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COVID-19: A Concern For Male Fertility?

Depiction of the SARS-CoV-2

What effect does COVID-19 have on the testes and male fertility? I have been asked this question by many patients and some colleagues. The bottom line is that it is too early to know. However, there is a recent review article that raises some concerns (see full reference below and link to the online paper). This paper, published online, but not yet peer-reviewed, has received much following and comments on Twitter. I usually do not write about papers that have not gone through the rigorous process of peer review, however, due to the amount of discussion surrounding this paper I will summarize their findings and give my thoughts. I will update this blog as more information develops. Please note that I am not endorsing this paper, nor am I advocating undue concern. However, the authors present interesting findings that must undergo review by experts in the field and be supported or refuted by additional research. At present, there is just too little work done on this disease to make recommendations.

Their work is a review paper from the Departments of Urology of the Nanjing Medical University in China, located approximately 300 miles from Wuhan China. Wuhun, was the epicenter of the coronavirus disease in 2019 (abbreviated COVID-19). The virus itself has been named “SARS-CoV-2”. Their review included a total of 146 cases from three prior published papers.

The authors reviewed studies demonstrating that the Angiotensin Converting Enzyme 2 receptor (ACE2) was a major cellular receptor that mediated the entrance of the SARS-CoV-2 into a human cell. ACE2 receptors have been implicated in other severe acute respiratory syndrome coronavirus (SARS). They also noted that a percentage (3% to 10%) of those infected with this virus exhibited kidney damage. They wanted to know if other cell types, that had large numbers of ACE2 receptors, were also affected by this virus. The cells they looked at were renal tubular cells, important for kidney function. They also reviewed two types of cells located in the testis, the Leydig cells, which produce testosterone, the major male hormone and the seminiferous tubule cells which are important in sperm production.

Their results were enlightening.

  1. The number of receptors in the renal tubular cells was high. The implication was that the ACE2 receptors provided access to the SARS-CoV-2 to these kidney cells and adversely affected kidney function. They suggested monitoring kidney function, especially if the patient is on medications that require modification when kidney function is compromised.
  2. In their review, they were surprised to find that ACE2 receptors in the seminiferous tubules and Leydig cells were some of the highest in the body. Their takeaway was that the testis is a potential target of SARS-CoV-2. Also, that follow-up evaluation of fertility is important in reproductive-aged men that have had COVID-19. This is particularly concerning in men that had orchitis (ie, an inflammation or infection of the testis) during their COVID-19 infection.

The authors concluded that reproductive function might be compromised in young males recovering from COVID-19. However, there are several concerns with the methodology of this study that need to be kept in mind.

  1. They reviewed prior work, which identifies a high density of ACE2 receptors in the testis. Although this might imply that the testis would be a target for SARS-CoV-2 it does not document damage that has occurred or provide data on the disease process that might occur.
  2. Their review included 146 cases in total compared to the 156,433 cases with 5,821 deaths that have occurred at the time of this blog. To make a conclusion based on such a small sample is at best challenging.

Nonetheless, we are only starting to identify the pathogenesis of this disease. We need to gather data continually. Only by the questions we ask, and meticulous collection of data will we get closer to the answers. I will continue to update the impact of COVID-19 on male fertility as we learn more.

Reference:

C Fan et al, ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection, MEDRXIV 2020.  HTTPS://WWW.MEDRXIV.ORG/CONTENT/10.1101/2020.02.12.20022418V1

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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com

microTESE – A cutting edge procedure for male infertility

Sperm production. Coloured scanning electron micrograph (SEM) of sperm cells (spermatozoa) in the seminiferous tubules of the testis. This is the site of spermatogenesis (sperm production). Sperm tails are very pale pink, sperm heads are pale pink

Sperm production. Colored scanning electron micrograph (SEM) of sperm cells (spermatozoa) in the seminiferous tubules of the testis. This is the site of spermatogenesis (sperm production). Sperm tails are very pale pink, sperm heads are pale pink

Many of the men seen in my practice for male infertility are azoospermic.  This means they have no measurable amount of sperm in their ejaculate. This is a significant issue for these men wanting to have a biological child. Approximately half of these men have Obstructive Azoospermia (OA). Their testes produce enough sperm, but a blockage exists in either the vas deferens or the epididymal tubules that prevent the transport of sperm from the testes to the tip of the penis. Sometimes the vas deferens and epididymal tubules are missing.  The remaining half of our azoospermic patients have Non-Obstructive Azoospermia (NOA).  Their vas deferens and tubules are clear and open, but the ability of their testes to produce sperm is impaired.

