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Iron Status and Non-Specific Symptoms of Female Students

School of Public Health, Curtin University of Technology, Australia

Address reprint requests to: Anna Rangan, BSc, NSW Breast Cancer Institute PO Box 143, Westmead, NSW 2145 AUSTRALIA

	ABSTRACT

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Objective: To examine the relationship between iron status and non-specific symptoms among female students.

Design: Cross-sectional study.

Subjects and Setting: Data were collected from 255 female students, aged 15 to 30 years, attending Curtin University of Technology, Perth or secondary schools in the Perth metropolitan area.

Main Outcome Measures: Frequency of non-specific symptoms, psychological distress based on the General Health Questionnaire (GHQ), and iron status measured by standard hematological and biochemical tests including serum transferrin receptor.

Results: Anemic subjects (hemoglobin < 12.0 g/dL) scored significantly higher on the GHQ than non-anemic subjects (p<0.05). Using univariate analysis, iron deficiency (serum ferritin 12 µg/L) was not associated with non-specific symptoms or psychological distress. Among iron-deficient subjects, those using the oral contraceptive pill reported significantly more symptoms (depression, irritability, difficulty concentrating) than non-users.

Conclusion: The evidence of an association between iron status and non-specific symptoms was weak with the exception of iron-deficient women using the oral contraceptive pill. Further studies are warranted to determine the role of the oral contraceptive pill in the etiology of depression and other symptoms among iron deficient women.

Key words: iron deficiency, psychological stress, depression, oral contraceptives, female, students

	INTRODUCTION

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Iron deficiency is a common nutritional disorder which has many adverse consequences including decreased work and exercise performance, immune system abnormalities and neurological dysfunction [1]. Most of the neurological studies have focused on cognitive function and affective behavior in children [2]. Relatively few similar studies have been conducted in older age groups, with some of these suggesting that iron therapy may improve aspects of cognitive function in iron-deficient adolescents [3,4].

In addition, fatigue, inability to concentrate and other non-specific symptoms are often attributed to iron deficiency, although the evidence to support this association is not strong. Two studies found a reduction in non-specific symptoms after iron supplementation [5,6] but others reported conflicting results [4,7,8]. As non-specific symptoms are relatively common among students and may potentially affect learning capacity, it is important to clarify the relationship between iron status and these symptoms. Furthermore, it has been suggested that oral contraceptive use by iron-deficient women may increase depressive symptoms [9].

Few studies have correlated biochemical variables with non-specific symptoms or psychological function and none to date have used serum transferrin receptor, a sensitive measure of tissue iron deficiency. The objectives of this study were a) to examine the relationship between iron status and non-specific symptoms among female students and b) to determine whether oral contraceptive use is associated with the reported frequency of symptoms.

	MATERIALS AND METHODS

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Subjects
A total of 255 female volunteer subjects, aged 15 to 30 years, participated in this cross-sectional study. All subjects were students at Curtin University of Technology, Perth (n=214) or at secondary schools in Perth metropolitan area (n=41). Subjects were recruited via publicity in the schools and university. Subjects were excluded from the study if they were pregnant, lactating or had resided in Australia for less than 1 year. Subjects were asked to complete a general information questionnaire to provide demographic details (e.g., age and social status) and medical history (e.g., oral contraceptive use), the 12-item General Health Questionnaire (GHQ) and a symptom scale. Social status was measured using the scale of Daniel which is based on the prestige ranking of the usual occupation of the head of the household [10]. All questionnaires were completed before the results of the iron status test became available. Subjects were measured without shoes and in light clothing. Height was determined to the nearest 0.5 cm and weight was measured to the nearest 0.5 kg. Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m). The study was approved by the Human Ethics Committee of Curtin University of Technology.

General Health Questionnaire
The GHQ, a widely used and validated psychometric instrument, was used to assess the level of psychological distress of subjects [11]. It has been validated in youth and adult sections of the Australian population [12,13]. The shortest version (12-item) of the GHQ has been shown to perform more efficiently than longer versions when used as part of a general survey [11,14]. The questionnaire can be scored in two ways. The conventional method takes the response "no more than usual" to an item describing a disease process as an indicator of no illness. The modified method, used in this study, takes the same response as an indicator of chronic illness [15]. This scoring method has been found to give a good measure of both acute and chronic morbidity [11]. The score was recorded as a continuum showing increasing levels of psychological distress on a scale from 0 to 12. The purpose of the questionnaire was explained to participants by way of measuring symptoms associated with their current lifestyle.

