Introduction and background

Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable

disease that is characterized by persistent respiratory symptoms and airflow limitation that is
due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious
particles or gases(1).Based on The Burden of Obstructive Lung Diseases (BOLD) program
and other large scale epidemiological studies, it is estimated that the number of COPD cases
was 384 million in 2010, with a global prevalence of 11.7%(2). More than 3 million people
died of COPD in 2012 accounting for 6% of all deaths globally.Chronic Obstructive
Pulmonary Disease (COPD) is currently the fourth leading cause of death in the world(3) but
is projected to be the 3rd leading cause of death by 2020.It is known that almost 90% of
COPD deaths occur in low and middle-income countries and it is a major cause of mortality
and morbidity in India. Considered formerly a disease of the lungs, COPD has significant
systemic manifestations, including weight loss, skeletal muscle dysfunction and nutritional
abnormalities, which are important determinants of physical capacity, health-related quality
of life and increased disability and mortality(4). The Indian subcontinent is unique due to
increased prevalence of malnutrition in the general population and time lapse before medical
attention for the disease is sought(5).Significant weight loss, resulting in a body weight of<
90% of ideal body weight (IBW), occurs in 25% to 43% of patients with COPD(6–8).Weight
loss and the attendant loss of lean body mass (LBM) have been associated with skeletal
muscle dysfunction, impacting not only the respiratory musculature, but also having effects
on peripheral skeletal muscle function(9). This results in weakness and fatigue, contributing
not only to dyspnea, but also leading to decreased strength, impaired mobility, and an
increased risk for falling. Overall, quality of life (QOL) is adversely affected(8,10).

Management of extra-pulmonary features associated with COPD is an important and often

ignored approach in treatment of COPD.Skeletal muscles in COPD patients have
diminishedaerobic enzymes, higher levels of cell apoptosis andearly-onset lactic acidosis,
suggesting that a COPDpatient’s exercise constraints are more than respiratorylimited.
Through pulmonary rehabilitationprogramme (PRP), patients can recondition
nonpulmonaryorgans to optimize exercise tolerance andexertional dyspnoea. Non
pharmacological interventions in various trials have demonstrated improvements in quality of
life (QOL) scores and medication compliance and have decreased COPD-related
hospitalizations, emergency department visits and healthcare utilization and
cost(11).Anabolic steroids increase muscle mass and performance among athletes. Muscle
mass is increased by inducing an anabolic effect on proteins via androgenic receptors as well
as by inhibiting protein catabolism via glucocorticoid receptors(12).Anabolic steroids could
be an additional mode of intervention to enhance the response to pulmonary rehabilitation.
Until now, only a few controlled studies(13,14) on anabolic steroid supplementation have
been performed in patients with COPD, reporting positive effects on fat-free mass (FFM) in
underweight patients with COPD. However, the effects on physical performance and health
status are still to be precisely defined.

Only one study involving use of anabolic steroids on COPD patients in India was found(5).
There is a paucity of studies showing effects of anabolic steroids in COPD patients who are
undergoing exercise therapy. Of the few studies conducted related to this topic, most have
been conducted outside India and involved short course of anabolic steroids. We were unable
to find any published Indian studies assessing influence of anabolic steroids on COPD
patients undergoing exercise therapy. We propose to assess the effects of longer courses
anabolic steroids on COPD patients undergoing exercise therapy in the Indian setting.
REVIEW OF LITERATURE

DIAGNOSIS

COPD should be considered in any patient who has dyspnoea, chronic cough or sputum
production, and/or a history of exposure to risk factors for the disease. Spirometry is required
to make the diagnosis in this clinical context. The presence of a post-bronchodilator
FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD in
patients with appropriate symptoms and significant exposures to noxious stimuli.

Risk factors Symptoms Spirometry

Host factors Chronic cough
post bronchodilator
Tobacco and pollution Exertional dyspnea
FEV1/FVC ratio of <0.70
Occupation Sputum

Pathways to the diagnosis of COPD

Classification of severity of airflow limitation(1)

Specific spirometric cut-points are used for classification of severity of airflow limitation. It
is performed after administration of an adequate dose of short acting inhaled bronchodilator.

