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Diminished ovarian reserve in women with transfusion-dependent beta-thalassemia major: Is iron gonadotoxic?
Abstract
Objective
Iron accumulation in the endocrine glands has been implicated in the aetiopathogenesis of decreased reproductive capacity in patients with beta-thalassemia major (β-TM). The aim of the current study was to investigate the serum concentration of anti-Müllerian hormone (AMH), a marker of ovarian reserve, in women with transfusion-dependent β-TM.
Study Design
In this case-control study, we recruited 43 women with transfusion-dependent TM and 44 age-matched healthy controls. Hormonal and haematological parameters, serum level of AMH, antral follicle count, and ovarian volume were assessed.
Results
Twenty-two of the 43 women were hypogonadotropic, 8 with primary amenorrhea and 14 with secondary amenorrhea. FSH, LH, estradiol, prolactin, and AMH levels; antral follicle count; and ovarian volume were significantly lower in women with TM compared with the control group (p < 0.05 for all).
Conclusion
AMH level and other ovarian reserve markers are significantly diminished in women with transfusion-dependent TM compared to age-matched controls. Our findings support a deleterious effect of iron overload on ovarian tissue.
... Hypothalamo-pituitary damage is usually irreversible (2) and hypogonadotropic hypogonadism still appears to be common despite advances in chelation regimens (6,9). Anti-mullerian hormone (AMH), secreted by granulosa cells of preantral and antral follicles, is a member of the transforming growth factor-β family (5,10) and its levels do not change throughout the menstrual period. It is the most reliable biochemical marker showing ovarian reserve. ...
... Hypogonadotropic hypogonadism (70-80%) and amenorrhea due to hemosiderosis of the hypothalamus and pituitary gland are common in BTM patients (2,11,13), however, the effect of iron load on the ovaries is unclear (14)(15)(16). There are only limited data available in the literature researching ovarian reserve in patients with BTM (2,5,9,10), In a study conducted with 17 BTM patients (9 amenorrheic, 8 with normal menstrual cycles), the mean age of the u n c o r r e c t e d p r o o f patients was found to be 33.8±5.6 years (2). AMH values of BTM patients were found to be significantly lower than the control group and those of the amenorrheic group were found to be lower than those of patients with normal menstrual cycles. ...
... All the studies above mentioned were retrospective and study populations were small (2,5,9). Uysal et al. compared AMH values between BTM patients (n=43) and healthy controls (n=44) in a prospectively designed case-control study (10). The mean age of patients with BTM was 23.4±5.1 years. ...
Objective:
Repeated blood transfusions in women with Beta-thalassemia major (BTM) may lead to iron overload and increase oxidative stress and consequently resulting in ovarian damage. We aimed to evaluate the alterations in the ovarian reserve of transfusion-dependent BTM patients over a time period of one year and compared the anti-mullerian hormone (AMH) levels between women with BTM and healthy population.
Material and methods:
This longitudinal prospective study was conducted in 41 women with transfusion-dependent BTM at the tertiary hospital. The hospital database between 1996 to 2021 was screened for women diagnosed with BTM. Anti-mullerian hormone levels were assessed at baseline and one year later.
Results:
Twenty-five (60.9%) of the patients had amenorrhea while 16 (39.1%) were observed to have normal cycles. The mean AMH values of all women were 2.7±1.8 ng/mL at the initial measurement which was significantly lower compared to age related AMH (mean 4.0±0.4 ng/mL) nomogram of healthy population (P= 0.001). The baseline AMH values of the patients with amenorrhea were found to be lower than the patients with normal menstrual cycles (2.1±1.8 vs 3.6±1.5 ng/mL, P= 0.009). After a one-year follow-up, there was a trend towards to a decrease in AMH levels of the patients with normal menstrual cycles.
Conclusion:
Serum AMH values is decreased in patients with transfusion-dependent BTM. It would be beneficial to inform all patients about possible effects of repeated blood transfusions on fertility.
... An ovarian lesion might co-exist with hypogonadotropic hypogonadism due to similar underling mechanisms [123]. The theory of iron gonadal toxicity is sustained by low Anti-Müllerian Hormone (AMH) and other ovarian reserve markers [123]. ...
... An ovarian lesion might co-exist with hypogonadotropic hypogonadism due to similar underling mechanisms [123]. The theory of iron gonadal toxicity is sustained by low Anti-Müllerian Hormone (AMH) and other ovarian reserve markers [123]. Uysal A et al. showed that secretion of AMH, FSH, LH, and antral follicle count (AFC), as well as estradiol and ovarian volume, is significantly decreased in women with major BTH [123]. ...
... The theory of iron gonadal toxicity is sustained by low Anti-Müllerian Hormone (AMH) and other ovarian reserve markers [123]. Uysal A et al. showed that secretion of AMH, FSH, LH, and antral follicle count (AFC), as well as estradiol and ovarian volume, is significantly decreased in women with major BTH [123]. Direct effects of iron on ovarian function are part of the complicated puzzle concerning females' fertility in major BTH. ...
Beta-thalassemia (BTH), a recessively inherited haemoglobin (Hb) disorder, causes iron overload (IO), extra-medullary haematopoiesis and bone marrow expansion with major clinical impact. The main objective of this review is to address endocrine components (including aspects of reproductive health as fertility potential and pregnancy outcome) in major beta-thalassemia patients, a complex panel known as thalassemic endocrine disease (TED). We included English, full-text articles based on PubMed research (January 2017–June 2022). TED includes hypogonadism (hypoGn), anomalies of GH/IGF1 axes with growth retardation, hypothyroidism (hypoT), hypoparathyroidism (hypoPT), glucose profile anomalies, adrenal insufficiency, reduced bone mineral density (BMD), and deterioration of microarchitecture with increased fracture risk (FR). The prevalence of each ED varies with population, criteria of definition, etc. At least one out of every three to four children below the age of 12 y have one ED. ED correlates with ferritin and poor compliance to therapy, but not all studies agree. Up to 86% of the adult population is affected by an ED. Age is a positive linear predictor for ED. Low IGF1 is found in 95% of the population with GH deficiency (GHD), but also in 93.6% of persons without GHD. HypoT is mostly pituitary-related; it is not clinically manifested in the majority of cases, hence the importance of TSH/FT4 screening. HypoT is found at any age, with the prevalence varying between 8.3% and 30%. Non-compliance to chelation increases the risk of hypoT, yet not all studies confirmed the correlation with chelation history (reversible hypoT under chelation is reported). The pitfalls of TSH interpretation due to hypophyseal IO should be taken into consideration. HypoPT prevalence varies from 6.66% (below the age of 12) to a maximum of 40% (depending on the study). Serum ferritin might act as a stimulator of FGF23. Associated hypocalcaemia transitions from asymptomatic to severe manifestations. HypoPT is mostly found in association with growth retardation and hypoGn. TED-associated adrenal dysfunction is typically mild; an index of suspicion should be considered due to potential life-threatening complications. Periodic check-up by ACTH stimulation test is advised. Adrenal insufficiency/hypocortisolism status is the rarest ED (but some reported a prevalence of up to one third of patients). Significantly, many studies did not routinely perform a dynamic test. Atypical EM sites might be found in adrenals, mimicking an incidentaloma. Between 7.5–10% of children with major BTH have DM; screening starts by the age of 10, and ferritin correlated with glycaemia. Larger studies found DM in up to 34%of cases. Many studies do not take into consideration IGF, IGT, or do not routinely include OGTT. Glucose anomalies are time dependent. Emerging new markers represent promising alternatives, such as insulin secretion-sensitivity index-2. The pitfalls of glucose profile interpretation include the levels of HbA1c and the particular risk of gestational DM. Thalassemia bone disease (TBD) is related to hypoGn-related osteoporosis, renal function anomalies, DM, GHD, malnutrition, chronic hypoxia-induced calcium malabsorption, and transplant-associated protocols. Low BMD was identified in both paediatric and adult population; the prevalence of osteoporosis/TBD in major BTH patients varies; the highest rate is 40–72% depending on age, studied parameters, DXA evaluation and corrections, and screening thoracic–lumbar spine X-ray. Lower TBS and abnormal dynamics of bone turnover markers are reported. The largest cohorts on transfusion-dependent BTH identified the prevalence of hypoGn to be between 44.5% and 82%. Ferritin positively correlates with pubertal delay, and negatively with pituitary volume. Some authors appreciate hypoGn as the most frequent ED below the age of 15. Long-term untreated hypoGn induces a high cardiovascular risk and increased FR. Hormonal replacement therapy is necessary in addition to specific BTH therapy. Infertility underlines TED-related hormonal elements (primary and secondary hypoGn) and IO-induced gonadal toxicity. Males with BTH are at risk of infertility due to germ cell loss. IO induces an excessive amount of free radicals which impair the quality of sperm, iron being a local catalyser of ROS. Adequate chelation might improve fertility issues. Due to the advances in current therapies, the reproductive health of females with major BTH is improving; a low level of statistical significance reflects the pregnancy status in major BTH (limited data on spontaneous pregnancies and growing evidence of the induction of ovulation/assisted reproductive techniques). Pregnancy outcome also depends on TED approach, including factors such as DM control, adequate replacement of hypoT and hypoPT, and vitamin D supplementation for bone health. Asymptomatic TED elements such as subclinical hypothyroidism or IFG/IGT might become overt during pregnancy. Endocrine glands are particularly sensitive to iron deposits, hence TED includes a complicated puzzle of EDs which massively impacts on the overall picture, including the quality of life in major BTH. The BTH prognostic has registered progress in the last decades due to modern therapy, but the medical and social burden remains elevated. Genetic counselling represents a major step in approaching TH individuals, including as part of the pre-conception assessment. A multidisciplinary surveillance team is mandatory.
