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Iron and Testosterone: Interplay and Clinical Implications

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Joseph Scott Gabrielsen at University of Rochester
Joseph Scott Gabrielsen
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Abstract

Purpose of Review The purpose of this review is to investigate the crosstalk between testosterone and iron metabolism in men and discuss the clinical implications. Recent Findings Testosterone directly regulates body iron levels through inhibition of the master regulator of iron metabolism, hepcidin. Summary There is significant overlap between the side effects of exogenous testosterone administration and iron overload. Testosterone increases dietary iron absorption, providing a direct link between the two. As the body is unable to eliminate excess iron, a negative feedback mechanism allowing iron to inhibit testosterone production to maintain body iron homeostasis is proposed. This review discusses the recent data demonstrating the regulation of body iron stores by testosterone, as well as data suggesting testosterone may be reciprocally regulated by iron. Crosstalk between testosterone and iron has significant implications in testosterone deficiency and therapy. Additionally, the regulation of testosterone by iron may indicate a significant role for iron in the development of the hypogonadotropic hypogonadism of aging and chronic disease.
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MALE SEXUAL DYSFUNCTION AND DISORDERS (A PASTUSZAK AND T KÖHLER, SECTION EDITORS)
Iron and Testosterone: Interplay and Clinical Implications
Joseph Scott Gabrielsen
1
Published online: 30 January 2017
#Springer Science+Business Media, LLC 2017
Abstract
Purpose of Review The purpose of this review is to investi-
gate the crosstalk between testosterone and iron metabolism in
men and discuss the clinical implications.
Recent Findings Testosterone directly regulates body iron
levels through inhibition of the master regulator of iron me-
tabolism, hepcidin.
Summary There is significant overlap between the side effects
of exogenous testosterone administration and iron overload.
Testosterone increases dietary iron absorption, providing a di-
rect link between the two. As the body is unable to eliminate
excess iron, a negative feedback mechanism allowing iron to
inhibittestosteroneproductiontomaintainbodyironhomeo-
stasis is proposed. This review discusses the recent data dem-
onstrating the regulation of body iron stores by testosterone, as
well as data suggesting testosterone may be reciprocally regu-
latedbyiron.Crosstalkbetweentestosterone and iron has sig-
nificant implications in testosterone deficiency and therapy.
Additionally, the regulation of testosterone by iron may indicate
a significant role for iron in the development of the
hypogonadotropic hypogonadism of aging and chronic disease.
Keywords Testosterone .Hypogonadotropic
hypogonadism .Iron .Hepcidin .Hereditary
hemochromatosis .Beta thalassemia
Introduction
Testosterone is critical for the embryologic development of
the reproductive tract, puberty, and sexual function in men.
Serum testosterone levels peak at puberty and subsequently
decline with age [1–3]. Low testosterone levels, particularly in
the aging male, have been associated with erectile dysfunc-
tion, decreased vitality, frailty, and many other health concerns
(reviewed in [4]). Increased awareness of the potential effects
of low testosterone has led to a dramatic increase in prescrip-
tions for testosterone therapy [5]. Increased use, however, has
led to considerable debate regarding the safety and efficacy of
testosterone therapy. Furthermore, anabolic steroid use is
prevalent among young adult men and severe health conse-
quences of supraphysiologic androgen levels have been well
reported [6–8]. The mechanisms underlying these effects re-
main incompletely understood.
Reported side effects of exogenous testosterone adminis-
tration—particularly supraphysiologic levels seen with ana-
bolic steroid use—include hypogonadotropic hypogonadism
(i.e., low testosterone with inappropriately low luteinizing
hormone levels), erythrocytosis, liver dysfunction, and heart
disease [8,9]. Interestingly, these conditions are also common
in iron overload diseases and suggest a potential relationship
between testosterone and iron metabolism. Indeed, many stud-
ies have reported an association between testosterone levels
and markers of body iron stores. Recently, a causative role for
testosterone in the regulation of body iron stores has been
demonstrated.
