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Reversibility of hypogonadotropic hypogonadism in a patient with the juvenile form of hemochromatosis
Reversibility of hypogonadotropic hypogonadism in a patient with the juvenile form of hemochromatosis Nicholas G. Angelopoulos, M.D.,a Anastasia Goula, M.D.,b Evagelos Dimitriou, M.D.,c and George Tolis, M.D., Ph.Da a Endocrine Department, Hippokrateion Hospital of Athens, Athens, Greece; bFirst Department, Agia Sophia Children’s Hospital, Athens, Greece; and cDepartment of Obstetrics and Gynaecology, St. Mary’s Hospital, Portsmouth, United Kingdom
Objective: To report a case of complete reversibility of hypogonadotropic hypogonadism with intensive venesection treatment in juvenile hemochromatosis. Design: Case report. Setting: Endocrine department of Hippocrateion Hospital of Athens. Patient(s): A 25-year-old man who presented with hypogonadotropic hypogonadism and severe iron overload due to juvenile hemochromatosis and who was initially treated with phlebotomies and androgen substitution. Intervention(s): Intensification of chelation therapy. Main Outcome Measure(s): Clinical evaluation, serum ferritin concentration, and biochemical assessment of pituitary function were performed periodically. Result(s): One year after normalization of serum ferritin levels and transferrin saturation was achieved, he became eugonadal. Conclusion(s): We believe that hypogonadotropic hypogonadism in juvenile hemochromatosis may be reversible by a consequent venesection therapy probably because treatment was intensive and promptly introduced at a young age. (Fertil Steril威 2005;84:1744.e11–13. ©2005 by American Society for Reproductive Medicine.) Key Words: Juvenile hemochromatosis, hypogonadotropic hypogonadism, venesection therapy
Hereditary hemochromatosis (HH) is a common recessive disorder characterized by progressive parenchymal iron overload (1). The appearance of clinical manifestations is typical in the fifth decade of life, generally consisting of a combination of liver cirrhosis, hypogonadism, diabetes mellitus, and cardiomyopathy (2, 3). HFE has been identified as the candidate gene, with most patients being homozygous for the C282Y mutation and a minority being C282Y/H63D compound heterozygotes (1). Juvenile hemochromatosis (JH) is an autosomal recessive condition clinically and genetically different from the classic adult disorder (4, 5). It has been recently shown that this more severe form is caused by mutations in two genes. Mutations in the chromosome 1q–linked gene hemojuvelin (HJV) have recently been found to be a cause of JH. This is the most frequent form of JH on the basis of the description of six mutations, found in either a homozygous or compound heterozygous state, in 12 unrelated families of Greek, Canadian, and French descent (6, 7). Another mutation, the G320V amino acid change, appears to be common: It has been detected in 34 of 60 (56.7%) patients with JH from 5 different populations (6). Families with JH not linked to 1q were recently found to have loss-of-function mutations in the gene encoding hepciReceived March 11, 2005; revised and accepted May 19, 2005. Reprint requests: N. Angelopoulos, M.D., Division of Endocrinology and Metabolism, Hippokrateion Hospital of Athens, Vassilisis Sofias Avenue 108, 115 27 Athens, Greece (FAX: ⫹30 210 7786889; E-mail: [email protected]).
din, an antimicrobial peptide mainly secreted by hepatocytes (8, 9). It seems that hepcidin plays a pivotal role as the dominant regulator of the absorption of dietary iron and the release of iron from macrophages (9). Iron begins to accumulate early in life, and symptoms are observed before the age of 30 years (4 – 6). hypogonadotropic hypogonadism and cardiac involvement are prominent in this clinical syndrome (10 –13). Phlebotomy requirements for maintenance of normal iron balance are clearly higher than that needed in subjects who are homozygous for the C282Y mutation, indicating a remarkable difference in iron overprocurement (5, 12, 13). CASE REPORT Transaminasemia was accidentally detected in a 25-year-old man working as a harbor guard during his routine annual screening blood tests in November of 2002. Further laboratory investigation documented high iron and ferritin levels: 61.6 mol/L and 5,250 ng/mL, respectively. Stainable iron found in liver biopsy established the diagnosis of hereditary hemochromatosis. However, analysis of known HFE-gene mutations associated with the classic form of hemochromatosis (HFE or type 1) was negative in our patient. Further genetic analysis revealed homozygosity for the commonest mutation observed in Greek families (6), the G320V missense variant. Simultaneously, he reported a 6-month history of impotency and decreased libido for which he hadn’t sought med-
0015-0282/05/$30.00 Fertility and Sterility姞 Vol. 84, No. 6, December 2005 1744.e11 doi:10.1016/j.fertnstert.2005.05.070 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
TABLE 1 Total and free testosterone during chelation therapy. Total testosterone (ng/dL)
Free testosterone (pg/mL)
Serum ferritin (ng/mL)
Transferrin saturation (%)
350–1100
19–41
20–280
14–40
25 550 317 480 500
1.5 31 18 25.3 27.2
5250 1563 43 56 40
100 98 12 13 11
Normal values Date at diagnosis 1/2003 9/2003a 1/2004b 6/2004c 10/2004c a
With androgen substitution. Substitution was discontinuated for 50 days in order to perform LHRH test. c Androgen replacement was stopped in April 2004. b
Angelopoulos. Hypogonadism in juvenile hemochromatosis. Fertil Steril 2005.