... After repeated red blood cell transfusions, patients with thalassemia major may have ovarian impairment due to iron overload, when the transferrin-dependent system is inhibited through ferritin saturation pathway and excessive iron accumulation occurs through the non-transferrin bound iron (NTBI) pathway (11). Although the most common endocrinopathy in patients with thalassemia is the hypogonadism resulting from iron deposition in the hypothalamic and/or pituitary cells (12), it is also worth noting that iron overload may affect ovarian function directly as well. An earlier study has shown an inverse correlation between AMH level and NTBI (13), suggesting suspected ovarian tissue iron overload in women with thalassemia major. ...
... An earlier study has shown an inverse correlation between AMH level and NTBI (13), suggesting suspected ovarian tissue iron overload in women with thalassemia major. Another study also demonstrated that AMH level and antral follicle count are significantly decreased in women with transfusion-dependent thalassemia major compared with age-matched controls (12). These findings support a deleterious effect of iron overload on ovarian tissue, which may result in an increase in reactive oxygen species and the subsequent acceleration in follicular aging (14). ...
Introduction: Iatrogenic factor is one of the recognized causes for premature ovarian insufficiency. The aim of this case report was to present a rare case with premature ovarian insufficiency and 46, XY karyotype after bone marrow transplant (BMT) for thalassaemia major at childhood. We also reviewed some relevant literature in this report.
Case Presentation: A 17-year-old girl was presented with primary amenorrhea and premature ovarian insufficiency after receiving chemotherapy and BMT from her brother due to thalassaemia major at childhood. She had poor secondary sex characteristics, assessed as stage I for the development of breasts and external genitalia based on the Tanner scale. Transabdominal ultrasound showed small uterus with visible endometrial lining and small ovaries. Laboratory data showed hypergonadotropic hypogonadism profile with low level of estrogen and high level of follicular-stimulating hormone (FSH). Patient's peripheral lymphocytes karyotype was 46, XY.
Conclusions: This case was diagnosed as a chemotherapy induced premature ovarian insufficiency. Patient's peripheral lymphocytes karyotype (46, XY) after she received BMT from a male donor was a misleading finding, and the case could be easily misdiagnosed as Swyer syndrome. A correct diagnosis in such cases should depend not only on the recent clinical findings, but also on the detailed medical history. To prevent premature ovarian insufficiency in similar cases, fertility preservation should be offered to girls before they receive chemotherapy, total body irradiation and BMT.
... After repeated red blood cell transfusions, patients with thalassemia major may have ovarian impairment due to iron overload, when the transferrin-dependent system is inhibited through ferritin saturation pathway and excessive iron accumulation occurs through the non-transferrin bound iron (NTBI) pathway. 11 Although the most common endocrinopathy in patients with thalassemia is the hypogonadism resulting from iron deposition in the hypothalamic and/or pituitary cells, 12 it is also worth noting that iron overload may affect ovarian function directly as well. An earlier study has shown an inverse correlation between AMH level and NTBI, 13 suggesting suspected ovarian tissue iron overload in women with thalassemia major. ...
... Another study also demonstrated that AMH level and antral follicle count are signi cantly decreased in women with transfusion-dependent thalassemia major compared with agematched controls. 12 These ndings support a deleterious effect of iron overload on ovarian tissue, which may result in an increase in reactive oxygen species and the subsequent acceleration in follicular aging. 14 An earlier study has found high redox activity in the ovarian follicular uid from a woman with thalassemia major, which suggested that redox-active iron ions may mediate free radical production and induce ovarian tissue injury. ...
Background: Iatrogenic factor is one of the recognized causes for premature ovarian insufficiency. The aim of this case report was to present a rare case with premature ovarian insufficiency and 46, XY karyotype after bone marrow transplant for thalassaemia major at childhood. We also reviewed some relevant literature in this report.
Case presentation: A 17-year-old girl was presented with primary amenorrhea and premature ovarian insufficiency after receiving chemotherapy and bone marrow therapy from her brother due to thalassaemia major at childhood. She had poor secondary sex characteristics, assessed as stage I for the development of breasts and external genitalia based on the Tanner scale. Transabdominal ultrasound showed small uterus with visible endometrial lining and small ovaries. Laboratory data showed hypergonadotropic hypogonadism profile with low level of estrogen and high level of follicular-stimulating hormone (FSH). Patient’s peripheral lymphocytes karyotype was 46, XY.
Conclusions: A correct diagnosis is not only dependent on clinical manifestations, but also the detailed medical history. In light of the relatively high prevalence of thalassemia, fertility preservation should be considered for young girls before they receive chemotherapy, radiation treatment and bone marrow transplant.
... Recent studies also revealed that patients with TM have lower levels of anti-Mullerian hormone (AMH) and reduced antral follicular count (AFC), suggesting that the peripheral excess of iron may also be toxic locally to the gonads, harming the ovarian reserve [4,[7][8][9][10][11]. In addition, iron excess, in particular non-transferrin-bound iron and its redox active form, may actually impact on oocyte quality. ...
... Previous studies on ovarian function and TM mainly focused on ovarian reserve and generally supported an impairment: AMH and AFC are consistently lower [4,[7][8][9][10][11]. Our data is in agreement with these findings since both biomarkers resulted reduced in exposed women. ...
Background:
Women with thalassaemia major typically experience hypogonadotropic hypogonadism because of the toxic effects of iron overload on the anterior pituitary. Moreover, in affected women, serum anti-Mullerian hormone (AMH) and antral follicle count (AFC) are also shown to be reduced, suggesting that the peripheral excess of iron could also harm the ovarian reserve. To date, the detrimental effects of the disease on oocyte quality have not been investigated.
Materials and methods:
Women with thalassaemia major who underwent in vitro fertilization (IVF) cycles were retrospectively identified over a 9 years period. They were matched (with a 1:5 ratio) by study period and age to a control group of infertile women undergoing IVF. Embriological variables were compared between the two groups. The primary outcome was the rate of top quality embryos.
