Looks Can Be Deceiving: Sperm DNA Fragmentation and Male Fertility

FecundationMany of our new male fertility patients are perplexed about their inability to conceive. They have been told that it is not a female factor and that their semen quality is excellent. Their sperm have perfectly shaped oval heads, normal-sized mid-pieces, and straight well aligned tails, and they demonstrate great motility (i.e. sperm movement) and forward progression. On visual inspection, one would assume that their sperm could fertilize an egg with ease producing a normal embryo that would develop into a beautiful baby.  Unfortunately, in spite of their good looks, their sperm may never be baby-makers. The integrity of their DNA might be impaired. Even if a sperm is able to fertilize an egg, DNA fragmentation will most likely prevent normal development of an embryo, resulting in a failed pregnancy or miscarriage.

It’s a growing concern amongst fertility specialists that sperm DNA fragmentation might be the cause of many couples’ inability to achieve a pregnancy naturally or through an assisted reproductive technology protocol using IUI, IVF, or ICSI.  Many medical practices specializing in fertility have added sperm DNA fragmentation testing to the battery of tests they typically perform to evaluate a man’s fertility potential. Our practice recently started screening male fertility patients with known association for higher levels of DNA fragmentation such as advanced male age, presence of large varicoceles, history of miscarriages. We have found greater than 40% of these men have abnormal levels of fragmentation. This has resulted in many questions from patients anxious to know what it means, how it happens, and what options are available to enable them to achieve a pregnancy. We hope to answer many of these questions here. We have provided links for those wanting additional information.

Genetic engineerring

The Nobel Prize in Physiology or Medicine 1962 was awarded jointly to Francis Harry Compton Crick, James Dewey Watson and Maurice Hugh Frederick Wilkins for their discovery of the molecular structure of DNA – the double helix shown here.

DNA is an organic molecule that consists of two strands (Double Helix) of repeating building blocks called nucleotides. Each nucleotide consists of a sugar, a phosphate group, and a nitrogen base. The nucleotides in each strand are tightly bonded. The two strands however are loosely held together by weaker bonds. DNA fragmentation occurs when separations and breaks occur in these bonds. Our chromosomes are composed primarily of DNA, and segments of that DNA form genes, whose specific sequence of nitrogen bases constitutes genetic code. DNA fragmentation can impair the transmission of this genetic code, disrupting a cell’s ability to function. For a sperm cell, DNA fragmentation can prevent fertilization or proper development of an embryo if fertilization occurs.

Scientists have identified several factors that contribute to an increase in sperm DNA fragmentation. Oxidative stress is a major cause of DNA damage. Oxidative stress is the damage caused by free radicals reacting with molecules like DNA and thus disrupting their bonds. Physical and environmental changes can increase the level of free radicals to which sperm DNA is exposed. Recent studies have linked environmental toxins in certain chemical air pollutants, pesticides, and plastics to elevated oxidative stress and sperm DNA fragmentation. Obesity, alcohol consumption, and tobacco have also been associated with DNA damage from increased oxidative stress.

Scrotal varicoceles have been shown to exacerbate sperm DNA fragmentation. Varicoceles elevate the temperature inside the testes to levels that disrupt the bonds of DNA molecules, resulting in fragmentation. Excess fat around the scrotum from being overweight will also elevate testicular temperatures to unfavorable levels that damage the DNA bonds.

Chemotherapy and radiation therapy have been linked to sperm DNA fragmentation, and further investigation is needed to determine if this is a long-term or even permanent side-effect of some cancer treatments. Reproductive aged men who have been diagnosed with cancer should be encouraged to cryopreserve sperm prior to starting treatment as a means of preserving their fertility. Post treatment fertility evaluations should include an assessment of sperm DNA fragmentation, especially since men with normal semen analyses can have high levels of sperm DNA fragmentation.