In patients with FEV1/FVC < 0.70

GOLD 1 Mild FEV1 ≥ 80% predicted
GOLD 2 Moderate 50% ≤ FEV1 ≤ 80% predicted
GOLD 3 Severe 30% ≤ FEV1 ≤ 50% predicted
GOLD 4 Very Severe FEV1 <30% predicted
FACTORS AFFECTING DISEASE DEVELOPMENT AND PROGRESSION

Genetic factors
The best documented genetic risk factor is severe hereditary deficiency of alpha-1 antitrypsin
(AATD). It illustrates the interaction between genes and environmental exposures that
predispose to COPD.A significant familial risk of airflow limitation has been observed in
people who smoke and are siblings of patients with severe COPD(15).

Age and gender

Aging of the airways and parenchyma mimic some of the structural changes associated with
COPD. It is unclear if healthy aging is as such leads to COPD or if age reflects the sum of
cumulative exposures throughout life(16). Some studies have suggested that women are more
susceptible to the effects of tobacco smoke than men.

Lung growth and development

Any factor that affects lung growth during gestation and childhood has the potential for
increasing an individual’s risk of developing COPD. Factors in early life termed “childhood
disadvantage factors” seem to be as important as heavy smoking in predicting lung function
in adult life(17).

Exposure to particles
Cigarette smoking is the most common risk factor for COPD. Cigarette smokers have a
higher prevalence of respiratory symptoms and lung function abnormalities and a greater
COPD mortality rate than non-smokers(18). Occupational exposures to organic and inorganic
dusts, chemical agents and fumes are also risk factors for COPD.

Worldwide, almost 3 billion people use biomass and coal as main source of energy. There is
evidence that indoor pollution from biomass cooking and heating in poorly ventilated
dwellings is an important risk factor for COPD(19).

Socioeconomic status
Lower socioeconomic status is associated with an increased risk of developing COPD(20).
Asthma
Both asthma and airway hyper-responsiveness without a clinical diagnosis asthma may be a
risk factor for development of chronic airflow limitation and COPD.

Infections
Tuberculosis has been identified as a risk factor for COPD(21). Severe childhood respiratory
infections have been associated with reduced lung function and increased respiratory
symptoms in adulthood.
SYMPTOMS

Chronic and progressive dyspnoea is the most characteristic symptom of COPD. Cough and
sputum production is present in up to 30% of patients.

Dyspnoea
Dyspnoea is a cardinal symptom of COPD. It is a major cause of the disability and anxiety
associated with the disease(22). Patients typically seek medical care because shortness of
breath limits their activity and quality of life. Dyspnoea is seldom a complaint until FEV1 has
fallen below 60% of predicted. However, the correlation between FEV1 and exercise
limitation is not strong. The discomfort associated with breathing is often associated with
inspiration rather than expiration(23)

Cough
Chronic cough is often the first symptom of COPD and is frequently neglected by the patient.
The cough may initially be intermittent, but subsequently may be present throughout the day.
Chronic cough in COPD may be productive or unproductive.

Sputum production
COPD patients commonly raise small quantities of tenacious sputum with coughing. Regular
production of sputum for three or more months in two consecutive years (in the absence of
any other conditions that may explain it) is the classical definition of chronic bronchitis(1).
The presence of purulent sputum reflects an increase in inflammatory mediators and its
development may identify the onset of a bacterial exacerbation.

Wheezing
Wheezing and chest tightness are symptoms that may vary over days or over the course of a
single day. Widespread inspiratory or expiratory wheeze can be often heard on chest
auscultation. Chest tightness is muscular in nature and may arise from isometric contraction
of the intercostal muscles(1).

Importantly, the perception that patients have about their chronic respiratory symptoms is a
relevant measure of the impact of their disease, which directly affects their functional
capacity, physical activity, HRQL, and prognosis(24).
TREATMENT

PHARMACOLOGIC THERAPY

Bronchodilators
Bronchodilators act by altering airway smooth muscle tone and improvements in expiratory
flow reflect widening of the airways. Theytend to reduce dynamic hyperinflation at rest and
during exercise, and improve exercise performance(25).

