Sperm Count Decline

A 2017 systematic review and meta-regression analysis, conducted by an international group of researchers, reported a significant decline in sperm count among Western countries from 1973 to 2011. Hagai Levine and colleagues searched PubMed/MEDLINE and EMBASE for English-language studies, published 1981-2013, that used sperm concentration (SC) and/or total sperm count (TSC) to assess fertility in men. Studies involving men with infertility issues or exposure to environmental factors known to affect sperm count were excluded. Sperm motility and morphology were not part of the analysis because these factors were rarely included in older studies.

To perform the meta-regression analysis, Levine et al used 244 estimates of SC and TSC from 185 studies, involving a total of 42,935 men who had provided semen samples in 1973-2011. The researchers divided the 185 studies into two groups: one group included studies of men with known fertility (men who had fathered a baby), and the other consisted of studies that did not specifically select men with known fertility (usually involving young men in college or the military). The researchers also divided the data into two geographical groups: Western (North America, Europe, Australia, and New Zealand) and Other (South America, Asia, and Africa).

Overall, sperm concentration declined significantly between 1973 and 2011 (slope in unadjusted simple regression models -0.70 million/ml/year; 95% CI: -0.72 to -0.69; P< 0.001; slope in adjusted meta-regression models = -0.64; -1.06 to -0.22; P = 0.003). Semen volume did not significantly change during the study period. The decline was driven by data from the Western countries; South America, Asia, and Africa showed no significant declines, which was consistent with earlier studies. Western men unselected by fertility showed the greatest decrease; SC in this group declined 52.4% (-1.4% per year) and TSC declined 59.3% (-1.6% per year) over the four decades. Controlling for pre-selected variables (age, abstinence time, method of semen collection, methods of counting sperm, selection of population and study exclusion criteria, number of samples per man and completeness of data) had little affect on the slopes of decline. The researchers also performed an analysis of data collected from 1996-2011; this analysis showed no evidence that the decline was ‘leveling off’. The researchers say that restricting their review to English language articles may have limited their results concerning non-Western countries.

“Declining mean SC implies that an increasing proportion of men have sperm counts below any given threshold for sub-fertility or infertility,” write Levine et al. “The high proportion of men from Western countries with concentration below 40 million/ml is particularly concerning given the evidence that SC below this threshold is associated with a decreased monthly probability of conception.” In addition to infertility, reduced sperm count is associated with overall morbidity and mortality. The authors say that environmental and lifestyle factors such as exposure to endocrine-disrupting chemicals (prenatally), pesticides, smoking, diet, and stress may be contributing to the decline. Levine et al state: “…a decline in sperm count might be considered as a ‘canary in the coal mine’ for male health across the lifespan. Our report of a continuing and robust decline should, therefore, trigger research into its causes, aiming for prevention.”

Levine H, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Human Reproduction Update. 2017; 1-14.

Preventing Flu

Annual vaccination for influenza is viewed as the best preventive intervention available for an illness that can lead to pneumonia and other complications for at-risk individuals; yet, several articles in medical literature discuss the difficulty of creating an effective vaccine and point to gaps in our understanding of immunity. Because influenza viruses mutate rapidly (antigenic drift) and dominant strains can vary from year to year, people are advised to be vaccinated yearly with the newest vaccine. Yet, evidence indicates that yearly vaccination does not increase protection from flu.

John Treanor in his editorial commentary “Flu Vaccine – Too Much of a Good Thing?” says, “Over the last several years, many of these studies have suggested that vaccination in prior seasons can reduce the effectiveness of vaccination in the current season, a phenomenon first identified by Hoskins and colleagues in a British boarding school…” (Hoskins TW, et al. Lancet. 1979;1:33-5). These studies led to the antigenic distance hypothesis, which posits that antigenically-similar vaccines given in two successive years cause the immune system to “…[focus] on the shared epitopes at the expense of novel epitopes on the second virus that might be important for the protection against a third, antigenically drifted virus.”

