP, procalcitonin, fibrinogen, ferritin, IL-1, IL-6, IL-10, TNF-alpha depending on the blood concentrations of TSH, a-TPO and a-TG in women in both study arms; Diagnostic test: Assessment of the impact of imbalance between anti- and pro-inflammatory factors in women with different PCOS and HPOD phenotypes on ovarian reserve indices; A venous blood sample of approximately 10 ml will be collected in the morning after 8 hours of fasting to determine and compare blood levels of leukocytosis, CRP, procalcitonin, fibrinogen, ferritin, IL-1, IL-6, IL-10, TNF-alpha and AMH, FSH in women in both study arms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Values of inflammation parameters - leukocytosis in peripheral blood in both study arms	Measurement and comparison of leukocyte count (n/µL) in peripheral blood in both study arms	up to 6 months
Values of inflammation parameters - CRP in peripheral blood in both study arms	Measurement and comparison of concentrations of CRP (mg/l) in peripheral blood in both study arms	up to 6 months
Values of inflammation parameters - procalcitonine in peripheral blood in both study arms	Measurement and comparison of concentrations of procalcitonin (μg/l) in peripheral blood in both study arms	up to 6 months
Values of inflammation parameters - fibrinogen in peripheral blood in both study arms	Measurement and comparison of concentrations of procalcitonin fibrinogen (g/l) in peripheral blood in both study arms	up to 6 months
Values of inflammation parameters - ferritin in peripheral blood in both study arms	Measurement and comparison of concentrations of procalcitonin ferritin (μg/l) in peripheral blood in both study arms	up to 6 months
Values of inflammation parameters - IL-1 in peripheral blood in both study arms	Measurement and comparison of concentrations of procalcitonin IL-1 (pg/ml) in peripheral blood in both study arms	up to 6 months
Values of inflammation parameters - IL-6 in peripheral blood in both study arms	Measurement and comparison of concentrations of procalcitonin IL-6 (pg/ml) in peripheral blood in both study arms	up to 6 months
Values of inflammation parameters - IL-10 in peripheral blood in both study arms	Measurement and comparison of concentrations of procalcitonin IL-10 (pg/ml) in peripheral blood in both study arms	up to 6 months
Values of inflammation parameters - TNF-alpha in peripheral blood in both study arms	Measurement and comparison of concentrations of procalcitonin TNF-alpha (pg/ml) in peripheral blood in both study arms	up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between the concentration of TSH (mIU/l) and the parameters of inflammation - leukocytosis in both arms of the study	Evaluation of the correlation between the concentration of TSH (mIU/l) and inflammatory parameters: leukocyte count (n/µL)	up to 6 months
Correlation between the concentration of TSH (mIU/l) and the parameters of inflammation - CRP in both arms of the study	Evaluation of the correlation between the concentration of TSH (mIU/l) and inflammatory parameters: CRP (mg/l)	up to 6 months
Correlation between the concentration of TSH (mIU/l) and the parameters of inflammation - procalcitonin in both arms of the study	Evaluation of the correlation between the concentration of TSH (mIU/l) and inflammatory parameters: procalcitonin (μg/l)	up to 6 months
Correlation between the concentration of TSH (mIU/l) and inflammatory parameters: fibrinogen (μg/l)	Evaluation of the correlation between the concentration of TSH (mIU/l) and inflammatory parameters: fibrinogen (g/l)	up to 6 months
Correlation between the concentration of TSH (mIU/l) and inflammatory parameters: ferritin (μg/l)	Evaluation of the correlation between the concentration of TSH (mIU/l) and inflammatory parameters: ferritin (μg/l)	up to 6 months
Correlation between the concentration of TSH (mIU/l) and inflammatory parameters: il-1	Evaluation of the correlation between the concentration of TSH (mIU/l) and inflammatory parameters: iL-1 (pg/ml)	up to 6 months
Correlation between the concentration of TSH (mIU/l) and inflammatory parameters: il-6	Evaluation of the correlation between the concentration of TSH (mIU/l) and inflammatory parameters: iL-6 (pg/ml)	up to 6 months
Correlation between the concentration of TSH (mIU/l) and inflammatory parameters: il-10	Evaluation of the correlation between the concentration of TSH (mIU/l) and inflammatory parameters: iL-10 (pg/ml)	up to 6 months
Correlation between the concentration of TSH (mIU/l) and inflammatory parameters: TNF-alpha	Evaluation of the correlation between the concentration of TSH (mIU/l) and inflammatory parameters: TNF-alpha (pg/ml)	up to 6 months
