News from ASRM 2018: Some interesting research papers on male factor infertility

The American Society of Reproductive Medicine just wrapped up its 2018 scientific congress and expo at Denver, Colorado.  Here are some of the research highlights presented at the society about male factor infertility. 

A diagnosis of azoospermia puts men at increased risk of death

Results of a large prospective cohort study report a link between azoospermia and increase the risk of mortality. The study findings were jointly presented by Scandinavian and American researchers at the meeting. Interestingly, the increased risk of dying was not observed for men with oligospermia. 

The authors analyzed data of 51,289 men from the Danish National IVF register from 2006 through 2016 and followed those with azoospermia till the end of study period, death or till they emigrated from Denmark. Vasectomized men and men with normal semen parameters were used as a reference.

The average follow-up period was eight years. Men with azoospermia faced twice the increased risk of dying as compared to men with oligospermia and normal semen parameters.  The mean age at death was 48.8, and the most common cause of death was CVD and cancer.  

Another previous cohort study from Denmark also documented that as the percentages of motile and morphologically normal spermatozoa and semen volume increased, mortality decreased in a dose-response manner (P(trend) < 0.05).

Peter Schlegel, MD, ASRM President-Elect, noted, “A man’s infertility status is a component of his whole health status. Semen analysis results exist on a continuum, but a diagnosis of azoospermia may be a call to take a closer look at a man’s overall health in addition to his reproductive function.”

Thus, Semen parameters could be a key biomarker of overall male health.

Abstract: Male factor infertility and risk of mortality: a register-based cohort study

Inadequate sleep is linked to Low Testosterone Levels in Men

Lack of sleep is associated with decreasing testosterone levels in US male reports the results of a study presented at the ASRM scientific congress at Denver, Colorado. The other culprits for low testosterone were aging, increasing BMI and alcohol consumption.

The researchers examined the data on nearly 2300 males, aged 16-80 years from The National Health and Nutrition Examination Survey (NHANES). The subjects reported an average sleep duration of 6.86 hours (2-12 hours) and had average serum testosterone levels of 303.33 ng/dL (43.39 ng/dL to 779.2 ng/dL).

After accounting for confounders, the researchers noted that serum testosterone levels decreased by 0.49 ng/dL per year of age, 5.85 ng/dL per lost hour of sleep, 6.18 ng/dL per BMI unit increase, and 2.99 ng/dL per each unit increase in alcohol consumption.

Robert Brannigan, MD, a member of ASRM’s Board of Directors, remarked “Reduction in testosterone level can have deleterious effects on a man’s health beyond his fertility and sexual function.  Testosterone is essential for good metabolic function and decreased levels of the hormone are associated with metabolic syndrome and cardiovascular disease.  Low testosterone can contribute to fatigue and depression, as well. A balanced diet and a healthy sleep routine are interventions a man can take on his own to help keep his T levels stable.”

Abstract: Impaired sleep is associated with low testosterone in us adult males: results from the national health and nutrition survey

A decline in sperm count and motility observed in North America and Europe

Two studies presented at the ASRM scientific congress showed that semen quality has seen a decline in patients undergoing fertility treatment and donors in this century. In the first study, researchers from one European and the other North American center evaluated the results of semen analysis from 119,972 men seeking infertility treatment between 2002 through 2017.

The researchers looked at the most reliable indicator of male fertility, the total motile sperm count (TMSC) and grouped the study population into 3 groups: TMSC greater than 15 million; TMSC 5 to 15 million: and TMSC zero to 15 million.

The percentage of patients in Group 1 (highest TMSC) declined from 84.7% in the time period 2002-2005 to 79.1% in 2014-2017, while the percentage in Group 3 (lowest TMSC) rose from 8.9% to 11.6% over those time periods.

TMSC decreased by 1.1% per year as the men aged and thus patients who belonged to Group 1 were slowly slipped into Group 2 as they age.   

For the second study researchers from the Ichan School of Medicine at Mount Sinai, California Cryobank, and Reproductive Medical Associates of New York observed a progressive decline in semen quality in donors over 11 years in six cities:  Los Angeles, Palo Alto, Houston, Boston, Indianapolis, and New York City.

