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Refractory Nonmotor Symptoms in Male Patients With Parkinson Disease Due to Testosterone Deficiency
A Common Unrecognized Comorbidity
Michael S. Okun, MD;
William M. McDonald, MD;
Mahlon R. DeLong, MD
Arch Neurol. 2002;59:807-811.
ABSTRACT
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Background Many patients with Parkinson disease (PD) suffer from nonmotor symptoms
including depression, anxiety, sexual dysfunction, decreased energy level,
and an overall decline in quality of life. Comorbid depression, hypothyroidism,
and sleep disorders may account for some, but not all, of these problems.
Testosterone deficiency affects 20% to 25% of males over the age of 60 years
in the general population and may cause signs and symptoms of the nonmotor
symptoms seen in PD. We observed numerous patients with PD whose nonmotor
symptoms were refractory to treatment.
Objective To determine whether treatment of comorbid testosterone deficiency in
male patients with PD can lead to improvements in refractory nonmotor symptoms.
Methods Case studies were reviewed of the first 5 male patients who had PD with
symptoms of testosterone deficiency who were treated in our clinic. All patients
had low serum testosterone levels. Screening for testosterone deficiency symptoms
using the St Louis Testosterone Deficiency Questionnaire was performed for
4 of the 5 patients. Additionally, to assess the prevalence of PD, total testosterone
levels in 68 patients in our PD registry were sent for evaluation.
Results Following testosterone replacement therapy, all 5 patients experienced
significant improvements in their refractory nonmotor symptoms. Of 68 male
patients with PD enrolled in our PD registry, 24 (35%) had plasma evidence
of testosterone deficiency. We also noted that the risk of testosterone deficiency
per decade was found to increase 2.8-fold per decade (P<.001),
paralleling that which is found in the general elderly male population.
Conclusions The findings from this study reveal the heretofore unrecognized high
prevalence of testosterone deficiency in elderly male patients with PD similar
to that found in the general population. These symptoms, which may be refractory
to antidepressants, anxiolytics, and antiparkinsonian medications, may respond
to treatment with testosterone. More rigorous controlled studies will need
to be undertaken to examine the treatment of this common comorbidity in male
patients with PD.
INTRODUCTION
PARKINSON DISEASE (PD) is a progressive neurodegenerative disorder characterized
by both motor and nonmotor signs and symptoms. Although attention has focused
largely on the motor aspects such as bradykinesia, rigidity, tremor, and gait
difficulties, of equal, and often even greater importance are the nonmotor
symptoms that affect quality of life such as depression, anxiety, sexual dysfunction,
and cognitive impairment. In some cases comorbid conditions such as depression,
hypothyroidism, and sleep disorders may account for some of the nonmotor symptoms.
Recognition of these comorbid conditions is important because, when untreated,
they may contribute significantly to the clinical burden. In male patients
with PD, we have identified an additional comorbidity, testosterone deficiency.
Testosterone deficiency is found in 20% to 25% of the adult males older than
age 60 years (depending on age) and is a well-documented cause of depression,
fatigue, decreased libido, and decreased work performance.1-4
These deficiency symptoms respond favorably to testosterone replacement therapy
(TRT).3, 5-7
We report our experience with TRT in 5 males with combined PD and symptoms
of testosterone deficiency. Such patients were poorly responsive to antiparkinsonian
and antidepressant medications. We observed significant clinical improvement
in specific nonmotor symptoms with the administration of TRT. We also report
the high prevalence of low testosterone levels in patients enrolled in our
PD registry.
PATIENTS AND METHODS
We present the results of a retrospective analysis of the first 5 patients
who were seen with combined PD and symptoms of testosterone deficiency. Patients
seen after our initial index patient were screened for testosterone deficiency
using the validated St Louis Testosterone Deficiency Questionnaire (SLTDQ)
(Table 1).8
Patients who met SLTDQ criteria were then screened for total and free testosterone
levels (Table 2). Patients with
levels of free testosterone less than 70 pg/mL with no potential medical contraindications
to TRT including sleep apnea, polycythemia, prostate cancer, urinary outlet
obstruction, or congestive heart failure were treated with a testosterone
gel (AndroGel; Unimed Pharmaceuticals Inc, Deerfield, Ill), 5 g/d, applied
locally to the skin. Prostate-specific antigen studies and a digital rectal
examination were performed to exclude the presence of prostate cancer. Unified
Parkinson's Disease Rating Scale motor scores were also recorded.