Correlation between the concentration of a-TPO (IU/ml) and the parameters of inflammation - leukocytosis in both arms of the study	Evaluation of the correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: leukocyte count (n/µL)	up to 6 months
Correlation between the concentration of a-TPO (IU/ml) and the parameters of inflammation - CRP in both arms of the study	Evaluation of the correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: CRP (mg/l)	up to 6 months
Correlation between the concentration of a-TPO (IU/ml) and the parameters of inflammation - procalcitonin in both arms of the study	Evaluation of the correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: procalcitonin (μg/l)	up to 6 months
Correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: fibrinogen (μg/l)	Evaluation of the correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: fibrinogen (μg/l)	up to 6 months
Correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: ferritin (μg/l)	Evaluation of the correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: ferritin (μg/l)	up to 6 months
Correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: il-1 (pg/ml)	Evaluation of the correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: il-1 (pg/ml)	up to 6 months
Correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: il-6 (pg/ml)	Evaluation of the correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: il-6 (pg/ml)	up to 6 months
Correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: il-10 (pg/ml)	Evaluation of the correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: il-10 (pg/ml)	up to 6 months
Correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: TNF-alpha (pg/ml)	Evaluation of the correlation between the concentration of a-TPO (IU/ml) and inflammatory parameters: TNF -alpha (pg/ml)	up to 6 months
Correlation between the concentration of a-TG (IU/ml) and the parameters of inflammation - CRP in both arms of the study	Evaluation of the correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: CRP (mg/l)	up to 6 months
Correlation between the concentration of a-TG (IU/ml) and the parameters of inflammation - leukocytosis in both arms of the study	Evaluation of the correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: leukocyte count (n/µL)	up to 6 months
Correlation between the concentration of a-TG (IU/ml) and the parameters of inflammation - procalcitonin in both arms of the study	Evaluation of the correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: procalcitonin (μg/l)	up to 6 months
Correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: fibrinogen (μg/l)	Evaluation of the correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: fibrinogen (μg/l)	up to 6 months
Correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: il-1 (pg/ml)	Evaluation of the correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: il-1 (pg/ml)	up to 6 months
Correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: il-6 (pg/ml)	Evaluation of the correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: il-6 (pg/ml)	up to 6 months
Correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: il-10 (pg/ml)	Evaluation of the correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: il-10 (pg/ml)	up to 6 months
Correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: TNF-alpha (pg/ml)	Evaluation of the correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: TNF-alpha (pg/ml)	up to 6 months
Correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: ferritin (μg/l)	Evaluation of the correlation between the concentration of a-TG (IU/ml) and inflammatory parameters: ferritin (μg/l)	up to 6 months
Correlation between the concentration of AMH (pmol/l) and the parameters of inflammation - leukocytosis in both arms of the study	Evaluation of the correlation between the concentration of AMH (pmol/l) and inflammatory parameters: leukocyte count (n/µL)	up to 6 months
Correlation between the concentration of AMH (pmol/l) and the parameters of inflammation - CRP in both arms of the study	Evaluation of the correlation between the concentration of AMH (pmol/l) and inflammatory parameters: CRP (mg/l)	up to 6 months
Correlation between the concentration of AMH (pmol/l) and the parameters of inflammation - procalcitonin in both arms of the study	Evaluation of the correlation between the concentration of AMH (pmol/l) and inflammatory parameters: procalcitonin (μg/l)	up to 6 months