Glitches in the process of sperm maturation can cause sperm DNA fragmentation. The structure of the human sperm cell makes it more susceptible to DNA fragmentation than any other cell in the body. Its nucleus has 40% less space compared to most other cells, so sperm DNA has to be highly compacted and coiled to enable it to fit in the nucleus. This highly compacted and structured arrangement protects the sperm cell’s genetic material (DNA) as it travels through the male and female reproductive tracts, and it enables the proper fusion of DNA from both sperm and egg at fertilization. Sperm maturation is a process that transforms a round germ cell into an elongated mature sperm cell with a head, acrosome, midpiece, and a tail. During this process DNA is uncoiled, transcribed (which is the process of reading the DNA’s genetic code) and recoiled a couple of times. Intentional nicks and breaks are made in sperm DNA to enable it to be tightly compacted and recoiled. These nicks are supposed to be repaired when the DNA is being transcribed, but external factors, such as oxidative stress and advanced paternal age, often prevent this and hence result in sperm DNA fragmentation.

Sertoli cells which function to support and nourish developing sperm cells in the testes also screen sperm cells and mark defective ones for elimination. Sometimes external factors disrupt this process and marked sperm cells are not eliminated, or apoptosis (cell death) is initiated but not completed. These sperm cells have a much higher incidence of DNA fragmentation.

SCSAnl

Sperm with normal DNA fluoresces green and can be quantified with a flow cytometer which can identify these sperm and count the number of them present

SCSAabn

Sperm with fragmented DNA fluoresces orange and can be counted with a flow cytometer which can identify these sperm and count the number of them present

Sperm DNA fragmentation can occur during the movement of sperm from the seminiferous tubules through the vas deferens, an event that allows immature and mature sperm to be tightly packed together.  Immature sperm produce a high level of reactive oxygen species (a type of free radical), which often react with and damage the DNA of mature sperm.  Reactive oxygen species also activate enzymes called caspases and endonucleases that are part of the process of apoptosis, further damaging sperm DNA. This is the primary reason that sperm retrieved from the testes has less DNA damage than sperm from ejaculate.

If you are reading this blog because your doctor has recommended you be tested for sperm DNA fragmentation or you recently had testing that indicated a high level of DNA damage, your situation is not hopeless. For many men, simple lifestyle changes can improve sperm DNA fragmentation. Weight loss, healthy diet, cessation of smoking, reduced consumption of alcohol, and antioxidants have all been shown to improve DNA integrity. For older men, who typically experience DNA damage because the mechanisms of sperm maturation function less efficiently, and men who have undergone treatment for cancer, it may not be possible to reduce sperm DNA damage. However, sperm can be surgically retrieved from the testis and used in IVF/ICSI, as the incidence of DNA fragmentation is usually much lower in sperm from the testes than from ejaculate.

References:

 Sakkas D, Alvarez J. Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. Fertil Steril, Mar 2010; 90(4): 1027-1036.

Ribas-Maynou J, Garcia-Peiro A, et al. Comprehensive analysis of sperm DNA fragmentation by five different assays: TUNEL assay, SCSA, SCD test and alkaline and neutral Comet assay. Andrology, 2013; 1: 715-722.

Erenpreiss J, Spano M, et al. Sperm chromatin structure and male fertility: biological and clinical aspects. Asian J Androl, 2006; 8(1): 11-29.

Agarwal A, Said T. Sperm chromatin assessment. From http://www.clevelandclinic.org/reproductiveresearchcenter/docs/agrach016.pdf

Weight Impacts Male Fertility, Too

AppleWaistThere are many factors that contribute to male fertility. Age, medical conditions, smoking, hormones, genetics—all of these considerations impact man’s ability to father a child. But recent studies have determined yet another factor: weight. It has been widely supposed that a woman’s weight impacts her fertility, but this issue crosses the gender line. A Man’s weight impacts his fertility, too. And it’s not just about losing those extra pounds. Even being underweight can reduce fertility.

Impacts of Being Overweight

A study done at Harvard1 looked at data from an infertility center, as well as the results from 14 studies on the subject of weight and sperm count. Researchers found that overweight and obese men are more likely to have lower sperm counts, or even to produce no sperm at all. This fact by itself might not be too surprising, but the numbers may come as a shock. Check out these figures unearthed by the study.