Results:
Twenty-one women with thalassaemia major (exposed group) and 105 controls (unexposed group) were ultimately included. Serum AMH was 0.6 [0.2-1.8] and 1.5 [0.7-3.5] ng/ml, respectively (p = 0.05). AFC was 4 (1-7.5) and 11 (5.5-16), respectively (p < 0.001). The total dose of gonadotropins used was higher in exposed women but the number of retrieved oocytes and oocytes used did not differ. The fertilization rate was higher in exposed compared to unexposed women, being 100% (76-100%) and 75% (50-100%). respectively (p = 0.03). The cleavage rate was also higher, being 75% (39-100%) and 50% (29-64%), respectively (p = 0.04). In contrast, the rate of top quality embryos did not differ, being 20% (0-76%) and 25% (5-50%), respectively (p = 0.98).
Conclusions:
Despite lower ovarian reserve, oocyte quality is not significantly affected in women with thalassaemia major.
... Assessment of functional ovarian reserve is essential to assess Premature Ovarian Insufficiency (POI) in women living with SCD. Studies have raised the hypothesis that, just as iron overload in female patients with SCD results in gonadal dysfunction (Chang et al., 2011;Uysal et al., 2017), frequent episodes of intravascular sickling, vascular occlusion and infarction, as well as tissue hypoxia in different tissues, including the ovaries, associated with chronic anemia, could explain ovarian dysgenesis and, therefore, premature ovarian insufficiency in women with SCD (Chase et al., 2009;Kopeika et al., 2019). ...
With the improvement in survival and the reduction in morbidity related to sickle cell disease (SCD), aspects related to reproductive health are emerging as a priority in the care of affected people. We conducted a systematic review looking for evidence describing the functional ovarian reserve levels in women with sickle cell disease. To locate studies, a search was performed in electronic databases, in addition to preprint servers and reference lists of selected publications. Two independent reviewers searched, and the risk of bias in the selected studies was assessed using the Newcastle-Ottawa scale. 1,086 records were initially retrieved, and one article was identified after consulting the reference lists of the screened articles, only four articles met the eligibility criteria. The quality of evidence was rated very low due to the design of the studies; however, the risk of bias was considered low. These are recent studies published between 2015 and 2021, whose main methodology was a cross-sectional or case-control study. All studies reported lower anti-mullerian hormone levels in women with sickle cell disease. Although lower, anti-mullerian hormone levels were within the normal range in young women with sickle cell disease only with supportive care, in those who used hydroxyurea, a decrease in ovarian reserve was observed. support insufficient evidence support a causal relationship between sickle cell disease and reduced ovarian reserve. From anti-mullerian hormone values a trend towards lower levels in women with sickle cell disease compared to healthy women, as reported in the four studies evaluated. Studies that analyze the ovarian reserve based on imaging and biochemical parameters are an important future focus.
... Data from the thalassaemia literature have suggested that there exists a weak negative correlation between ferritin levels and AMH, supporting the notion of a deleterious effect of iron overload on the ovaries. 32 We defined iron overload by current ferritin values and R2-MRI LIC. The proposed mechanism of ovarian damage from iron overload is ROS generation that causes DNA damage. ...
We compared serum anti‐Mullerian hormone (AMH) levels in women with sickle cell disease (SCD) (n = 152) to those of Black comparison women (n = 128) between the ages of 20 and 45 years and evaluated the impact of hydroxyurea (HU) and iron overload on ovarian reserve in those with SCD. SCD treatment was abstracted from medical records. Linear regression models were fit to examine the relationship between log(AMH) and SCD, adjusting for age. The analysis was repeated to account for HU use (current, previous, never) and iron overload (ferritin ≥1000 ng/mL vs. <1000 ng/mL). AMH estimates among women with SCD were lower than those among comparison women (2.23, 95% confidence interval [CI] 1.80–2.76 vs. 4.12, 95% CI 3.11–5.45, respectively). Women with SCD who were currently using HU had 63% lower (95% CI 43–76) AMH values than comparison women; those with SCD with prior or no HU use also had lower AMH estimates than comparison women, but the difference was less pronounced. There were no differences in predicted AMH values among women with SCD for those with and without iron overload. Women with SCD and low AMH may have a shorter reproductive window and may benefit from referral to a reproductive specialist.
... Recent studies revealed that thalassemia major decreases ovarian reserve. Patients with this disease have lower levels of AMH and Antral Follicular Count [AFC] [55,56]. ...
Background: The role of assisted reproductive technologies, including in-vitro fertilization [IVF], is increasing daily because of the significant rise in subfertility cases. Among women, the most observed causes of infertility are primary ovarian insufficiency and premature ovarian failure, accounting for 25% of cases, followed by tubal damage (20%) and uterine abnormalities (10%), all contributing to the increase in IVF cases among couples. The success of IVF depends on various factors; however, the role of oocyte quality and maturation level is considered a pivotal cardinal factor for the success rates of IVF.
... Mekanizmalara bakıldığında, reaktif oksijen türlerinin üretiminde bir artış, azaltılmış enzimatik antioksidan savunma mekanizmaları, mitokondriyal kusurlar, riskli mikroçevresel ortam nedeni ile granüloza hücresinde östradiol üretimi yetersiz kalır. 5 Transfüzyon bağımlı talasemili kadınlarda, üreme dokusunda demirin neden olduğu bozulmanın, foliküler sıvıda artan redoks aktivitesi seviyesi ve aşırı demir yükünün, endometriyal glandüler epitelinde hemosiderin birikimi yoluyla meydana geldiğine inanılmaktadır. Kadınlarda, infertilite üzerine yapılan araştırmalar oksidatif stresin, kadınların üreme potansiyelindeki düşüşte önemli bir role sahip olduğunu göstermektedir. ...
Talasemi taşıyıcı oranı, tüm dünyanın yaklaşık %1,5 kadarını oluşturmaktadır. Transfüzyon bağımlı talasemi hastalarında, infertiliteyle ilişkili hipogonadizm hâlen en önemli sorun olarak görülmektedir. Hipogonadotropik, hipogonadizmin yanı sıra özellikle doğurganlık ve gebelikle ilgili diğer endokrin bozukluklar (diyabet ve hipotiroidizm gibi) gebelik için önemli bir engel oluşturmaktadır. Reaktif oksijen türlerinin üretiminde bir artış, azaltılmış enzimatik antioksidan savunma mekanizmaları, mitokondriyal kusurlar, riskli mikroçevresel ortam nedeni ve transfüzyon bağımlı talasemili kadınlarda oksidatif stresin, kadınların üreme potansiyelindeki düşüşte önemli bir role sahip olduğunu göstermektedir. Talasemide, doğurganlık potansiyelinin değerlendirilmesi için yaygın olarak kullanılan LH/FSH ve E2'nin zayıf bir prediktif değere sahip olduğunu, anti-Müllerian hormonun ise transfüzyon bağımlı talasemili kadınlarda üreme kapasitesi için daha öngördürücü olabileceğini göstermiştir. Miyokardiyal demir birikimi, pankreas, tiroid ve hipofiz gibi farklı organ işlev bozuklukları, komplikasyon riskini artırmaktadır. Talasemili kadınların gebeliklerinde, en sık görülen komplikasyonlar arasında; intrauterin büyüme geriliği, düşük doğum ağırlığı, prematüre ve çoğul gebeliklerden oluşmaktaydı. İnfertilite başarısı için multidisipliner bir yaklaşım gereklidir.
... (POF), such as reduced ovarian volume, diminished number of antral follicle count (AFC), low AMH level and insufficient gonadotrophic hormone [16][17][18] . The BTM patients may even become infertile and those who conceive successfully might also be confronted with complications, including miscarriage, intrauterine growth retardation, low birth weight, prematurity, and multiple gestations due to hormonal stimulation or in-vitro fertilization (IVF) [19] . ...
