Testosterone level and the effect of levodopa and agonists in early Parkinson disease: results from the INSPECT cohort
© Okun et al.; licensee BioMed Central Ltd. 2014
Received: 25 June 2014
Accepted: 15 August 2014
Published: 26 November 2014
To determine if testosterone levels are influenced by dopaminergic therapy in Parkinson disease (PD) patients. Testosterone level has been reported to be low in patients with PD and other neurodegenerative diseases. In this study, we sought to determine whether dopaminergic therapy (i.e. levodopa and dopamine agonist) influenced testosterone levels. We used a cohort of consecutive male patients from the INSPECT trial--a multi-center, prospective, study that primarily investigated the effects of short-term treatment with pramipexole or levodopa on [123I] B-CIT SPECT imaging in early PD.
Testosterone levels were drawn on consenting male subjects with early PD who enrolled in the INSPECT trial at three study visits (baseline, 12 weeks post-treatment, and 8–12 weeks post-washout). Subjects were randomized to: no treatment, pramipexole (up to 3 mg) or levodopa (up to 600 mg). Testosterone levels were obtained twice (prior to 10 AM) and averaged for each of three study visits.
Thirty two male patients participated in this sub-study and there were no significant differences in disease characteristics in the 3 groups at baseline. Twenty-nine patients completed the follow-up visits and were suitable for analysis. There were statistically significant differences in the change in free testosterone level, increased in both the levodopa group and pramipexole group but decreased in the untreated group at 12-weeks post-treatment. There were no significant differences in the changes of UPDRS total or motor scores, although there was a strong trend toward improvement in motor scores. The testosterone level persisted in its increase only in the pramipexole group at the end of the washout period.
These preliminary data support the premise that dopaminergic medications do not reduce testosterone levels in early PD patients.
There has been mounting evidence suggesting that inappropriately low plasma testosterone levels commonly exist in male patients with Parkinson disease (PD) [1–6]. The relevance and underlying cause of this endocrine disturbance remain unknown. Additionally, replacement of testosterone has not to date been proven to significantly improve the motor and non-motor symptoms of these patients, though there have been anecdotal successes [4–7]. Two main hypotheses have been proposed to explain the low testosterone levels: the levels are reduced by dopaminergic medications, or the testosterone level is a surrogate marker for pathology known to occur in the hypothalamus and in other relevant regions of the PD brain . We sought to examine the former hypothesis that dopaminergics may lower testosterone. In this study we utilized the INSPECT cohort of early PD subjects.
Baseline characteristics of subjects in the study
Summary of changes from baseline to 12 weeks post treatment
p = 0.12
p = 0.06
p = 0.12
Summary of changes from baseline to the end of washout period
p = 0.01
p = 0.95
p = 0.88
Discussion and conclusions
These results suggest that neither levodopa nor pramipexole decrease testosterone level in early PD. The observation that the untreated group experienced further lowering of free testosterone levels lends support to the hypothesis that testosterone decline in PD may be a result of disease-specific factors, and that the decline is less likely iatrogenically induced by dopaminergic medications. It is not entirely clear why the increase in free testosterone levels persisted in the dopamine agonist group post-washout. Dopamine agonists have been used in the treatment of prolactinoma, because dopamine is a natural inhibitor of prolactin [9, 10]. Prolactin lowers leutenizing hormone (LH) which in turn lowers testosterone level [11–16]. Thus, dopamine agonists may theoretically increase testosterone levels by inhibiting prolactin. This point will need further clarification.
Sinhamahapatra and Kirschner in 1971 published a detailed analysis of the effect of levodopa on testosterone level . They sought in their study to answer the question as to whether levodopa stimulated LH production and Leydig cell activity. They utilized an electron capture gas liquid chromatographor, an older technique now considered less accurate when compared to more modern techniques for measuring testosterone. Seven PD men staged using an older system devised by Leon were included in the analysis . Very high doses of levodopa were used (2–6 grams/day). There were other methodological limitations including baseline normal levels in all patients enrolled (>325 ng/ml), and 2/7 PD patients who did not improve on levodopa. One interesting aspect of their study was the calculation of testosterone production and metabolism, as well as the measurement of LH. The study concluded that levodopa did not have an impact on plasma testosterone or LH . Despite methodological limitations this data is supportive of our findings.
We suspect based on our results that the finding of low testosterone in PD patients is indicative of intrinsic PD pathology. It is well known that Lewy Body pathology is present in PD patients at post-mortem examination, and lesions includes hypothalamic involvement [18–22]. Braak has shown that this hypothalamic pathology may be present relatively early in the course of PD [18–21]. We propose this as a plausible explanation for the low testosterone levels.
There were several limitations in this study that should be addressed in future investigations. These limitations included a small sample size, the lack of non-PD controls, the use of early PD patients, differences between free and total testosterone levels, and observed changes in testosterone level were small and not likely clinically relevant. There were changes seen between free testosterone and total testosterone and this highlighted difficulties in laboratory measurements. Most experts use a free or bioavailable testosterone level as the gold standard rather than utilizing both a free and total testosterone level [23–25]. Despite these limitations we conclude as did Sinhamahapatra, that dopaminergics are probably not the cause of low testosterone in PD. Clinicians should not assume that low testosterone levels are an effect of PD medications. There is currently no evidence that checking a testosterone level prior to dopaminergic therapy will be clinically useful. We suggest that future research on this topic should focus on disease related factors as the potential culprits in the low testosterone PD story, however a larger study of the effects of medication can confirm our results.
We would like to acknowledge the support of the National Parkinson Foundation Center of Excellence at the University of Florida, the UF Foundation, and the NIH NS044997.
