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Secondary hypogonadism in hemochromatosis
FERTILITY AND STERILITY
Vol. 54, No.4, October 1990
Printed on acid-free paper in U.S.A.
Copyright 0 1990 The American Fertility Society
Secondary hypogonadism in hemochromatosis
William R. Meyer, M.D. *t Karen A. Hutchinson-Williams, M.D.:j: Ervin E. Jones, M.D., Ph.D.* Alan H. DeCherney, M.D.* Yale University School of Medicine, New Haven, Connecticut
It is generally accepted that idiopathic hemochromatosis is a hereditary disorder involving the regulation of iron absorption that results in the toxic accumulation of tissue iron. Less understood is the pathogenesis of the hypogonadism commonly seen in patients with long-standing disease. A number of hypotheses including hypothalamicpituitary dysfunction, gonadal lesions, hepatic damage, and/or diabetic autonomic neuropathy have been proposed to account for the observed sexual hypofunction. This case report documents pituitary dysfunction as the cause of hypogonadism in a female patient with hemochromatosis and intact gonadal reserve. CASE REPORT
This patient is a 28-year-old gravida one, abortus one who presented for evaluation of secondary amenorrhea. Menarche began at age 11 and secondary sexual development progressed normally. Complaints of generalized malaise and fatigue at age 13 led to an evaluation that revealed abnormally elevated liver function tests: serum glutamicoxaloacetic transaminase 82 U/L (10 to 40), alkaline phosphatase 214 U/L (30 to 85), and lactate dehydrogenase 241 U/L (100 to 225). Fluctuation Received February 22, 1990; revised and accepted June 20, 1990. *Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology. t Reprint requests and present address: William R. Meyer, M.D., Montgomery Infertility Institute, Suite 303, 10215 Fernwood Road, Bethesda, Maryland 20817. :j: Department of Internal Medicine, Division of Endocrinology and Metabolism.
740
Meyer et al.
Communications-in-brief
of these parameters continued for 4 years despite a negative hepatitis B surface antigen, negative monospot, normal liver scan, and normal ceruloplasmin levels. At the age of 16, her serum iron level was 232 J.lg (75 to 100), total iron binding capacity was 297% (250 to 410), and serum ferritin was 419 ng/mL (8 to 192). Her menstrual pattern was normal. At age 17, she became pregnant and underwent a therapeutic abortion. Subsequently, she was placed on oral contraceptives for 8 years. During this time her complaints of malaise and fatigue subsided. At the age of 21, she noted progressive proximal and distal interphalangeal joint pain of her hands and also her right shoulder. Hepatomegaly was found on physical exam. A liver biopsy obtained confirmed the diagnosis of idiopathic hemochromatosis by demonstrating iron saturation of the Kupffer cells and hepatocytes with focal fibrosis. At age 26, serial phlebotomies were initiated on a bimonthly schedule for 14 months with improvement in her arthralgia. Certain parameters responded well to phlebotomy: her ferritin level at the termination of treatment was 14.7 ng/mL (10 to 107), and serum iron had fallen to 13.0 J.lg (40 to 180). However, despite the phlebotomies, 18 months of secondary amenorrhea occurred after oral contraceptive use was discontinued, and an endocrine evaluation was undertaken. Her physical exam was unremarkable and she did not offer any specific complaints. Baseline studies included a serum thyroxine concentration of 6.1 J.lg/dL (5.0 to 10.6) and a thyroxine binding capacity of 20.9 J.lg/dL (21.0 to 31.0), a prolactin level of 14 ng/mL, a morning cortisol of 13 J.lg/dL, a luteinizing hormone (LH) value of 3.1 miU/mL, Fertility and Sterility
30
were noted by transvaginal sonography ranging in size from 1.2 to 1.8 em.
o FSH o LH 20
DISCUSSION
-'
§ E 10
-<>-
..... 0 -30
30
60
90
120
150
180
Minutes
Figure 1 Blunted gonadotropin response to 100 !lg IV LHRH in patient with hemochromatosis.