ical assistance. Owing to the progressively deteriorating erectile dysfunction, he was referred to the endocrinology department in January 2004. Clinical examination revealed scanty axillary and pubic hair and soft nontender testes of subnormal volume (10 mL). Gynecomastia was absent. The thyroid gland was not palpable and there was no skin hyperpigmentation. There was no family history of hypogonadism. He claimed no history of drug abuse, opiate use, anabolic steroid exposure, or use of any other medication that could interfere with the development of hypogonadism. According to his medical history, the time of onset of puberty and progress of pubertal development was normal and there were no eunuchoidal proportions. Basal testosterone and gonadotropin concentrations were markedly suppressed. Responsiveness of pituitary gonadotropins to luteinizing-hormone–releasing-hormone (LHRH) was subsequently tested. A bolus of 100 g synthetic LHRH was administered intravenously, and serum samples for gonadotropin measurements were drawn 0, 30, and 60 minutes after LHRH injection. Even after stimulation with LHRH, pituitary response was subnormal. Values of DHEA and insulin-like growth factor were within normal range. Further evaluation of pituitary reserve with stimulation tests (corticotropin-releasing factor test, thyrotropin-releasing hormone test, growth hormone–releasing hormone test) was performed, and no impairment in the secretion of ACTH, cortisol, prolactin, TSH, or GH was detected (data not shown). Semen analysis revealed oligoasthenospermia (sperm count 4 ⫻ 106/mL, motile sperm ⬍30%, and ⬎40% with normal morphology). After establishing the diagnosis of hypogonadotropic hypogonadism due to juvenile hemochromatosis, substitution with testosterone (IM injection of 125 mg testosterone enantheate every 20 days) was initiated. Starting in January 2003, the patient underwent venesection sessions, which were initially performed every 7 days. After 6 months, because ferritin levels remained quite elevated (2,171 ng/mL), and we therefore in1744.e12 Angelopoulos et al.
tensified the therapy by removing 450 mL blood twice a week until January 2004, when iron and ferritin levels were found to have decreased within normal range. Venesection therapy was again tapered to a monthly schedule for 3 months, and, after that, he has been continuing with phlebotomies every 75 days (Table 1). The hypothalamuspituitary-gonadal axis was re-evaluated after 12 months of therapy, when the patient’s ferritin and transferrin saturation were within normal range, and was without any remarkable improvement. In April 2004 we recommended stopping androgen substitution for 2 months in order to retest gonadotrophin secretion after LHRH stimulation. The response was slightly improved (June 2004), and for the first time he was able to maintain basal testosterone levels within a normal range without any medication. Six months after substitution discontinuation, testosterone secretion was sufficient, and his LHRH response had strikingly improved. Clinical symptoms (libido, impotence) were concomitantly improved after the complete biochemical recovery of hypogonadism. Parameters of a new semen analysis were also improved (sperm count 16 ⫻ 106/mL, motile sperm 50%, and 60% with normal morphology). DISCUSSION Hypogonadism in hemochromatosis is believed to be irreversible (5, 14, 15). Only a few patients (a total of 5 patients) with hypogonadotropic hypogonadism have been reported to recover from their symptoms after venesection therapy (16 –20). However, to our knowledge, this is the first report in the literature of reversible hypogonadism in a patient with the genetically documented juvenile form of hemochromatosis. Although none of the previously reported patients fulfilled the criteria for JH, their relatively young age (33– 42 years) might have played a crucial role in the success of venesection therapy, because they started
Hypogonadism in juvenile hemochromatosis
Vol. 84, No. 6, December 2005
treatment at an early stage of the disease. Our patient had enormously elevated ferritin and iron concentrations at diagnosis, but he responded quickly and successfully, probably because intensive venesection therapy was instituted from the beginning. One other factor that might have contributed to the effectiveness of the patient’s management is that the iron accumulation (as often observed in JH) was rapid. We speculate that this excessive iron overload led initially to an immediate impairment of gonadotrophic cell function. However, this impairment was temporary and pituitary secretory function was recovered, indicating that iron-induced detrimental effect is mainly time dependent. It is interesting that massive deposition of iron predominately affected gonadotrophic cells and that all the other pituitary cells remained undisturbed. This case illustrates that hypogonadotropic hypogonadism due to JH may be reversible by venesection therapy when treatment is introduced early and continued intensively. Recovery of pituitary function may present several months after normalization of iron overload, and gonadotrophin secretion should be tested periodically. Because our observations are limited in a single case, larger clinical trials should be conducted in order to validate this hypothesis.
