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Assessment of late-onset hypogonadism among male patients with chronic obstructive pulmonary disease

S. Youssef, Sahara; Abdel Dayem, Aya M.b; Abouelezz, Nahla F.c; Mostafa, Mohamed S.d

doi: 10.1097/01.XHA.0000432479.09384.00
Original articles
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Background Chronic obstructive pulmonary disease (COPD) is now considered a systemic disease that affects organs beyond the lungs and airways. The endocrine functions, primarily the gonads, are affected in COPD.

Purpose To assess late-onset hypogonadism (LOH) among male patients with COPD.

Materials and methods This case–control study included 90 male patients with different degrees of COPD and another 90 age-matched and sex-matched control participants with normal pulmonary function that were subjected to assessment of symptoms of hypogonadism and measurement of free and total testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), and dehydroepiandrosterone-sulfate (DHEAS).

Results Serum levels of FSH, LH, DHEAS, total, and free testosterone of patients with mild COPD were nonsignificantly different from those of controls. In moderate disease, only DHEAS was significantly lower in comparison with the controls. Patients with severe COPD had significantly lower FSH and total testosterone levels in comparison with the controls. There was a positive correlation between pulmonary function tests and serum levels of sex hormones. There was a significant relation between the severity of COPD and total and free testosterone, DHEAS, and FSH levels, with the lowest levels of hormones in the severe grade. Twenty-five percent of patients with COPD fulfilled the diagnostic criteria of LOH versus 10% in their age-matched controls.

Conclusion LOH is more common in men with COPD and occurs at a younger age than their matched controls with normal pulmonary functions. The severity of the disease leads to increased incidence of LOH. Therefore, screening for hypogonadism in patients with severe COPD is recommended.

Departments of aDermatology, Venereology & Andrology

bChest

cCommunity, Environmental & Occupational Medicine

dBiochemistry, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Correspondence to Sahar S. Youssef, MD, Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Ain Shams University, PO 11381, Cairo, Egypt Tel/fax: +20 226 830 767; e-mail: saharsyoussef@hotmail.com

Received March 19, 2013

Accepted June 12, 2013

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Introduction

Chronic obstructive pulmonary disease (COPD) is a devastating, debilitating, progressive disease afflicting millions of individuals worldwide, with no curative therapies to date 1. The disease is characterized by irreversible airflow obstruction and progressive weight loss, especially loss of lean body mass, which is associated with skeletal muscle dysfunction 2,3. Reduced testosterone levels and hypogonadism have been described in COPD 4. Low testosterone level is not only associated with increased cardiovascular disease mortality in community-based studies in men but it can also affect the quality of life of the patients 5. The effects of low testosterone level in adults are reduced sexual desire; gynecomastia; loss of body (axillary and pubic) hair; hot flushes; sweats; low trauma fracture; low bone mineral density; decreased energy, motivation, initiative, and self-confidence; depressed mood; poor concentration and memory; reduced muscle bulk and strength; increased body fat; and diminished physical or work performance 6,7.

There are no absolute testosterone levels below which a man can unambiguously be considered to be hypogonadal 6,8. However, The Endocrine Society recommends 10.4 nmol/l (300 ng/dl or 3.0 ng/ml) as a good level to consider as the lower limit of normal total testosterone 9. The clinical and biochemical syndrome associated with advancing age and characterized by consistent symptoms and signs of testosterone deficiency and unequivocally low serum testosterone levels has been described by many names, including late-onset hypogonadism (LOH), which best describes the nature of the syndrome 6,8.

Among the frequent sexual, physical, and psychological symptoms of LOH, only three sexual symptoms were found to be correlated and showed a syndromic association with low testosterone. These sexual symptoms are lessened sexual thoughts, weakened morning erections, and erectile dysfunction 10. The definition of LOH in the aging male is controversially debated 11. The criteria for the diagnosis of LOH according to the European Male Aging Study (EMAS) data are as follows: the presence of the previous three sexual symptoms and either a reproducible serum total testosterone level less than 8 nmol/l (<2.3 ng/ml) or serum total testosterone level of 8–11 nmol/l (2.3–3.17 ng/ml) and free testosterone level less than 220 pmol/l (<6.34 ng/dl) 10–12.

