1Erciyes University Medical School, Department of Endocrinology, 2Erciyes University Medical School, Department of Pediatric Endocrinology, 3Erciyes University, Faculty of Arts and Sciences, Department of Chemistry, Kayseri, 38039, Turkey
The Prasad S yndrome is characterized by iron deficiency anemia, hepatosplenomegaly, skin changes, hypogonadism, dwarfism and geophagia. Hypogonadism is a major manifestation of zinc (Zn) deficiency in both humans and animals. T he mechanism of hypogonadism caused by Zn deficiency has not been clarified. We present a 19 year-old boy with short stature, pubertal arrest, iron deficiency anemia and Zn deficiency. B ased on the dynamic tests, the hypogonadism seems to be due to hypothalamic dysfunction. T he growth retardation was associated with low IGF-I and normal growth hormone (GH) secretion, indicating GH receptor or post receptor defect. Growth acceleration and testicular development was observed after Zn supplementation. Zn deficiency, although very rare, should be considered in patients with poor growth and hypogonadism associated with skin changes and anemia.
Anemia, Gonadal axis, Hypogonadism, Pubertal arrest, Zinc deficiency
INTRODUCTION
The Prasad Syndrome, first reported by Prasad et al in 1960, is clinically characterized by iron deficiency anemia, hepatosplenomegaly, skin changes, hypogonadism, dwarfism and geophagia. Since these findings could not be solely explained by iron deficiency, the possibility of Zn deficiency was suggested.1 Zn deficiency was first documented in Egyptian subjects with growth retardation.2 Further studies showed that the growth rate was higher in subjects who received supplemental Zn than in those who received iron instead or an adequate animal-protein diet. Gonadal changes were also reversed by Zn supplementation.3
It was initially suggested that hypogonadism seen in Zn deficiency was due to decreased pituitary gonadotropin output.1,4 However, studies later showed that the effect of Zn deficiency was exerted directly on testicular steroidogenesis, whereas gonadotropins were found not to be affected.4-6 Other studies indicated that Zn deficiency may be associated with increased Follicle stimulating hormone (FSH) and normal Luteinizing hormones (LH) levels.7,8
In developing countries, zinc deficiency is still present and is usually associated with iron deficiency.2,9,10 Hypogonadism is a major manifestation of Zn deficiency in both humans and animals. The mechanism of hypogonadism due to Zn deficiency has not been clarified.
Although primary or secondary hypogonadism due to Zn deficiency has been reported, pubertal arrest due to Zn deficiency has not to our knowledge been described. We therefore present a case of Zn deficiency and pubertal arrest, which was reversed by Zn supplementation.
PATIENT DESCRIPTION
The patient was a 19 year-old male from a rural area of Central Anatolia. He lived with his parents, whose socioeconomical status was low, resulting in his diet generally being poor in animal protein. He was first admitted to the hospital complaining of fatigue and short stature. He had visual problems at school, but an eye examination had not been carried out.
The medical history revealed geophagia and anorexia in his childhood. On physical examination there was scarce scalp hair and no axillary or pubic hair had developed. Hepatosplenomegaly was detected. His height was 141 cm (SDS:-5.2), body weight was 41 kg (SDS:-2.5) and body mass index was 20.7kg/m2 (15-50 percentile). The testicular volume was 8 and 10 ml for the left and the right test is, respectively.
The complete blood count was compatible with iron deficiency anemia (Hb 5.3g/dl; MCV 52 fl; peripheral blood smear showed hypochromic-micro-cytic anemia; serum ferritin 1.3ng/ml (normal range: 22-322ng/ml); serum iron 6µg/dl (normal range: 65-175µg/dl); serum iron binding capacity 444µg/dl (normal range: 70-380µg/dl). Serum concentration of Zn was 0.43g/ml (normal range: 0.5-1.2.g/ml). Serum biochemistry was normal,except for increased levels of alkaline phosphatase 160U/l (normal range: 38-126U/l).Duodenal biopsy showed normal appearance of the mucosa.