Overloaded iron can deposit in the reproductive system and impair ovarian function. But few studies have identified the exact effect of overloaded iron on the endocrine function and fertility capacity in female mice. Here, we established iron-overloaded mouse models by intraperitoneal injection of iron dextran to adult female C57BL/6 J mice at 0.1 g/kg (LF group), 0.5 g/kg (MF group) and 1.0 g/kg (HF group) concentrations once a week for eight consecutive weeks. We found that overloaded iron resulted in smaller ovaries, as well as accumulated oxidative damages. The endocrine function and follicle development were also impeded in the MF and HF groups. The 10-month breeding trial indicated that (1) Low concentration of iron (0.1 g/kg) wasn’t detrimental to the ovary; (2) Middle concentration of iron (0.5 g/kg) impeded the childbearing process, though it could be recovered following the iron excretion; (3) High concentration of iron (1.0 g/kg) damaged the fertility, even gave rise to sterility. Yet for those fertile mice, litter number and litter size were smaller and the ovarian reserve of their offspring was impaired. Transcriptome profiling results indicated that overloaded iron could compromise ovarian function by disrupting ovarian steroidogenesis, interfering with ovarian microenvironment and inhibiting Wnt signaling. Taken together, we have demonstrated the effect that chronic concentration-dependent iron overload exerted on mouse ovarian function, which may act as a preliminary basis for further mechanism and intervention investigations.
... Beta-TM patients require frequent blood transfusions to maintain normal hemoglobin levels and to suppress ineffective erythropoiesis [3]. Frequent RBC transfusions may cause a state of iron overload, which may cause precipitation of iron in most vital organs [4][5][6]. As a consequence, patients with transfusion-dependent thalassemia (TDT) frequently develop immune disorders including decreased synthesis or increased consumption of complement factors (C3 and C4) [7], aberrations in cell-mediated immunity [8], lymphocyte proliferative responses to mitogens and antigens [9], and antibody production and responses, decreased activity of T-and B-lymphocytes, alterations in cytokine responses [10], changes in natural killer cell activity, neutrophil chemotaxis, phagocytic and chemotaxis activity of macrophages, and increased susceptibility to infections [11][12][13][14]. ...
Background
Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results.
Aim of the study
To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables.
Methods
This study recruited 60 children with TDT and 30 healthy controls aged 3-12 years old.
Results
Zinc was significantly higher in TDT children than in controls, while copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children.
Conclusion
Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.
... Beta-TM patients require frequent blood transfusions to maintain normal hemoglobin levels and to suppress ineffective erythropoiesis (3). Frequent RBC transfusions may cause a state of iron overload, which may cause precipitation of iron in most vital organs (4)(5)(6). As a consequence, patients with transfusion-dependent thalassemia (TDT) frequently develop immune disorders including decreased synthesis or increased consumption of complement factors (C3 and C4) (7), aberrations in cell-mediated immunity (8), lymphocyte proliferative responses to mitogens and antigens (9), and antibody production and responses, decreased activity of T-and B-lymphocytes, alterations in cytokine responses (10), changes in natural killer cell activity, neutrophil chemotaxis, phagocytic and chemotaxis activity of macrophages, and increased susceptibility to infections (11)(12)(13)(14). ...
Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results.Aim of the study: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables. Methods: This study recruited 60 children with TDT and 30 healthy children aged 3-12 years old.Results: Zinc was significantly higher in TDT children than in control children, whilst copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children. Conclusion: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.
... Beta-TM patients require frequent blood transfusions to maintain normal hemoglobin levels and to suppress ineffective erythropoiesis (3). Frequent RBC transfusions may cause a state of iron overload, which may cause precipitation of iron in most vital organs (4)(5)(6). As a consequence, patients with transfusion-dependent thalassemia (TDT) frequently develop immune disorders including decreased synthesis or increased consumption of complement factors (C3 and C4) (7), aberrations in cell-mediated immunity (8), lymphocyte proliferative responses to mitogens and antigens (9), and antibody production and responses, decreased activity of T-and B-lymphocytes, alterations in cytokine responses (10), changes in natural killer cell activity, neutrophil chemotaxis, phagocytic and chemotaxis activity of macrophages, and increased susceptibility to infections (11)(12)(13)(14). ...
Abstract
Background: Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results.
Aim of the study: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables.
Methods: This study recruited 60 children with TDT and 30 healthy children aged 3-12 years old.
Results: Zinc was significantly higher in TDT children than in control children, whilst copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children.
Conclusion: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.
Objective: This study analyzed anti-mullerian hormone (AMH) levels in patients with non-transfusion-dependent thalassemia (NTDT) to evaluate their ovarian function.
Introduction:
Females with transfusion-dependent β-thalassemia (TDT) display menstrual irregularities and subfertility at certain points in their lives, even if well-chelated, representing a significant physical and psychological burden. Little is known about the effects of pituitary and ovarian iron contents on ovarian reserve and function. Hence, this study aimed to assess ovarian reserve and pituitary-gonadal axis function in adolescent females with TDT and correlate them with pituitary and ovarian volume, pituitary iron load, and serum ferritin.
Methods:
Fifty adolescent females with TDT were compared to 50 age-matched healthy females. Age of diagnosis of TDT, transfusion index, type of chelation therapy, age at menarche, and Tanner breast stage were assessed. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), and ferritin were measured. Magnetic resonance imaging (MRI) pituitary iron content R2* and T2* were measured, and 3-D transabdominal ovarian ultrasound performed.
Results:
The mean age of the studied females with TDT was 14.54 ± 2.24 years. Ovarian insufficiency was found in 20 of them (40%). Compared to controls, adolescent females with TDT had significantly delayed age of menarche, AMH, FSH, LH, antral follicle count (AFC), and ovarian volume. Upon comparing those with ovarian insufficiency and those without, adolescents with TDT having ovarian insufficiency had significantly higher serum ferritin and pituitary MRI-R2* than those without insufficiency. Multivariate-logistic regression showed that pituitary MRI-R2* was the most significant independent variable associated with ovarian insufficiency among adolescent females with TDT.
Conclusion:
Adolescent females with TDT have decreased ovarian reserve, AFC, and gonadotropins that are correlated with serum ferritin, pituitary iron load, and ovarian volume. Hence, regular ovarian reserve assessment should be implemented as a part of endocrinological follow-up of females with TDT advising procedures to preserve fertility to those who are likely to have ovarian insufficiency.
STUDY QUESTION
Is there an association between iron intake and ovarian reserve among women seeking fertility care?
SUMMARY ANSWER
Supplemental iron intake above 45 mg/day is associated with lower ovarian reserve among women seeking fertility care.
WHAT IS KNOWN ALREADY
Although the literature regarding iron intake in relation to ovarian reserve is scant and inconsistent, some evidence suggests that iron may have gonadotoxic effects.
STUDY DESIGN, SIZE, DURATION
This observational study included 582 female participants attending the Massachusetts General Hospital Fertility Center (2007–2019) enrolled in the Environment and Reproductive Health (EARTH) Study.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Iron intake was estimated using a validated food frequency questionnaire. Markers of ovarian reserve included antral follicle count (AFC) (assessed via transvaginal ultrasound) and Day 3 FSH, both obtained during the course of an infertility evaluation.
MAIN RESULTS AND THE ROLE OF CHANCE
Participants had a median age of 35 years and median total iron intake of 29 mg/day. Total iron intake was inversely related to AFC and this association was driven by intake of supplemental iron. Compared to women with a supplemental iron intake of ≤20 mg/day, women consuming 45–64 mg/day of supplemental iron had a 17% (−35%, 0.3%) lower AFC and women consuming ≥65 mg/day of supplemental iron had a 32% (−54%, −11%) lower AFC after adjusting for potential confounders (P, linear trend = 0.003). Similarly, in a multivariable-adjusted analysis, Day 3 FSH levels were 0.9 (0.5, 1.3) IU/ml higher among women with a supplemental iron intake of ≥65 mg/day when compared to women with a supplemental iron intake of ≤20 mg/day (P, linear trend = 0.02).