follicle-stimulating hormone value of 4.0 miU /mL, and a random plasma glucose level of 126 mg/dL. Dynamic studies consisted of assessment of hypothalamic-pituitary and gonadal function. The patient initially received 1 week of 2.5 daily oral conjugated equine estrogen (Premarin; Wyeth-Ayerst Laboratories, Philadelphia, PA). A luteinizing hormone-releasing hormone (LH-RH) stimulation test was performed subsequently using 300 ~J,g of intravenous LH- RH (Factrel; Ayerst Laboratories, New York, NY). Her gonadotropin response to LH-RH was suboptimal with only two gonadotropin samplings obtained. Consequently, a repeat intravenous LH-RH (100 ~J,g) stimulation test was performed with more frequent samplings (Fig. 1). Yen and associates 1 have recorded net increases in LH during the early follicular phases of the menstrual cycle in normal women of 56.9 ± 11.2 miU/mL. Subsequent to a 14-hour overnight fast, an insulin tolerance test (.15 units/kg of body weight) was performed. Plasma glucose, cortisol, and prolactin levels were obtained. Greenwood et al. 2 have previously reported plasma cortisol levels to range from 21.7 to 37.61-lg/dL after .15 units/kg of insulin. Although adequate growth hormone and prolactin responses were observed, a subnormal glucocorticoid response was obtained (Fig. 2). An oral 100-g glucose tolerance test revealed normal glucose and insulin responses. Magnetic resonance imaging of the pituitary was normal. As a result of her insulin tolerance testing, supplemental glucocorticoids were recommended for instances of increased physiological stress. To assess gonadal reserve, human menopausal gonadotropin (hMG, Pergonal; Serono Laboratories, Randolph MA, 150 IU /d) intramuscularly was given for 6 days beginning on menstrual cycle day 3. A serum estradiol response of 1,4 72 pg/mL was achieved on cycle day 9. Preovulatory follicles Vol. 54, No.4, October 1990
Idiopathic hemochromatosis, transmitted as an autosomal recessive trait, demonstrates partial expression in one-third of male heterozygotes and one-sixth of female heterozygotes. 3 The classical triad of symptoms, including liver disease, diabetes, and skin siderosis, along with gonadal hypofunction usually becomes clinically evident when total body iron stores exceed 20 gm. 4 In particular instances, menstruation may be potentially protective against the clinical manifestations of hemochromatosis. The cause of the gonadal dysfunction, more prevalent in males, remains uncertain but is unlikely due to increased iron deposition in the gonads. Instead, iron deposition in the gonadotropes of the anterior pituitary may be responsible, 5 and as is demonstrated in this patient, hypothalamicpituitary function usually fails to improve after serial phlebotomies. In this case, the subnormal cortisol response to a hypoglycemic challenge and the inadequate release of gonadotropins after LH-RH stimulation 1' 2 suggest a central defect as the cause for the observed hypogonadism. Repetitive infusions of LHRH may have more clearly localized the defect to either a hypothalamic or pituitary origin. 6 Regardless, the preservation of end-organ function is directly demonstrated via the patient's response to exogenous gonadotropins. Women desiring fertility with hypogonadotropic hypogonadism secondary to hemochromatosis should be managed with hMG. SUMMARY
Hemochromatosis is a rare disorder of iron storage. This report illustrates a case of hypogonado-
Minutes
Figure 2 Hormonal response to insulin tolerance test. (Lowest plasma glucose value of 26 recorded at 30 minutes.) Meyer et al.
Communications-in-brief
741
tropic-hypogonadism in a female with biopsyproven hemochromatosis. Dynamic pituitary and gonadal testing revealed subnormal gonadotropin responses to gonadotropin-releasing hormone (GnRH) but normal ovarian reserve, as shown by normal follicular stimulation with hMG. Thus, abnormalities of ovulation and menstruation in patients with hemochromatosis are most likely because of inadequate pituitary responsiveness to GnRH.
2.
3.
4.
5. REFERENCES 1. Yen SSC, VandenBerg G, Rebar R, Ebara Y: Variation of pituitary responsiveness to synthetic LRF during different
742
Meyer et al.
Communications-in-brief
6.
phases of the menstrual cycle. J Clin Endocrinol Metab 35: 931, 1972 Greenwood FC, Landon J, Stamp TCB: The plasma sugar, free fatty acid, cortisol and growth hormone response to insulin I. In control subjects. J Clin Invest 45:429, 1966 Kravitz K, Skolnick M, Cannings C, Carmelli D, Baty B, Amos DB, Johnson A, Mendell N, Edwards C, Cartwright G: Genetic linkage between hereditary hemochromatosis and HLA. Am J Hum Genet 31:601, 1979 Bothwell TH, Charlton RW, Cook JD, Finch CA: Iron Metabolism in Man. Oxford, Blackwell Scientific Publications, 1979 MacDonald RA, Mallory GK: Haemochromatosis and hemosiderosis. Arch Intern Med 105:686, 1960 Snyder PJ, Rudenstein RS, Gardner DF, Rothman JG: Repetitive infusion of gonadotropin-releasing hormone distinguishes hypothalamic from pituitary hypogonadism. J Clin Endocrinol Metab 48:864, 1979
Fertility and Sterility
Vol. 54, No.4, October 1990
Printed on acid-free paper in U.S.A.
