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Testosterone Treatment Enhances Regional Brain Perfusion in Hypogonadal Men

Medical (N.A., S.P.) and Nuclear Medicine Services (W.E.B., N.F.), Department of Veterans Affairs, Edward Hines Jr. Hospital, Hines, Illinois 60141; and Departments of Medicine (N.A., S.P.) and Nuclear Medicine (W.E.B., N.F.), Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153

Address all correspondence and requests for reprints to: Nasrin Azad, M.D. (111A), Edward Hines Jr. Veterans Affairs Hospital, Medical Service/ Endocrinology Section, Building 200, Suite 1422, Hines, Illinois 60141. E-mail: nasrin.azad{at}med.va.gov.

	Abstract

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The positive effect of testosterone replacement therapy on psychosocial well-being in hypogonadal men has been demonstrated by various psychometric tests. However, there is no report available that objectively demonstrates the effect of testosterone on the function of the central nervous system in men. In this report we studied cerebral perfusion in seven hypogonadal men on testosterone replacement therapy. The blood perfusion to the central nervous system was assessed using single-photon emission-computed tomography. ^{99 m}Tc-hexamethyl-propylene-amine oxime crosses the blood brain barrier and localizes in brain tissue, depending on the intensity of the local blood flow. Psychosocial well-being was assessed with an Androgen Deficiency in Aging Men questionnaire. The study demonstrated that testosterone replacement enhanced cerebral perfusion in midbrain and superior frontal gyrus (Brodman area 8) at 3–5 wk of treatment. At 12–14 wk the study continued to show increased perfusion in midbrain in addition to the appearance of a new activated region in the midcingulate gyrus (Brodman area 24). The results of this study provide objective evidence that testosterone and /or its metabolites increased cerebral perfusion in addition to the improvement in cognitive function.

	Introduction

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THE MAJORITY OF hypogonadal men on testosterone replacement therapy report substantial improvement in mental and in overall well-being (1, 2, 3, 4). The brain is recognized as a steroidogenic organ on the basis of its ability to produce and metabolize steroid hormones (5). Testosterone present in the brain, as in the other organs, can be either reduced to a more potent androgen, dihydrotestosterone, by 5-reductase or aromatized to estradiol (6, 7, 8, 9). The presence of specific receptors for androgen and estrogen further supports the hypothesis that steroid hormones play an active role in neuronal functions (10, 11, 12). Furthermore, it has been demonstrated that steroid hormones promote neuronal cell growth and survival (13).

Steroid hormones may play a role as a neuromodulator. Studies have demonstrated that testosterone decreases -aminobutyric acid levels in hypothalamus (14, 15). Testosterone and estradiol stimulate 5-hydroxytryptamine receptors and serotonin transporter protein metabolism in the central nervous system (CNS) (15, 16, 17, 18, 19, 20).

In this study, we have tested the hypothesis that testosterone replacement therapy will increase CNS blood perfusion in hypogonadal men. This was done using single-photon emission-computed tomography (SPECT) technique. The study demonstrates a novel finding that testosterone replacement therapy in hypogonadal men significantly increases cerebral perfusion in areas of the CNS, which are rich in serotonin and instrumental in memory and cognitive function.

	Subjects and Methods

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Seven hypogonadal men, aged 58–72 yr, with decreased sexual function manifested by lack of libido and inability to maintain erection, and mean serum free testosterone levels of 29.5 ± 5.8 pg/ml (normal range 50–210 pg/ml) were studied. The hormonal profile for each individual was evaluated two or more times. These individuals were in reasonably good health.

Specific criteria were used to exclude patients suffering from a variety of diseases that might have influenced CNS and hypothalamic-pituitary-gonadal (H-P-G) axis function. The exclusion criteria were as follows: 1) pituitary and adrenal diseases; 2) current untreated and active thyroid disorders; 3) renal insufficiency defined as a serum creatinine greater than 2 mg/dl; 4) advanced cardiac disease, New York Heart Association functional class III and IV; 5) gastrointestinal problems causing malabsorption syndromes and liver disorders; 6) active malignancies or the presence or history of prostate cancer; 7) autoimmune disorders; 8) chronic obstructive pulmonary disease; 9) cerebral vascular events; 10) history of thromboembolic disorders; and 11) use of medications that might have influenced the function of CNS and the H-P-G axis such as glucocorticoids, psychoactive drugs, and antiandrogens.