Overweight men are:

  • 11% more likely to have a low sperm count
  • 39% more likely to have no sperm in their ejaculate

Obese men are:

  • 42% more likely to have a low sperm count
  • 81% more likely to produce no sperm

Impacts of Being Underweight

Being underweight also has a significant impact on male fertility. Being too lean drives down sperm count and motility2. This is because sperm production is most effective when your body has the appropriate nutrients and protein that are a part of a healthy lifestyle and weight. Without these essential components, the body produces less sperm (and less mobile sperm).

Impacts of Over-Exercising

While you are seeking your ideal weight (weather you are shedding some pounds or building muscle), keep in mind that exercising too much can have its own risks. As you exercise, you raise your body temperature. This includes the temperature of your testicles. Raising your testicular temperature kills your sperm3, and raising the temperature too much and too often will lower your sperm count.

Finding an ideal weight is important to overall health of the body, and it is also an important factor in male fertility. If you are experiencing infertility and are over- or underweight, talk with a physician or nutritionist to find a healthful way to reach an ideal weight. This might just be the issue that is keeping you from optimal fertility.

References

1. Harvard School of Public Health News (2012). Excess weight may affect sperm production, reduce fertility in men. Retrieved from http://www.hsph.harvard.edu/news/hsph-in-the-news/excess-weight-sperm-fertility/

2. Levine, D. (1999). Boxers or briefs: Myths and facts about men’s infertility. Retrieved from http://www.webmd.com/infertility-and-reproduction/features/male-infertility-facts

3. UK Health Centre. Fertility and weight. Retrieved from http://www.healthcentre.org.uk/fertility-treatment/fertility-and-weight.html

Testosterone and the aging male – Balancing risks and benefits

balance strong manLast summer I took Bruno, my ten-year-old cairn terrier, to the vet for his annual check-up.  “Wow, he has some energy level for an older dog,” commented my vet as he watched Bruno dart around the exam room. My vet started to examine Bruno. “Aha”, he exclaimed. “He’s intact. That’s why he’s still so quick moving and trim. It’s all that testosterone.”

My vet is not alone in his opinion that adequate testosterone levels benefit the aging male. Over the last ten years, prescriptions for testosterone for men over forty have tripled. Testosterone is essential for maintaining muscle and lean body mass, strength and energy levels, fertility, libido and sexual performance. It is needed to maintain normal bone density and prevent osteoporosis. It also positively impacts cognitive function and mood. Unfortunately for men, testosterone progressively declines as they age. Sometimes to levels low enough to impair the numerous functions listed above, leading to adverse health conditions and significant changes in quality of life. So it is easy to see why healthcare providers and their aging male patients would consider testosterone replacement therapy to reverse symptoms related to low testosterone and restore better quality of life.

Several recent studies, however, indicate that testosterone replacement therapy may not be as beneficial to the aging male as originally thought.  Their findings link testosterone replacement therapy to an increase in cardiovascular problems. The New York Times and several other national news outlets ran features last month highlighting the findings of a recent study that showed a correlation between testosterone replacement therapy and increased cardiac risk, setting off a bit of a frenzy over the need to better scrutinize how and to whom this medication should be dispensed. There is also discussion over the need for pharmaceutical companies to put a warning label on testosterone replacement therapies and their relevant advertising material, and for doctors to have patients sign a consent indicating an awareness of the potential side effects of testosterone prior to being prescribed this drug.

So how concerned should you be if you are currently on testosterone replacement therapy, or you are experiencing symptoms of low testosterone and are considering discussing testosterone replacement therapy with your health care provider? Will testosterone replacement therapy increase your risk of having an adverse cardiac event?