Medical interventions exist that enable many men with azoospermia to father their own biological children.  Blockages can be surgically removed, and sperm production can sometimes be improved with pharmacological treatments.  However, for most men with NOA and many with OA, the only avenue available for achieving a pregnancy with a partner is to have sperm surgically retrieved from the testes and then used in an assisted reproductive technology (ART) treatment protocol involving in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

What is TESE?

In conventional testicular sperm extraction (TESE), a small incision is made in the scrotum exposing the testes.  An incision is then made in one of the testes, through the tunica albuginea (protective outer covering of the testis) to expose its parenchymal (working) tissue.  Special care is taken to avoid blood vessels. Pressure is applied along the incision until tissue containing seminiferous tubules protrudes through the incision site.  This tissue is surgically removed and set aside for cryopreservation and/or immediate use in IVF/ICSI.  The procedure is then repeated on the other testis.

Seminiferous tubules are the site of spermatogenesis (sperm production). However, spermatogenesis is not uniform throughout the testes, and so at any given time, some seminiferous tubules will have much higher concentrations of sperm than others.  It is not possible to evaluate the degree of spermatogenesis in seminiferous tubules with the naked eye.  So a surgeon has no way of visually assessing the tissue he intends to extract during a TESE for the presence of sperm.  For men with OA this conundrum is usually not problematic. They produce plenty of sperm, so chances are quite good that testis tissue retrieved by conventional TESE will contain sufficient sperm for IVF/ICSI.  This is not the case however for men with NOA.  Because their ability to produce sperm is impaired, the sperm concentration in their seminiferous tubules can range from adequate in some tubules to non-existent in others. As a result, they run the very real risk of having testis tissue retrieved by conventional TESE that is devoid of sperm and therefore unsuitable for IVF/ICSI despite having sufficient sperm production in another portion of the testicle.

When sperm are not found in conventional TESEs, fertility specialists often counsel patients that no viable option exists to achieve a pregnancy with a partner. Patients are encouraged to start looking at sperm donors.  This is outdated advice given by professionals who are unfamiliar with microdissection testicular sperm extraction (micro TESE).

Left image: Seminiferous tubules with and without sperm as seen using an operating microscope (20x magnification).
Right image: Confirmation of this by fixing and staining the tissue shown on the left and viewed under higher power magnification (400x).

What is microTESE?

A microTESE is a very different, far more complex type of surgical sperm retrieval compared to a conventional TESE. It is performed by an experienced urologic surgeon, who is an expert in the use of an operating microscope. The surgeon is assisted by a team of laboratory andrologists (specialists in the laboratory techniques required to identify and extract sperm from testicular tissue). An incision is made in the scrotum exposing the testes. Thirty or more microscopic specimens containing seminiferous tubules are taken from multiple sites on each testis. Individual seminiferous tubules in each of these samples are examined in the operating room by the laboratory andrologist to determine the presence of sperm. Seminiferous tubules containing sperm are usually plumper, light yellow in color, and often situated close to blood vessels. The surgeon is thus able to extract only tissue with the best potential to contain sperm, which is key to the success of the procedure (1). Once the tissue has been extracted, the laboratory andrologist will further examine it to assess sperm quality (concentration, maturation, morphology).  The andrologist will also prepare the tissue for immediate use or cryopreservation.  Using this approach, the operating team can focus on sites that appear to yield the best sperm concentration and quality, ensuring that a sufficient quantity of the most “promising” tissue is extracted.  A microTESE typically takes several hours from the first incision to last suture. A conventional TESE is usually completed in under an hour.