To understand the interplay between testosterone and iron,
this paper will briefly review the regulation of iron metabo-
lism in humans. The data linking testosterone to body iron
metabolism will then be discussed in detail. Subsequently, a
potential role for iron in the regulation of serum testosterone
levels will be presented. Better understanding of the crosstalk
This article is part of the Topical Collection on Male Sexual Dysfunction
and Disorders
*Joseph Scott Gabrielsen
j.scott.gabrielsen@gmail.com
1
Department of Urology, Massachusetts General Hospital, 55 Fruit
Street, GRB1102, Boston, MA 02114, USA
Curr Sex Health Rep (2017) 9:5–11
DOI 10.1007/s11930-017-0097-2
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Among older men with low testosterone levels, testosterone treatment can increase the serum iron levels and correct ID anemia [218]. Also, data are showing significant overlap between the testosterone administration and IO [219]. ...
... Furthermore, as the body is unable to eliminate excess iron, a negative feedback mechanism that allows iron to inhibit testosterone production to maintain body iron homeostasis is proposed [219]. The body iron stores can be regulated by testosterone, and vice versa, the testosterone may be reciprocally regulated by iron. ...
... Crosstalk between testosterone and iron has significant implications in testosterone deficiency and therapy. Additionally, the regulation of testosterone by iron may indicate a significant role of iron in the development of the hypogonadotropic hypogonadism in aging and chronic disease in men [219][220][221]. In a study from Jeppesen et al., 1996 both total and free testosterone were significantly inversely associated with stroke severity, and total testosterone was significantly inversely associated with infarct size [222]. ...
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... In the case of the hematological variables, the higher platelet count observed in juveniles may be associated with a physiological decrease of hematopoietic stem-cell reserves from birth to adulthood, resulting in a decline in thrombopoietin levels (Ishiguro et al. 1999). In the same reasoning, the higher MCV values observed in juvenile coatis may be associated with the reduced lifespan of RBC in older individuals and the consequent release of larger and immature RBCs into the bloodstream, as reported by Gamaldo et al. (2011) The higher levels of Hb observed in males are physiologically related to the effect of sexual hormones on erythropoiesis in the bone marrow and erythropoietin production in the kidney (Shahani et al. 2009;Murphy 2014), as seen by the positive correlation between Hb and testosterone (Gabrielsen 2017), and were also reported in previous studies with free-living and captive coatis (Rodrigues et al. 1996;Repolês et al. 2022). ...
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... Our results also revealed that female participants had a lower cardiorespiratory fitness when compared to males (Figure 1). This significant difference could be partially explained by differences in the serum testosterone concentration if we consider the documented erythrogenic effects of this hormone [41]. ...
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... During infancy, a "mini-puberty" takes place: the hypothalamic-pituitary-gonadal (HPG) is activated leading to a surge of testosterone in male infants [84]. Testosterone has been shown to inhibit hepcidin transcription and stimulate iron absorption, which in the context of the current study may increase the risk of excess iron exposure [85]. In line with this hypothesis, growth acceleration during infancy has been linked to greater demand for iron and decreased hepcidin expression [86]. ...
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... As the body is unable to eliminate excess iron, a negative feedback mechanism allowing iron to inhibit testosterone production to maintain body iron homeostasis is proposed. [48] A high TIBC, UIBC, or transferrin usually indicates iron deficiency, but they are also increased in pregnancy and with the use of oral contraceptives. A low TIBC, UIBC, or transferrin may also occur if someone has malnutrition, inflammation, liver disease, or nephrotic syndrome. ...