Beta 2 agonist
Relax the airway smooth muscle by stimulating beta 2 adrenergic receptors, which increases
cyclic AMP and produces functional antagonism to bronchoconstriction.
Beta 2 agonists are of two types – short acting (SABA) and long acting (LABA). Effect of
SABA lasts for 4-6 hours and that of LABA last for 12 or more hours. Stimulation of Beta 2
adrenergic receptors can produce sinus tachycardia and has potential to precipitate tachy-
arrhythmias is susceptible patients.

Anti-muscarinic agents
Anti-muscarinic agents block the bronchoconstrictor effects of acetylcholine on M3
muscarinic receptors in the airway smooth muscle(26). Further, anti-muscarinic agents may
be short acting (SAMA) or long acting (LAMA) depending on their duration of action.
Treatment with tiotropium (LAMA) has shown to improve symptoms, health status,
effectiveness of pulmonary rehabilitation and reduce exacerbation-related
hospitalizations(26,27). Trials have shown greater effect on exacerbation rates for Tiotropium
treatment versus LABA treatment(28). Inhaled anticholinergic agents has been shown to be
very safe and the main side effect being dryness of mouth.

Methylxanthines
The three important methylxanthines are theophylline, theobromine and caffeine.
Theophylline is the most commonly used methylxanthine. Theophylline’s low cost is an
important advantage for economically disadvantaged patients. Mechanism of action of
methylxanthines has not been firmly established. They may act as a non-selective inhibitors
of the phosphodiesterases (PDE) enzyme family. Inhibition of PDE results in higher
concentrations of intracellular cAMP. Cyclic AMP is responsible for a myriad of cellular
functions including, but not limited to, stimulation of cardiac function, relaxation of smooth
muscle and reduction in the immune and inflammatory activity of specific cells(29).

Combination bronchodilator therapy

Combining bronchodilators may increase the benefits and lower the side effects as compared
to increasing the dose of a single bronchodilator. Combinations of SABA and SAMA are
superior compared to either medication alone in improving FEV1 and symptoms.
Combination treatment with a LABA and LAMA reduces exacerbations compared to
monotherapy or ICS/LABA combination(1).

Inhaled corticosteroids (ICS)

Studies have found that regular treatment with ICS alone does not modify the long-term
decline of FEV1 nor mortality in patients with COPD(30). In patients with moderate to very
severe COPD and exacerbations, an ICS combined with a LABA is more effective than either
component alone in improving lung function, health status and reducing exacerbations. Most
studies that found a beneficial effect of LABA/ICS fixed dose combination (FDC) over
LABA alone on exacerbation rate(31). Evidence from RCTs show that ICS use is associated
with higher prevalence of oral candidiasis, hoarse voice, skin bruising and pneumonia(32).

Oral glucocorticoids
Systemic glucocorticoids for treating acute exacerbations in hospitalized patients, or during
emergency department visits, have been shown to reduce the rate of treatment failure, the rate
of relapse and improve lung function and breathlessness(33). But long term oral
glucocorticoids have numerous side effects, hence, while oral glucocorticoids play a role in
the acute management of exacerbations, they have no role in the chronic daily treatment in
COPD because of a lack of benefit balanced against a high rate of systemic complications.

