Fertility thal: Reproductive Capacity and Iron Burden in Thalassemia

Sponsor

UCSF Benioff Children's Hospital Oakland (Other)

Overall Status

Completed

CT.gov ID

NCT02308904

Collaborator

Novartis Pharmaceuticals (Industry)

Enrollment

Location

Arms

Actual Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The improved long-term survival of thalassemia major (TM) patients has resulted in increased focus on the ability to preserve fertility. While the association of iron toxicity with vital organ dysfunction, heart and liver, has been extensively investigated, the correlation of reproductive capacity and extent of iron overload is not well understood. Despite remarkable progress in methodology for prediction of reproductive status and intervention for preserving fertility, implementation in thalassemia is lacking.

The investigators hypothesize that iron toxicity to the anterior pituitary occurring in the process of transfusional iron loading is directly associated with a decline in gonadal function. The investigators expect pituitary MRI measurements of iron deposition as well as markers of oxidative damage to correlate with the functional studies of pituitary-gonadal axis performed in this study. This cross sectional study will examine the relation of pituitary iron deposition and pituitary volume; serum iron and oxidative stress measures, liver iron concentration (LIC), cardiac iron and chelation adequacy with pituitary and gonadal reproductive hormone levels (and spermatogenesis in adult male patients), in order to better define the association of iron burden and chelation patterns with fertility potential, in thalassemia patients with iron overload. The study will assess whether the current chelation treatment regimens, in particular during the pubertal developmental age, are adequate for preserving fertility and could lead to improved chelation routines for preventing the high prevalence of compromised fertility. In addition, by utilizing state-of-the-art markers for fertility status, findings from this study may improve current methods for screening for hypogonadism and reproductive potential and allow earlier intervention.

The investigators propose to examine 26-30 patients, 12 years and older, with measures of fertility potential, and correlate them to their current iron burden parameters and to the cumulative iron effect as indicated by past iron overload patterns and chelation history.

Condition or Disease	Intervention/Treatment	Phase
THALASSEMIA MAJOR	Other: Blood Draw/Semen Exam Other: Retrospective data/Chart Review/Relevant Clinical Results Other: Pituitary MRI	N/A

Study Design

Study Type:

Interventional

Actual Enrollment :

59 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

Reproductive Capacity and Association to Iron Burden and Chelation Patterns in Thalassemia Major Patients

Actual Study Start Date :

Jun 1, 2013

Actual Primary Completion Date :

Sep 1, 2020

Actual Study Completion Date :

Sep 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Other: Laboratory Studies for Pituitary-Gonadal Function Females: We expect to enroll approximately 15 females ages 12 years and older. Males: We expect to enroll approximately 15 males ages 12 years and older.	Other: Blood Draw/Semen Exam Females: 1. Obtain levels of LH/FSH, Estradiol, and AMH in all enrolled women. Males: We expect to enroll approximately 15 males ages 12 years and older. Levels of FSH/LH and testosterone will be obtained. In addition, we will examine the association of the hormone inhibin B with mean fertility measures. Inhibin B levels were shown to correlate with azospermia and could demonstrate better prediction of reproductive potential. Semen exam for determination of volume, sperm count, motility and sperm DNA integrity will be determined for interested adult thalassemia males (age ≥18 years and older). Other Names: Screening for biomarkers and correlations with iron load
Other: Data on iron burden and chelation history Retrospective data, as listed in this section, will be obtained from chart review and results of relevant clinical data. Iron burden data Assay for non-transferrin bound iron (NTBI) Chelation data Oxidant stress History or presence of hypogonadism	Other: Retrospective data/Chart Review/Relevant Clinical Results 1. Documentation of liver iron from SQUID or MRI. 2. Transfusion data on age at onset of regular transfusions, transfusion frequency over the previous five years, and years of chronic transfusion therapy (defined as 8 or more per year). 3. Data on cardiac iron as indicated by T2* MRI. 4. Ferritin levels. NTBI will be accessed using a mobilizer ligand to collect NTBI from all pools as Fe-NTA which is then measured by HPLC. 1. Age at onset of chelation 2. Estimated periods of known or recalled non-compliance with regular chelation. 3. Listing of all chelation drugs previously used including dose and time period. 1. Vitamins E and C, at time closest to obtaining reproductive hormone levels. 2. Measuring the ratio of reduced gluthatione (GSH) to oxidized gluthatione (GSSG). Assessment of time for pubertal development, assessment of menstrual history and need for treatment with gonadal hormone replacement.
Other: Pituitary MRI MRI has been shown to demonstrate well the changes related to iron toxicity in the pituitary gland.	Other: Pituitary MRI MRI has been shown to demonstrate well the changes related to iron toxicity in the pituitary gland. An MRI protocol was optimized at Children's Hospital and Research Center Oakland (CHRCO) and Texas Children's Hospital. Utilizing 1.5 T clinical scanner to evaluate the iron accumulation in the anterior pituitary. The total data acquisition time is approximately 32 minutes. No sedation will be given. MRI data will be sent to Dr. Wang, department of Radiology, Children's Medical Center, University of Texas Southwestern Medical Center, Dallas, Texas. Quantification of R2, pituitary height and volume will be conducted.