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Full-text available
  • Apr 2016
Iron overload used to be considered rare in hemodialysis patients but its clinical frequency is now increasingly realized. The liver is the main site of iron storage and the liver iron concentration (LIC) is closely correlated with total iron stores in patients with secondary hemosideroses and genetic hemochromatosis. Magnetic resonance imaging is now the gold standard method for LIC estimation and monitoring in non-renal patients. Studies of LIC in hemodialysis patients by quantitative magnetic resonance imaging and magnetic susceptometry have demonstrated a strong relation between the risk of iron overload and the use of intravenous (IV) iron products prescribed at doses determined by the iron biomarker cutoffs contained in current anemia management guidelines. These findings have challenged the validity of both iron biomarker cutoffs and current clinical guidelines, especially with respect to recommended IV iron doses. Three long-term observational studies have recently suggested that excessive IV iron doses may be associated with an increased risk of cardiovascular events and death in hemodialysis patients. We postulate that iatrogenic iron overload in the era of erythropoiesis-stimulating agents may silently increase complications in dialysis patients without creating frank clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It is therefore tempting to postulate that the main pathophysiological pathway leading to these events may involve the pleiotropic master hormone hepcidin (synergized by fibroblast growth factor 23), which regulates iron metabolism. Oxidative stress as a result of IV iron infusions and iron overload, by releasing labile non-transferrin-bound iron, might represent a 'second hit' on the vascular bed. Finally, iron deposition in the myocardium of patients with severe iron overload might also play a role in the pathogenesis of sudden death in some patients.
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Testosterone alters iron metabolism and stimulates red blood cell production independently of dihydrotestosterone
Article
  • Jul 2014
Beggs LA, Yarrow JF, Conover CF, Meuleman JR, Beck DT, Mor-row M, Zou B, Shuster JJ, Borst SE. Testosterone alters iron metabolism and stimulates red blood cell production independently of dihydrotestoster-one. (T) stimulates erythropoiesis and regulates iron homeostasis. However, it remains unknown whether the (type II) 5-reduction of T to dihy-drotestosterone (DHT) mediates these androgenic effects, as it does in some other tissues. Our purpose was to determine whether inhibition of type II 5-reductase (via finasteride) alters red blood cell (RBC) production and serum markers of iron homeostasis subsequent to testosterone-enanthate (TE) administration in older hypogonadal men. Sixty men aged 60 yr with serum T 300 ng/dl or bioavailable T 70 ng/dl received treatment with TE (125 mg/wk) vs. vehicle paired with finasteride (5 mg/day) vs. placebo using a 2 2 factorial design. Over the course of 12 mo, TE increased RBC count 9%, hematocrit 4%, and hemoglobin 8% while suppressing serum hepcidin 57% (P 0.001 for all measurements). Most of the aforementioned changes occurred in the first 3 mo of treatment, and finasteride coadministra-tion did not significantly alter any of these effects. TE also reduced serum ferritin 32% (P 0.002) within 3 mo of treatment initiation without altering iron, transferrin, or transferrin saturation. We conclude that TE stimulates erythropoiesis and alters iron homeostasis independently of the type II 5-reductase enzyme. These results demonstrate that elevated DHT is not required for androgen-mediated erythropoiesis or for alterations in iron homeostasis that would appear to support iron incorporation into RBCs. androgen; testosterone; finasteride; hypogonadal; hematocrit; hepci-din IRON METABOLISM AND ERYTHROPOIESIS are intrinsically interrelated because incorporation of iron into the heme group of erythrocytes is necessary for oxygen transport (38). It is well established that testosterone (T) regulates erythropoietic activity in men (32, 33). Clinically, this remains an important concept given the five-to 13-fold higher prevalence of anemia in hypogonadal men compared with their eugonadal counterparts (14) and by the ability of T replacement therapy (TRT) to