6.
7.
8. 9. 10.
11.
12. 13.
14.
15.
16.
REFERENCES 1. Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 2004;350:2383–97. 2. Barton JC, Rao SV, Pereira NM, Gelbart T, Beutler E, Rivers CA, et al. Juvenile hemochromatosis in the southeastern United States: a report of seven cases in two kinships. Blood Cells Mol Dis 2002; 29:104 –15. 3. Haddy TB, Castro OL, Rana SR. Hereditary hemochromatosis in children, adolescents, and young adults. Am J Pediatr Hematol Oncol 1988; 10:23–34. 4. Rivard SR, Mura C, Simard H, Simard R, Grimard D, Le Gac G, et al. Clinical and molecular aspects of juvenile hemochromatosis in Saguenay–Lac-Saint-Jean (Quebec, Canada). Blood Cells Mol Dis 2000;26:10 – 4. 5. De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou
Fertility and Sterility姞
17.
18.
19.
20.
G, et al. Natural history of juvenile haemochromatosis. Br J Haematol 2002;117:973–9. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, et al. Mutations in HFE2 cause iron overload in chromosome 1q–linked juvenile hemochromatosis. Nat Genet 2004;36:77– 82. Lee PL, Beutler E, Rao SV, Barton JC. Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood 2004;103:4669 –71. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:783– 8. Ganz T. Hepcidin in iron metabolism. Curr Opin Hematol 2004;11: 251– 4. Montes-Cano M, Gonzalez-Escribano MF, Aguilar J, Nunez-Roldan A. Juvenile hemochromatosis in a Spanish family. Blood Cells Mol Dis 2002;28:297–300. Filali M, Le Jeunne C, Durand E, Grinda JM, Roetto A, Daraio F, et al. Juvenile hemochromatosis HJV-related revealed by cardiogenic shock. Blood Cells Mol Dis 2004;33:120 – 4. Pietrangelo A. Non-HFE hemochromatosis. Hepatology 2004;39:21–9. Pietrangelo A, Montosi G, Totaro A, Garuti C, Conte D, Cassanelli S, et al. Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N Engl J Med 1999;341:725–32. Duranteau L, Chanson P, Blumberg-Tick J, Thomas G, Brailly S, Lubetzki J, et al. Non-responsiveness of serum gonadotropins and testosterone to pulsatile GnRH in hemochromatosis suggesting a pituitary defect. Acta Endocrinol (Copenh) 1993;128:351– 4. Farina G, Pedrotti C, Cerani P, Rovati A, Strada E, Bergamaschi G, et al. Successful pregnancy following gonadotropin therapy in a young female with juvenile idiopathic hemochromatosis and secondary hypogonadotropic hypogonadism. Haematologica 1995;80:335–7. Kelly TM, Edwards CQ, Meikle AW, Kushner JP. Hypogonadism in hemochromatosis: reversal with iron depletion. Ann Intern Med 1984; 101:629 –32. Siemons LJ, Mahler CH. Hypogonadotropic hypogonadism in hemochromatosis: recovery of reproductive function after iron depletion. J Clin Endocrinol Metab 1987;65:585–7. Cundy T, Butler J, Bomford A, Williams R. Reversibility of hypogonadotropic hypogonadism associated with genetic haemochromatosis. Clin Endocrinol (Oxf) 1993;38:617–20. Gama R, Smith MJ, Wright J, Marks V. Hypopituitarism in primary haemochromatosis; recovery after iron depletion. Postgrad Med J 1995; 71:297– 8. Hamer OW, Gnad M, Scholmerich J, Palitzsch KD. Successful treatment of erectile dysfunction and infertility by venesection in a patient with primary haemochromatosis. Eur J Gastroenterol Hepatol 2001;13:985– 8.