MicroTESE offers several advantages over conventional TESE (2,3). Studies show that for men with NOA, sperm retrieval rates (SRR) by micro TESE are significantly higher than conventional TESE. “Sperm was recovered from those with hypospermatogenesis in 84% and 92.9% by conventional and microdissection TESE, respectively. In the case of maturation arrest, SRR was 27.3% and 36.4% respectively. In cases of Sertoli-cell-only syndrome (SCOS), the SRR was 6.2% and 26.9% respectively.”1 The use of an operating microscope minimizes the amount of tissue that is removed, as many microscopic specimens are taken rather than larger biopsies. The use of an operating microscope also enables the surgeon to avoid disrupting blood vessels, decreasing the likelihood of damaging vascularized areas of the testes. This minimizes trauma and the resulting loss of functionality, such as a decline in testosterone production.  Better retrieval rates enable andrologists to cryopreserve testicular tissue for later use. Using cryopreserved sperm eliminates the need for synchronizing egg and sperm retrievals. It also eliminates the trauma and potential tissue damage caused by multiple sperm retrievals.

There has been some debate over the use of fresh versus thawed sperm for ICSI (4).  Many fertility specialists believed better outcomes are achieved with fresh sperm, as cryopreservation damages both cell and acrosome membranes and increases the damage caused by sperm oxidative stress. However several recent studies refute this assumption.  A recent review of data from 224 studies focusing on men with NOA revealed no difference in fertilization and pregnancy rates with fresh versus cryopreserved sperm used for ICSI.

The Bottom Line

Microdissection testicular sperm retrieval is offering new hope to men with NOA. However, I am ending this blog on a cautionary note.  This is not a procedure that can be done by all urologic surgeons. It requires a highly skilled urologic surgeon who has extensive experience using an operating microscope and doing testicular sperm retrievals. In addition, it requires a fertility laboratory with experienced and well-trained staff. Together, the surgeon’s and laboratory’s skill and experience is key to the success of this procedure (5).

References

  1. Caroppo E, Colpi EM et al. The seminiferous tubule caliber pattern as evaluated at high magnification during microdissection testicular sperm extraction predicts sperm retrieval in patients with non-obstructive azoospermia. Andrology 2019; 7: 8-14
  2. Ghalayini IF, A-Ghazo M, et al. Clinical Comparison of Conventional Testicular Sperm Extraction and Microdissection Techniques for Non-Obstructive Azoospermia. J Clin Med Res. 2011; 3(3): 124-131.
  3. Ravissini PC, Azevedo M, et al. Success rate in ICSI treatment of men with non-obstructive azoospermia (NOA): a comparative study between TESE (testicular sperm extraction) and microdissection-TESE. Fertil Steril.  2008; 90: S382-S383.
  4. Ohlander S, Hotaling J, et al. Impact of fresh versus cryopreserved testicular sperm upon intracytoplasmic sperm injection pregnancy outcomes in men with azoospermia due to spermatogenic dysfunction: a meta-analysis.  Fertil Steril. 2014; 101(2): 344-349.
  5. Ishikawa T, Nose R, et al. Learning curves of microdissection testicular sperm extraction for nonobstructive azoospermia. Fertil Steril 2010; 94(3): 1008-1011.
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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com

Directed Donation: A Novel Treatment Option for Fertility

A little-known fertility option is Directed Donation.  I thought a brief overview would be appreciated by those seeking additional options. I have included links at the end for those looking for additional information. A Directed Donor is a man storing sperm for use by a known recipient with whom he is not sexually intimate. This is in contradistinction to an  Anonymous Donor who is a donor whose identity is unknown to the recipient or a male Client Depositor who is an individual who deposits reproductive tissue prior to intended or potential use in artificial insemination or assisted reproductive procedures performed on his regular sexual partner.

The recipient for a Directed Donor might be a woman without a male partner who would like to have a child with sperm from an individual she knows, a woman in a relationship with a male partner who is not able to produce sperm or a transgender female wanting to have a child with a female partner or surrogate.