The prevalence of hypogonadism in men with COPD was found to range from 22 to 69% in previous studies 4,13–16. However, these studies estimated only serum testosterone levels and did not evaluate sexual symptoms of hypogonadism. This study aimed to assess the prevalence of LOH among male patients with COPD through assessment of their serum sex hormone levels and the presence of symptoms of hypogonadism.

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Materials and methods

The study included a total of 90 male patients diagnosed with COPD by a respiratory physician. The diagnosis and severity of COPD were established on the basis of international guidelines 17. All patients were recruited from the outpatient clinics and inpatient section of Chest Department, Ain Shams University Hospital. Ninety age-matched individuals with normal pulmonary function were included as controls.

Exclusion criteria were: primary infertility, presence of other significant chronic diseases such as diabetes mellitus, hypertension, cardiovascular disease, renal, hepatic, endocrine or metabolic disturbance, and previous diagnosis or treatment of malignancy or urogenital disease.

All participants signed an informed consent and the study was carried out according to the Declaration of Helsinki Principles, and was approved by the ethical committee of Faculty of Medicine, Ain Shams University.

All patients and control groups were subjected to the following:

  • Assessment of chest condition by the following:
    • Full assessment of history with a focus on history of smoking and previous or current inhalant or systemic corticosteroid therapy, both general and local chest examination, and chest radiograph to diagnose COPD and exclude any other chest diseases.
    • Pulmonary function tests (PFTs) were performed by Flomate Spirometry 2500 using standard spirometric techniques according to the ATS criteria 18 (Minato AutoPal Spirometry, Osaka, Japan) in the Pulmonary Function Unit in Chest Department, Ain Shams University Hospital. The pulmonary function results were expressed as percentages of predicted normal values. This method selects, prints, and summarizes the best test results, in addition to calculating the measured and predicted values of forced vital capacity (FVC% of the predicted), forced expiratory volume in the first second (FEV1% of the predicted), and ratio of FEV1 to FVC (FEV1/FVC).
      • The COPD patients were selected and classified into three groups according to the results of PFTs 17; each group included 30 patients:
      • Group I: Mild COPD with FEV1/FVC<70% and FEV1≥80%.
      • Group II: Moderate COPD with FEV1/FVC<70% and FEV1 <80% and ≥50%.
      • Group III: Severe COPD with FEV1/FVC<70% and FEV1<50%.
  • Assessment of hypogonadism by the following:
    • Evaluation of serum level of sex hormones: a single fasting 5 ml venous blood sample was withdrawn from all participants in the morning (before 10 a.m.), and centrifuged and stored at −20°C until used for assays. Measurements of follicle stimulating hormone (FSH), luteinizing hormone (LH), and dehydroepiandrosterone-sulfate (DHEAS) were performed using an electrochemiluminescence immunoassay (Elecsys 2010; Hitachi Ltd, Roche, Tokyo, Japan). Total testosterone was measured by gas chromatography–mass spectrometry (GC–MS) 19; free testosterone levels were derived from measurements of total testosterone, sex hormone-binding globulin, and albumin according to Vermeulen’s formula 20. The cut-off point for the diagnosis of LOH was 2.3 ng/ml for total testosterone or 3.2 and 6.34 ng/dl for total and free testosterone, respectively, according to Wu et al.12.
    • Answering questions about the nine symptoms that were found to be related to low total or free serum testosterone levels 12. The questions assess three items: the sexual, physical, and psychological symptoms of LOH in at least 1 month before evaluation of hormone levels. The sexual items were as follows: presence of full morning erection according to the EMAS Sexual Function Questionnaire 21, presence of erection sufficient for intercourse according to the Massachusetts Male Aging Study 22, and occurrence of sexual thoughts according to the EMAS Sexual Function Questionnaire 21. The physical items were as follows: ability to do vigorous activity (running, lifting heavy objects, or participating in strenuous sports), capability of walking more than 1 km, and ability to bend and kneel. Each item was evaluated according to the FS-36 Quality of Life Index 23. The psychological items were as follows: feeling of sadness or downheartedness according to the SF-36 Quality of Life Index 23, loss of energy, and fatigue, both according to the Beck Depression Inventory 24.
    • A general examination was performed for signs of hypogonadism such as sparse axillary and pubic hair, muscle wasting, and gynecomastia. Measurements of height and nude weight after an overnight fasting and calculation of BMI according to the equation of: BMI=weight (kg)/square of height (m2). BMI between 19 and 25 was considered as normal 25.
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Statistical analysis