Arm

Intervention/Treatment

Other: Laboratory Studies for Pituitary-Gonadal Function

Females: We expect to enroll approximately 15 females ages 12 years and older. Males: We expect to enroll approximately 15 males ages 12 years and older.

Other: Blood Draw/Semen Exam

Females: 1. Obtain levels of LH/FSH, Estradiol, and AMH in all enrolled women. Males: We expect to enroll approximately 15 males ages 12 years and older. Levels of FSH/LH and testosterone will be obtained. In addition, we will examine the association of the hormone inhibin B with mean fertility measures. Inhibin B levels were shown to correlate with azospermia and could demonstrate better prediction of reproductive potential. Semen exam for determination of volume, sperm count, motility and sperm DNA integrity will be determined for interested adult thalassemia males (age ≥18 years and older).

Other Names:

Screening for biomarkers and correlations with iron load

Other: Data on iron burden and chelation history

Retrospective data, as listed in this section, will be obtained from chart review and results of relevant clinical data. Iron burden data Assay for non-transferrin bound iron (NTBI) Chelation data Oxidant stress History or presence of hypogonadism

Other: Retrospective data/Chart Review/Relevant Clinical Results

1. Documentation of liver iron from SQUID or MRI. 2. Transfusion data on age at onset of regular transfusions, transfusion frequency over the previous five years, and years of chronic transfusion therapy (defined as 8 or more per year). 3. Data on cardiac iron as indicated by T2* MRI. 4. Ferritin levels. NTBI will be accessed using a mobilizer ligand to collect NTBI from all pools as Fe-NTA which is then measured by HPLC. 1. Age at onset of chelation 2. Estimated periods of known or recalled non-compliance with regular chelation. 3. Listing of all chelation drugs previously used including dose and time period. 1. Vitamins E and C, at time closest to obtaining reproductive hormone levels. 2. Measuring the ratio of reduced gluthatione (GSH) to oxidized gluthatione (GSSG). Assessment of time for pubertal development, assessment of menstrual history and need for treatment with gonadal hormone replacement.

Other: Pituitary MRI

MRI has been shown to demonstrate well the changes related to iron toxicity in the pituitary gland.

Other: Pituitary MRI

MRI has been shown to demonstrate well the changes related to iron toxicity in the pituitary gland. An MRI protocol was optimized at Children's Hospital and Research Center Oakland (CHRCO) and Texas Children's Hospital. Utilizing 1.5 T clinical scanner to evaluate the iron accumulation in the anterior pituitary. The total data acquisition time is approximately 32 minutes. No sedation will be given. MRI data will be sent to Dr. Wang, department of Radiology, Children's Medical Center, University of Texas Southwestern Medical Center, Dallas, Texas. Quantification of R2, pituitary height and volume will be conducted.

Outcome Measures

Primary Outcome Measures

Laboratory studies for pituitary and gonadal function and for iron level measures [Up to 12 months]
Each patient's pituitary iron and pituitary volume will be correlated with each hormone levels: LH, FSH, estrogen and AMH (Females), testosterone Inhibin B and (males). We will then evaluate potential associations using Pearson correlations. Univariate analyses on all variables and it's relation with iron, will also be conducted.

Secondary Outcome Measures

Retrospective analysis of annual LIC and of type and dose of iron chelation agent in the parallel time period [Up to 12 months]
We will evaluate potential associations using Pearson correlations of each measure: Mean LIC with each of the fertility hormone levels and with pituitary volume and height. Mean ferritin with each of the fertility hormone levels and with pituitary volume and height. NTBI with each of the fertility hormone levels and with pituitary volume and height. Oxidative measures (Vit C, Vit E, GSH/GSSG) with each of the fertility hormone levels and with pituitary volume and height. Regression analysis will be utilized to assess correlation of pituitary iron, LIC and cardiac iron. We will compute descriptive statistics for all measures by group. We will assess differences between the 2 groups using Student's t-test for continuous data and chi-square or Fisher's exact for categorical. A detailed retrospective analysis of LIC and chelation patterns (type of chelator and average dose) on these 2 groups will also be performed and fertility measures will be compared.

Other Outcome Measures

Pituitary MRI and Male: Semen analysis [Up to 12 months]
Pituitary iron and pituitary volume will be correlated with sperm count and with DNA breakage in males (≥18 years old) who have these test results. Statistical methods as detailed under primary objective, will be utilized.

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Transfusion-dependent* females and males with thalassemia (any genotype) who are 12 to 45 years of age.
History of at least 5 years of chronic transfusion (defined as ≥ 8 transfusions/year) (Age of initiation of transfusions does not matter)
Any pubertal stage.
Liver iron evaluated by SQUID, MRI or liver biopsy within 12 months prior to enrollment in the study.
Need to be able to stop hormonal therapy for 3 weeks (males) and one month (females) prior to study enrollment.