The bone age was 11 years. The thyroid hormone levels and serum prolactin (PRL) levels were within the normal ranges. Gonadotropins, testosterone (T), free testosterone (FT) and insulin like growth factor-1 (IGF-1) levels were low (Table 1 ). Insulin tolerance test (ITT), Gonadotropin releasing hormone (GnRH) and human chorionic gonadortopin (hCG) stimulation tests were performed and the responses were normal (Tables 2 , 3 , 4 ). Pituitary magnetic resonance imaging showed no abnormality.
His eye examination prior to Zn supplementation revealed partial keratopathy and signs of optic atrophy; the optic discs were pale, visual acuity of the patient was decreased and minimal latency was observed in the visual evoked potentials.
Based on the physical examination and the laboratory results, the patient’s condition was diagnosed as pubertal arrest due to Zn deficiency. Following intravenous replacement of 300mg/day ferric hydroxyl sucrose for 5 days, the patient received 160mg/day ferrous sulphate and 50mg/day Zn for 6 months.
After 6 months, his complaints were resolved. He had a weight gain of 5.5kg and his height increased by 7cm. Testicular volume increased up to 15 and 18 ml for the left and the right testis, respectively. Axillary and pubic hair appeared and there was also increase in scalp hair. His anemia improved markedly (Hb 15.5gr/dl) and basal serum levels of gonadotropins, T, FT and IGF-1, increased to normal range (Table 1 ). The patient reported that his vision was better after Zn supplementation, but eye examination was not carried out.
DISCUSSION
The importance of zinc (Zn) for the growth of Aspergillus niger was recognized for the first time in 1869. Several decades later, it was reported that Zn should be present in sufficient amounts for the growth of the plant and the rat.11 Essentiality of Zn in man was first described by Prasad1 and later studies supported this.2,3 The presumptive cause of Zn deficiency was phytate, present in cereal grains, which impairs the absorption of Zn.2,3 During the following decade some investigators questioned the existence of Zn deficiency in humans.11 An important development in the early 1970s ended the controversy. A fatal genetic disorder, Acrodermatitis Enteropathica caused by a defect in the absorption of dietary Zn, was reported. The disorder was completely cured by Zn supplementation.12
Before the recognition of Zn deficiency, a group of patients with the findings of anemia, hepato-splenomegaly and hypogonadism were treated with 1 g/day ferrous sulfate and animal protein. Anemia and hepatosplenomegaly improved, while pubic hair and size of genitalia increased in these patients. Retrospectively, it was thought that the pharmaceutical preparation of iron also contained Zn as a concominant and along with a well-balanced diet containing animal protein provided sufficient amounts of Zn, which led to improvement of the hypogonadism.11
Animal protein is the most important dietary source of bioavailable iron and Zn. Phytate, which is present in cereal proteins, inhibits the absorption of both iron and Zn.11 Clinical iron deficiency anemia is one of the features of the Zn deficiency syndrome. Therefore, it was not surprising to detect iron deficiency besides Zn deficiency in our patient. Excepting the experimental studies, Zn deficiency without iron deficiency has not been reported. As far as we know, lack of testicular development due to iron deficiency has not been reported either. Thus, the pubertal arrest seen in our patient cannot be explained by iron deficiency alone.
It was initially suggested that Zn deficiency caused hypogonadotropic hypogonadism.1,4 However, studies later showed that the effect of Zn deficiency was exerted direct lyon testicular steroid ogenesis and that the gonadotropins were not affected.4-6
In our patient, we demonstrated a decrease in both serum gonadotropins as well as T and FT levels. Hence, the patient had hypogonadotropic hypogonadism, and since the testicular volume was greater than 4 ml, we assumed that puberty had started but was arrested due to Zn deficiency.