Phosphodiesterase-4 (PDE4) inhibitors

PDE4 inhibitors reduce inflammation by inhibiting the breakdown of intracellular cAMP.
Roflumilast is an oral medication with no direct bronchodilator activity.
NON-PHARMOCOLOGIC THERAPY

Pulmonary rehabilitation
The American Thoracic Society (ATS) and the European Respiratory Society (ERS) have
adopted the following definition of pulmonary rehabilitation: “Pulmonary rehabilitation is a
comprehensive intervention based on a thorough patient assessment followed by patient
tailored therapies that include, but are not limited to, exercise training, education, and
behaviour change, designed to improve the physical and psychological condition of people
with chronic respiratory disease and to promote the long-term adherence to health-
enhancing behaviours.”(34)Pulmonary rehabilitation should be considered part of
integrated patient management, and usually includes a range of healthcare professionals to
ensure optimum coverage of the many aspects involved.Optimum benefits are achieved
from programs lasting 6 to 8 weeks. Systematic reviews have shown that among those
patients who have had a recent exacerbation (≤ 4 weeks from prior hospitalization),
pulmonary rehabilitation can reduce readmissions and mortality(35)

Education and self-management

Patient education assumes that knowledge about their health condition will lead to behaviour
change. Topics such as smoking cessation, correct use of inhaler devices, early recognition of
exacerbation, considering advance directives will be better dealt with using self-management
interventions.
OTHER TREATMENTS

Oxygen therapy and ventilator support

The long term administration of oxygen (>15 hours per day) to patients with chronic
respiratory failure has been shown to increase survival in patients with severe resting
hypoxemia(36).

Ventilatory support
Non-invasive positive pressure ventilation (NPPV) is the standard of care for decreasing
morbidity and mortality in patients hospitalized with an exacerbation of COPD and acute
respiratory failure. If NPPV is found to be inadequate, Invasive ventilator support is often
required.

INTERVENTIONAL THERAPY

Lung volume reduction surgery(LVRS)

LVRS is a surgical procedure in which parts of the lungs are resected to reduce
hyperinflation, making respiratory muscles more effective pressure generators by improving
their mechanical efficiency.

Bullectomy
In selected patients with relatively preserved underlying lung, bullectomy is associated with
decreased dyspnoea, improved lung function and exercise tolerance(37).

Lung transplantation

In appropriately selected patients with very severe COPD, lung transplantation has been
shown to improve health status and functional capacity but not prolong survival. The median
survival for lung transplantation in all COPD patients is 5.5 years.
Pathogenesis

Etiology
Smoking and pollutants
Host factors

H
Pathobiology
Impaired lung growth
Accelerated decline
Lung injury
Lung & Systemic inflammation

Pathology
Small airway disorders/abnormalities
Emphysema
Systemic effects

Clinical manifestations
Airflow limitation Symptoms
Persistent airflow limitation Exacerbations
Co-morbidities

Figure :Etiology, Pathobiology and pathology of COPD leading to airflow limitation and
clinical manifestations

The chronic airflow limitation that is characteristic of COPD is caused by a mixture of small
airways disease (e.g., obstructive bronchiolitis) and parenchymal destruction (emphysema),
the relative contributions of which vary from person to person. These changes do not always
occur together, but evolve at different rates over time. Airflow limitation is usually measured
by spirometry as this is the most widely available and reproducible test of lung function.
Many previous definitions of COPD have emphasized the terms “emphysema” and “chronic
bronchitis”, which are not included in the definition used in GOLD reports. Emphysema, or
destruction of the gas-exchanging surfaces of the lung (alveoli), is a pathological term that is
often (but incorrectly) used clinically and describes only one of several structural
abnormalities present in patients with COPD. Chronic bronchitis, or the presence of cough
and sputum production for at least 3 months in each of two consecutive years, remains a
clinically and epidemiologically useful term, but is present in only a minority of subjects
when this definition is used. Chronic respiratory symptoms also exist in individuals with
normal spirometryand a significant number of smokers without airflow limitation have
structural evidence of lung disease manifested by the varying presence of emphysema, airway
wall thickening and gas trapping.

The current hypothesis for the pathogenesis of COPD is that it is caused by an

abnormalresponse to the inhalation of toxic particles and gases. This response has both local
(lung) and systemic manifestations(38). Studies support the hypothesis that the lungs respond
to relativelysmall changes in atmospheric pollution by increasing pro-inflammatory cytokine
productionwith subsequent release into the blood, which leads to increased production of
acute-phaseproteins in the liver and the release of leukocytes from the bone marrow into the
circulatingblood(39,40).