The data collected were revised, coded, tabulated, and entered in a PC using the Statistical package for Social Science (SPSS 15.0.1 for windows; SPSS Inc,, Chicago, Illinois, USA). Quantitative data (e.g. age) were presented as mean±SD. Independent t-test (Student’s t-test) was used to compare these data between two groups. Qualitative data (e.g. vigorous activity) were presented as frequencies (count) and percents. The χ2 test was used to compare these data between two or more groups. The analysis of variance test was used to compare a continuous variable between more than two study groups. Correlation analysis using Pearson’s method was used.The r2 value represents the proportion of variation of the dependent variable that is predicted from the independent variable. An r2 of 1.0 indicates that all the plotted points lie on a straight line and that the dependent variable can be predicted from the independent variable with 100% accuracy. A significance level of P value less than 0.05 was used in all tests.

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Results

  • The demographic data, BMI, PFT, and symptoms and signs of hypogonadism in COPD patients and control participants are listed in Tables 1 and 2. Patients with COPD with different grades of severity had significantly worse pulmonary function than their matched controls (Table 1).
  • In terms of serum levels of FSH, LH, DHEAS, and total and free testosterone in mild (FEV1≥80%) and moderate (FEV1 ≥50 and <80%) COPD, there was no statistically significant difference between cases and controls, except for DHEAS, which was significantly lower in patients with moderate COPD in comparison with the controls (P=0.008). Patients with severe COPD (FEV1<50%) had significantly lower FSH and total testosterone levels in comparison with the controls (P=0.008 and 0.000, respectively).
  • The percentages of patients with low levels of total and free testosterone (<3.0 and<6.5 ng/dl, respectively) according to the Endocrine Society 9 were significantly higher among patients with COPD versus their controls (37.7 and 22.2% in patients with COPD vs. 10 and 6.7%, respectively, in their matched controls with normal pulmonary functions, with P=0.00 and 0.03, respectively) (Table 3).
  • There was no statistical difference between patients with different grades of COPD and their controls in BMI or smoking (number of packs/year), whereas patients with severe COPD had statistically significant higher inhalant steroid intake than their controls (Tables 1 and 2).
  • There was a positive correlation between PFTs (FEV1 and FEV1/FVC) and serum levels of total testosterone, FSH, and LH. FEV1 was also positively correlated to serum levels of free testosterone and DHEAS (Figs 1 and 2).
  • There was a significant difference between the different grades of COPD in the sex hormone levels (DHEAS, FSH, and total and free testosterone), with the lowest levels of hormones in the severe grade. However, the different grades of COPD did not show such a relation in terms of the LH (Table 4).
Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

Table 4

Table 4

Figure 1

Figure 1

Figure 2

Figure 2

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Diagnosis of late-onset hypogonadism

  • Twenty-three patients (25.5%) with COPD fulfilled the EMAS diagnostic criteria 10 of LOH, versus nine (10%) of their age-matched controls and the difference was statistically significant (P=0.026). The mean age of the patients with LOH was significantly lower than that of their matched controls with LOH (P=0.019) (Table 5).
  • Most LOH cases were in the severe COPD group (Table 2), but the difference between groups was not significant (P=0.09).
  • Among patients with LOH, there was no significant difference when comparing COPD patients with controls with normal pulmonary functions in the smoking index, steroid intake, BMI, symptoms and signs of LOH, and hormonal profile, except for the total testosterone, which was significantly lower (P=0.009) in patients with COPD (Table 5).
  • A significantly lower hormonal profile of DHEAS, FSH, LH, and total and free testosterone was found on comparing COPD patients with LOH and COPD patients without LOH (Table 6). The sexual, physical, and psychological symptoms and signs of LOH were significantly higher among patients with COPD and hypogonadism compared with COPD patients in a eugonadal state. However, there was no statistical difference between both groups in BMI, smoking index, or steroid intake (Table 6).
Table 5