The study protocol was approved by the Human Studies Subcommittee of Hines VA Hospital. All subjects had signed the consent form before initiation of the study. Each individual had a complete physical examination including a rectal exam to assess the prostate gland. Any patient with an enlarged and /or nodular prostate and /or an elevated prostate-specific antigen was excluded from this study and referred to a urologist for further evaluation. Serum-free testosterone, LH, and FSH were measured at least two times, and hypogonadism was documented before initiation of treatment. Prostate-specific antigen, alanine aminotransferase, aspartate aminotransferase, and complete blood count, and lipid profile were performed at baseline and at the end of the study. All the blood samples for the study were obtained between 0800 and 1100 h.

The subjects were asked to respond to the Androgen Deficiency in Aging Men (ADAM) questionnaire (7, 21) before starting testosterone therapy. The initial SPECT study was also performed before testosterone replacement therapy. Treatment was then started with testosterone enanthate 200 mg im, and continued every 2 wk for 3 months. SPECT studies and the ADAM questionnaire were repeated at 3–5 and 12–14 wk after the initiation of the testosterone treatment.

The ADAM questionnaire was chosen for its simplicity. We are aware of the fact that this questionnaire was not sufficient to assess patients’ psychosocial response to treatment in detailed fashion.

SPECT study

^99mTc-hexamethyl-propylene-amine-oxime (HMPAO) was used to assess cerebral perfusion in brain SPECT studies. Studies were performed in an isolated room free from external stimuli (light, noise, excessive movement). Controlled environmental conditions began at least 15 min before the administration of radiopharmaceutical agent and continued throughout the test. Imaging was initiated 1 h after the administration of 740–925 MBq of ^99mTc HMPAO. Special care was applied to minimize head motion during the course of data acquisition (22, 23).

The SPECT studies were performed with a triple-head gamma camera (Trionix Triad, Trionix Gammasonics, Twinsberg, OH) fitted with ultrahigh-resolution fanbeam collimators. Images were taken at three-degree intervals in a 128 x 128 matrix with a total acquisition time of 27 min. Following acquisition, transverse brain images oriented parallel to the canthomeatal line were reconstructed with a Hanning filter using a cutoff frequency of 0.9 cycle/cm. All sets of images were analyzed by Statistical Parametric Mapping (SPM 96) (24) software (Wellcome Department of Cognitive Neurology, London, UK). SPM analysis spatially aligns and normalizes each SPECT study to standardized stereotactic space and performs a statistical comparison for differences in perfusion on a regional basis in an objective and operator-independent manner. The gray matter of the CNS has a significantly higher rate of blood flow that results in a higher count in this area. To increase the specificity, each tomographic study was scaled to the same total count as gray matter threshold and consequently eliminated all the voxels having count values less than 80% of the mean voxel values. The tomographic studies for each subject were aligned using rigid body translations and rotations and the aligned studies summed to form a mean study for each patient. Each mean study was registered to the Montreal Neurological Institute (MNI) stereotactic space by a set of 12 transformation parameters. Then each individual study was registered to MNI space using the same set of transformation parameters obtained for that subject’s mean image. Finally the registered individual studies were smoothed with a 16-mm full width, half maximum filter.

Assessment of serum-free testosterone, LH, and FSH

The serum-free testosterone levels were measured by Quest Diagnostics, Inc. Laboratory (Wood Dale, IL). A combination of equilibrium dialysis, extraction, chromatography, and RIA were used for this purpose. The normal serum-free testosterone ranges from 50 to 210 pg/ml.

The kits for serum LH and FSH were purchased from Bio-Rad Laboratories, Inc. Diagnostics Group (Hercules, CA), and both assays were performed at Hines VA Hospital. Two-site sandwich immunoassay applying direct chemiluminometric technology was used to measure the LH and FSH. The sensitivity of the assay for LH is 0.07 IU/liter and for FSH 0.3 IU/liter. Both assays measure up to 200 IU/liter of LH and FSH in serum. The interassay coefficient of variation is 10% for LH and 6.7% for FSH and intraassay coefficient of variation is 3.8% for LH and 4.5% for FSH. All other blood tests were performed in the clinical laboratory of the Hines VA Hospital.