1744.e13
Objective: To report a case of complete reversibility of hypogonadotropic hypogonadism with intensive venesection treatment in juvenile hemochromatosis. Design: Case report. Setting: Endocrine department of Hippocrateion Hospital of Athens. Patient(s): A 25-year-old man who presented with hypogonadotropic hypogonadism and severe iron overload due to juvenile hemochromatosis and who was initially treated with phlebotomies and androgen substitution. Intervention(s): Intensification of chelation therapy. Main Outcome Measure(s): Clinical evaluation, serum ferritin concentration, and biochemical assessment of pituitary function were performed periodically. Result(s): One year after normalization of serum ferritin levels and transferrin saturation was achieved, he became eugonadal. Conclusion(s): We believe that hypogonadotropic hypogonadism in juvenile hemochromatosis may be reversible by a consequent venesection therapy probably because treatment was intensive and promptly introduced at a young age. (Fertil Steril威 2005;84:1744.e11–13. ©2005 by American Society for Reproductive Medicine.) Key Words: Juvenile hemochromatosis, hypogonadotropic hypogonadism, venesection therapy
Hereditary hemochromatosis (HH) is a common recessive disorder characterized by progressive parenchymal iron overload (1). The appearance of clinical manifestations is typical in the fifth decade of life, generally consisting of a combination of liver cirrhosis, hypogonadism, diabetes mellitus, and cardiomyopathy (2, 3). HFE has been identified as the candidate gene, with most patients being homozygous for the C282Y mutation and a minority being C282Y/H63D compound heterozygotes (1). Juvenile hemochromatosis (JH) is an autosomal recessive condition clinically and genetically different from the classic adult disorder (4, 5). It has been recently shown that this more severe form is caused by mutations in two genes. Mutations in the chromosome 1q–linked gene hemojuvelin (HJV) have recently been found to be a cause of JH. This is the most frequent form of JH on the basis of the description of six mutations, found in either a homozygous or compound heterozygous state, in 12 unrelated families of Greek, Canadian, and French descent (6, 7). Another mutation, the G320V amino acid change, appears to be common: It has been detected in 34 of 60 (56.7%) patients with JH from 5 different populations (6). Families with JH not linked to 1q were recently found to have loss-of-function mutations in the gene encoding hepciReceived March 11, 2005; revised and accepted May 19, 2005. Reprint requests: N. Angelopoulos, M.D., Division of Endocrinology and Metabolism, Hippokrateion Hospital of Athens, Vassilisis Sofias Avenue 108, 115 27 Athens, Greece (FAX: ⫹30 210 7786889; E-mail: [email protected]).
din, an antimicrobial peptide mainly secreted by hepatocytes (8, 9). It seems that hepcidin plays a pivotal role as the dominant regulator of the absorption of dietary iron and the release of iron from macrophages (9). Iron begins to accumulate early in life, and symptoms are observed before the age of 30 years (4 – 6). hypogonadotropic hypogonadism and cardiac involvement are prominent in this clinical syndrome (10 –13). Phlebotomy requirements for maintenance of normal iron balance are clearly higher than that needed in subjects who are homozygous for the C282Y mutation, indicating a remarkable difference in iron overprocurement (5, 12, 13). CASE REPORT Transaminasemia was accidentally detected in a 25-year-old man working as a harbor guard during his routine annual screening blood tests in November of 2002. Further laboratory investigation documented high iron and ferritin levels: 61.6 mol/L and 5,250 ng/mL, respectively. Stainable iron found in liver biopsy established the diagnosis of hereditary hemochromatosis. However, analysis of known HFE-gene mutations associated with the classic form of hemochromatosis (HFE or type 1) was negative in our patient. Further genetic analysis revealed homozygosity for the commonest mutation observed in Greek families (6), the G320V missense variant. Simultaneously, he reported a 6-month history of impotency and decreased libido for which he hadn’t sought med-
0015-0282/05/$30.00 Fertility and Sterility姞 Vol. 84, No. 6, December 2005 1744.e11 doi:10.1016/j.fertnstert.2005.05.070 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
TABLE 1 Total and free testosterone during chelation therapy. Total testosterone (ng/dL)
Free testosterone (pg/mL)
Serum ferritin (ng/mL)
Transferrin saturation (%)
350–1100
19–41
20–280
14–40
25 550 317 480 500
1.5 31 18 25.3 27.2
5250 1563 43 56 40
100 98 12 13 11
Normal values Date at diagnosis 1/2003 9/2003a 1/2004b 6/2004c 10/2004c a
With androgen substitution. Substitution was discontinuated for 50 days in order to perform LHRH test. c Androgen replacement was stopped in April 2004. b
Angelopoulos. Hypogonadism in juvenile hemochromatosis. Fertil Steril 2005.