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Table 1. Pretreatment (Pre) and Posttreatment (Post) Patient Responses
to the St Louis Testosterone Deficiency Questionnaire*
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Table 2. Patients Treated for Parkinson Disease (PD) and Testosterone
Deficiency
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To better assess the prevalence of low testosterone levels in PD, we
assessed total testosterone levels in male patients with PD enrolled in our
PD registry with a confirmed diagnosis of idiopathic PD. A multiple linear
regression model was used to analyze the potential increase in risk of testosterone
deficiency per decade.
There is, as yet, no universally accepted testosterone value (total
testosterone or free testosterone) that defines an older man as being testosterone
deficient.1 Many investigators in the field
have used testosterone levels at or below the lower limit of normal for young
adult men as their working definition of testosterone deficiency, or older
male "hypogonadism."1 Using the large Baltimore
Longitudinal Study data set, Harman et al2
have defined older men as being hypogonadal if their total testosterone plasma
level was below 325 ng/dL (11.3 nmol/L), or their free testosterone index
was less than 0.153.2 We extrapolated, based
on the more sensitive test for testosterone deficiency, free testosterone,
a level of less than 70 pg/mL to define testosterone deficiency.
RESULTS
Five patients were treated with daily applications of testosterone gel
who had free testosterone levels of 56 pg/mL or less (averages: free testosterone
level, 37.6 pg/mL; total testosterone level, 243.6 ng/dL [8.4 nmol/L]). Following
TRT all patients experienced significant improvement in refractory nonmotor
symptoms of PD, especially fatigue, depression, anxiety, and sexual dysfunction.
Parkinsonian features seemed to improve in several men, but we were unsure
whether these improved secondarily as a result of the improvement in mood
and energy or if TRT had a direct effect. Data from the first 5 cases that
we have encountered and treated with TRT are summarized in Table 1 and Table 2
with individual case descriptions presented below.
CASE 1
An 87-year-old man had a 7-year history of PD with tremor, rigidity,
bradykinesia, and unsteady gait. After experiencing an excellent response
to levodopa replacement therapy for many years, over the span of 1 year he
experienced a rather marked decline with depressed mood, fatigue, decreased
energy level, and an overall withdrawal from life and decreased well-being.
He was diagnosed as having depression and had therapeutic trials of buproprion,
sertraline, and paroxetine, and multiple adjustments of his antiparkinsonian
medications with little effect on his symptoms. His plasma free testosterone
level was 42 pg/mL and his total testosterone level was 305 ng/dL (10.6 nmol/L).
A 1-month follow-up visit after receiving TRT revealed marked improvements
in mood, energy, libido, and well-being. His PD symptoms were improved with
regard to gait and balance, but it was unclear whether this improvement was
due to TRT or to an adjustment of his dosage of fludrocortisone acetate (Florinef;
Apothecon, Bristol-Myers Squibb Co, Princeton, NJ) that was being used for
symptomatic orthostatic hypotension.
CASE 2
An 87-year-old man with a 12-year history of tremor-predominant PD reported
5 years of progressively worsening depression, anxiety, and other nonmotor
symptoms. His PD symptoms were optimally treated with antiparkinsonian medications.
He was treated with therapeutic doses of sertraline with a partial improvement
in his mood and anxiety symptoms. His SLTDQ score was positive for 7 of 10
symptoms (Table 1). His plasma
free testosterone level was 25 pg/mL; his total testosterone level was 166
ng/dL (5.8 nmol/L).
After 1 month of receiving TRT, his SLTDQ score reflected improvement
in libido, and during the patient interview he reported significant improvements
in mood, anxiety, and libido. During the month of treatment his quality of
life improved on the Parkinson Disease Quality of Life Questionnaire especially
in the categories of activities of daily living, mobility, and emotional well-being.
He felt his parkinsonism was improved although there was no change in his
Unified Parkinson's Disease Rating Scale motor scores before and after TRT.
CASE 3
A 59-year-old man with a 7-year history of tremor-predominant PD developed
significant depression that was not relieved by therapeutic trials of citalopram
and venlafaxine. His PD symptoms were optimally treated with antiparkinsonian
medications. His SLTDQ score was positive for 6 of 10 symptoms (Table 1). His free testosterone level was 55.5 pg/mL; his total
testosterone level was 353 ng/dL (12.2 nmol/L).
