Thyroid Function and Structure in Klinefelter Syndrome (THINKS)

Thyroid Function and Structure in Klinefelter Syndrome (THINKS)

This is a longitudinal retrospective study for the evaluation of thyroid function and structure in patients with Klinefelter syndrome compared to healthy controls and patients affected by chronic lymphocytic thyroiditis.

Study Overview

• Status: Recruiting
• Conditions: Hypothyroidism; Thyroiditis, Autoimmune; Klinefelter Syndrome

Detailed Description

This is a longitudinal retrospective study for the evaluation of thyroid function and structure in patients with Klinefelter syndrome compared to healthy controls and patients affected by chronic lymphocytic thyroiditis (CLT).

The investigators will retrospectively enroll patients with Klinefelter syndrome followed at the host institution and will retrieve data with regards to peripheral hormone levels (thyroid function) and ultrasonographic appearance (thyroid structure) according to pubertal status and gonadal status. Data will be compared with male age- and pubertal stage-matched euthyroid controls, as well as with male patients affected by CLT.

The primary outcome will be the thyroid function compared to healthy controls, by the assessment of peripheral blood TSH, free T3 (fT3) and free T4 (fT4) levels according to pubertal status (pre-pubertal, pubertal and adult subjects) as well as according to gonadal status (eugonadal subjects, hypogonadal subjects and subjects receiving testosterone replacement therapy [TRT]).

Secondary Outcome Measures will be:

Thyroid function indexes (fT3/fT4 ratio, fT4/TSH ratio, TSH*fT4 product)

Quantitative ultrasonographic thyroid structure parameters, comprising: thyroid volume and echogenicity index, as well as the echotexture parameters of homogeneity and entropy evaluated by Gray Levels Co-occurrence Matrices (GLCM).

In vitro assay of testosterone and estradiol effects on deiodinase type 2 (DIO2) activity in a rat pituitary cell line.

• Study Type: Observational
• Enrollment (Estimated): 600

Contacts and Locations

• Study Contact: Name: Andrea M Isidori, MD, PhD; Phone Number: 0039649970711; Email: andrea.isidori@uniroma1.it

Study Locations

• Italy
  • Roma, Italy, 00161
    • Recruiting
    • 'Sapienza' University of Rome
    • Contact: Andrea Isidori, MD, Ph.D.; Email: andrea.isidori@uniroma1.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study will enroll three cohorts of patients:

• Patients with a confirmed diagnosis of classic, non-mosaic 47,XXY Klinefelter syndrome;
• Males with a diagnosis of chronic lymphocytic thyroiditis (CLT); adult male patients affected by CLT, defined by positivity to anti-thyroglobulin antibodies (Ab-Tg) and/or anti-thyroperoxidase antibodies (Ab-TPO);
• Euthyroid, healthy controls with no clinical signs or symptoms of thyroidal or testicular disease and meeting the same inclusion and exclusion criteria described above (except for KS diagnosis and availability of thyroid US in pre-pubertal and pubertal children).

Description

Inclusion Criteria:

• Patients with a confirmed diagnosis of classic, non-mosaic 47,XXY Klinefelter syndrome based on a peripheral blood 97 karyotype analysis;
• Availability of thyroid function test results (TSH, fT3, and fT4) and/or thyroid US imaging;
• Availability of concurrent clinical data.

Exclusion Criteria:

• Presence of other known genetic conditions or chromosomal abnormalities;
• Use of levothyroxine or other drugs that are either active on the hypothalamic-pituitary-thyroid (HPT) axis or that may interfere with thyroid function tests;
• History of previous surgery or radiotherapy on the thyroid or pituitary glands;
• Current or previous T therapy (for the pre-pubertal and pubertal groups).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Klinefelter syndrome; Males affected by 47,XXY non-mosaic Klinefelter syndrome. Subgroups according to pubertal stage: pre-pubertal, pubertal and adults. Subgroups according to gonadal status: eugonadal, hypogonadal and receiving testosterone replacement therapy (TRT).
Healthy controls; Euthyroid, age- and pubertal stage-matched males Subgroups according to pubertal stage: pre-pubertal, pubertal and adults.
Chronic lymphocytic thyroiditis; Adult males affected by chronic lymphocytic thyroiditis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral blood TSH concentration	Thyroid function will be assessed by peripheral blood TSH levels, taking into account pubertal status (pre-pubertal, pubertal and adult subjects) as well as to gonadal status (eugonadal subjects, hypogonadal subjects and subjects receiving TRT).	Through study completion, an average of 6 years
Peripheral blood fT3 concentration	Thyroid function will be assessed by peripheral blood free T3 (fT3) levels, taking into account pubertal status (pre-pubertal, pubertal and adult subjects) as well as to gonadal status (eugonadal subjects, hypogonadal subjects and subjects receiving TRT).	Through study completion, an average of 6 years
Peripheral blood fT4 concentration	Thyroid function will be assessed by peripheral blood free T4 (fT4) levels, taking into account pubertal status (pre-pubertal, pubertal and adult subjects) as well as to gonadal status (eugonadal subjects, hypogonadal subjects and subjects receiving TRT).	Through study completion, an average of 6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral deiodinase 2 (DIO2) activity	The investigators will derive the the fT3/fT4 ratio as a surrogate marker of peripheral deiodinase 2 (DIO2) activity.	Through study completion, an average of 6 years
Pituitary sensitivity sensitivity to thyroid hormones	The investigators will derive the fT4/TSH ratio as surrogate marker of pituitary sensitivity.	Through study completion, an average of 6 years
Thyroid hormone resistance index	The investigators will derive the TSH*fT4 product as a surrogate marker of thyroid hormone resistance.	Through study completion, an average of 6 years
Thyroid volume	The investigators will assess ultrasonography-derived thyroid volume (in mL) by the sum of the left and right lobe volumes, derived by the ellissoid formula (d1 x d2 x d3 x 0,5233).	Through study completion, an average of 6 years
Quantitative thyroid echogenicity	The investigators will assess the ultraonographic thyroid echogenicity index, derived by the histogram mean of thyroid parenchyma in a standardized scan, normalized by the histogram mean of the pre-thyroid muscles.	Through study completion, an average of 6 years
Thyroid echotexture (homogeneity)	The investigators will assess the ultrasonographic thyroid parenchymal echotexture via the analysis of Grey Levels Co-occurrence Matrices (GLCM) second-order parameter homogeneity (or IDM).	Through study completion, an average of 6 years
Thyroid echotexture (entropy)	The investigators will assess the ultrasonographic thyroid parenchymal echotexture via the analysis of Grey Levels Co-occurrence Matrices (GLCM) second-order parameter entropy.	Through study completion, an average of 6 years
In vitro assay of deiodinase type 2 (DIO2) activity	The investigators will assess in vitro modulation of DIO2 activity by sex hormones testosterone and 17-beta estradiol in a rat pituitary cell line (GH4C1) by using a thyroid hormone-responsive artificial promoter (TRE3Tk-Luc).	At study end (May 2022).

Collaborators and Investigators

• Sponsor: University of Roma La Sapienza
• Investigators: Principal Investigator: Andrea M Isidori, MD, PhD, andrea.isidori@uniroma1.it

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2007
• Primary Completion (Actual): October 15, 2019
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: October 4, 2022
• First Submitted That Met QC Criteria: October 11, 2022
• First Posted (Actual): October 14, 2022

Study Record Updates

• Last Update Posted (Actual): March 30, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Hypothyroidism; Puberty; Testosterone; Thyroiditis; Klinefelter syndrome; Prepuberty
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Autoimmune Diseases; Immune System Diseases; Disease; Gonadal Disorders; Congenital Abnormalities; Disorders of Sex Development; Urogenital Abnormalities; Thyroid Diseases; Sex Chromosome Disorders; Chromosome Disorders; Sex Chromosome Disorders of Sex Development; Hypogonadism; Syndrome; Hypothyroidism; Klinefelter Syndrome; Thyroiditis; Thyroiditis, Autoimmune
• Other Study ID Numbers: THINKS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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