An experimental study in man demonstrated that Zn deficiency was associated with decreased sperm counts and serum T levels. In that study serum FSH levels were found to be increased and there was no change in the serum LH level. The increase in serum TafterGnRHstimulationwaslower,butthegonadotropin response was greater after Zn restriction in comparison to the stabilization period.7
An animal study has demonstrated that Zn deficiency has no effect on pituitary gonadotropin output and that Zn deficiency most likely affects testicular function, either directly through its effect on testicular steroidogenesis and/or indirectly through its effect on the pituitary synthesis and/or secretion of prolactin.4 A correlation between serum T levels and cellular Zn levels has been described in healthy adults.13
Despite the studies demonstrating an effect of Zn directly on testicular function,4,12,13 in our patient the findings are compatible with hypothalamic dysfunction. The gonadotropins were decreased, but rose post GnRH stimulation and gonadal response to hCG was preserved. Since the gonadotropins and T levels returned to normal after Zn supplementation, we can suggest that Zn has a role in the function of the hypothalamic pituitary gonadal axis.
In conclusion, Zn deficiency can lead to pubertal arrest, possibly through its effect on hypothalamic function, which is reversible by Zn supplementation. More studies are needed to understand the effect of Zn on the gonadal axis.
REFERENCES
1. Prasad AS, Halsted JA, Nadimi M, 1961 Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 31: 532-546.
2. Prasad AS, Miale A Jr, Farid Z, Sanstead HH, Schulert A, 1963 Zinc metabolism in patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarfism, and hypogonadism. J Lab Clin Med 61: 537-549.
3. Sanstead HH, Prasad AS, Schulert AR, et al, 1967 Human zinc deficiency, endocrine manifestations and response to treatment. Am J Clin Nutr 20: 422-442.
4. Hafiez AA, el-Kirdassy ZH, Mansour MM, Sharada HM, el-Zayat EM, 1989 Role of zinc in regulating the testicular function. Part 1. Effect of dietary zinc deficiency on serum levels of gonadotropins, prolactin and testosterone in male albino rats. Nahrung 33: 935-940.
5. Hamdi SA, Nassif OI, Ardawi MSM, 1997 Effect of marginal or severe dietary zinc deficiency on testicular development and functions of the rat. Arch Androl 38: 243-253.
6. McClain CJ, Gavaler JS, Van Thiel DH, 1984 Hypogonadism in the zinc-deficient rat: localization of the functional abnormalities. J Lab Clin Med 104: 1007-1015.
7. Abbasi AA, Prasad AS, Rabbani PR, 1979 Experimental zinc deficiency in man: effect on spermatogenesis. Trans Assoc Am Physicians 92: 292-302.
8. Salem SI, Coward WA, Lunn PG, Hudson GJ, 1984 Response of the reproductive system of male rats to protein and zinc deficiency during puberty. Ann Nutr Metab 28: 44-51.
9. Hettiarachchi M, Liyanage C, Wickremasinghe R, Hilmers DC, Abrahams SA, 2006 Prevalence and severity of micronutrient deficiency: a cross-sectional study among adolescent girls in Sri Lanka. Asia Pac J Clin Nutr 15: 56-63.
10. Thurlow RA, Winichagoon P, Pongcharoen T, et al, 2006 Risk of zinc, iodine and other micronutrient deficiencies among school children in North East Thailand. Eur J Clin Nutr 60: 623-632.
11. Prasad AS, 2001 Discovery of human zinc deficiency: impact on human health. Nutrition 17: 685-687.
12. Barnes PM, Moynahan EJ, 1973 Zinc deficiency in acrodermatitis enteropathica: multiple dietary intolerance treated with synthetic diet. Proc R Soc Med 66: 327-329.
13. Prasad AS, Mantrozos CS, Beck FW, Hess JW, Brewer GJ, 1996 Zinc status and serum testosterone levels of healthy adults. Nutrition 12: 344-348.
Address for correspondence:
Prof. Fahrettin Kelestimur, Erciyes University Medical
School, Department of Endocrinology, 38039 Kayseri, Turkey,
Tel: +90 352 4374901/21900 Fax: +90 352 4375807,
E-mail: fktimur@erciyes.edu.tr
Received 04-08-06, Revised 10-12-06, Accepted 15-12-06