The andropause and memory loss: is there a link between androgen decline and dementia in the aging male?

Robert S. Tan, Shou-Jin Pu

Geriatric Medicine Fellowship Program, University of Texas, Houston, United States

Asian J Androl  2001 Sep; 3: 169-174

Keywords:  andropause; memory loss; androgens; testosterone; aging; dementia

Abstract

1 Introduction

The andropause can be defined as a time in the life of aging males where hormones decline including that of androgens^[1]. Alternative names for the Andropause have been suggested including the Male Menopause, Androgen Deficiency in Aging Male (ADAM) and Partial Androgen Deficiency in Aging Male (PADAM)^[2,3]. While we argue for more accuracy in defining this physiological process of aging, the lay press has predicted that the term that will likely stick in the minds of the public is the andropause^[4].

Cognition on the other hand, is the mental process that includes language, calculation, visual-spatial abilities, memory, reasoning, learning, social skills,imagination and attention span. With age, cognitive function may remain stable or decline. In general, cognitive function that remains stable includes attention span, everyday communication skills, language skills, and simple visual perception. Cognitive function that decline includes selective attention, naming of objects, verbal fluency, complex visualspatial skills and language analysis^[5] . Moreover, age-related memory changes vary depending on the type of memory. The acquisition and early retrieval of recently acquired information is diminished; long-term memory retention does not seem to change with increasing age^[6,7]. The cognitive tests commonly administered are modified Mini-Mental Status Examination, the Digital Symbol subset of the WAIS-R, and the Trail B section of the Trail Making Test. Imaging with MRI and PET scans are supplementary to the clinical assessment of cognitive decline.

Memory loss, a domain of cognitive function, occurs during the andropause. This may be secondary to the effects of declining hormones. With age, the levels of hormones may remain the same, elevated or reduced. The circulating levels of hormones that decline in aging males are

• Testosterone: total and free testosterone

• Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS)

• Growth hormone and insulin-like growth factor-1 (IGF-1)

• Other hormones including triiodothyronine, renin and aldosterone

2 Is there a link between   memory loss to  low endogenous levels of testosterone in the andropause?

The level of total, bioavailable and free testosterone declines in aging male. Testosterone declines about 100 ng/dL per decade after age 50, but bioavailable testosterone and free testosterone decline far more dramatically. Bioavailable testosterone level<70 ng/dL or total testosterone level<300 ng/dL are diagnostic of male hypogonadism^[10]. Male hypogonadism can lead to symptoms such as decreased libido, erectile dysfunction, fatigue, loss of energy, muscle weakness and even memory loss^[11,12]. 

In a study design that was described as exploratory analysis in a population based cohort, Barrett-Connor et al studied 547 community dwelling men aged 59-89 years in Rancho Bernado in California^[13]. Serum total and bioavaiable testosterone as well as estradiol levels were measured. Subsequent to the blood tests, 12 standard neuropsychological instruments were administered including two items from the Blessed Information Memory Concentration (BIMC) Test, three measures of retrieval from Buschke-Fuld Selective Reminding Test, a category fluency test, immediate and delayed recall from Visual Reproduction Test, the Mini-Mental State Examination with individual analysis of the Serial Sevens and the World Backwards components, and the Trail-Making Test Part B. In age and education adjusted analyses, men with higher levels of total and bioavailable estradiol had poorer scores on the BIMC Test and Mini Mental State Examination. Men with higher levels of bioavailable estradiol had poorer scores on the BIMC Test and the Mini Mental State Examination. Men with higher levels of bioavailable testosterone levels had better scores on the BIMC Test and the Selective Reminding Test.

3 Does replacing testosterone improve memory in the andropause?

Epidemiological studies like that above suggest a link; it will be interesting to determine the therapeutic effects of testosterone. Janowsky et al reported that an increase in spatial cognition, but no change in other cognitive domain in healthy old men after transdermal testosterone treatment for three months^[15]. He also found that working memory improved in healthy old men after testosterone supplementation for one month^[16]. It is to be noted that this study was performed on healthy older men with no prior history of memory loss. This study suggests that testosterone may enhance memory even in normal men. This study unfortunately has not been replicated.

Memory loss is an established symptom in the andropause according to our study of 302 men^[17]. Our study on older patients describes how they perceive and understand this aging process. We performed a non-interventional, cross-sectional study to determine what male patients report as symptoms of the andropause. In particular, we wanted to ascertain if memory loss was a predominant feature. Our hypothesis was that androgens, such as testosterone were responsible for visual-spatial and memory development. As such the aging process of andropause, which is associated with declines in testosterone levels would lead to memory loss. A standardized questionnaire of 22 questions was administered to 302 outpatients of a medical center. Information on patient demographics, understanding of the andropause, and concomitant risk factors were collected.

Of the 302 patients, 71 % were above 60 years and whites predominated at 87 %. Memory loss was reported in 36 % of the patients who felt that they had experienced the andropause. It was the third most common symptom after erectile dysfunction (46 %) and general weakness (41 %). Twenty two percent of the 302 patients had a history of diabetes. Among those that reported to have undergone the andropause, diabetic patients were more likely to report memory loss (P=0.03, OR=1.9, CI=1.1-3.4). Sixty-four percent of patients reported the onset of andropause to be between 50-70 years (the median age being 50-60 years).

Our own study highlights the importance of testosterone in maintaining cognitive functions. It supports studies of testosterone replacement in men undergoing the andropause and who have concomitant dementia. This results parallel recent reports of the neuroprotective effects of estrogens in preventing dementia. We feel that diabetes is associated with memory loss in our study because of the additional insults to cognitive function of the brain secondary to ischemia.