Symptom Scale
Non-specific symptoms believed to be associated with iron deficiency include chronic fatigue, listlessness, difficulty concentrating, irritability, poor memory and depression [16]. A scale was developed which allowed subjects to report the frequency of these six symptoms as experienced during the weeks prior to survey completion as never, sometimes, often or always. A copy of this instrument is available from the authors.

Laboratory Analysis
A non-fasting venous blood sample was taken to measure standard parameters of iron status; hemoglobin (Hb), mean cell volume (MCV), serum iron (SI), serum transferrin (Tn), transferrin saturation (TS) and serum ferritin (SF) as well as a relatively new assay, serum transferrin receptor (TfR). A Coulter Counter (Model STKS) was used to determine the hematological parameters (Hb, MCV). Serum iron was assayed colorimetrically using the guanidine/ferrozine method and was performed without deproteinisation [17]. Serum ferritin was assayed by immunoturbidometry using latex particles coated with antibodies to ferritin (Tina-quant®, Boehringer Mannheim). Transferrin was assayed by immunoturbidometry using goat anti-human-transferrin/TRIS/polyethylene glycol (Tina-quant®, Boehringer Mannheim). Transferrin saturation was calculated using the formula: serum iron/(transferrinx20)x100. Serum transferrin receptor was analysed using a commercial kit (Clinigen; R&D Systems, Minneapolis, MN) if sufficient serum was available (n=201). Iron deficiency was defined as serum ferritin 12 µg/L [18].

Statistics
Prior to statistical analyses, skewed distributions were transformed using logarithms (serum ferritin) or the reciprocal values (serum transferrin receptor). Pearson correlations were used to correlate GHQ scores with parameters of iron status. Multiple linear regression was used to evaluate the relationship between the parameters of iron status and GHQ score while controlling for potential confounders (age, social status, BMI and oral contraceptive use). Both crude and adjusted regression coefficients are reported. Differences between groups were detected by analysis of variance for continuous variables, or chi-square tests for categorical variables.

	RESULTS

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The age range of the subjects was 15 to 30 years with a mean of 20.7 (SD 3.5) years. Most subjects (55%) were classified in the healthy weight range (BMI 20.0–25.0) although 32% of students were underweight (BMI <20.0) and 13% were overweight (BMI >25.0). These percentages are similar to Australian data for the same age-sex distribution [19]. The study sample represented a wide spectrum of social status with occupational prestige rankings ranging from 1.2 to 6.9. The mean prestige ranking was 3.9 (SD 1.06) which is equivalent to semi-professional and middle management groups. Thirty-five percent of the sample were currently taking the oral contraceptive pill with highest use among 22 to 30 year olds. These levels are similar to those reported in a national Australian study [19].

The mean values, 95% confidence intervals of the mean (95% CI) and percentiles for the measured parameters of iron status are presented in Table 1 and the prevalence of iron deficiency and anemia are reported in Table 2. Anaemia was attributed to iron deficiency in half of the subjects; other causes included thalassemia, chronic infection or inflammation. There were no significant associations between iron deficiency or anemia and potential confounders (age, social status, BMI or oral contraceptive use).

Using analysis of variance, no significant associations were found between the reported frequency of any of the symptoms and serum concentrations of hemoglobin, ferritin or transferrin receptor. For example, the mean serum ferritin concentrations for fatigue frequencies were: 19 µg/L for never, 28 µg/L for sometimes, 30 µg/L for often and 27 µg/L for always, p=0.13. Similarly, none of the symptoms were associated with iron deficiency (SF12 µg/L) or anemia (Hb<12.0 g/dL) (results not shown).

Oral Contraceptive Use
Table 4 reports the GHQ scores and non-specific symptoms of users and non-users of the oral contraceptive pill. Oral contraceptive users were more likely to be fatigued than non-users but the occurrence of other symptoms was similar between users and non-users.