- Chou KL, Moro-De-Casillas ML, Amick MM, Borek LL, Friedman JH: Testosterone not associated with violent dreams or REM sleep behavior disorder in men with Parkinson’s. Mov Disord 2007, 22: 411–414. 10.1002/mds.21339View ArticlePubMedGoogle Scholar
- Okun MS, Crucian GP, Fischer L, Walter BL, Testa CM, Vitek JL, DeLong MR, Hanfelt J, Huang X: Testosterone deficiency in a Parkinson’s disease clinic: results of a survey. J Neurol Neurosurg Psychiatry 2004,75(1):165–166.PubMedPubMed CentralGoogle Scholar
- Okun MS, DeLong MR, Hanfelt J, Gearing M, Levey A: Plasma testosterone levels in Alzheimer and Parkinson diseases. Neurology 2004, 62: 411–413. 10.1212/01.WNL.0000106840.72938.84View ArticlePubMedGoogle Scholar
- Okun MS, Fernandez HH, Rodriguez RL, Romrell J, Suelter M, Munson S, Louis ED, Mulligan T, Foster PS, Shenal BV, Armaghani SJ, Jacobson C, Wu S, Crucian G: Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study. Arch Neurol 2006,63(5):729–735. 10.1001/archneur.63.5.729View ArticlePubMedGoogle Scholar
- Okun MS, McDonald WM, DeLong MR: Refractory nonmotor symptoms in male patients with Parkinson disease due to testosterone deficiency: a common unrecognized comorbidity. Arch Neurol 2002, 59: 807–811. 10.1001/archneur.59.5.807View ArticlePubMedGoogle Scholar
- Okun MS, Walter BL, McDonald WM, Tenover JL, Green J, Juncos JL, DeLong MR: Beneficial effects of testosterone replacement for the nonmotor symptoms of Parkinson disease. Arch Neurol 2002,59(11):1750–1753. 10.1001/archneur.59.11.1750View ArticlePubMedGoogle Scholar
- Mitchell E, Thomas D, Burnet R: Testosterone improves motor function in Parkinson’s disease. J Clin Neurosci 2006, 13: 133–136. 10.1016/j.jocn.2005.02.014View ArticlePubMedGoogle Scholar
- Hughes AJ, Daniel SE, Kilford L, Lees AJ: Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992, 55: 181–184. 10.1136/jnnp.55.3.181View ArticlePubMedPubMed CentralGoogle Scholar
- Molitch ME: Pharmacologic resistance in prolactinoma patients. Pituitary 2005, 8: 43–52. 10.1007/s11102-005-5085-2View ArticlePubMedGoogle Scholar
- Shimon I, Benbassat C, Hadani M: Effectiveness of long-term cabergoline treatment for giant prolactinoma: study of 12 men. Eur J Endocrinol 2007, 156: 225–231. 10.1530/EJE-06-0646View ArticlePubMedGoogle Scholar
- Treatment of androgen deficiency in the aging male Fertil Steril 2006, 86: S236–240.Google Scholar
- Haren MT, Kim MJ, Tariq SH, Wittert GA, Morley JE: Andropause: a quality-of-life issue in older males. Med Clin North Am 2006, 90: 1005–1023. 10.1016/j.mcna.2006.06.001View ArticlePubMedGoogle Scholar
- Harman SM: Testosterone in older men after the Institute of Medicine Report: where do we go from here? Climacteric 2005, 8: 124–135. 10.1080/13697130500118001View ArticlePubMedGoogle Scholar
- Kaku H, Saika T, Tsushima T, Ebara S, Senoh T, Yamato T, Nasu Y, Kumon H: Time course of serum testosterone and luteinizing hormone levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer. Prostate 2006,66(4):439–444. 10.1002/pros.20341View ArticlePubMedGoogle Scholar
- Morley JE: Androgens and aging. Maturitas 2001, 38: 61–71. discussion 71–63 10.1016/S0378-5122(00)00192-4View ArticlePubMedGoogle Scholar
- Morley JE, Haren MT, Kim MJ, Kevorkian R, Perry HM 3rd: Testosterone, aging and quality of life. J Endocrinol Invest 2005, 28: 76–80.PubMedGoogle Scholar
- Sinhamahapatra SB, Kirschner MA: Effect of L-dopa on testosterone and luteinizing hormone production. J Clin Endocrinol Metab 1972, 34: 756–758. 10.1210/jcem-34-4-756View ArticlePubMedGoogle Scholar
- Braak H, Braak E: Pathoanatomy of Parkinson’s disease. J Neurol 2000,247(Suppl 2):II3–10.PubMedGoogle Scholar
- Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U: Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol 2002,249(Suppl 3):III/1–5.PubMedGoogle Scholar
- Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E: Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003, 24: 197–211. 10.1016/S0197-4580(02)00065-9View ArticlePubMedGoogle Scholar
- Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K: Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004, 318: 121–134. 10.1007/s00441-004-0956-9View ArticlePubMedGoogle Scholar
- Jellinger KA: Post mortem studies in Parkinson’s disease–is it possible to detect brain areas for specific symptoms? J Neural Transm Suppl 1999, 56: 1–29. 10.1007/978-3-7091-6360-3_1View ArticlePubMedGoogle Scholar
- Morley JE, Kim MJ, Haren MT: Frailty and hormones. Rev Endocr Metab Disord 2005, 6: 101–108. 10.1007/s11154-005-6722-9View ArticlePubMedGoogle Scholar
- Tan RS, Salazar JA: Risks of testosterone replacement therapy in ageing men. Expert Opin Drug Saf 2004, 3: 599–606. 10.1517/14740318.104.22.1689View ArticlePubMedGoogle Scholar
- Vermeulen A: Androgen supplementation in elderly males: is dihydrotestosterone to be preferred? Aging Male 2004, 7: 325–327. 10.1080/13685530400016672View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.