Tobacco smoke is the primary source of inhaled toxins and vapours in most individuals
diagnosed to have COPD.The innate inflammatory immune system provides the primary
protection against this insult.
The protective features of the innate system include

(a) The tight junctions that join epithelial cells and keep foreign material on the surface.
(b)An efficient muco-ciliary clearance apparatusthat rapidly clears foreign material out
of the lower respiratory tract.
(c) A system of macrophages that take up foreign material deposited on the bronchial and
alveolar surface.
(d) A very thin alveolar surfaceliquid layer that carries macrophages and associatedforeign
debris from the alveolar surface.

A second line of the innate defence system is the exudation of plasma and circulating effector
cells into the damaged tissue in both large and small conducting airways,as well as in the gas-
exchanging tissue of those who smoke(38).Dendritic cells link the innate and adaptive
immune responses by presenting antigen to lymphocytes located in the T and B cell regions
oflymphoid follicles with germinal centers. This process occurs in lymphoid follicles and
adjacent T cell areas leading to release of antibodies and effector T-cells.

Patients with stable COPD are in a state of chronic inflammation of the entire
tracheobronchial tree. They have increased macrophages and CD8 T-lymphocytes in the
airway wall and neutrophils in the airway lumen. During states of exacerbation of COPD, the
inflammatory pattern changes and eosinophils, neutrophils and various inflammatory
mediators become the major component of inflammatory response. Increased inflammation
leads to increased bronchial tone, increased bronchial wall oedema, increased vascular and
airway smooth muscle proliferation and increased mucous production. As a result of this,
there is worsening of ventilation-perfusion mismatch, expiratory flow limitation due to
increased airway resistance and hyperinflation of lungs. These changes lead to impeding of
ventilatory pump by decreasingthe efficiency of respiratory muscles, worsening dyspnoea
and cough with purulent sputum(41).

COPD is associated with clinically significant systemic alterations in biochemistry and organ
functions. An imbalance between oxidants and antioxidants is hypothesized as being
pathogenesis of COPD related systemic effects. Reactive oxygen species generated by
neutrophils are scavenged by blood antioxidants and antioxidant enzymes, indicating that the
ability of an individual to prevent the injurious effects of oxidative stress depends on the
antioxidant capacity of blood and tissues. Wasting is a common manifestation of chronic
illness. Selective wasting of Fat free mass(FFM), despite relative preservation of fat mass has
been reported in COPD patients. This loss of FFM adversely affects respiratory and
peripheral muscle function, exercise capacity and health status. Imbalance in protein
degradation and replacement is hypothesized as mechanism contributing to wasting.
Decreased levels of anabolic steroids has a significant role in poor anabolic response in
COPD patients(42).
Testosterone and other anabolic steroids
The use of testosterone and related steroids like nandrolone was a widespread phenomenon
among top athletes, bodybuilders and a large part of the population who simply desire to
improve their appearance. The popularity of testosterone and related steroids among drug
users is due to the powerful effects of these substances on muscle strength and mass.
Testosterone is a 19-carbon steroid with powerful androgenic and anabolic effects. It is
primarily produced by the leydig cells in testes and a small quantity comes from the adrenal
cortex and peripheral conversion of androstenedione. Anabolic androgenic steroids are taken
orally, by intramuscular injection and as gels and creams(43).Studies have shown positive
relationship between circulating testosterone concentration and fat-free mass, muscle size and
strength, haemoglobin, HDL cholesterol and IGF-1 levels (44)(45).Further, data also suggest
that the effects of testosterone administration on human skeletal muscle mass is dose
dependent(44).