Copyright 0 1990 The American Fertility Society
Secondary hypogonadism in hemochromatosis
William R. Meyer, M.D. *t Karen A. Hutchinson-Williams, M.D.:j: Ervin E. Jones, M.D., Ph.D.* Alan H. DeCherney, M.D.* Yale University School of Medicine, New Haven, Connecticut
It is generally accepted that idiopathic hemochromatosis is a hereditary disorder involving the regulation of iron absorption that results in the toxic accumulation of tissue iron. Less understood is the pathogenesis of the hypogonadism commonly seen in patients with long-standing disease. A number of hypotheses including hypothalamicpituitary dysfunction, gonadal lesions, hepatic damage, and/or diabetic autonomic neuropathy have been proposed to account for the observed sexual hypofunction. This case report documents pituitary dysfunction as the cause of hypogonadism in a female patient with hemochromatosis and intact gonadal reserve. CASE REPORT
This patient is a 28-year-old gravida one, abortus one who presented for evaluation of secondary amenorrhea. Menarche began at age 11 and secondary sexual development progressed normally. Complaints of generalized malaise and fatigue at age 13 led to an evaluation that revealed abnormally elevated liver function tests: serum glutamicoxaloacetic transaminase 82 U/L (10 to 40), alkaline phosphatase 214 U/L (30 to 85), and lactate dehydrogenase 241 U/L (100 to 225). Fluctuation Received February 22, 1990; revised and accepted June 20, 1990. *Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology. t Reprint requests and present address: William R. Meyer, M.D., Montgomery Infertility Institute, Suite 303, 10215 Fernwood Road, Bethesda, Maryland 20817. :j: Department of Internal Medicine, Division of Endocrinology and Metabolism.
740
Meyer et al.
Communications-in-brief
of these parameters continued for 4 years despite a negative hepatitis B surface antigen, negative monospot, normal liver scan, and normal ceruloplasmin levels. At the age of 16, her serum iron level was 232 J.lg (75 to 100), total iron binding capacity was 297% (250 to 410), and serum ferritin was 419 ng/mL (8 to 192). Her menstrual pattern was normal. At age 17, she became pregnant and underwent a therapeutic abortion. Subsequently, she was placed on oral contraceptives for 8 years. During this time her complaints of malaise and fatigue subsided. At the age of 21, she noted progressive proximal and distal interphalangeal joint pain of her hands and also her right shoulder. Hepatomegaly was found on physical exam. A liver biopsy obtained confirmed the diagnosis of idiopathic hemochromatosis by demonstrating iron saturation of the Kupffer cells and hepatocytes with focal fibrosis. At age 26, serial phlebotomies were initiated on a bimonthly schedule for 14 months with improvement in her arthralgia. Certain parameters responded well to phlebotomy: her ferritin level at the termination of treatment was 14.7 ng/mL (10 to 107), and serum iron had fallen to 13.0 J.lg (40 to 180). However, despite the phlebotomies, 18 months of secondary amenorrhea occurred after oral contraceptive use was discontinued, and an endocrine evaluation was undertaken. Her physical exam was unremarkable and she did not offer any specific complaints. Baseline studies included a serum thyroxine concentration of 6.1 J.lg/dL (5.0 to 10.6) and a thyroxine binding capacity of 20.9 J.lg/dL (21.0 to 31.0), a prolactin level of 14 ng/mL, a morning cortisol of 13 J.lg/dL, a luteinizing hormone (LH) value of 3.1 miU/mL, Fertility and Sterility
30
were noted by transvaginal sonography ranging in size from 1.2 to 1.8 em.
o FSH o LH 20
DISCUSSION
-'
§ E 10
-<>-
..... 0 -30
30
60
90
120
150
180
Minutes
Figure 1 Blunted gonadotropin response to 100 !lg IV LHRH in patient with hemochromatosis.