elevate hematocrit (HCT) and hemoglobin (HGB) in androgen-deficient men (4, 12, 25). In this regard, classical studies have established that androgen-stimulated erythropoiesis is mediated by erythropoietin (EPO) (32, 33), as evidenced by the complete inhibition of erythropoiesis in androgen-treated animals receiving anti-EPO antibody (15, 31). However, andro-gens may also indirectly support erythropoiesis by altering iron homeostasis (5) via the suppression of hepcidin (3, 4), a negative regulator of the iron transporter ferroportin (38). Hepcidin binds to and internalizes ferroportin within cells, limiting transport of intracellular iron into the circulation (28). Elevated hepcidin underlies anemia of chronic disease (38), and androgen-induced hepcidin suppression increases splenic ferroportin expression, which effectively increases iron absorption and iron incorporation into red blood cells (RBCs) in mice (17). Interestingly, androgen-induced hepcidin suppression occurs in a dose-dependent manner within 7 days of TRT initiation in men (4), preceding the time frame in which HGB is elevated subsequent to androgen administration (4). Additionally , the androgen-induced suppression of hepcidin appears independent of EPO, given that T-stimulated hepcidin suppression persists in mice administered anti-EPO antibody (17). However, the mechanisms underlying this effect require further elucidation. In addition, many of the biological effects of T are mediated by the type II 5-reductase enzyme (22) that converts T to dihydrotestosterone (DHT), a more potent and longer-acting androgen (37). This is an important clinical concept given the increasing prevalence of TRT in older hypogonadal men and our recent findings that pharmacological 5-reductase inhibition prevents prostate enlargement (a primary clinical concern associated with TRT) without inhibiting the musculoskeletal or lipolytic benefits of this therapy (10). Interestingly, hepatocytes (the predominant source of circulating hepcidin) express 5-reductase (27), and human liver extracts actively convert T to DHT (16), indicating that 5-reductase influences hepatic androgen metabolism. Additionally, 5-reductase is thought to be involved in erythropoiesis in mammals (23). However, few studies have examined the influence of type II 5-reductase on iron homeostasis or androgen-stimulated erythropoiesis in humans. The primary purpose of this study was to determine whether type II 5-reductase activity influences androgen-stimulated erythropoiesis in elderly hypogonadal men. A secondary purpose was to determine the role of type II 5-reductase in regulating iron homeostasis subsequent to andro-gen administration. METHODS Study design. The 52-wk, double-blind, randomized controlled trial (RCT) involved men aged 60 yr with a serum T concentration of 300 ng/dl or bioavailable fractions of T (BioT) of 70 ng/dl. Participants were randomized to receive one of four treatments: 1) vehicle-placebo, 2) vehicle-finasteride, 3) T-enanthate (TE)-placebo,
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The relationship between serum total testosterone and free testosterone levels with serum hemoglobin and hematocrit levels: a study in 1221 men
Article
  • Oct 2016
Objective: To investigate the relationship between serum total testosterone (TT) and free testosterone (FT) levels in men with anemia. Methods: We reviewed the records of 1221 subjects between March 2009 and December 2014. All the subjects’ blood samples were drawn for TT and FT assays. Their serum hemoglobin (Hb) and serum hematocrit (Hct) levels were measured. The primary objective of our study was to investigate the association between TT and FT levels with Hb and Hct levels. Results: The mean age was 59.82 ± 12.71 years. The mean TT and FT levels were 4.54 ± 2.02 ng/mL and 10.63 ± 3.69 pg/mL, respectively. The mean Hb and Hct levels were 14.72 ± 1.34 g/dL and 43.11 ± 3.75%, respectively. Subjects with low TT (<2.35 ng/mL) had low Hb and Hct levels (p < 0.001, p < 0.001, respectively). TT was positively associated with FT, Hb, and Hct. TT and FT levels were significantly lower in older men. Conclusions: Subjects with low TT and FT levels had low Hb and Hct levels. This suggests that TT and FT play a significant role in erythropoiesis. Testosterone replacement therapy may be effective in men with hypogonadism to reduce the incidence of anemia.