The study receiving so much recent media attention was funded by the National Institute of Health (NIH) and was published in the journal PLoS ONE. It found that men over the age of 65 had double the rate of heart attacks within the first 90 days of starting testosterone. Men younger than 65 with a history of heart disease had triple the rate of heart attacks within the first 90 days of starting testosterone. Men younger than 65 with no history of heart disease showed no increased risk of heart attack.  Other studies have also produced similar findings. None of these studies have been able to demonstrate specifically how testosterone is causing adverse cardiovascular incidents. Some are suggesting increased physical activity elicited by the physical improvements gained from testosterone replacement therapy is placing too much stress on the cardiovascular systems of men already at risk. However, if you are over 65 or have a history of cardiovascular disease, testosterone replacement therapy may not be for you.

Another source of concern is the growing number of health clinics that cater to the needs of men interested in extending the vigor and virility of youth into old age with the help of testosterone replacement therapy.  Many of these “male rejuvenation” clinics are billing testosterone as a panacea for all that ails the aging male. These clinics are prescribing testosterone without properly screening for this condition and without properly following up with those patients given prescriptions and refills.  Testosterone replacement therapy benefits many aging men, but it is not for all.  Like all medications, testosterone can pose health risks if prescribed to men who do not need it or have pre-existing conditions that contradict it.

Because of the steep increase in the number of prescriptions being written for testosterone, as well as the number of clinics actively marketing testosterone replacement to aging men, the Endocrine Society updated its clinical practice guideline in 2010 to provide a better protocol for evaluating and treating patients with low testosterone.

If you are currently on testosterone replacement therapy (TRT) or considering seeing a healthcare professional about starting it, your initial and follow-up evaluations should adhere to the Endocrine Society’s guidelines.  A healthcare professional should never, ever prescribe testosterone based solely on a patient having symptoms of low testosterone. Your initial examination should include a serum (blood) sample evaluated by a reference lab using a standardized method for testosterone measurement. Initial blood tests often include total and free testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), prostate specific antigen (PSA), prolactin, and hematocrit (measurement of red blood cells). The sample should be drawn between 7:00am and 11:00am, particularly for men under 50 as testosterone levels are highest in the morning.

Due to the lack of standardization in testosterone measurement there is not a level below which testosterone is considered ‘low’.  However, a total testosterone level below 300 ng/dl is usually considered the lower limit of normal.  If your total testosterone level is low, evaluating hormones secreted by the pituitary, LH and FSH will help your healthcare provider determine if the cause is impaired production in the testes (primary hypogonadism) or a problem with the hypothalamus and/or pituitary (secondary hypogonadism). If secondary hypogonadism is suspected, additional testing should be done to determine the cause. If your total testosterone level is low or borderline-low, bone mineral density should be evaluated with a DEXA scan to determine if you have decreased bone density (eg osteopenia or osteoporosis).

A clinical diagnosis of low testosterone based on symptoms and blood work demonstrating low serum testosterone makes you a good candidate for TRT. However your healthcare provider might not suggest TRT if:

  1. You are 65 years of age and older.
  2. You have a history of cardiovascular disease.
  3. You have prostate cancer or a PSA level above 4 ng/ml. (TRT can stimulate the growth of prostate cancer in men with prostate cancer.)
  4. You have severe lower urinary tract symptoms.
  5. You have a history of breast cancer.
  6. You have hematocrit above 50%. (TRT stimulates the production of red blood cells. Excessive levels can cause formation of blood clots.)
  7. You have severe sleep apnea. (Severe sleep apnea might be a sign of cardiovascular disease.)
  8. You are concerned about your fertility. (TRT impairs sperm production in testes.)

Once you have started testosterone replacement therapy, your healthcare provider should monitor your progress. You should be evaluated every three to six months to determine if your symptoms are improving. Your serum testosterone level and several other hormones should be measured, and the goal should be to maintain a testosterone level in mid-normal range (ie, 400 to 600 ng/dl). You should be assessed for any adverse effects (cardiovascular disease, PSA/prostate cancer, hematocrit/erythrocytosis). You bone density should be re-evaluated by DEXA scan every one to two years.  Your healthcare provider should not be refilling your prescription without doing this type of periodic assessment.