follicle-stimulating hormone value of 4.0 miU /mL, and a random plasma glucose level of 126 mg/dL. Dynamic studies consisted of assessment of hypothalamic-pituitary and gonadal function. The patient initially received 1 week of 2.5 daily oral conjugated equine estrogen (Premarin; Wyeth-Ayerst Laboratories, Philadelphia, PA). A luteinizing hormone-releasing hormone (LH-RH) stimulation test was performed subsequently using 300 ~J,g of intravenous LH- RH (Factrel; Ayerst Laboratories, New York, NY). Her gonadotropin response to LH-RH was suboptimal with only two gonadotropin samplings obtained. Consequently, a repeat intravenous LH-RH (100 ~J,g) stimulation test was performed with more frequent samplings (Fig. 1). Yen and associates 1 have recorded net increases in LH during the early follicular phases of the menstrual cycle in normal women of 56.9 ± 11.2 miU/mL. Subsequent to a 14-hour overnight fast, an insulin tolerance test (.15 units/kg of body weight) was performed. Plasma glucose, cortisol, and prolactin levels were obtained. Greenwood et al. 2 have previously reported plasma cortisol levels to range from 21.7 to 37.61-lg/dL after .15 units/kg of insulin. Although adequate growth hormone and prolactin responses were observed, a subnormal glucocorticoid response was obtained (Fig. 2). An oral 100-g glucose tolerance test revealed normal glucose and insulin responses. Magnetic resonance imaging of the pituitary was normal. As a result of her insulin tolerance testing, supplemental glucocorticoids were recommended for instances of increased physiological stress. To assess gonadal reserve, human menopausal gonadotropin (hMG, Pergonal; Serono Laboratories, Randolph MA, 150 IU /d) intramuscularly was given for 6 days beginning on menstrual cycle day 3. A serum estradiol response of 1,4 72 pg/mL was achieved on cycle day 9. Preovulatory follicles Vol. 54, No.4, October 1990
Idiopathic hemochromatosis, transmitted as an autosomal recessive trait, demonstrates partial expression in one-third of male heterozygotes and one-sixth of female heterozygotes. 3 The classical triad of symptoms, including liver disease, diabetes, and skin siderosis, along with gonadal hypofunction usually becomes clinically evident when total body iron stores exceed 20 gm. 4 In particular instances, menstruation may be potentially protective against the clinical manifestations of hemochromatosis. The cause of the gonadal dysfunction, more prevalent in males, remains uncertain but is unlikely due to increased iron deposition in the gonads. Instead, iron deposition in the gonadotropes of the anterior pituitary may be responsible, 5 and as is demonstrated in this patient, hypothalamicpituitary function usually fails to improve after serial phlebotomies. In this case, the subnormal cortisol response to a hypoglycemic challenge and the inadequate release of gonadotropins after LH-RH stimulation 1' 2 suggest a central defect as the cause for the observed hypogonadism. Repetitive infusions of LHRH may have more clearly localized the defect to either a hypothalamic or pituitary origin. 6 Regardless, the preservation of end-organ function is directly demonstrated via the patient's response to exogenous gonadotropins. Women desiring fertility with hypogonadotropic hypogonadism secondary to hemochromatosis should be managed with hMG. SUMMARY
Hemochromatosis is a rare disorder of iron storage. This report illustrates a case of hypogonado-
Minutes
Figure 2 Hormonal response to insulin tolerance test. (Lowest plasma glucose value of 26 recorded at 30 minutes.) Meyer et al.
Communications-in-brief
741
tropic-hypogonadism in a female with biopsyproven hemochromatosis. Dynamic pituitary and gonadal testing revealed subnormal gonadotropin responses to gonadotropin-releasing hormone (GnRH) but normal ovarian reserve, as shown by normal follicular stimulation with hMG. Thus, abnormalities of ovulation and menstruation in patients with hemochromatosis are most likely because of inadequate pituitary responsiveness to GnRH.
2.
3.
4.
5. REFERENCES 1. Yen SSC, VandenBerg G, Rebar R, Ebara Y: Variation of pituitary responsiveness to synthetic LRF during different
742
Meyer et al.
Communications-in-brief
6.
phases of the menstrual cycle. J Clin Endocrinol Metab 35: 931, 1972 Greenwood FC, Landon J, Stamp TCB: The plasma sugar, free fatty acid, cortisol and growth hormone response to insulin I. In control subjects. J Clin Invest 45:429, 1966 Kravitz K, Skolnick M, Cannings C, Carmelli D, Baty B, Amos DB, Johnson A, Mendell N, Edwards C, Cartwright G: Genetic linkage between hereditary hemochromatosis and HLA. Am J Hum Genet 31:601, 1979 Bothwell TH, Charlton RW, Cook JD, Finch CA: Iron Metabolism in Man. Oxford, Blackwell Scientific Publications, 1979 MacDonald RA, Mallory GK: Haemochromatosis and hemosiderosis. Arch Intern Med 105:686, 1960 Snyder PJ, Rudenstein RS, Gardner DF, Rothman JG: Repetitive infusion of gonadotropin-releasing hormone distinguishes hypothalamic from pituitary hypogonadism. J Clin Endocrinol Metab 48:864, 1979
Fertility and Sterility