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Effect of Testosterone on Hepcidin, Ferroportin, Ferritin and Iron Binding Capacity in Patients with Hypogonadotropic Hypogonadism and Type 2 Diabetes
Article
  • Jun 2016
  • CLIN ENDOCRINOL
ContextAs the syndrome of hypogonadotropic hypogonadism (HH) is associated with anaemia and the administration of testosterone restores haematocrit to normal, we investigated the potential underlying mechanisms. DesignRandomized, double-blind, placebo-controlled trial. Methods We measured basal serum concentrations of erythropoietin, iron, iron binding capacity, transferrin (saturated and unsaturated), ferritin and hepcidin and the expression of ferroportin and transferrin receptor (TR) in peripheral blood mononuclear cells (MNC) of 94 men with type 2 diabetes. Forty-four men had HH (defined as subnormal free testosterone along with low or normal LH concentrations) while 50 were eugonadal. Men with HH were randomized to testosterone or placebo treatment every 2 weeks for 15 weeks. Blood samples were collected at baseline, 3 and 15 weeks after starting treatment. Twenty men in testosterone group and 14 men in placebo group completed the study. ResultsHaematocrit levels were lower in men with HH (411 39% vs 438 +/- 34%, P = 0001). There were no differences in plasma concentrations of hepcidin, ferritin, erythropoietin, transferrin or iron, or in the expression of ferroportin or TR in MNC among HH and eugonadal men. Haematocrit increased to 453 +/- 45%, hepcidin decreased by 28 +/- 7% and erythropoietin increased by 21 +/- 7% after testosterone therapy (P < 005). There was no significant change in ferritin concentrations, but transferrin concentration increased while transferrin saturation and iron concentrations decreased (P < 005). Ferroportin and TR mRNA expression in MNC increased by 70 +/- 13% and 43 +/- 10%, respectively (P < 001), after testosterone therapy. Conclusions The increase in haematocrit following testosterone therapy is associated with an increase in erythropoietin, the suppression of hepcidin, and an increase in the expression of ferroportin and TR.
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Study of Male Sex Hormone Levels in Male Egyptian Children with Beta-Thalassemia: Correlation with Iron load
Article
  • May 2016
Background: Beta thalassemia is an inherited hemoglobin disorder resulting in chronic hemolytic anemia. RBCs hemolysis and repeated blood transfusions are the major causes of secondary iron overload which leads to deposition of iron in different endocrine glands. Delayed puberty and hypogonadism are the most obvious clinical consequences of iron overload. The aim of this study was to evaluate male sex hormone levels in male children with β- thalassemia major in correlation with iron overload. Material and methods: The present study was conducted on 60 male children with β- thalassemia major with serum ferritin of more than 1000 ng/ml with their age ranging from 11-18 years and mean age value of 14.16±2.48 (Group I) and 60 male children with β- thalassemia major of matched age with no iron overload (Group II). For all children in both groups the following were done: Complete blood count, Hb electrophoresis, serum ferritin, serum iron, TIBC, serum testosterone levels and assessment of testicular volume by ultrasound and Orchidometer. Results: Serum iron and ferritin were significantly higher while TIBC, serum testosterone levels and testicular volume were significantly lower in Group I than Group II (Mean serum iron was 221.70 ± 46.76 in group I versus 122.45 ± 14.32 in group II with p value of 0.001, mean serum ferritin was 2595.06 ± 903.43 in group I versus 373.75 ± 6.82 in group II with p value of 0.001, mean serum TIBC was 210.93 ± 18.17 in group I versus 311.40 ± 13.57 in group II with p value of 0.001, mean serum testosterone was 1.01±1.61 in group I versus 2.73±2.66 in group II with p value of 0.006, mean testicular volume was 4.45± 4.92 in group I versus 8.66±7.08 in group II with p value of 0.016). There was significant negative correlation between serum ferritin and serum testosterone and between serum ferritin and testicular volume in studied patients in group I (r = -0.457 and p value = 0.011 for correlation between ferritin and testosterone and r = -0.908 and p value = 0.001 for correlation between ferritin and testicular volume). Conclusion: Male sex hormone and testicular volume were significantly lower in thalassemic patients with iron overload with significant negative correlation with serum ferritin. Recommendations: Regular follow up for thalassemia patients for early detection of iron overload with regular assessment of puberty as thalassemic patients are vulnerable to develop hypogonadism and may require sex hormone replacement therapy.
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Trends in Testosterone Prescription and Public Health Concerns
Article
  • May 2016
Testosterone supplementation therapy (TST) has become increasingly popular since the turn of the century. Most prescriptions in the U.S. are written by primary care providers, endocrinologists, or urologists. The FDA has requests pharmaceutical companies provide more long term data on efficacy and safety of testosterone products. Results from these studies will help define the appropriate population for TST going forward. It is hoped that these data combined with physician and public education will minimize inappropriate prescribing and allow those likely to benefit from TST to receive it.
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