Over a period of 10 years, the researchers analyzed 124,107 semen specimens provided by 2586 donors aged 19 to 38. They looked at three semen parameters- total count, average concentration, and TMSC-  as a whole and region by region.

A decrease in all three parameters was observed in all regions, except New York. ASRM President-elect Peter Schlegel, MD, said, “The trend toward lower sperm counts in this study is concerning.  Whether the causes underlying it are environmental or lifestyle-related, they will be difficult to parse out.  Pollution, endocrine disrupting chemicals, poor exercise habits and convenient, yet nutritionally poor, dietary choices could all play a part.  Similarly, men may now be referred for advanced medical care despite having lower sperm numbers, reflecting our improved reproductive treatments.  Men planning to conceive should do what they can to achieve their best overall health to optimize their sperm quality.”

Abstract: Total motile sperm count trend over time across two continents: evaluation of semen analyses from 119,972 infertile men

Abstract: Eleven-year longitudinal study of U.S. sperm donors demonstrates declining sperm count and motility

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How to evaluate the azoospermic male? ASRM committee recommendations

The Practice Committee of the American Society for Reproductive Medicine (ASRM) in collaboration with the Society for Male Reproduction and Urology recently issued guidelines about the diagnosis and evaluation of the azoospermic male partner. The committee opinion was published recently in journal Fertility and Sterility.

Of all the infertility cases about 30% is because of ‘male-factor’ of whom about 10-15% of men will receive the diagnosis of azoospermia. Recent studies have documented a decline in sperm count globally with a concurrent increase in male factor infertility.

Azoospermia is classified into 3 categories-pre-testicular, testicular, and post-testicular according to the etiology but in clinical practice, azoospermia is commonly classified as obstructive azoospermia (OA) and nonobstructive azoospermia (NOA) which can be of central or testicular origin. 

 

Azoospermic men with normal size testes with normal serum follicle-stimulating hormone (FSH) levels are more likely to have obstructive azoospermia, while men with a significant elevation in FSH have a testicular failure, and thus testicular NOA.

On the other hand, low gonadotropins levels with low to low-normal T points towards a diagnosis of central NOA.

According to the American Society for Reproductive Medicine (ASRM) Practice Committee, the evaluation begins with a standard reproductive history and physical examination, followed by measurement of serum FSH and testosterone(T), luteinizing hormone (LH), free T, estradiol, and prolactin. Most experts state that an FSH >7.6 mIU/mL would be considered abnormal.

Semen volume and FSH levels play an essential part in determining the etiology of azoospermia. If men have low semen volume and normal FSH the lab test should be repeated after 2-3 days of abstinence, with attention to proper collection technique. A post-ejaculate urinalysis is advised to rule out retrograde ejaculation. If there is no retrograde ejaculation and semen pH is < 7.2, a transrectal ultrasound (TRUS) is the next step to identify a possible ejaculatory duct obstruction (EDO).

In men with normal semen volume, determining serum FSH and testicular volume is critical to decide in favor of testicular biopsy for the prognostic purpose. Elevation of serum FSH along with low testicular volume strongly suggests NOA. In case sperm retrieval is planned for ICSI, the testicular biopsy is deferred till the sperm retrieval when a biopsy sample is concurrently sent to the lab.

A normal testicular biopsy indicates an obstruction at some level in the reproductive tract. If the cause of OA is not iatrogenic, then the cause is a bilateral epididymal obstruction. It should be confirmed by surgical exploration. Vasography is only indicated if reconstructive surgery is planned simultaneously.

In men with the congenital bilateral absence of the vasa deferentia (CBAVD or vasal agenesis), unilateral renal agenesis should be ruled out. Most men with vasal agenesis will also have seminal vesicle hypoplasia or agenesis which manifests as low semen volume and pH.