ical assistance. Owing to the progressively deteriorating erectile dysfunction, he was referred to the endocrinology department in January 2004. Clinical examination revealed scanty axillary and pubic hair and soft nontender testes of subnormal volume (10 mL). Gynecomastia was absent. The thyroid gland was not palpable and there was no skin hyperpigmentation. There was no family history of hypogonadism. He claimed no history of drug abuse, opiate use, anabolic steroid exposure, or use of any other medication that could interfere with the development of hypogonadism. According to his medical history, the time of onset of puberty and progress of pubertal development was normal and there were no eunuchoidal proportions. Basal testosterone and gonadotropin concentrations were markedly suppressed. Responsiveness of pituitary gonadotropins to luteinizing-hormone–releasing-hormone (LHRH) was subsequently tested. A bolus of 100 g synthetic LHRH was administered intravenously, and serum samples for gonadotropin measurements were drawn 0, 30, and 60 minutes after LHRH injection. Even after stimulation with LHRH, pituitary response was subnormal. Values of DHEA and insulin-like growth factor were within normal range. Further evaluation of pituitary reserve with stimulation tests (corticotropin-releasing factor test, thyrotropin-releasing hormone test, growth hormone–releasing hormone test) was performed, and no impairment in the secretion of ACTH, cortisol, prolactin, TSH, or GH was detected (data not shown). Semen analysis revealed oligoasthenospermia (sperm count 4 ⫻ 106/mL, motile sperm ⬍30%, and ⬎40% with normal morphology). After establishing the diagnosis of hypogonadotropic hypogonadism due to juvenile hemochromatosis, substitution with testosterone (IM injection of 125 mg testosterone enantheate every 20 days) was initiated. Starting in January 2003, the patient underwent venesection sessions, which were initially performed every 7 days. After 6 months, because ferritin levels remained quite elevated (2,171 ng/mL), and we therefore in1744.e12 Angelopoulos et al.
tensified the therapy by removing 450 mL blood twice a week until January 2004, when iron and ferritin levels were found to have decreased within normal range. Venesection therapy was again tapered to a monthly schedule for 3 months, and, after that, he has been continuing with phlebotomies every 75 days (Table 1). The hypothalamuspituitary-gonadal axis was re-evaluated after 12 months of therapy, when the patient’s ferritin and transferrin saturation were within normal range, and was without any remarkable improvement. In April 2004 we recommended stopping androgen substitution for 2 months in order to retest gonadotrophin secretion after LHRH stimulation. The response was slightly improved (June 2004), and for the first time he was able to maintain basal testosterone levels within a normal range without any medication. Six months after substitution discontinuation, testosterone secretion was sufficient, and his LHRH response had strikingly improved. Clinical symptoms (libido, impotence) were concomitantly improved after the complete biochemical recovery of hypogonadism. Parameters of a new semen analysis were also improved (sperm count 16 ⫻ 106/mL, motile sperm 50%, and 60% with normal morphology). DISCUSSION Hypogonadism in hemochromatosis is believed to be irreversible (5, 14, 15). Only a few patients (a total of 5 patients) with hypogonadotropic hypogonadism have been reported to recover from their symptoms after venesection therapy (16 –20). However, to our knowledge, this is the first report in the literature of reversible hypogonadism in a patient with the genetically documented juvenile form of hemochromatosis. Although none of the previously reported patients fulfilled the criteria for JH, their relatively young age (33– 42 years) might have played a crucial role in the success of venesection therapy, because they started
Hypogonadism in juvenile hemochromatosis
Vol. 84, No. 6, December 2005
treatment at an early stage of the disease. Our patient had enormously elevated ferritin and iron concentrations at diagnosis, but he responded quickly and successfully, probably because intensive venesection therapy was instituted from the beginning. One other factor that might have contributed to the effectiveness of the patient’s management is that the iron accumulation (as often observed in JH) was rapid. We speculate that this excessive iron overload led initially to an immediate impairment of gonadotrophic cell function. However, this impairment was temporary and pituitary secretory function was recovered, indicating that iron-induced detrimental effect is mainly time dependent. It is interesting that massive deposition of iron predominately affected gonadotrophic cells and that all the other pituitary cells remained undisturbed. This case illustrates that hypogonadotropic hypogonadism due to JH may be reversible by venesection therapy when treatment is introduced early and continued intensively. Recovery of pituitary function may present several months after normalization of iron overload, and gonadotrophin secretion should be tested periodically. Because our observations are limited in a single case, larger clinical trials should be conducted in order to validate this hypothesis.