Muscle satellite cells are the stem cells of skeletal muscle. They have the ability to maintain a
ready source of muscle fibre precursors. Existing myonuclei in adult muscle fibres are post
mitotic, and muscle satellite cells are the major source for the addition of new myonuclei into
the hypertrophying muscle fibre. A variety of alterations in the surrounding environment of
the satellite cell, including mechanical and growth factors and also hormonal signalling might
regulate the activation and proliferation of satellite cells. Testosterone is able to stimulate
mitotic activity of satellite cells. Satellite cells can proliferate and withdraw from
differentiation to return to quiescence to replenish satellite cell pool, or to enter
differentiation to provide new myonuclei or to generate new muscle fibres.Satellite cells are
activated by stimulation of androgen receptors. These activated satellite cells function as
mediators of the myotrophic action of testosterone on skeletal muscle(43).

Further, Testosterone can also reduce body fat, as it is a potentregulator of lipolysis by

influencing catecholamine signaltransduction in fat cells(46). It has beensuggested that
testosterone inhibits lipid uptake in adipocytesand stimulates lipolysis(47). It has been
demonstrated in mice that testosterone can recruit mesenchymal pleuripotent stem cells into
the myogenic lineage(48).
Mechanism of action of testosterone leading to muscle hypertrophy.

Low BMI and COPD

Loss of body cell mass is a common and serious problem for patients with end-stage chronic
obstructive pulmonary disease (COPD). Many COPD patients are malnourished at the time of
admission and are subject to further weight loss during hospitalization(49). Low BMI is an
independent risk factor for mortality in subjects with COPD, and the association is strongest
in patients with severe COPD. A study by Landbo C et al. showed that in severe COPD,
mortality decreased with increasing BMI(50). Further, it has been demonstrated that the
negative effect of low body weight can be reversed by appropriate therapy in some of the
patients with COPD(51).Patients with low body weights have greater gas trapping, lower
diffusing capacity, and less exercise capacity than do persons with similar respiratory
mechanics but normal body weights. Loss of body cell mass is associated with a reduction in
the mass of the diaphragm and of the respiratory muscles, resulting in declines in strength and
endurance. A malnutrition-related decline in immune status may further blunt airway
defenses. These effects can contribute to undesirable clinical sequelae that include
hypercapnic respiratory failure, difficulty with weaning from mechanical ventilation, and
nosocomial lung infections(49).Malnourished patients with COPD are characterized by a
relative increase in resting energy requirements and, specifically, increased energy
requirements for augmenting ventilation. This increase in energy requirements may result
from the increased mechanical work load associated with severe COPD and/or a
reducedventilatory muscle efficiency. The elevated oxygen cost of respiration would produce
a hypermetabolic state leading to progressive weight loss, especially during periods of
increased respiratory effort and restricted caloric intake like COPD exacerbation. This
combination leads to a vicious cycle of increased energy expenditure and weight loss, finally
leading to ventilatory muscle failure(52). These factors explain the increased mortality seen
in COPD patients with low BMI.

Creutzberg, et al.(53)conducted a double-blinded, placebo-controlled, randomized trial where

63 male COPD patients who participated in a standardized pulmonary rehabilitation program
were randomly assigned to receive 50mg nandrolone intramuscular injections on a biweekly
basis for 8 weeks. Treatment with nandrolone decanoate resulted in a greater increase in fat
free mass. Muscle function, exercise capacity and health status improved both in treated and
placebo groups to the same extent. They concluded that Nandrolone has a role in the
treatment of patients with COPD, especially in those patients treated long term with low-dose
systemic corticosteroids.

Daga, et al.(5)assessed the effects of anabolic steroids in terms of a daily high-protein, high-
calorie diet alone or one combined with anabolic steroids on body composition, lung function
and health related quality of life (HRQL). They conducted a double blinded randomized
controlled trial on 32 moderate to severe COPD patients. 25mg nandrolone was administered
to the treatment group weekly and patients followed for 6 weeks. At the end of the study
period, a significant difference between the study and control groups was observed in the six
minute walk test and HRQL. Although they found improvement in exercise capacity, body
weight gain, respiratory muscle strength in both treatment and control groups, it was noted
that there was larger improvements in 6-minute walk test, muscle mass and HRQL scores in
the group treated with nandrolone. Spirometry results showed no significant changes after
the intervention in both treatment and control group. Their study was limited by the small
sample size and lack of long term follow up. They call for further research using higher doses
of anabolic steroids and for longer duration of study which will be needed to assess changes
especially in physiologic functions. They advocated a short course use of anabolic steroids to
enhance HRQL in patients with COPD.