Table 5

Table 6

Table 6

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Discussion

The present study has found that serum levels of sex hormones were significantly different among male patients with different grades of COPD, with the lowest levels of hormones being recorded in the severe form of the disease. There were a significantly higher percentage of patients with COPD who fulfilled the diagnostic criteria 10 of LOH (25.5%) versus their age-matched controls with LOH (10%). Those patients with COPD and LOH were found to be significantly younger and had significantly lower total testosterone levels than their controls with normal pulmonary function and LOH. Moreover, a significantly lower sex hormones profile plus a significantly higher incidence of sexual, physical, and psychological symptoms and signs of LOH were found in cases with COPD and hypogonadism when compared with COPD cases in a eugonadal state. This indicates that the clinical manifestations of hypogonadism in these patients are not only because of the end-stage pulmonary dysfunction but because of the hormone deficiency with advanced COPD. The results of the present study reinforce that COPD is an independent risk factor for the development of LOH in men.

The prevalence of LOH in men with COPD was recorded to be 22% in one study 15, 38% in another study of 101 men with stable COPD 14, 69% in men with concurrent chronic diseases 4, and 51% among 76 men with COPD versus 26% among their 21 matched controls in a later study 13. Previous studies depended on platform-based immunoassays estimation of the serum level of total testosterone – either alone or with free testosterone – to assess for LOH in COPD patients 26. Laboratory measurements of total and free testosterone were carried out in the present study by applying the most recent recommendations of the Endocrine Society to avoid the drawbacks of the variability and lack of accuracy of the previously used method 27.

Although low serum levels of total and free testosterone hormones were found in 38.3 and 21.7%, respectively, of patients with COPD, the diagnostic criteria of LOH – which depend on the presence of low serum testosterone and the presence of sexual symptoms – were found only in 25% of COPD patients. This difference may be because of patient-to-patient variation in the testosterone threshold where symptoms of hypogonadism become manifest 12,28,29. This is the first study, to our knowledge, that applies the EMAS criteria 10 for the diagnosis of LOH in patients with COPD in comparison with their age-matched controls. Application of this strict criteria for the diagnosis of LOH will prevent overdiagnosis of LOH as there is a considerable overlap between the symptoms of LOH and symptoms of both aging and COPD, and will prevent overdescription of testosterone replacement therapy 30.

The mechanism of hypogonadism in COPD was considered to be multifactorial and many factors such as aging, obesity, systemic inflammation, hypoxemia, hypercapnia, and administration of glucocorticoids were suggested to contribute toward the pathogenesis of such a condition 30,31. Patients with severe disease in the present study had significantly lower total testosterone and FSH in comparison with their controls with normal pulmonary function, whereas patients with mild and moderate disease did not show such a decrease in the total testosterone level compared with their controls. Moreover, there was a positive correlation between FEV1 and FEV1/FVC – which reflects the severity of pulmonary disease – and the levels of total and free testosterone, FSH, LH, and DHEAS. These findings are in accordance with reports of a large cross-sectional study on 2197 men from the general population where low levels of both total and free testosterone were found to be associated with reduced pulmonary function and men with severe pulmonary obstruction had lower levels of free testosterone compared with the remaining cohort 32. Makarevich 33 compared patients with moderate and severe COPD and observed that testosterone and DHEAS were lower in patients with severe COPD who had FEV1 less than 50%. He also detected a positive correlation between testosterone and FEV1 and concluded that the intensity of sex hormone changes was correlated with the stage of COPD. Semple et al.34 found such a relationship only when the partial pressure of oxygen decreased below 55 mmHg. Similarly, we found that the lowest levels of hormones were recorded in the severe form of COPD. A strong correlation between the degree of hypoxia and the degree of testosterone reduction was found previously 35–37. However, some investigators found that the prevalence of hypogonadism is unaffected by the severity of COPD in patients with stable clinical condition and only acute exacerbations and the need for prolonged mechanical ventilation can further decrease testosterone 16,38.