A 2017 Canadian study from the Canadian Vaccine Effectiveness network found evidence that prior vaccination affects the response to current vaccination. This study, led by Danuta M. Skowronski, showed that vaccine effectiveness (VE) declined when the current vaccine was similar to the previous one and the circulating virus was a drift variant. When two successive vaccines were identical and a poor match for the circulating virus, as in the 2014-15 season, the effect of prior vaccination was “pronounced and statistically significant,” according to Skowronski et al. Vaccine effectiveness for that year was 65%; when that vaccine was given to people who had also been vaccinated the previous year, VE was -33%; they were more likely to get the flu.

Arnold S. Monto and colleagues at University of Michigan School of Public Health (Ann Arbor) point out that “…prior infection is more effective than vaccination in preventing subsequent infection, an observation that remains undisputed.” In their review article, Monto et al refer to animal research in which ferrets infected with A(H3N2) virus displayed more protection against the lethal A(H5N1) virus than ferrets vaccinated with A(H3N2). Although animal research does not necessarily translate to human experience, Monto et al say, “…there is clearly a need to balance the prevention of severe influenza in young children, who are at high risk of complications, and the possible benefits of allowing the first infection in life to take place without modification by prior vaccination.”

The observation that flu infection provides better protection than vaccination was supported by a 2011 Dutch study, led by Rogier Bodewes. Bodewes and Dutch colleagues compared virus-specific CD8 T cell immunity in 14 children with cystic fibrosis (mean age 6.2 years) who were vaccinated annually to CD8 T cell immunity in 27 unvaccinated children (mean age 5.9 years). The Netherlands recommends flu vaccination for children who are at high risk for complications but does not recommend universal vaccination for healthy children; so, the researchers did not have access to a group of healthy, vaccinated children for the study. Despite the difference in health status, the two groups of children had similar virus-specific CD4 T cell and antibody responses. However, only the unvaccinated group showed an age-dependent increase in virus-specific CD8 T cell response, as children experienced infection. The authors say, “Our results indicate that annual influenza vaccination is effective against seasonal influenza but hampers the development of virus-specific CD8 T cell responses.” CD8 T cells secret gamma-interferon against viruses and prevent unnecessary antibody formation. In addition, “…memory CD8 T cells provoked against seasonal influenza A viruses will cross-react with other influenza A viruses, even with those of other subtypes.”

Are there ways to prevent flu and lessen its severity besides vaccination? A 2008 commentary by John J. Cannell and colleagues reported, “Vitamin D alone, whether from ultraviolet lamps, the sun, or from supplements, reduces the incidence of respiratory infections.” This article cautions against using cod liver oil because today’s products typically contain too much vitamin A and too little D.

A 2016 review reported that supplementation with the antioxidant vitamin C decreased pneumonia risk in people who were C-deficient but not in the well-nourished. Its use also decreased the time that patients with community-acquired pneumonia spent on mechanical ventilation. Vitamin C plays a role in regulating the lung’s immune system.

Some botanicals also have anti-flu effects. James A. Duke, PhD, in his book The Green Pharmacy recommends elderberry, echinacea root, and fresh ginger root (in boiling water as a tea) for their anti-viral activity. Vaccination is just one, not the only, method for reducing risks from flu.

Bodewes R, et al. Annual Vaccination Against Influenza Virus Hampers Development of Virus-Specific CD8 T Cell Immunity in Children. Journal of Virology. November 2011: 11995-12000.

Cannell JJ, et al. Cod Liver Oil, Vitamin A Toxicity, Frequent Respiratory Infections, and the Vitamin D Deficiency Epidemic. Annals of Otology, Rhinology & Laryngology. 2008;117(11):864-870.

Li Y, Li G. Is Vitamin C Beneficial to patients with CAP? (abstract) Curr Infect Dis Rep. Aug 2016;18(8):24.

Monto AS, et al. The Doctrine of Original Antigenic Sin: Separating Food From Evil. J Infect Dis. June 15, 2017;215:1782-1788.

Skowronski DM, et al. Serial vaccination and the antigen distance hypothesis: effects on influenza vaccine effectiveness during A(H3N2) epidemics in Canada, 2010-11 to 2014-15. J Infect Dis. 2017;215:1059-69.

Treanor J. Flu Vaccine—Too Much of a Good Thing? J Infect Dis. April 1, 2017;215:1017-1019.