Sharma, et al.(54)assessed the effects of anabolic steroids in COPD patients when used
outside of a dedicated pulmonary rehabilitation program. Sixteen patients were included in
the study and were randomly allocated into two groups of eight patients each. The study
duration was 16 weeks. It was a double blinded study with the treatment group receiving
intramuscular nandrolone injections every two weeks and control group receiving placebo
deep intramuscular injection. Men received 50 mg and women received 25 mg dose of
nandrolone decanoate. At the end of the study duration, lean body mass, 6-minute walk test,
CRQ , Body mass index did not show an did not significantly differ from the baseline values.
They concluded that administration of anabolic steroids outside a dedicated pulmonary
rehabilitation program is not beneficial.

Yeh, et al.(9)conducted a prospective, open-label, 4-month clinical trial to assess the effects
of oral anabolic drug Oxandrolone in the reversal of COPD associated weight loss.
Intervention was use of oral Oxandrolone of 10mg twice a day. Results from 82 patients at 2
months and 55 patients at 4 months demonstrated an increase in body weight, primarily in the
form Lean Body Mass (LBM). This effect was significant by 2 months and maintained
through the 4 months of treatment despite the absence of deliberate dietary or exercise
regimens. This study is in contrast with the findings of Sharma, et al. where administration of
anabolic steroids outside an extensive rehabilitation program didn’t show any changes in lean
body mass. This study also showed a significant increase in 6 Minute walk distance (6MWD)
of >65 metres in a majority of the patients suggesting that an improvement in the health
status may have occurred during the study although there were no corresponding
improvements in the pulmonary function tests. Since the study was an open-label study, it
lacked a control group. This study also witnessed a high rate of early discontinuations;
however 71% of the dropouts were due to events unrelated to the drug.

Ferreira, et al.(13)conducted a prospective, randomized controlled, double blinded study in a

pulmonary rehabilitation program setting to evaluate the influence of oral anabolic steroids
on COPD patients. Patients belonging to the study group received 250mg of testosterone
intramuscularly at baseline followed by stanozolol 12mg/day for 27 weeks. At the end of 6
month study, patients receiving anabolic steroids gained an average of 2kg more than control
group with a documented increase in lean body mass. The relatively small sample size of the
study may have influenced the power of measurements. Further, the study did not evaluate
the effect of anabolic steroids on health-related quality of life.

Pulmonary rehabilitation requires infrastructure and a multi-disciplinary approach and is

neither feasible nor affordable to most COPD patients in India. In this study patients will be
taught respiratory and physical exercises in the hospital by physiotherapists at the beginning
of the study. These exercises will be continued at home for the rest of the study.
Aims and objectives

To assess the effects of anabolic steroids on COPD patients undergoing respiratory exercise
therapy in addition to pharmacological management.

Primary objectives include assessment of changes in exercise tolerance and Health related
quality of life as assessed by

1. The six minute walk test

2. COPD assessment test

Secondary objectives include assessment of changes in

1. FEV1 / FVC ratio

2. Hand grip strength
3. Fat free mass
Materials and methods

Study area
Patients will be recruited from the out-patient department of general medicine department in
CSI Holdsworth Memorial Hospital, Mysore.

Study Population

Inclusion Criteria - The study population will include patients who have symptoms of COPD
and airflow obstruction as confirmed by post bronchodilator FEV1/FVC ratio of < 0.7.
Severity of COPD will be graded according to the GOLD COPD classificationand only stable
patients belonging to moderate and severe category will be chosen for the study.

Exclusion criteria- will include history of asthma, unstable COPD, obesity, malignancy,
ischemic heart disease, renal failure. Study subjects will be picked by purposive sampling.

Sample size
This study will include 40 patients who will be randomly allotted to be part of the control or
study group with 20 patients each.