LIMITATIONS, REASONS FOR CAUTION
Iron intake was estimated using a method that relies on self-report and we had no biomarkers of iron status in our participants; only 36 women consumed ≥45 mg/day of supplemental iron.
WIDER IMPLICATIONS OF THE FINDINGS
Since all study participants were seeking fertility treatment, our findings may not apply to women in the general population. Although our findings are consistent with studies of women with iron overload, given the paucity of literature on this topic, it is essential that this question is revisited in studies designed to better understand the dose–response relation of this association across the entire distribution of ovarian reserve and the risk–benefit balance of pre-conceptional iron supplementation given its many positive effects on pregnancy outcomes.
STUDY FUNDING/COMPETING INTEREST(S)
The project was funded by Grants R01ES022955, R01ES033651, R01ES009718, P30ES000002, and P30DK046200 from the National Institutes of Health. N.J.-C. was supported by a Fulbright Scholarship. N.J.-C., M.M., L.M.-A., E.O.-P., S.W., I.S., and J.E.C. declare no conflict of interest related to the work in the manuscript. R.H. has received grants from the National Institute of Environmental Health Sciences.
TRIAL REGISTRATION NUMBER
N/A.
Disruption of iron homeostasis plays a negative role in follicle development. The dynamic changes in follicle growth are dependent on Hippo/YAP signaling and mechanical forces. However, little is known about the liaison between iron overload and the Hippo/YAP signalling pathway in term of folliculogenesis. Here, based on the available evidence, we established a hypothesized model linking excessive iron, extracellular matrix (ECM), transforming growth factor-β (TGF-β) and Hippo/Yes-associated protein (YAP) signal regarding follicle development. Hypothetically, the TGF-β signal and iron overload may play a synergistic role in ECM production via YAP. We speculate that the dynamic homeostasis of follicular iron interacts with YAP, increasing the risk of ovarian reserve loss and may enhance the sensitivity of follicles to accumulated iron. Hence, therapeutic interventions targeting iron metabolism disorders, and Hippo/YAP signal may alter the consequences of the impaired developmental process based on our hypothesis, which provides potential targets and inspiration for further drug discovery and development applied to clinical treatment.
Because women with transfusion-dependent thalassemia are seeking pregnancy, ensuring the best outcomes for both mother and baby require concerted and collaborative efforts between the hematologist, obstetrician, cardiologist, hepatologist, and genetic counselor among others. Proactive counseling, early fertility evaluation, optimal management of iron overload and organ function, and application of advances in reproductive technology and prenatal screening are important in ensuring a healthy outcome. Many unanswered questions remain requiring further study, including fertility preservation, non-invasive prenatal diagnosis, chelation therapy during pregnancy, and indications and duration of anticoagulation.
Iron is essential for the health of reproductive system, and women with iron overload suffer from ovarian dysfunction and lack effective treatment in fertility preservation. However, the underlying mechanism of the detrimental effects of iron overload on ovarian function remains ambiguous. Here, we confirmed the excess iron in the circumjacent follicle near endometriomas, which negatively impacted the oocyte development in the affected ovaries. Further, by integrating cell line and chronic iron overload mice model, we demonstrated that iron overload can function as a ROS inducer to amplify mitochondria damage, which significantly elevated the release of cytochrome C and ultimately induced the apoptosis of granular cells. Besides, for the first time, our findings revealed that disruption of HIF-1α/FSHR/CYP19A1 signaling was critical for decreased estrogen synthesis of granular cells in response to iron overload, which can lead to apparent oocyte maldevelopment and subfertility. Overall. this study uncovered that iron overload modulated the follicular microenvironment and generated a deleterious effect on female infertility via ROS/HIF-1α/FSHR signaling. These results might provide potential implications for future clinical risk management of patients with endometrioma and hemopathy.
Hematological diseases, both malignant and benign, can now be considered as potentially “curable” in many circumstances. The treatments, however, may carry a significant impact on fertility, especially high-dose conditioning treatments for hematopoietic stem cell transplantation which results in a 90% chance of premature ovarian insufficiency (POI). Fertility preservation in this group of patients involves some specific challenges, which include: (1) the age of patient, as many patients will be pre-pubertal; (2) urgency, as treatments often need to be started immediately; thus a delay for ovarian stimulation is not possible; and (3) the potential presence of malignant cells within ovarian tissue remains a major concern.
Homeostasis disturbance of trace elements has been linked to adverse reproductive consequences, including premature ovarian insufficiency (POI) in women, but limited evidence has been reported so far. This case-control study evaluated the associations between 5 common urinary trace elements [copper (Cu), manganese (Mn), Iron (Fe), Selenium (Se), and zinc (Zn)] and the odds for POI. Urinary concentrations of these 5 metals and serum levels of POI-related reproductive hormones of 169 cases and 209 healthy controls were measured. The urinary levels of Cu and Se in women with POI were significantly higher than those in the controls. The positive associations were observed between Cu levels and the odds of POI [for the medium tertile: odds ratio (OR) = 3.79, 95% CI: 1.98–7.27, p < 0.001; for the highest tertile: OR = 3.85, 95% CI: 2.00–7.41, p < 0.001]. The highest tertile of urinary Se levels was associated with increasing POI risk (for the highest tertile: OR = 2.54, 95% CI: 1.38–4.70, compared with the lowest tertile, p for trend = 0.001). In POI patients, urinary concentrations of Zn and Fe were negatively associated with serum levels of follicle-stimulating hormone (FSH). Our findings suggested that higher exposure levels of Cu and Se might lead to an increased risk of POI.
Poor ovarian response in assisted reproductive techniques is defined by an association of clinical features, hormonal markers and ultrasound parameters that have been grouped by ESHRE under the name of Bologna criteria. The incidence of poor ovarian responders among infertile women has been estimated within the range of 9% to 22%. Poor response to controlled ovarian hyperstimulation reflects advanced ovarian aging, which may be associated with early vascular aging. The aim of this research is to identify whether poor perinatal outcomes and pregnancy complications are higher among women with poor ovarian response.
The thalassemias are an inherited group of disorders caused by absent or abnormal globin chain synthesis and insufficient hemoglobin production resulting in moderate to severe anemia. Curative treatment with bone marrow transplant or gene therapy and more recent treatment advances are limited to a small number of patients. Thus, blood transfusion remains the mainstay of treatment for the severe disease forms. Resultant excess transfusional iron requires lifelong iron chelation therapy and, if not effectively removed, causes deleterious effects on the heart, liver, and endocrine organs.
Objective:
Although spontaneous fertility and successful pregnancies have been reported in well-chelated and transfused women with beta thalassaemia major (BTM), majority of women are subfertile due to hypogonadotropic hypogonadism (HH). Little is known about the effect of iron overload on ovarian follicles and whether ovarian reserve is affected by the disease or treatment status. This study compares the markers of ovarian reserve in women with transfusion-dependent BTM over a period of ten years with healthy women from a control population.
Study design:
We performed a 10-year mixed (retrospective and prospective) longitudinal study in 17 women with transfusion-dependent BTM from our thalassaemia clinic between July 2007 to June 2017. The results were compared with 52 age-matched healthy women without any medical conditions (control population) attending our fertility clinic. Patient demographics, medical history, menstrual history, hormonal parameters (serum levels of FSH, estradiol, TSH and AMH) and antral follicle count were recorded in all women from both groups. Serum levels of ferritin, cardiac T2*, liver iron concentration, thyroid function (TSH) and liver function test results were also recorded at three different time points.
Results:
Serum AMH levels, estradiol levels and antral follicle count were significantly lower in women with BTM compared with the control group (p < 0.05 for all). Low AMH levels were noted in both groups of women (with and without HH) with a background of BTM. Serum AMH levels positively correlated with AFC in women with BTM.
Conclusion:
Serum AMH level and AFC were significantly lower in women with transfusion dependent BTM as compared to age-matched healthy controls suggesting a direct impact of the disease activity or iron overload on the ovary.