Hypoxia can affect the hypothalamic–pituitary–gonadal axis at multiple levels and was found to suppress testosterone secretion independent of glucocorticoid therapy in men with COPD 1. Hypogonadism in COPD in the present study appears to be caused primarily by a testicular dysfunction that is manifested as decreased serum level of total testosterone. In addition, the presence of a low concentration of serum FSH in patients with COPD and the absence of a compensatory increase of LH despite a low serum testosterone level indicates an affection of the pituitary gland and reinforces the previous proposal of hypoxic inhibition of pituitary gland LH secretion in those patients 39. The findings of Aasebo et al.40 supported these data as they found that that long-term oxygen treatment increased sexual function and testosterone levels in COPD patients.

Previous studies suggested that smoking increases total testosterone, whereas cessation of smoking decreases testosterone 31. In the present study, smoking index was not significantly different among cases and controls with LOH or among cases with LOH and without hypogonadism, a result that is in agreement with the recent view of absence of an association between current smoking and testosterone level or hypogonadism 41.

Obesity did not appear to be the main determinant of hypogonadism in patients with COPD in the present study as there was no significant difference in BMI among patients with LOH, either patients with COPD or controls with normal pulmonary functions. However, a previous study by Laghi et al.14 showed that men with COPD and hypogonadism had greater BMI than that of the eugonadal men with COPD of similar age and with similar severity of lung disease characteristics. They proposed increased adipose deposition and neuronal energy imbalance because of leptin resistance. They also suggested a reduction in serum concentrations of ghrelin, which regulates fat utilization, as the main mechanism for this observation. In the present study, most patients with COPD and LOH were older than those in Laghi’s study and had severe hypoxia, which may affect their satiety negatively and may even result in weight loss.

Administration of glucocorticoids either systemically or by inhalation methods is a common modality in the management of COPD cases and most patients receive short or long courses of steroids according to their severity 36. It was believed that high-dose glucocorticoid in the management of COPD may result in hypogonadism either primary by direct inhibitory effects on testicular function or by secondary inhibition of hypothalamic gonadotropin-releasing hormone secretion 42,43. Inhalation corticosteroid therapy in the present study was not significantly different among COPD cases with LOH and COPD cases without hypogonadism. This result reinforces the findings of recent studies on COPD that failed to show a significant correlation between glucocorticoid therapy and testosterone deficiency in men 13–15.

Among patients with COPD in the present study, comparing those with LOH with patients in a eugonadal state, patients with hypogonadism were found to have worse quality of life manifested by having less physical activity, worse psychological symptoms, and more muscle wasting. However, although Laghi et al.14 found hypogonadism to be common among men with COPD, they found that hypogonadism did not worsen the quality of life in men with COPD when compared with men with COPD and normal testosterone levels. The difference between their results and the results of the present study may be because of the wider age difference in the present study (78.8 years for patients with LOH vs. 58.6 for patients without hypogonadism) or may be because the diagnosis of hypogonadism in Laghi’s study depended only on estimation of serum levels of sex hormones without evaluation of patients’ symptoms.

Hence, combining the biochemical hormonal assay and the symptomatic complaints of the patients for the diagnosis of LOH seems to be more realistic in evaluation of a patient’s endocrine condition than the snapshot evaluation of serum level of sex hormones in previous studies. This will enable patients with COPD to receive testosterone replacement, which would improve erectile function and sexual thoughts and motivations 32.

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Conclusion

Patients with COPD are more prone to developing LOH even at a younger age than their controls with normal pulmonary functions. There is an overlap between the symptoms of hypogonadism and those of aging and COPD. Therefore, application of strict criteria for screening for hypogonadism should be considered in these patients to allow for testosterone replacement therapy for only those patients who need it.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

chronic obstructive pulmonary disease; hypogonadism; sex hormones

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