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Letters to the Editor
Pituitary iron and factors predictive of fertility status
in transfusion-dependent thalassemia
Long-term survival of patients with transfusion-depen- dent thalassemia (TDT) raises hopes of attaining a decent quality of life, having a family and maintaining reproduc- tive potential. However, for many these remain signifi- cant challenges despite advances in the management of iron overload. While pregnancies are possible, there is inadequate information to guide patients on their repro- ductive ability and on markers that predict when they will have infertility issues. Preservation of fertility and timely interventions remain pervasive concerns. Although the association of iron toxicity with cardiac and pancreatic dysfunction has been investigated extensively, the progression of iron deposition in the anterior pitu- itary leading to hypogonadotropic hypogonadism and infertility has not been adequately explored.1
To address these issues, we sought to investigate pitu- itary dysfunction and stratify the risk of infertility utiliz- ing reproductive data and information on systemic iron load. We also evaluated the progression of pituitary dys- function and systemic iron parameters and their effect on reproductive capacity. Magnetic resonance imaging (MRI) measurements of anterior pituitary iron (R2) and volume have established reference data in normal con- trols and proved an adequate method to predict clinical hypogonadism in thalassemia.2-4 Identifying risk thresh- olds could assist in establishing the timing and effective- ness of intensifying chelation treatment to halt further damage and potentially restore function.
The study was approved by institutional review boards and all patients provided written informed consent to participation.
Fifty-three TDT patients, 10 years and older, and 12 healthy subjects (age 12-40 years) underwent MRI (Philips Achieva®, 1.5 T) to determine cardiac iron (T2*), anterior pituitary iron (R2) and three-dimensional vol- ume.5 Levels of non-transferrin bound iron, labile plasma iron (LPI), and ferritin were measured in blood samples, and liver iron concentration (LIC) and myocardial iron were quantified by MRI and a superconducting quantum interference device (SQUID), respectively. In order to assess fertility, plasma gonadotropins (luteinizing hor- mone [LH] and follicular-stimulating hormone [FSH]), estradiol and testosterone levels were assayed. Anti- Müllerian hormone (AMH) levels were determined in women in order to evaluate ovarian reserve and inhibin B levels were measured in men to assess impairment of spermatogenesis.6,7 In 17 patients these measures were repeated 2-3 years later to assess for changes over time. The patients’ pubertal and reproductive history was recorded. Z scores for anterior pituitary iron accumula- tion, Z(R2), and volume, Z(V), were calculated for each patient.3 Parametric statistics were applied to characterize patients: mean ± standard deviation, t-test, and Pearson correlation. Associations of Z(R2) and Z(V) with age and LH and FSH levels were demonstrated by boxplots and linear regression. Receiver operating characteristic (ROC) curve analysis was used in patients for categorization into Z(R2) ≤4 and >4 to examine the sensitivity and specificity for systemic iron parameters.
Moderate-severe pituitary iron deposition Z(R2) >2, mean 5.4) was observed in 33 patients (62%, age 26±7 years), a rate comparable to that in the report by Noetzli et al.4 The rest of the patients (32%, age 23±8 years) had no iron accumulation (mean Z(R2) of 0.03). Thirty-two patients (60%) had a Z(V) < -2 (mean -2.8) indicating sig-
nificant gland shrinkage; the remaining 40% had a Z(V) of -0.7. There was a negative correlation between Z(R2) and Z(V): r=-0.36, P=0.02 (Figure 1A). We found that a Z(R2) value >4.0 predicted pituitary volume loss: Z(V) < -2.0 was present in 17/20 patients with a Z(R2) >4 and in only 16/33 with a Z(R2) <4.0 (P<0.009).
Twenty-three patients (43%, 28±6 years) simultane- ously had Z(R2) >4 and Z(V) <-2, of whom ten (43%) were splenectomized. Overall, patients who underwent splenectomy had higher pituitary R2, smaller gland vol- ume and a significantly higher cardiac iron in comparison to the non-splenectomized patients (P<0.004) while LIC was similar (Table 1). This supports the notion that
Table 1. Patients’ disease characteristics.
Characteristics
Study patients
N (%) or mean ± SD
Females:males Age (years)
53*
27:26
25±8 (range 10-45) 34
18
1
18.7±6 19.7±6
17±5
29 (55%) 24 (45%)
15±11 27.2±10 2620±2332 1.9±1.3 0.25±0.5
14.5±3 3.4±3.6 5.4 3.2±4.4 3.7±4.5 377±110 -2.0±1.2 -2.8 -2.3±1.1 -1.7±1.3
17 31±6 15±8 17±6 5.2±3 -2.7±1 21±11 17±11 2982±2800
35 21±6 2.6±3 -1.6±1 30±9 14±11 2450±2050
b0 thalassemia
E/b0 thalassemia
Hb H-Constant Spring
Years on regular transfusions
b0 thalassemiamajor(meanage24±6)
E/b0 thalassemia(meanage28±6) Chelation treatment
Mono therapy (DFX)
Combination therapy (DFX & DFO)
Systemic iron measures
LIC (mg/g dw)
Cardiac T2* (ms)
Mean annual ferritin (mg/L) NTBI (mmol/L)
LPI (mmol/L)
Anterior pituitary
R2 (s-1)
Z score of R2: Z(R2)
Pituitary Z(R2) > 2 (n=33; 62%) Females’ Z(R2)
Males’ Z(R2)
Volume (mm3)
Z score of volume: Z(V)
Pituitary Z(V) < -2 (n=32; 60%) Females’ Z(V)
Males’ Z(V)
Spleen status
Group I: splenectomized Age (years)
Age at splenectomy (years) Years since splenectomy Z(R2) score
Z(V) score
Cardiac T2*(ms)
LIC (mg/g dw)
Mean annual ferritin (μg/L)
Group II: non-splenectomized Age (years)
Z(R2) score
Z(V) score
Cardiac T2* (ms)
LIC (mg/g dw)
Mean annual ferritin (mg/L)
1740
*Two individuals died from iron overload complications during the study period. SD: standard deviation; DFX: deferasirox; DFO: deferoxamine; LIC: liver iron concen- tration; dw: dry weight; NTBI: non-transferrin bound iron; LPI: labile plasma iron;. LIC and cardiac iron (T2*) were obtained within 6 months of laboratory studies. Normal NTBI and LPI: not detectable.
haematologica | 2021; 106(6)