In this study, we compared the long-term effects of different iron chelation regimens (deferoxamine, deferiprone, deferoxamine + deferiprone, and deferasirox) in preventing or reversing endocrinopathy (diabetes mellitus, hypothyroidism, or hypogonadism) and bone disease (measured through DEXA) in 165 adults with β-thalassemia major (TM) (mean age 39.9 ± 8.3 years, 43 % males). After five consecutive years of therapy, patients on deferasirox had the highest decrease in the prevalence of any endocrinopathy compared to other chelators which either had no change (deferiprone and deferoxamine) or had an increase (deferoxamine + deferiprone), p = 0.015. This was attributed to a lower proportion of patients on deferasirox developing new-onset endocrinopathy and higher proportion showing reversal of disease, compared to other chelators. A serum ferritin level of >1300 ng/mL predicted the development of new endocrinopathy (p = 0.025) while a level of <200 ng/mL predicted reversal of existing endocrinopathy (p = 0.147). A significant increase in mean BMD T-score (p < 0.001) and a considerable decrease in osteoporosis prevalence were observed in patients receiving deferasirox but not other chelators. Iron chelation therapy with deferasirox has a role in the prevention of endocrinopathy and reversal of existing disease.
Under conditions of iron overload, which are now reaching epidemic proportions worldwide, iron-overload cardiomyopathy is the most important prognostic factor in patient survival. We hypothesize that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron (Fe2+) permeation through the L-type voltage-dependent Ca2+ channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis and elevated oxidative stress. Treatment with LVDCC blockers (CCBs; amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension and preserved heart structure and function. Consistent with the role of LVDCCs in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of the LVDCC alpha1-subunit had twofold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls; LVDCC blockade was again protective. Our results indicate that cardiac LVDCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions, and potentially represent a new therapeutic target to reduce the cardiovascular burden from iron overload.
The role of serum AMH levels in prediction of ovarian response in idiopathic hypogonadotropic hypogonadism (IHH) was evaluated. MATERIAL METHOD(S): Twelve patients with IHH underwent controlled ovarian hyperstimulation (COH) for IVF were enrolled in this prospective study. Serum AMH levels were studied on the 2nd or 3rd day of an induced menstrual cycle by a preceding low-dose oral contraceptive pill treatment. A fixed dose (150-300 IU/day) of hMG was given in all COH cycles. Correlations between serum AMH levels, COH outcomes and embryological data were investigated.
Mean serum AMH levels was 3.47 ± 2.15 ng/mL and mean serum peak estradiol was 2196 ± 1705 pg/mL. Mean number of follicles >14 mm, >17 mm on hCG day and MII oocytes were 4.14 ± 3.2, 4 ± 2.5 and 7.28 ± 3.5, respectively. Mean number of grade A embryos and transferred embryos were 3.28 ± 2.4 and 2.5 ± 0.7, respectively. The clinical pregnancy rate per patient was 41.6 % (5/12). Positive correlations were observed between serum AMH levels and MII oocytes (r = 0.84), grade A embryos (r = 0.85), serum peak estradiol levels (r = 0.87), and number of follicles >14 mm (r = 0.83) and >17 mm (r = 0.81) on hCG day, respectively.
AMH appears as a promising marker of ovarian response in patients with IHH undergoing IVF.
The pathophysiology of iron-induced compromised fertility in women with thalassemia major (TM) was evaluated in 26 adult TM females. Low gonadotropin secretion resulted in reduced ovarian antral follicle count and ovarian volume, but levels of anti-müllerian hormone (AMH), a sensitive marker for ovarian reserve independent of gonadotropin effect, were mostly normal. AMH correlated with non-transferrin-bound iron (NTBI), suggesting a role of labile iron in the pathogenesis of decreased reproductive capacity, possibly occurring in parallel to cardiac iron toxicity, as cardiac iron was associated with the presence of amenorrhea and with NTBI levels. AMH emerges as an important biomarker for assessment of reproductive capacity in TM, demonstrating that fertility is preserved in the majority of those younger than 30 to 35 years. AMH can be useful in future studies aiming at improved chelation for fertility preservation, whereas NTBI and labile plasma iron may be valuable for monitoring iron effect on the reproductive system.
Under conditions of iron overload, which are now reaching epidemic proportions worldwide, iron-overload cardiomyopathy is the most important prognostic factor in patient survival. We hypothesize that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron (Fe2+) permeation through the L-type voltage-dependent Ca2+ channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis and elevated oxidative stress. Treatment with LVDCC blockers (CCBs; amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension and preserved heart structure and function. Consistent with the role of LVDCCs in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of the LVDCC alpha1-subunit had twofold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls; LVDCC blockade was again protective. Our results indicate that cardiac LVDCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions, and potentially represent a new therapeutic target to reduce the cardiovascular burden from iron overload.
Anti-Müllerian hormone (AMH) is a member of the transforming growth factor-beta superfamily, which plays an important role in both ovarian primordial follicle recruitment and dominant follicle selection in mice. However, the role of AMH in folliculogenesis in humans has not been investigated in detail. In the present study, AMH expression was assessed using immunohistochemistry in ovarian sections, obtained from healthy regularly cycling women. To this end, a novel monoclonal antibody to human AMH was developed. AMH expression was not observed in primordial follicles, whereas 74% of the primary follicles showed at least a weak signal in the granulosa cells. The highest level of AMH expression was present in the granulosa cells of secondary, preantral and small antral follicles <or=4 mm in diameter. In larger (4-8 mm) antral follicles, AMH expression gradually disappeared. In conclusion, in the human AMH expression follows a similar pattern as compared to the mouse and rat, suggesting an important role of AMH in folliculogenesis.
Seven Italian centers reported data on survival, causes of death and appearance of complications in patients with thalassemia major. The interactions between gender, birth cohort, complications, and ferritin on survival and complications were analyzed.
Survival after the first decade was studied for 977 patients born since 1960 whereas survival since birth and complication appearance was studied for the 720 patients born after 1970. Better survival was demonstrated for patients born in more recent years (p<0.00005) and for females (p=0.0003); 68% of the patients are alive at the age of 35 years. In the entire population 67% of the deaths were due to heart disease.
There was a significant association between birth cohort and complication-free survival (p<0.0005). The prevalence of complications was: heart failure 6.8%, arrhythmia 5.7%, hypogonadism 54.7%, hypothyroidism 10.8%, diabetes 6.4%, HIV infection 1.7%, and thrombosis 1.1%. Lower ferritin levels were associated with a lower probability of heart failure (hazard ratio =3.35, p<0.005) and with prolonged survival (hazard ratio = 2.45, p<0.005), using a cut-off as low as 1,000 ng/mL.
Survival and complication-free survival of patients with thalassemia major continue to improve, especially for female patients born shortly before or after the availability of iron chelation.
The scarcity of human ovarian tissue is a major problem in developing research on ovarian cryopreservation. We were interested in ovarian cortex surrounding benign ovarian cysts harvested during their requisite operations.
Ovarian tissue was collected from 25 women (mean age = 27.7 +/- 1.0 SEM) and frozen in serum-free cryoprotective medium. Histological and viability analysis were performed on fresh and frozen-thawed slices of tissue.
Dermoid (n = 7), endometriosis (n = 13) and serous (n = 5) cysts were observed. Follicular densities (expressed per mm3) in ovarian cortex surrounding dermoid cysts were higher than in endometriosis and serous cysts for both histological (median of follicular densities: 13.04, 0.31 and 0.89 respectively) and viability analysis (2.93, 0.05 and 0.71 respectively). Freezing-thawing did not result in gross abnormality of follicle population either in number or morphology (80% of follicles preserved a normal pattern). However, a slight decrease of the density of living follicles (expressed per mm2) was reported.
Ovarian cortex surrounding ovarian cysts, especially dermoid cysts, could be considered a source of ovarian tissue for future research. In our study, the cryopreservation procedure resulted in high follicular survival assessed by both histological and viability analysis. Nevertheless, further studies of in vivo and in vitro follicular maturation are needed to strengthen this model.