Malnutrition and Aging

A Belgium research team conducted a systematic review of six high-quality, longitudinal studies that investigated risk factors for malnutrition in the older population. Malnutrition is associated with increased morbidity, mortality, and cost of care; yet, it is too often undetected or ignored. These studies assessed nutritional status using anthropometric measurements (body weight, BMI data) and/or nutritional screening tools that look at factors like loss of appetite, difficulty eating, weight loss, and mobility.

The variables that statistically correlated with the development of malnutrition between baseline and reassessment included frailty (for institutionalized people), excessive polypharmacy (defined as taking ≥ 10 drugs), functional decline, difficulty walking stairs (for persons under 75 years old), decline in cognitive capacity and dementia, Parkinson’s disease, constipation, loss of over 5% of initial handgrip strength, and poor or moderate self-reported health status. Poor appetite, difficulty swallowing, and needing assistance to eat were other risk factors. Loss of interest in life among people living in institutions or communities was the only psychological factor linked to the development of malnutrition. Age, in itself, was not a risk factor for malnutrition, according to most of the reviewed studies.

The review also found three variables linked to better nutritional status: daily oral hygiene, sustained interest in life, and ability to eat unaided (community subjects). The reviewers comment, “Even in cases of adequate nutrient and energy intake, the nutritional

status of older adults can be challenged by a compromised nutrient metabolism (such as absorption, distribution, storage, utilization, and excretion), drug-nutrient interactions, or altered nutrient needs.”

While highlighting malnutrition in older population is useful, using anthropometric measures and nutrition screening tools seem blunt instruments for assessing malnutrition to me. Ralph Campbell, MD, points out that common conditions, such as low energy or depression, memory loss, insomnia, reduced alertness, dry skin, and cold hands and feet can, themselves, indicate nutrient deficiencies that can be reversed with supplementation. “Rather than passing off these conditions as just being a product of ageing, how much better if would be to find more tangible causes….Supplements of essential nutrients such as vitamins and minerals including iodine taken in adequate doses can prevent or reverse many of the symptoms associated with age.”

Campbell R. Much More Than “Ageing.” Orthomolecular Medicine News Service. July 17, 2017.

Fávaro-Moreira NC, et al. Risk Factors for Malnutrition in Older Adults: A Systematic Review of the Literature Based on Longitudinal Data. Adv Nutr. 2016;7:507-22.

Mind-Body Interventions Change Gene Expression

Mind-body interventions (MBI), such as mindfulness, yoga, Tai Chi, Qigong, breath regulation, and relaxation response exercises, downregulate the nuclear factor kappa B (NF-κB) pathway, according to a 2017 review by Ivana Buric and colleagues: “…this is the opposite of the effects of chronic stress on gene expression and suggests that MBI practices may lead to a reduced risk of inflammation-related diseases.” NF-κB is produced when stress activates the sympathetic nervous system. It activates the expression of genes responsible for inflammatory cytokine production: “Lower activity of NF-κB suggests reduced inflammation.”

Buric et al found 18 studies in PubMed (through September 2016) that investigated mind-body practices using gene expression analysis. Eighty-one percent found statistically significant downregulation in the NF-κB pathway with MBI use. Two uncontrolled studies that found no change in gene-expression had small sample sizes (ten participants and two participants), inadequate for providing statistical power. The third study used a different method for detecting gene expression; the others used the TELiS bioinformatics analysis.

Biological inflammation markers were not affected as quickly as gene expression: “…the studies that employed circulating proteins (eg, CRP, interleukins, or cortisol) generally did not find significant results.” Buric et al note that the two studies that controlled for practice frequency found some significant biological results when people who used MBI regularly were analyzed separately. Also, most of the reviewed studies lasted for no more than three months. While gene expression changes after a few weeks or less, circulating biological proteins did not.

The review authors say, “Although the studies reviewed here provide preliminary evidence that MBIs are associated with a reduced risk of inflammation-related diseases, it is unclear whether they are more effective than a range of lifestyle changes commonly recommended as a part of healthy lifestyle, such as regular exercise and a Mediterranean diet.”

Buric I, et al. What Is the Molecular Signature of Mind-Body Interventions? A Systematic Review of Gene Expression Changes Induced by meditation and Related Practices. Front Immunol. June 2017; 8:670.