Statistical analysis

A multistudy, different-conditions statistical design was used to make paired comparisons on a regional basis between the studies performed at baseline and 3–5 wk. The baseline studies were also compared with those performed at 12–14 wk after the initiation of testosterone replacement. Studies from the control group (a group of normal individuals) were performed and assessed in the same manner and intervals as the hypogonadal patients receiving testosterone replacement therapy. The changes in the study group were compared with the corresponding control group as well as with baseline (pretreatment) assessment. To reduce the influence of random variation and potential order effects, the magnitude of the regional differences between the study group at each time interval was required to significantly exceed that between groups of normal subjects (control group), scanned twice, who did not undergo therapy. SPM software reports the regions in which deviations between baseline and therapy groups significantly exceeded merely random variation. A correction was made for multiple comparisons, and all areas of activation with significance greater than Z = 3.1 or P = 0.01 were corrected for multiple comparison and displayed in coronal, transverse, and sagittal planes.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
One patient had history of hypothyroidism but had been euthyroid on replacement therapy for more than 3 yr. Two patients were taking terazosin 2 mg for more than 2 yr for benign prostate enlargement without any side effect.

Response to the ADAM questionnaire demonstrated that all of the patients reported a significant improvement in social interaction and mental well-being on testosterone therapy. Various degrees of enhanced physical performance and endurance were noticed in 80% of patients. Satisfactory improvement in sexual performance was reported by four of the seven patients. Using t test, the "yes" response to the questionnaire decreased from 57 ± 4 to 14 ± 2 at 3–5 wk, P less than 0.0001, and to 5 ± 2, P less than 0.0001 at 12–14 wk. A low score in "yes" response indicates enhanced well-being.

SPM grouped analysis of the changes at 3–5 wk after the initiation of testosterone replacement therapy from baseline, compared with those of controls, showed enhanced cerebral perfusion in midbrain and superior frontal gyrus (Brodman area 8) (Fig. 1). The activated area in the midbrain was located slightly below the left thalamus with a Z value of 4.40, uncorrected P less than 0.001 and corrected P less than 0.029 for multiple comparisons (Table 1). The second significantly activated area was shown at Brodman area 8 with a Z value of 3.35, uncorrected P less than 0.001 and corrected P less than 0.625 for multiple comparisons (Fig. 1 and Table 1). At 12–14 wk after the initiation of testosterone replacement therapy, the activated area in midbrain continued with Z value of 3.92, uncorrected P less than 0.001 and corrected P less than 0.14 for multiple comparisons. At this point, a newly activated area appeared in cingulated gyrus (Brodman area 24) with Z value 3.38, uncorrected P less than 0.001 and corrected P less than 0.577 for multiple comparison (Fig. 2 and Table 1). These brain regions are superimposed on the standard magnetic resonance tomographic slices.

View larger version (72K): [in this window] [in a new window]   FIG. 1. SPM-grouped analysis of the changes at 3–5 wk after the initiation of testosterone replacement therapy, compared with those from baseline, showed enhanced cerebral perfusion in midbrain best shown on sagittal (left) and superior frontal gyrus (Brodman area 8) shown on the section. These brain regions are superimposed on the standard brain magnetic resonance imaging.

View larger version (83K): [in this window] [in a new window]   FIG. 2. SPM-grouped analysis of the changes at 12–14 wk after the initiation of testosterone replacement therapy, compared with those from baseline, showed enhanced cerebral perfusion in midbrain best shown on sagittal section (left) and a new activated region in the cingulated gyrus (Brodman area 24) in all the sections. These brain regions are superimposed on the standard brain magnetic resonance imaging.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The presence of a strong bidirectional interaction between the H-P-G axis and the CNS has been generally well accepted. Several clinical trials have demonstrated testosterone replacement therapy in hypogonadal men improves mood and sense of well-being (1) and enhances the spatial cognition (25). Using standard neuropsychological instruments indicates the presence of linear and nonlinear associations between serum testosterone level and better mental control and maintaining verbal memory (3, 4). Although in this study we did not use a detailed neuropsychological instrument, our results have coincided with others. All of our patients experienced a significant degree of improvement in their psychosocial and sexual activities. Improvement in psychosocial and sexual functions, reported by these patients, was expected. However, increased blood perfusion in various regions of CNS is unique. Our data demonstrated for the first time that testosterone replacement therapy in hypogonadal men increased cerebral perfusion in various parts of the brain.

Accumulating in vitro and in vivo studies have demonstrated that testosterone and other steroids are present in the CNS. Moreover, it has been shown that various neuronal cells in rat such as astrocytes, oligodendrocytes, and neurons express enzymes that are involved in steroid production and metabolism (26). Testosterone in the CNS of man and other species, as in other organs, is either reduced to a more potent androgen dihydrotestosterone or aromatized to estradiol (27, 28, 29, 30, 31).