In our pilot study with testosterone replacement in 6 demented hypogonadic men, we hypothesized that testosterone replacement in elderly hypogonadic males may improve cognition, in particular visual-spatial^[18].

The pilot study design was single blind and interventional in nature. Eighteen consecutive male patients with a diagnosis of dementia had their testosterone levels measured. Five patients of 18 (28 %) were deemed biochemically hypogonadic ( 240 ng/dL). Initial MMSE ranged from 17 to 22. The Clock Drawing Test (CDT), being a good measure of visualspatial abilities was used. Normal PSA levels were essential before treatments. The baselines were repeated at 3, 6 and 9 months of treatment with intramuscular testosterone 200 mg.

Results obtained were baseline mean testosterone=126.4 ng/dL, MMSE=19.4, CD=2.2, PSA=0.98. At 9 months of treatment, testosterone levels increased in the 5 patients from a mean of 126.4 ng/dL to 341 ng/dL (P=0.11). PSA were also elevated from a mean of 0.98 to 1.37 (P=0.07). MMSE improved from a mean of 19.4 to 23.2 (P=0.02) (Figure 1), CDT also improved from 2.2 to 3.2 (P=0.03) (Figure 2). Four of the 5 patients continued treatments beyond the 9 months; one was stopped because of hypersexual behavior.

This pilot study performed in aging males suggested that testosterone could indeed improve cognition, including visual-spatial skills in mild to moderate dementia. This could be due to the modulation of neurotransmitters by testosterone. The next step would be for a randomized, placebocontrolled double blind study to confirm these preliminary findings.  

Although our study suggests that replacing testosterone does improve cognition in hypogonadic demented older men; other researchers have not found similar effects. For example, Sih et al reported no effect on memory; recall or verbal fluency tests in older hypogonadal men after testosterone replacement for 12 months. One possible reason for the failure to find such an effect was because spatial cognition was not measured in this study^[19]. We on the other hand, distinctly found improvements in visual-spatial skills in our study. We are supported by the study of Cherrier et al. They also reported that testosterone treatment increase spatial verbal memory^[20]. It is also possible that effects of testosterone on memory do not become apparent until after several treatments and till eugonadic levels are reached^[21].

4 Is there a link between memory loss to low endogenous levels of DHEA and DHEA-S in the andropause?

DHEA is a steroid secreted by the adrenal cortex. In circulation, DHEA exists both free and bound to sulfate (DHEA-S). Secretion of DHEA is controlled by adrenocorticotrophin. DHEA has been shown to have antiglucocorticoid action. Its physiological role and mechanism of action are unclear.  It has been suggested that DHEA may have protective effect on diabetes, cancer, aging and autoimmune diseases^[22]. The secretion of DHEA decreases significantly with age. Age-related androgen failure has been called the adrenopause.

The observation that DHEA and DHEA-S concentration decrease markedly with age has led to the hypothesis that decline of DHEA level may contribute to age-related changes in cognition. It has been suggested that one contributing factor to the progress of Alzheimer's disease may be lack of protective effect of DHEA^[23]. Sunderland et al demonstrated that there are reduced DHEA-S levels in Alzheimer's disease^[24].

Carlson et al in Canada studied the relationships between DHEAS levels and memory in both male and female Alzheimer's patients. In that study, 52 patients with a mean age of 76.2 were studied. Each was assessed using the Rivermead Behavioral Memory Test and also had their DHEAS levels measured. Those with higher levels of DHEAS scored better in remembering name associated with a picture, digit span and the Mini Mental Status Examination^[25]. Yanase and his colleagues in Japan found that the level of DHEA and DHEA-S levels decreased in patients with dementia either from Alzheimer's disease or cerebrovascular disease^[26]. His study notably only had a small sample of 19 patients with Alzheimer's disease. Kalmijn et al in the Netherlands reported that there was an inverse, but non-significant, association between DHEA-S and cognitive decline^[27]. This was based on a community study of 189 healthy subjects. Interestingly, it was found in this study that basal free cortisol was positively related to cognitive impairment.

Table 1.  summarizing relationship of endogenous DHEAS and Cognition.

5 Does DHEA replacement improve memory in the andropause?

DHEA is widely used as a health supplement. Many older adults use this steroid to retard age-related cognition as well as physical changes. Investigations of the effects of endogenous DHEA and DHEA-S on age-related cognition changes and the efficacy of DHEA supplementation in slowing cognitive decline are an important public health issue. The Baltimore Longitudinal Aging Study do not support the hypothesis that decline in endogenous DHEA-S contributes to cognitive decline in older men after 31 years follow up^[28]. The study of Carlson et al also failed to provide any evidence that DHEA-S is protective against declarative memory decline with aging in healthy elderly men and women^[29].

Wolf et al reported that after two weeks of DHEA replacement has no strong beneficial effect on any of the cognitive tests in healthy elderly men and women^[30]. In that study, 40 men took 50mg of DHEA daily for 2 weeks, followed by a 2 weeks wash out period and a 2 weeks placebo period. In the study, women showed better cognitive performance in one of six cognitive tests (picture memory) after DHEA. However, DHEA replacement did not show any strong beneficial effect on any measured psychological or cognitive parameters. The study could be criticized because of the study design, small size and the many possible confounders in the study. In another study conducted in France with a double blind randomized fashion, 280 healthy elderly subjects were given either a placebo or DHEA. After one year, of 50mg/day, no difference in cognition was reported^[31].

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Correspondence to: Dr. Robert S. Tan, Geriatric Medicine Fellowship Program, University of Texas, Houston, USA.
E-mail:  robert.s.tan@uth.tmc.edu
Received 2001-07-16    Accepted 2001-08-13