CBAVD is also strongly associated with mutations of the CFTR gene. Hence, before planning a sperm retrieval for ICSI in men with CBAVD or congenital unilateral absence of the vas deferens (CUAVD), genetic testing should be offered to female partner to rule out her carrier status (∼4%) for CFTR gene.

Men with suspected NOA due to an elevated FSH and a normal ejaculate volume have bilateral testicular atrophy.  They should be offered genetic testing to exclude chromosomal abnormalities and Y-chromosome microdeletions (YCMD). A diagnostic testicular biopsy is not usually indicated in such cases. 

Low gonadotropins levels may be because of feedback inhibition secondary to exogenous T or illicit anabolic-androgenic steroid use, a high T level with suppressed gonadotropins will be confirmatory in such instances.

In men with markedly elevated serum FSH levels, the diagnostic testicular biopsy is only indicated when there is uncertainty about the etiology of the azoospermia- obstructive or nonobstructive. In all other cases, a testicular biopsy is done when sperm retrieval is planned for ICSI.

A diagnostic biopsy is also not necessary in patients with expected obstruction and normal FSH levels.

Full-text Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology

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Continuing and Robust decline in sperm count in men signals catastrophic implications beyond fertility.

Courtesy: bbc.com 

A huge systematic review and meta-analysis has found a continuing decline in sperm count by an average 1.4% per year among western men between the year 1973 to 2011. The results made headlines and were published 25 July 2017 in Journal of Human Reproduction Updates. The decline of 50% in four decades was so significant that the study results made headlines.

Hagai Levine, the lead researcher and faculty member of the Braun School of Public Health and Community Medicine at Hebrew University-Hadassah in Jerusalem says, “This is a wake-up call to study the causes of this decline, aiming to prevent further deterioration.” 

Whether sperm counts have declined or not is debated since very long and the controversy remains fluid because of limited number of studies addressing this issue.

Besides being the first step in diagnosing male factor infertility, sperm count is of considerable public health importance. Reduced sperm count is a predictor of high all-cause morbidity and mortality, besides incurring a high financial burden on the society. It is also linked to a range of male reproductive problems like cryptorchidism, hypospadias, testicular cancer, low testosterone levels and increased utilization of Assisted Reproductive Techniques.  There has been a 65% increase in IVF treatments since 2003 according to a survey results of young US adults by the Reproductive Medicine Associates of New Jersey.

Low Sperm Counts is also a mirror of environmental influences on our endocrine system because of modern life style. They reflect the influence of endocrine disrupting chemicals, pesticides, changes in environmental temperature and life style factors like smoking, diet, stress and BMI.

The researchers identified 7518 studies meeting the study protocols, from which 185 studies amounting to nearly 43000 subjects who provided samples between 1973–2011 were selected for final analysis.

Data was available across 6 continents and nearly 50 countries.

For final analyses, the countries were grouped into ‘Western’ including studies from North America, Europe, Australia and New Zealand and ‘Other’/ ‘Non-Western’ including studies from all other countries like South America, Asia and Africa.

Meta- regression analyses showed that mean sperm concentration (SC) was 81 million/ml, the mean total sperm count (TSC) was 260 million and the mean year of data sample collection was 1995.

Sperm concentrations declined by 50% and total sperm count by nearly 60% over the years among men unselected by fertility primarily from North America, Europe, Australia and New Zealand. The study saw no significant declines for studies from South America, Asia and Africa, possibly because of limited number of studies available from these geographic areas. 

The statistic reflects the fact that an increasing number of men will have sperm counts below any given threshold for sub-fertility or infertility. Quite a large percentage of Western men have concentration below 40 million/ml, decreasing the probability of natural conception.

This decline remained unchanged after controlling for various confounders like age, abstinence time, method of semen collection, method of counting sperm, selection of population and study exclusion criteria, number of samples per man and completeness of data.

While it is not possible to rule out the falling trend in semen parameters in non-western countries it is certain that the decline is not as steep as observed for their western counterparts.

The continuing decline of sperm count in western males is regarded as ‘canary in the coalmine’ for male health across the life span and calls for more studies and research urgently to put a stop to this damning trend.

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