The enhancement in blood perfusion in selected areas of the brain such as midbrain and Brodman areas 8 and 24 could be caused by selective responsiveness of these areas to androgen. This is supported by presence of specific steroid receptors in the CNS in various species. Androgen receptors have been identified in the temporal lobe of human male brain, but the exact distribution and factors that modulate these receptors have not been well studied yet (10). Steroid receptors are also identified in preoptic, hypothalamus, amygdala, midbrain, frontal, prefrontal areas and cingulate gyrus in several species including primates (32, 33). To further support the direct effect of steroid hormones on the CNS, it was shown that androgen receptor production in the CNS is regulated by androgen (33) or perhaps estrogen (34) and blocked with flutamide, a specific androgen receptor antagonist (34). The increased blood perfusion in these areas of the brain could be due to the direct effect of testosterone on neuronal tissue and enhancement of metabolic functions of neurons that requires increased blood perfusion. However, it also could be due to the direct vasodilatory effect of testosterone on these areas. Despite some controversy, recent literature has demonstrated that testosterone treatment induced endothelium-independent relaxation in isolated rabbit coronary artery and aorta (35). Testosterone therapy has also been shown to improve angina pectoris and ST segment elevation in men (36, 37). Therefore, the idea of a testosterone-induced vasodilatation is not without precedent.

Furthermore, a growing body of evidence strongly suggests that steroid hormones including testosterone stimulate CNS growth, development, and function through an initial organizational role in prenatal period to the prevention of dementia during aging (15), and androgen is also involved in regulating synaptic neurotransmission (13).

Moreover, it is established that androgen modulates various neurotransmitters in the CNS. Testosterone decreases -aminobutyric acid concentration in the hypothalamus, which is blocked by flutamide, a testosterone receptor blocker (14, 15). Testosterone, probably by its conversion to estradiol, increases serotonin transporter mRNA expression in dorsal raphe nucleus (16), and it also increases the density of 5-hydroxytryptamine receptors and serotonin transporter sites in the forebrain (3, 16) of castrated male rats.

The SPECT technology has allowed many investigators to assess various pathophysiological processes in the CNS (22, 23, 24). HMPAO, a lipophilic radio pharmaceutical agent used in this study, crosses the blood brain barrier and localizes in neurons. Cerebral distribution of these radiotracers is proportional to the regional blood flow (22, 23, 24). Enhancement in blood perfusion in midbrain and Brodman areas 8 and 24 noted in this study objectively supports the influential role of testosterone in the CNS.

The midbrain has an important role in arousal and consciousness and is also involved in controlling eye, head, and body movement and coordination. Substantia nigra and red nuclei, which are part of reticular formation, are located in the midbrain. The largest cluster of serotonin-containing cells is located along the midbrain, and their axons innervate nearly every area of the CNS including cortex (22). Serotonin is involved in inducing sleep, sensory perception, temperature regulation, and mood control. Brodman areas 8 and 24 are part of the association areas of the cerebral cortex. Although these areas of the cortex are involved with higher mental functions, they are also associated with primary sensory and motor cortex (23). Brodman area 8 receives a prominent afferent input from the medial thalamic nucleus, and it is involved in strategic planning, higher motor action, and cognitive behavior (23). The cingulate gyrus (Broadman area 24), which is also a part of limbic cortex, is involved in emotional behavior and generalized arousal reaction, wakefulness, and memory (23, 38, 39). The anterior cingulate circuit is one of the main cerebral areas that are involved in motivation by balancing the inhibitory input of the supplemental motor area with its own stimulus that supports wakefulness and arousal (38). Increased blood perfusion in the areas of the brain that are rich in various neurotransmitters, serotonin in particular, and improvement in mental and physical function reported in this study and others lead us to suggest that the improvement in psychometric tests in hypogonadal man is, at least, partially due to the improvement in serotonin action and metabolism induced by testosterone replacement therapy.

In summary, testosterone replacement therapy, in our study, enhanced blood flow in the brain regions that are involved in memory, reasoning, judgment, emotions, and motor behavior, and it correlated very well with the clinical improvement seen in patients in our study as well as others. Whether these effects are due to direct androgen action or androgen conversion to estrogen will require further studies.

	Footnotes

 
This work was supported by a grant from Illinois AMVETS.

Abbreviations: ADAM, Androgen Deficiency in Aging Men questionnaire; CNS, central nervous system; HMPAO, ^99mTc-hexamethyl-propylene-amine-oxime; H-P-G, hypothalamic-pituitary-gonadal; MNI, Montreal Neurological Institute; SPECT, single-photon emission-computed tomography; SPM, statistical parametric mapping.

Received April 24, 2002.

Accepted April 11, 2003.

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