Study design
This will be a comparative, double-blinded, placebo controlled, parallel study. Patients will
be randomized and allotted into either the control or study group. 6 doses of placebo or drug
would be placed in each numbered, unlabelled container. Randomization will be done using
an online software (available at randomizer.org) and the list was provided to the staff nurse
in-charge of maintaining and administering the contents of the container. In this way, double
blind in the study would be maintained.
Study intervention
The study group patients will receive monthly 100mg of nandrolone decanoate injection
intramuscularly in gluteal region whereas the control group will receive 0.5ml of normal
saline in the gluteal region. Injections will be administered once every month for a span of 20
weeks, totally comprising of 6 doses of nandrolone decanoate or normal saline. All patients in
the study will be given advice and guided to carry out exercise sessions at home comprising
of
a) Incentive spirometry
b) Self-paced walks for up to 30 minutes atleast three times a week
c) Upper extremity exercises including breathing exercises and Yoga techniques.

Study duration
Patients will be assessed at the beginning of the trial and at the end of 20 weeks of trial
afterreceiving 6 doses of placebo or anabolic steroids.

Data Collection Methods

Measurements of
a) FEV1,
b) FEV1/FVC,
c) 6 minute walk test,
d) Hand-grip test,
e) Health-related quality of life(HRQL) will be measured using COPD Assessment Test®
(CAT)
f) Fat free mass
will be done at baseline and at completion of study.
Methods of measurement of outcome of interest

Six minute walk test

Six-minute walk test, a test of functional exercise capacity, will be measured by the distance
covered (in meters) during 6 minutes of walking before starting the study and after
completion of study period. The distance covered in 6 minutes of walking
has been shown to be a reproducible measure of effort tolerance in
patients with COPD. The walk will be carried out in a level-enclosed hospital corridor with
the researcher accompanying the patient. Each patient received standard instructions as
mentioned in the American Thoracic Society guidelines(55).

Hand grip test

The hand grip test is a test for upper limb muscle strength which requires the use of the flexor
muscles of the fingers. We will be using the JAMAR® hydraulic hand dynamometer for
measurement of hand grip strength. The test will be carried out on the non-dominant hand at
room temperature with the patient sitting in a chair, their elbow by their side flexed at right
angle and a neutral wrist position and provision of support underneath the dynamometer. This
position, followed by calculation of the mean of three trials of grip strength for each hand,
has been well-documented as reliable(56). Peripheral muscle strength of upper limb as
assessed by the hand grip test is shown to correlate positively with respiratory muscle
strength(57).

COPD Assessment Test®

The care of COPD patients can only be optimised if there is a reliable, standardised measure
of the overall effect of disease on each patient’s health. Unfortunately, commonly used lung
function measurements such as FEV1 do not reflect the full impact of COPD. The CAT is a
validated, short (8-item) and simple patient completed questionnaire, with good discriminant
properties, developed for use in routine clinical practice to measure the health status of
patients with COPD.(58) Despite the small number of component items, it covers a broad
range of effects of COPD on patients’ health. Studies have shown that it is responsive to
changes in the disease and to treatment like rehabilitation.(59,60)The CAT has undergone a
rigorous, scientific development process and the first validation studies show that it has
properties very similar to much more complex health status questionnaires such as the St
George’s Respiratory Questionnaire (SGRQ) that are used in research studies. It takes only a
fraction of the time to complete, however, making it suitable for routine use. It is being used
in COPD studies in Europe, USA and Asia.

Fat Free Mass

Fat free mass will be measured using BODYSTAT® 500 hand-held body composition
monitoring unit which works on the principle of Bioelectrical Impedance Analysis (BIA).

Spirometry
Post bronchodilator FEV1, FVC and FEV1/FVC will be determined using portable
Spirometer Helios 401® at the beginning and end of study period.
 Data collection form

Trial ID -

1] Name -

2] Age -

3] Sex -

4] Height -

5] Weight-

At the beginning of study End of study period

FEV1

FVC

FEV1/FVC

6 Minute walk distance

Hand grip strength

Fat free mass

COPD assessment test score

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