Anti-Müllerian hormone (AMH) is a member of the transforming growth factor beta family of growth and differentiation factors. In the ovary, AMH has an inhibitory effect on primordial follicle recruitment as well as on the responsiveness of growing follicles to follicle-stimulating hormone (FSH). The ovary-specific expression pattern in granulosa cells of growing nonselected follicles makes AMH an ideal marker for the size of the ovarian follicle pool. This review summarizes recent findings concerning AMH and its role as a marker for the quantitative aspect of ovarian reserve as well as ovarian dysfunction.
BACKGROUND Clinical data suggest that the presence of an ovarian endometrioma may cause per se damage to the surrounding otherwise healthy ovarian tissue. However, the basic research has so far done a limited job in
trying to understand the potential detrimental effect of an endometrioma presence in the context of the ovarian physiology.
We have reviewed the literature with the aim of characterizing the pathophysiology of the endometrioma focusing mostly on
factors and mechanisms potentially affecting the surrounding, otherwise normal, ovarian tissue.
Objective:
To investigate the effects of antimüllerian hormone (AMH) on basal and FSH-induced cytochrome P450 aromatase (aromatase) expression and E2 production in human granulosa-lutein (hGL) cells, and to elucidate the mechanism by which AMH exerts its effects.
Design:
Experimental study.
Setting:
Academic medical center for reproductive science.
Patient(s):
The hGL cells were obtained from consenting patients undergoing IVF treatment.
Intervention(s):
None.
Main outcome measure(s):
Primary cultures of hGL cells were used to examine the effects of AMH (10 ng/mL) on basal and FSH (0.2 IU/mL)-stimulated E2 and intracellular cyclic adenosine 3':5' monophosphate (cAMP) accumulation, as well as aromatase and FSH receptor expression. Small interfering RNA targeting type II AMH receptor (AMHR2) was used to verify the specificity of the effects.
Result(s):
Treatment with AMH significantly reduced FSH-stimulated aromatase expression and E2 accumulation, whereas it had no measurable effects on basal and/or 8-Br-cAMP-stimulated levels. The FSH receptor messenger RNA and protein levels were not altered in AMH-treated cells. Cotreatment with AMH suppressed FSH-induced increases in intracellular cAMP. Knockdown of AMHR2 reversed the effects of AMH on aromatase expression.
Conclusion(s):
The AMH acts through AMHR2 to inhibit FSH-induced adenylyl cyclase activation, aromatase expression, and E2 production.
In thalassemia, iron overload is the joint outcome of excessive iron absorption and transfusional siderosis. While iron absorption is limited by a physiologic ceiling of about 3 mg/d, plasma iron turnover in thalassemia may be 10 to 15 times normal, caused by the wasteful, ineffective erythropoiesis of an enormously expanded erythroid marrow. This outpouring of catabolic iron exceeds the iron-binding capacity of transferrin and appears in plasma as non-transferrin-plasma iron (NTPI). The toxicity of NTPI is much higher than of transferrin-iron as judged by its ability to promote hydroxyl radical formation resulting in peroxidative damage to membrane lipids and proteins. In the heart, this results in impaired function of the mitochrondrial respiratory chain and abnormal energy metabolism manifested clinically in fatal hemosiderotic cardiomyopathy. Ascorbate increases the efficacy of iron chelators by expanding the intracellular chelatable iron pool, but, at suboptimal concentrations is a pro-oxidant, enhancing the catalytic effect of iron in free radical formation. NTPI is removed by i.v. DFO in a biphasic manner and reappears rapidly upon cessation of DFO, lending support to the continuous, rather than intermittent, use of chelators. Unlike DFO and other hexadentate chelators, bidentate chelators such as L1 may produce incomplete intermediate iron complexes at suboptimal drug concentrations.
The association between iron overload indices and pathology of the heart and liver in transfusion-dependent patients with β thalassemia major (TM) has been extensively studied. Nonetheless, data on endocrine disease remains limited. This was a cross-sectional study of 382 TM patients treated with regular transfusions and desferrioxamine at the Thalassemia Center in Dubai, UAE. Retrieved data included demographics, splenectomy status, steady-state serum ferritin levels, and the presence of endocrinopathies (diabetes mellitus, hypothyroidism, hypoparathyroidism, and hypogonadism). Multivariate logistic regression analyses were used to determine which variables were independently associated with the occurrence of each endocrinopathy. The mean age of patients was 15.4 ± 7.6 years, with an equal sex distribution. The mean serum ferritin level was 2597.2 ± 1976.8 μg/l. The frequencies of specific endocrinopathies were diabetes mellitus (10.5%), hypothyroidism (6.3%), hypoparathyroidism (10.5%), and hypogonadism (25.9%). On multivariate logistic regression analysis, patients with a serum ferritin level >2,500 μg/l, but not >1,000-2,500 μg/l, were 3.53 times (95% CI 1.09-11.40) more likely to have diabetes mellitus, 3.25 times (95% CI 1.07-10.90) more likely to have hypothyroidism, 3.27 times (95% CI 1.27-8.39) more likely to have hypoparathyroidism, and 2.75 times (95% CI 1.38-5.49) more likely to have hypogonadism compared to patients with a serum ferritin level ≤1,000 μg/l. However, splenectomized patients with serum ferritin levels ≤2,500 μg/l had comparably high rates of all endocrinopathies as patients with serum ferritin levels >2,500 μg/l. Endocrinopathy is common in TM patients treated with desferrioxamine therapy, especially in patients with serum ferritin levels >2,500 μg/l or those splenectomized.
Hypogonadism is the most common morbidity in patients with transfusion-dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < -2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r(2) of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy. Am. J. Hematol. 2011. © 2011 Wiley Periodicals, Inc.
Pancreatic iron overload and diabetes mellitus (DM) are common in thalassemia major patients. However, the relationship between iron stores and glucose disturbances is not well defined. We used a frequently sampled oral glucose tolerance test (OGTT), coupled with mathematical modeling, and magnetic resonance imaging (MRI) to examine the impact of pancreatic, cardiac, and hepatic iron overload on glucose regulation in 59 patients with thalassemia major. According to OGTT results, 11 patients had DM, 12 had impaired glucose tolerance (IGT), 8 had isolated impaired fasting glucose (IFG), and 28 patients had normal glucose tolerance (NGT). Patients with DM had significantly impaired insulin sensitivity and insulin release. Insulin resistance was most strongly associated with markers of inflammation and somatic iron overload, while disposition index (DI) (a measure of beta cell function) was most strongly correlated with pancreas R2*. Patients with DM and IGT had significantly worse DI than those with NGT or IFG, suggesting significant beta cell toxicity. One-third of patients having elevated pancreas R2* had normal glucose regulation (preclinical iron burden), but these patients were younger and had lower hepatic iron burdens. Our study indicates that pancreatic iron is the strongest predictor of beta cell toxicity, but total body iron burden, age, and body habitus also influence glucose regulation. We also demonstrate that MRI and fasting glucose/insulin are complementary screening tools, reducing the need for oral glucose tolerance testing, and identify high-risk patients before irreversible pancreatic damage. Am. J. Hematol., 2011. © 2011 Wiley Periodicals, Inc.
To evaluate the adverse effects of endometriomas on ovarian reserve.
Analysis of prospectively collected biopsy samples.
Gynecology research unit in a university hospital.
Women younger than age 35 years with endometriomas.
Biopsy of normal cortex from ovaries affected by endometriomas (≤4 cm) and contralateral ovaries without cysts.
Presence of cortex-specific stroma, observation of superficial endometriosis, follicular density, and presence of fibrosis.
Twenty samples of cortical tissue from ovaries with endometriomas and 11 from contralateral ovaries without cysts were analyzed. Follicular density was significantly lower in cortex from ovaries with endometriomas than in cortex from contralateral ovaries without cysts (mean ± SD = 6.3 ± 4.1/mm(3) vs 25.1 ± 15.0/mm(3)). Eleven (55%) cortical samples from ovaries with endometriomas showed fibrosis and concomitant loss of cortex-specific stroma, not observed in contralateral normal ovaries. Multivariate analysis revealed that the presence of endometrioma and fibrosis were significantly and independently associated with follicular density.