View this table: [in this window] [in a new window]   Table 5. General Health Questionnaire Score and Non-Specific Symptoms in Iron-Deficient Subjects (SF12 µg/L) Using Oral Contraceptives Versus Non-Users

	DISCUSSION

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Although the study population consisted of volunteers, it was a representative sample of young Australian women with respect to BMI, oral contraceptive use [19] and iron status [20,21]. The iron status of the students was also comparable to that of other healthy premenopausal women in industrialized countries where the median serum ferritin concentration lies close to 25–30 µg/L [22–25]. Serum transferrin receptor is a relatively new measure of iron status and recent studies have shown it to be a sensitive single indicator of early tissue iron deficiency because its concentration increases rapidly once storage iron is depleted [26,27]. The major benefits of serum transferrin receptor are that it is relatively non-invasive (compared to the bone marrow biopsy which is still considered to be the gold standard for measuring iron deficiency) and, unlike serum ferritin, is unaffected by inflammation or infection [28]. These attributes make it a useful indicator to investigate the relationship between iron status and psychological function.

A significant inverse association was found between psychological distress (GHQ score) and hemoglobin concentration among female students, regardless of age, social status, BMI or oral contraceptive use. No associations were found between GHQ score and concentrations of serum transferrin receptor, iron transport parameters (serum iron, transferrin, transferrin saturation) or iron stores (serum ferritin). This may suggest that a decrease in oxygen transport, rather than any direct effect of iron deficiency, leads to poorer mental health.

Non-specific symptoms which are often reported as being associated with iron deficiency include fatigue, listlessness, irritability, difficulty concentrating, poor memory and depression [16]. These symptoms were, however, not associated with any parameter of iron status in this sample of young women, who displayed a wide spectrum of iron status reflected by the range of serum ferritin from 1 to 165 µg/L. As only a small proportion of women were iron-deficient anemic (4.3%), it was not possible to assess the effect of more severe iron deficiency on the frequency of symptoms. Previous studies have found little evidence to support an association between anemia and the severity of symptoms [7,8], although symptoms do occur at hemoglobin concentrations approximating 7 or 8 g/dL [29].

Oral contraceptive users were more likely to be fatigued than non-users in this sample of young women. The reason for this association is not known but may be due to chance as a large number of statistical comparisons were made and the frequency of other symptoms was similar between users and non-users of the oral contraceptive pill. Fordy and Benton [9] hypothesized that oral contraceptive use causes depression in iron-deficient women. This hypothesis is supported by results from this study with iron-deficient subjects using oral contraceptives reporting a higher frequency of depression than non-users (75% vs. 12.5% were often or always depressed, p<0.001). These subjects also reported being more irritable and having difficulties concentrating on their studies. Other symptoms (fatigue, listlessness and poor memory) and psychological distress were also higher (but not statistically significant) in this group. Depression is a known side effect of oral contraceptive therapy even though premenstrual symptoms are relieved in the majority of women using oral contraceptives [30,31]. The biochemical link between iron deficiency, oral contraceptive use and depression is not known although iron is required in the synthesis, function, and degradation of several neurotransmitters including dopamine, serotonin and catecholamines [2]. As the number of iron-deficient women using oral contraceptives in this study was relatively small, it is worthwhile repeating this study using a larger sample of iron-deficient women.

	CONCLUSION

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This study found little evidence to support the clinical belief that non-specific symptoms are associated with iron deficiency. However, the use of the oral contraceptive pill by iron-deficient women was found to be related to an increased frequency of symptoms such as depression, irritability and difficulty concentrating.

	FOOTNOTES

 
Abbreviations: GHQ=General Health Questionnaire, Hb=Hemoglobin, ID=Iron deficiency, MCV=Mean cell volume, OCP=Oral contraceptive pill, SF=Serum ferritin, SI=Serum iron, TfR=Serum transferrin receptor, Tn=Serum transferrin, TS=Transferrin saturation

Received November 1, 1997. Accepted January 1, 1998.

	REFERENCES

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