On a follow-up visit 4 months after beginning TRT, he reported that
within weeks of beginning treatment there was a sustained and marked improvement
in his mood and strength. Both libido and erectile dysfunction had improved
and he no longer felt depressed. He reported increased involvement and satisfaction
with his daily activities. His SLTDQ score improved from 6 positive symptoms
to 2 positive symptoms (Table 1).
There was a slight improvement in his Unified Parkinson's Disease Rating Scale
motor score.
CASE 4
A 59-year-old man who had idiopathic PD for 20 years noted worsening
and intractable depression over several months. He had undergone a right-sided
pallidotomy 7 years earlier for treatment of dyskinesias. His symptoms included
tremor, bradykinesia, on-off motor fluctuations, dyskinesias, fatigue, and
depression. His parkinsonian symptoms were optimally treated with antiparkinsonian
medications, and he had been treated previously with therapeutic doses of
citalopram and venlafaxine without improvement in depression and nonmotor
symptoms. His SLTDQ score was positive for all 10 symptoms of testosterone
deficiency (Table 1). His plasma
free testosterone level was 31.9 pg/mL; his total testosterone level was 162
ng/dL (5.6 nmol/L).
At a 1-month follow-up visit after starting TRT, he reported a marked
improvement in depression, anxiety, and overall strength. He was again able
to mow his lawn and perform yard work unassisted. His SLTDQ score improved
after TRT from 10 to 4 positive symptoms (Table 1). He reported improvement in PD symptoms particularly in
regard to his overall mobility and gait, but also noted some worsening of
his dyskinesias.
CASE 5
A 73-year-old man with idiopathic PD for 12 years with tremor, rigidity,
bradykinesia, and gait difficulties presented with reports of increasing fatigue
and depression. He had undergone a left-sided pallidotomy 5 years prior to
presentation for treatment of dyskinesias. He was previously treated with
therapeutic doses of sustained-release buproprion and venlafaxine without
a change in his depressive symptoms. His SLTDQ score was positive for 8 of
10 symptoms (Table 1). His plasma
free testosterone level was 33.2 pg/mL; his total testosterone level was 232
ng/dL (8.0 nmol/L).
At a 1-month follow-up visit after receiving TRT, he reported marked
improvement in his depression symptoms including mood, energy, and anhedonia.
His SLTDQ score improved to only 5 of 10 positive symptoms with his most marked
improvements in libido and erectile dysfunction (Table 1). His PD symptoms also improved, however, it was unclear
whether adjustments in his levodopa and dopamine agonist dosages along with
his improvement in mood were responsible for the motor improvement he exhibited.
RESULTS OF PREVALENCE OF TESTOSTERONE DEFICIENCY IN A PD REGISTRY
Data derived from a PD registry showed an age-related decline in testosterone
levels in 68 male patients with PD. Twenty-four male patients with PD (35%)
in this registry had low testosterone levels (<325 ng/dL [<11.3 nmol/L]).
A multiple linear regression model revealed a 2.8-fold increase per decade
in risk of testosterone deficiency in male patients with PD (Figure 1). The results indicated a significant relationship between
age and testosterone deficiency in male patients with PD (P<.001), as is found in the general male population older than 60
years.1-2
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Risk of testosterone deficiency with age in 64 male patients with
Parkinson disease (PD) entered in the Parkinson Disease–Alzheimer Disease
Registry, Emory University, Atlanta, Ga.
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COMMENT
The findings from this study points to the heretofore unrecognized high
prevalence of testosterone deficiency in male patients with PD. The prevalence
of low testosterone levels in a PD registry (24 patients [35%]) is considerably
higher than that in the general male population over the age of 60 years with
increasing prevalence for each decade.1-2
The high prevalence of low testosterone levels found in a PD registry may
be higher than the general population with PD because of a referral bias,
ie, refractory patients were referred for a second opinion or for surgery.
Further studies will be needed to determine the true prevalence of low testosterone
levels in patients with PD.
Patients who have PD with low testosterone levels typically exhibit
nonmotor symptoms suggestive of depression and anxiety, ie, decreased libido,
decreased energy, decreased endurance, and anhedonia. Most striking in this
patient group was the refractoriness of the symptoms to optimal parkinsonian,
antidepressant, and anxiolytic treatments. In this respect they were similar
to patients with unrecognized hypothyroidism who are also poorly responsive
to these treatments.9-11
Numerous studies in the geriatric population have revealed that testosterone
deficiency symptoms such as lack of energy, fatigability, irritability, anxiety,
and depression will respond to TRT.3-5,12-16
Patients with depression refractory to antidepressant medication in the setting
of testosterone deficiency have also been shown to respond to TRT. In the
study by Seidmann and colleagues,3, 17
all of the men treated had significant improvement in their symptoms of depression.