Endometriotic cyst formation and associated structural tissue alterations in apparently normal ovarian cortex may be a cause of reduced ovarian reserve. Early diagnosis and intervention may be beneficial in women with endometriomas to protect their ovarian function.
To evaluate whether neuroendocrine forms of secondary amenorrhea (hypothalamic nervosa (HA) and anorexia nervosa (AN)) affect serum anti-Müllerian hormone (AMH), inhibin B, and total inhibin levels.
Amenorrheic women (n = 82) (aged between 16 and 35 years old) according to diagnosed with neuroendocrine forms of amenorrhea: HA (n = 64), AN (n = 18), and healthy women (n = 41) (control group) were enrolled. Serum AMH, inhibin B, and total inhibin levels were measured by specific ELISA.
No statistically significant difference of AMH serum levels between women with HA, AN, and control group was observed. Serum inhibin B and total inhibin levels in women with HA (p < 0.0001), AN (p < 0.05) resulted significantly lower than in control healthy women.
The present data showed that neuroendocrine forms of amenorrhea are associated with an impaired inhibin secretion while not AMH. These data indirectly support that AMH is an excellent marker of ovarian reserve and its secretion is not influenced by the hypothalamic-ovarian axis activity.
To investigate anti-müllerian hormone (AMH) as a best test of ovarian reserve in women with transfusion-dependent β-thalassaemia, and the relationship between AMH and iron overload.
A case-control study in a tertiary medical centre.
Twenty-nine women with transfusion-dependent β-thalassaemia and 29 healthy controls of a similar age were recruited.
Blood sampling, questionnaires and medical record reviews were used.
The history of iron overload-related morbidities, haematological phenotypes, serum levels of AMH and ferritin, and hormonal profiles were analysed.
The serum levels of AMH, luteinising hormone, and estradiol were lower in women with transfusion-dependent β-thalassaemia than in age-matched normal controls. In women with transfusion-dependent β-thalassaemia, the serum AMH level was significantly inversely related to the ferritin level, but not related to the presence of hypogonadotrophic hypogonadism, diabetes and haematological phenotypes. The serum ferritin level was positively associated with advanced age and the presence of hypogonadotrophic hypogonadism in the study participants. However, the inverse relationship between AMH and ferritin still exists after further adjustment for advanced age in women with transfusion-dependent β-thalassaemia.
The present study indicates that the serum AMH levels in women with transfusion-dependent β-thalassaemia are lower when compared with normal healthy women of a similar age, and are significantly negatively correlated with their serum ferritin levels. This implies that ovarian function might be impaired by the chronic iron overload status in women with transfusion-dependent β-thalassaemia.
Iron overload is a major cause of morbidity and mortality in transfusion-dependent anemias. Greater understanding of the mechanisms of iron regulation and the role of toxic iron moieties and their predilection for certain organs has enhanced our ability to better target therapies in recent years, as illustrated by the Thalassemia syndromes.
Patients with thalassemia major (TM) require lifelong transfusion therapy to survive, leading to toxic iron overload in the endocrine glands and heart. The pituitary gland is one of the most vulnerable targets, leading to irreversible hypogonadotropic hypogonadism in approximately half of patients. Improvements in magnetic resonance imaging (MRI) technology and understanding have allowed earlier recognition of preclinical iron deposition in the heart, pancreas, and liver; prior work also supports a similar role for the pituitary. The purpose of this study is threefold, (1) to develop age-specific nomograms for pituitary iron and volume metrics; (2) to determine the prevalence, severity, and age of onset of pituitary iron deposition and volume loss in TM patients, and (3) to determine whether deferasirox monotherapy can modify the trajectory of pituitary iron accumulation and damage over a two-year period. This article outlines relevant background studies and methodological details as well as providing preliminary results from our first two aims.
Cardiac and endocrine disorders are common sequelae of iron overload in transfused thalassaemia patients. Combined chelation with desferrioxamine (DFO) and deferiprone (DFP) is well tolerated and produces an additive/synergistic effect superior to either drug alone. 52 thalassaemia major patients were transitioned from DFO to combined chelation with DFO and DFP. Serum ferritin, cardiac and hepatic iron levels were monitored regularly for up to 7 years, as were cardiac and endocrine function. Patients' iron load normalized, as judged by ferritin and cardiac and hepatic magnetic resonance imaging findings. In all 12 patients receiving treatment for cardiac dysfunction, symptoms reversed following combined chelation, enabling nine patients to discontinue heart medications. In the 39 patients with abnormal glucose metabolism, 44% normalized. In 18 requiring thyroxine supplementation for hypothyroidism, 10 were able to discontinue, and four reduced their thyroxine dose. In 14 hypogonadal males on testosterone therapy, seven stopped treatment. Of the 19 females, who were hypogonadal on DFO monotherapy, six were able to conceive. Moreover, no patients developed de novo cardiac or endocrine complications. These results suggest that intensive combined chelation normalized patients' iron load and thereby prevented and reversed cardiac and multiple endocrine complications associated with transfusion iron overload.
Our purpose was to assess the functional morphologic features of the ovarian cortex surrounding benign cysts.
Fifty-four specimens (13 mature teratomas, nine benign cystadenomas, and 32 endometriomas) were obtained from the area of maximum distention of the ovarian cortex overlying benign cysts from 48 patients. The type and number of follicles were scored on a semiquantitative scale (0 to 4). Alterations of the cortical stroma that were related to the primary tumor were investigated. The vascular network was assessed by means of monoclonal antibodies directed against endothelial cells (anti-VW, QBEND/10) and scored on a scale from 0 to 2. The chi 2 and Mann-Whitney U test were used for statistical analysis.
Morphologic patterns similar to those of the normal ovarian cortex were observed in the cortical tissue surrounding mature teratomas, benign cystomas, and endometriomas in 92%, 77%, and 19% (p < 0.01) of specimens, respectively, and a regular vascular network was observed in 84%, 78%, and 22% (p < 0.01). Although microscopic endometriosis was observed surrounding the endometrioma in the stroma of 82% of specimens, stromal alterations related to the ovarian tumor were absent in the cortex surrounding mature teratomas and cystadenomas.
The study shows that the ovarian cortex, which is stretched and thinned by the growth of a benign tumor, is not morphologically altered in the presence of teratomas or benign cystadenomas. Endometriomas are associated with microscopic stromal implants and reduced follicular number and activity.
In thalassemia, iron overload is the joint outcome of excessive iron absorption and transfusional siderosis. While iron absorption is limited by a physiologic ceiling of about 3 mg/d, plasma iron turnover in thalassemia may be 10 to 15 times normal, caused by the wasteful, ineffective erythropoiesis of an enormously expanded erythroid marrow. This outpouring of catabolic iron exceeds the iron-binding capacity of transferrin and appears in plasma as non-transferrin-plasma iron (NTPI). The toxicity of NTPI is much higher than of transferrin-iron as judged by its ability to promote hydroxyl radical formation resulting in peroxidative damage to membrane lipids and proteins. In the heart, this results in impaired function of the mitochrondrial respiratory chain and abnormal energy metabolism manifested clinically in fatal hemosiderotic cardiomyopathy. Ascorbate increases the efficacy of iron chelators by expanding the intracellular chelatable iron pool, but, at suboptimal concentrations is a pro-oxidant, enhancing the catalytic effect of iron in free radical formation. NTPI is removed by i.v. DFO in a biphasic manner and reappears rapidly upon cessation of DFO, lending support to the continuous, rather than intermittent, use of chelators. Unlike DFO and other hexadentate chelators, bidentate chelators such as L1 may produce incomplete intermediate iron complexes at suboptimal drug concentrations.