Before I end this blog, I want to mention that life style interventions have been shown to improve testosterone levels. Studies show there is a link between obesity and low testosterone. Men who are overweight tend to have lower testosterone levels than men who are normal weight. Weight loss, improved diet, and exercise have been shown to boost testosterone levels.

Testosterone replacement therapy, when prescribed and monitored properly, has been proven to be safe and effective for men over forty with low testosterone. It has been shown to improve energy level, libido, muscle and bone loss, and mood. Studies have shown it can lower blood pressure and blood sugar and can improve cholesterol levels.  Studies also demonstrate that men with normal testosterone levels have a 40% lower death rate compared with men who have low testosterone levels.  If you think you suffer from low testosterone, testosterone replacement therapy could be of great benefit. Just make sure you are evaluated and monitored by a physician who is experienced with hormone replacement therapy in men.

References:

 Bhasin S, Cunningham GR, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Jun; 95(6): 2536-2559.

Finkel W, Greenland S, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLOS ONE. 2014 Jan; DOI: 10.1371.

Brawer MK. Testosterone replacement in men with andropause: an overview. Rev Urol. 2004; 6(Suppl 6): S9-S15.

O’Connor A. New concern about testosterone and heart risks. NYT, Jan 29, 2014.

La Puma J. Don’t ask your doctor about low T. NYT, Feb 3, 2014.

Male menopause: testosterone therapy marketing frenzy draws skepticism. From voxxi.com, Sep 9, 2012.

A Man’s #1 Reason to Stop Smoking

ManSmokingAccording to the CDC1, Smoking causes more deaths each year than all of the following things combined:

  • Human immunodeficiency virus (HIV)
  • Illegal drug use
  • Alcohol use
  • Motor vehicle injuries
  • Firearm-related incidents

Smoking is a hard habit to break. But if the health hazards haven’t persuaded you to go cold turkey, this one fact just might: Smoking can hit you below the belt.

Erectile Dysfunction

When it comes to the bedroom, lightning up might not be so hot. Numerous studies2 have linked smoking to erectile dysfunction. Smoking restricts blood flow in your veins and arteries, and proper blood flow is essential for erectile function. If you smoke, you are at greater risk of developing this condition.

Reproductive Issues

If you are considering having a family, smoking might keep you from that goal. One study3 compared semen from smokers to semen of non-smokers and found that smokers suffered from the following complications:

  • low testosterone
  • low sperm motility
  • impaired sperm fertilizing capacity

Testicular Cancer

According to one study done in Canada4, smoking was shown to increase the risk of testicular cancer. The researchers stated that “smoking to any degree was suggestive of an increased risk.” They additionally noted that there was “no association with age of initiation and no reduction of risk with smoking cessation.” So what does that mean for you? If you have ever smoked, at any age, for any length of time, you have increased your risk of testicular cancer. Even if you have stopped smoking, you have permanently elevated your risk. And the longer you smoke (the higher your pack-year ratio), the more you increase your risk.

So the next time you consider taking a smoking break, think instead of taking a break from smoking. If you won’t do it for your lungs, do it for the family jewels.

References

1. Centers for Disease Control and Prevention (2014). Health effects of cigarette smoking. Retrieved from http://www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/effects_cig_smoking/

2. Gades, N. M., Nehra, A., Jacobson, D. J., McGree, M. E., Girman, C. J., Rhodes, T. . . . & Jacobsen, S. J. (2005). Association between Smoking and Erectile Dysfunction: A Population-based Study. Americal Journal of Epidemiology, 161(4), 346–351. doi: 10.1093/aje/kwi052

3. Sofikitis, N., Miyagawa, I., Dimitriadis, D., Zavos, P., Sikka, S., & Hellstrom, W. (1995). Effects of smoking on testicular function, semen quality and sperm fertilizing capacity. Journal of Urology, 154(3), 1030–4. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7637048