Additionally, symptoms of depression have been treated successfully with testosterone
in men with human immunodeficiency virus–infected symptomatic hypogonadism.18-19
Since 1948 it has been known that treatment of men with low testosterone
levels can improve deficiency symptoms.20 Functional
improvement in rehabilitation scores and grip strength improved in men receiving
TRT and increased their rehabilitation potential.21
Logistically, older men who have PD and testosterone deficiency should also
benefit by TRT. Since patients with PD are prone to falling, improvements
in strength and rehabilitation potential are important for their long-term
management. Clinicians should consider screening elderly male patients with
PD who have treatment refractory nonmotor symptoms of PD for the treatable
and common comorbidity of testosterone deficiency, before attributing symptoms
directly to PD.
Data from the PD registry (Figure 1) reported in this article should increase awareness of a common
and treatable comorbidity in this population. This comorbidity should not
be confused with nonmotor symptoms that are a direct result of PD. Testosterone
levels decline with normal aging probably secondary to a decline in Leydig
cell functioning. Although the rate of decline can vary greatly between individuals,
both cross-sectional and longitudinal studies, in general, have confirmed
this decline.2, 22-23
Long-term illness and certain medications are associated with lower testosterone
levels.24-25 A significant proportion
of older men (perhaps 20%) will experience a decline in the level of testosterone
to the extent that they will develop symptoms of testosterone deficiency.1, 5
Although the men in our study experienced improvement in mobility, it
was unclear whether this was a primary or secondary effect of TRT. To our
knowledge, there have been no prior clinical studies of the effects of TRT
on motor and nonmotor symptoms in PD. Since androgen receptors have been found
to anatomically co-localize with dopamine neurons in the midbrain and hypothalamus,26-27 TRT may conceivably have an effect
on the motor symptoms in PD. More studies will be needed to evaluate the efficacy
of TRT on motor symptoms of PD. Additionally, it has been suggested that androgens
may play a neuroprotective role in some neurodegenerative diseases. Estrogen
has been observed to promote in vitro neurite growth in the mesencephalon
of tyrosine hydroxylase immunoreactive neurons,28
and a recent study revealed that estrogen coadministered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
was neuroprotective against the loss of substantia nigra cells in primates,29 and in males, testosterone is the major source of
estrogen.
It is unknown whether testosterone deficiency and PD represent independent
entities, ie, comorbidities that overlap, and whose symptoms are simply additive
or whether testosterone deficiency may influence age of onset, the rate of
progression, overall clinical severity, and specific nonmotor and motor features
of the disease. Although all patients showed improvement in their symptoms
of testosterone deficiency, since there may be a large placebo effect in therapy
with testostrone or estrogen, a blinded, placebo-controlled study is clearly
necessary to demonstrate clinical efficacy. The finding, however, that the
prevalence of PD in males outnumbers females by a significant extent30 may be due in part to the effect of testosterone
deficiency in males older than 60 years. Finally, it remains to be determined
whether a low testosterone level could contribute to the clinical picture
in other neurodegenerative diseases affecting older males such as Alzheimer
disease, stroke, and neuromuscular disease. Such questions will necessarily
remain for future epidemiological and clinical studies to address.
AUTHOR INFORMATION
Accepted for publication February 18, 2002.
Author contributions: Study concept and design (Drs Okun, McDonald, and DeLong); acquisition of data (Drs Okun and DeLong); analysis and interpretation of data (Drs Okun, McDonald, and DeLong); drafting of the manuscript (Drs Okun and McDonald); critical revision of the manuscript
for important intellectual content (Drs Okun, McDonald,
and DeLong); statistical expertise (Dr Okun);
obtained funding (Dr Okun); administrative, technical,
and material support (Drs Okun, McDonald, and DeLong);
study supervision (Drs Okun, McDonald, and DeLong).
We deeply appreciated the statistical expertise of John Hanfelt, PhD,
as well as the support of the Emory University Alzhemier's Disease Center.
Corresponding author and reprints: Michael S. Okun, MD, Department
of Neurology, Emory University, 1639 Pierce Dr, Suite 6000, Atlanta, GA 30322
(e-mail: msokun{at}dnamail.com).
From the Departments of Neurology (Drs Okun and DeLong) and Psychiatry
and Behavioral Sciences (Dr McDonald), Emory University, Atlanta, Ga.
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