Correlation between the concentration of AMH (pmol/l) and the parameters of inflammation - fibrinogen in both arms of the study	Evaluation of the correlation between the concentration of AMH (pmol/l) and inflammatory parameters: fibrinogen (μg/l)	up to 6 months
Correlation between the concentration of AMH (pmol/l) and the parameters of inflammation - ferritin in both arms of the study	Evaluation of the correlation between the concentration of AMH (pmol/l) and inflammatory parameters: ferritin (μg/l)	up to 6 months
Correlation between the concentration of AMH (pmol/l) and the parameters of inflammation - il-1 in both arms of the study	Evaluation of the correlation between the concentration of AMH (pmol/l) and inflammatory parameters: il-1 (pg/ml)	up to 6 months
Correlation between the concentration of AMH (pmol/l) and the parameters of inflammation - il-6 in both arms of the study	Evaluation of the correlation between the concentration of AMH (pmol/l) and inflammatory parameters: il-6 (pg/ml)	up to 6 months
Correlation between the concentration of AMH (pmol/l) and the parameters of inflammation - il-10 in both arms of the study	Evaluation of the correlation between the concentration of AMH (pmol/l) and inflammatory parameters: il-10 (pg/ml)	up to 6 months
Correlation between the concentration of AMH (pmol/l) and the parameters of inflammation - TNF-alpha in both arms of the study	Evaluation of the correlation between the concentration of AMH (pmol/l) and inflammatory parameters: TNF-alpha (pg/ml)	up to 6 months
Correlation between the concentration of FSH (IU/l) and the parameters of inflammation - leukocytosis in both arms of the study	Evaluation of the correlation between the concentration of FSH (IU/l) and inflammatory parameters: leukocyte count (n/µL)	up to 6 months
Correlation between the concentration of FSH (IU/l) and the parameters of inflammation - CRP in both arms of the study	Evaluation of the correlation between the concentration of FSH (IU/l) and inflammatory parameters: CRP (mg/l)	up to 6 months
Correlation between the concentration of FSH (IU/l) and the parameters of inflammation - procalcitonin in both arms of the study	Evaluation of the correlation between the concentration of FSH (IU/l) and inflammatory parameters: procalcitonin (μg/l)	up to 6 months
Correlation between the concentration of FSH (IU/l) and the parameters of inflammation - fibrinogen in both arms of the study	Evaluation of the correlation between the concentration of FSH (IU/l) and inflammatory parameters: fibrinogen (μg/l)	up to 6 months
Correlation between the concentration of FSH (IU/l) and the parameters of inflammation - ferritin in both arms of the study	Evaluation of the correlation between the concentration of FSH (IU/l) and inflammatory parameters: ferritin (μg/l)	up to 6 months
Correlation between the concentration of FSH (IU/l) and the parameters of inflammation - il-1 in both arms of the study	Evaluation of the correlation between the concentration of FSH (IU/l) and inflammatory parameters: il-1 (pg/ml)	up to 6 months
Correlation between the concentration of FSH (IU/l) and the parameters of inflammation - il-6 in both arms of the study	Evaluation of the correlation between the concentration of FSH (IU/l) and inflammatory parameters: il-6 (pg/ml)	up to 6 months
Correlation between the concentration of FSH (IU/l) and the parameters of inflammation - il-10 in both arms of the study	Evaluation of the correlation between the concentration of FSH (IU/l) and inflammatory parameters: il-10 (pg/ml)	up to 6 months
Correlation between the concentration of FSH (IU/l) and the parameters of inflammation - TNF-alpha in both arms of the study	Evaluation of the correlation between the concentration of FSH (IU/l) and inflammatory parameters:TNF-alpha (pg/ml)	up to 6 months

Collaborators and Investigators

• Sponsor: Jagiellonian University
• Investigators: Study Chair: Robert Jach, Prof., Ph.D., Jagiellonian University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2024
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: March 26, 2023
• First Submitted That Met QC Criteria: April 29, 2023
• First Posted (Actual): May 3, 2023

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 4, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Thyroid Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Polycystic Ovary Syndrome; Hypothyroidism; Inflammation; Physiological Effects of Drugs; Immunologic Factors; Antibodies
• Other Study ID Numbers: 1072.6120.292.2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No