4. Srivastava, A & Kreiger, N. (2004). Cigarette smoking and testicular cancer. Cancer Epidemiology, Biomarkers, and Prevention, 13; 49–54. doi: 10.1158/1055-9965.EPI-03-0133

You Are What You Eat … And Your Children May Be Too

AbdObeseMaleLeaf through any magazine dedicated to health and wellness, whether its intended audience is the general consumer or a medical professional, and you will invariably come across an article whose focus is some obesity related health condition.  The CDC considers obesity an epidemic responsible for a host of chronic diseases affecting every major organ system of the body, and the male reproductive system is not immune. Over the last couple of years, researchers have linked obesity to several factors causing male infertility.

Obesity is an endocrine disrupter resulting in lower levels of reproductive hormones that are critical to spermatogenesis, the development of sperm cells. Spermatogenesis requires sufficient testosterone and properly functioning Sertoli cells, which provide physical and nutritional support to developing sperm cells. Luteinizing hormone (LH) stimulates testosterone production, which in turn stimulates sperm cell maturation under the “care and protection” of Sertoli cells. Follicle stimulating hormone (FSH) and Inhibin B regulate the function of Sertoli cells. Sub-optimal levels of any of these four hormones will lead to fewer mature sperm cells and a lower sperm count, and researchers have linked obesity to lower levels of all four. They are exploring the possibility that elevated insulin levels, a hallmark of metabolic syndrome, is a factor in the dysregulation of these reproductive hormones. (Metabolic syndrome is a group of risk factors, brought on by obesity, that increase an individual’s risk for cardiovascular disease and type-2 diabetes. These risk factors are high blood pressure, abnormal cholesterol levels, high blood sugar, elevated insulin levels, and excessive abdominal fat.)

Obesity has been linked to a higher level of sperm oxidative stress.  Oxidative stress is the damage caused by free radicals reacting with molecules in an organism. This happens when physical and environmental changes occur that prevent antioxidants from reacting with, and thus eliminating, these free radicals. Oxidative stress damages the molecular composition of sperm. It compromises DNA integrity and decreases the acrosome reaction. The acrosome reaction occurs in the head of sperm and involves the release of enzymes that enable sperm to penetrate an egg. Oxidative stress is also implicated in decreased motility and disrupted cell signaling (communication).  All these factors impair the ability of sperm to fertilize an egg.

The development and maturation of sperm is highly sensitive to heat. The presence of excessive fat around the testes elevates the temperature in the testes to damaging levels, reducing the amount of mature sperm produced. Higher gonadal temperatures also contribute to sperm oxidative stress.

Some of the most recent and quite possibly most disturbing research findings involve obesity and epigenetic inheritance. Epigenetic inheritance involves changes in gene expression, as opposed to physical changes to the genes themselves. Scientists are studying the link between obesity in fathers and reproductive and metabolic disturbances in their children.  Studies are being conducted on rats and mice that show a strong correlation between paternal obesity at the time of conception, and fertility and metabolism disorders in offspring. Altered methylation of sperm DNA and damage to sperm RNA from oxidative stress are being explored as possible culprits.

If you are an overweight male who is having trouble achieving a pregnancy with your partner, all is not lost.  Each of the outcomes described above can be improved with weight loss, proper nutrition, and exercise. Considering the devastating impact obesity has on all major organ systems, weight loss will not only be an investment in your future fertility, but also an investment in your future health and well-being.

 References:

Palmer NO, Hassan WB, Fullston T, Lane M. Impact of obesity on male fertility, sperm function and molecular composition. Spermatogenesis. 2012; 2(4): 253-263.

McPherson NO, Fullston T, Hassan WB, Setchell BP, Lane M. Obese father’s metabolic state, adiposity, and reproductive capacity indicate son’s reproductive health. Fertil Steril. 2014; 101(3): 865-873.

Hammoud AO, Wilde N, et al. Male obesity and alteration in sperm parameters. Fertil Steril. 2008; 90(6): 2222-2225.