6.
7.
8. 9. 10.
11.
12. 13.
14.
15.
16.
REFERENCES 1. Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 2004;350:2383–97. 2. Barton JC, Rao SV, Pereira NM, Gelbart T, Beutler E, Rivers CA, et al. Juvenile hemochromatosis in the southeastern United States: a report of seven cases in two kinships. Blood Cells Mol Dis 2002; 29:104 –15. 3. Haddy TB, Castro OL, Rana SR. Hereditary hemochromatosis in children, adolescents, and young adults. Am J Pediatr Hematol Oncol 1988; 10:23–34. 4. Rivard SR, Mura C, Simard H, Simard R, Grimard D, Le Gac G, et al. Clinical and molecular aspects of juvenile hemochromatosis in Saguenay–Lac-Saint-Jean (Quebec, Canada). Blood Cells Mol Dis 2000;26:10 – 4. 5. De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou
Fertility and Sterility姞
17.
18.
19.
20.
G, et al. Natural history of juvenile haemochromatosis. Br J Haematol 2002;117:973–9. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, et al. Mutations in HFE2 cause iron overload in chromosome 1q–linked juvenile hemochromatosis. Nat Genet 2004;36:77– 82. Lee PL, Beutler E, Rao SV, Barton JC. Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood 2004;103:4669 –71. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:783– 8. Ganz T. Hepcidin in iron metabolism. Curr Opin Hematol 2004;11: 251– 4. Montes-Cano M, Gonzalez-Escribano MF, Aguilar J, Nunez-Roldan A. Juvenile hemochromatosis in a Spanish family. Blood Cells Mol Dis 2002;28:297–300. Filali M, Le Jeunne C, Durand E, Grinda JM, Roetto A, Daraio F, et al. Juvenile hemochromatosis HJV-related revealed by cardiogenic shock. Blood Cells Mol Dis 2004;33:120 – 4. Pietrangelo A. Non-HFE hemochromatosis. Hepatology 2004;39:21–9. Pietrangelo A, Montosi G, Totaro A, Garuti C, Conte D, Cassanelli S, et al. Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N Engl J Med 1999;341:725–32. Duranteau L, Chanson P, Blumberg-Tick J, Thomas G, Brailly S, Lubetzki J, et al. Non-responsiveness of serum gonadotropins and testosterone to pulsatile GnRH in hemochromatosis suggesting a pituitary defect. Acta Endocrinol (Copenh) 1993;128:351– 4. Farina G, Pedrotti C, Cerani P, Rovati A, Strada E, Bergamaschi G, et al. Successful pregnancy following gonadotropin therapy in a young female with juvenile idiopathic hemochromatosis and secondary hypogonadotropic hypogonadism. Haematologica 1995;80:335–7. Kelly TM, Edwards CQ, Meikle AW, Kushner JP. Hypogonadism in hemochromatosis: reversal with iron depletion. Ann Intern Med 1984; 101:629 –32. Siemons LJ, Mahler CH. Hypogonadotropic hypogonadism in hemochromatosis: recovery of reproductive function after iron depletion. J Clin Endocrinol Metab 1987;65:585–7. Cundy T, Butler J, Bomford A, Williams R. Reversibility of hypogonadotropic hypogonadism associated with genetic haemochromatosis. Clin Endocrinol (Oxf) 1993;38:617–20. Gama R, Smith MJ, Wright J, Marks V. Hypopituitarism in primary haemochromatosis; recovery after iron depletion. Postgrad Med J 1995; 71:297– 8. Hamer OW, Gnad M, Scholmerich J, Palitzsch KD. Successful treatment of erectile dysfunction and infertility by venesection in a patient with primary haemochromatosis. Eur J Gastroenterol Hepatol 2001;13:985– 8.
1744.e13