There are several steps by which the Medical Director qualifies a directed donor for specimen use by a recipient. These steps are similar to those required for an anonymous donor. If the qualification is performed in NY State the Directed Donor must be found eligible by the Medical Director of the facility prior to collection of the first semen sample for processing and storage. Determination of Eligibility includes the following components:

  1. A physical examination of the Directed Donor, as well as blood testing for indications of sexually transmissible diseases.
  2. A complete medical history, both individual and family, including first-degree and second-degree relatives.
  3. Genetic testing for major genetic disorders in consultation with a geneticist.
  4. Psychological evaluation and counseling to access psychological risks and evaluate financial and emotional coercion.
  5. Evaluation of a semen specimen
  6. Written informed consent must be obtained, and discussion had with the Recipient, Recipient’s Partner (if any) and Directed Donor about the results of the evaluation and use of the specimens.

The cryopreserved specimens are then quarantined as required by state regulations. In New York State this is 6 months but can be waived by the Recipient after a discussion of the potential risks of doing so. In all non-traditional fertility options, it is always prudent to seek advice from your Physicians assisting you with your fertility treatment as well as your legal advisors.

If you have any questions, please contact us at 516-487-2700.

Links to NY State and Federal Regulations:

  1. NY State Department of Health Reproductive Tissue Banking Regulations
  2. FDA Code of Regulations Title 21

You can sign up for my Blog at Men’s Reproductive Health Blog

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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com

Fertility Preservation and Gender Transitioning: The Decision to Bank Sperm

The desire to have children is common among individuals transitioning with 38% of respondents of the National Transgender Discrimination Survey indicating they are parents1. A Belgium study surveyed 121 patients transitioning and found that 40% would want children and that half of these would like a biologic child2.  Also in this study, 77% of 101 transgender women wanted the professionals treating them to discuss fertility options with 51% stating that they would have cryopreserved sperm, or at least seriously considered this if it had been discussed.

The World Professional Organization for Transgender Health (WPATH, http://www.wpath.org) first developed the Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People in 1979. However, it wasn’t until 2011 that they introduced specifics on the Reproductive Health needs of transgender people3. In the current WPATH Standards (http://bit.ly/2msEoQl) they recommend that prior to the initiation of therapy fertility preservation options are discussed, even if the person is currently not interested in future fertility.

Ideally, sperm should be collected before hormones are prescribed. However, it is possible in male to female transitioning that stopping feminizing hormones might provide a window to retrieve sperm. Even in the individual who does not have sperm in the ejaculate, or cannot produce an ejaculate, the potential for sperm retrieval and banking is possible with other modalities. Testicular biopsy with banking of tissue excised during the procedure can be used for conception with in vitro fertilization (IVF) couple with single sperm injection (ICSI). In addition, a recent study4 found normal spermatogenesis in 24% of testes removed at the time of sex reassignment surgery for individuals on long term estrogen therapy.  This suggests that banking of testicular tissue may still be possible in 1/4 of patients treated with long term hormonal therapy.  However, it must be noted that 75% of patients treated with long term estrogen therapy did not have sperm in the ejaculate or on biopsy.

At one fertility clinic11 patients were referred for sperm banking between January 2010 and May 2014. Nine of these patients banked sperm for future potential use. During this 52 month period, 1 couple used the stored sperm, which resulted in a pregnancy. It should be noted, however, that the mean age of the patients preserving sperm was 26.5 years of age which might account for the low usage rate of the banked sperm during this study. What was interesting in this study is that there was an increase in yearly referrals to their clinic over the 4.3 years they collected data. However, they found that referrals remained low which they postulated was due to both cost of sperm banking as well as lack of awareness that fertility preservation was an option.

Unfortunately, the reproductive needs of transgender individuals are still largely unmet6. Hopefully, this will be changing as more health professionals provide much-needed information on reproductive health to individuals undergoing gender transition.

References:

  1. James SE, Herman JL, Rankin S, Keisling M, Mottet L, Anafi M. 2015 U.S. Transgender Survey. December 2016:1-302.
  2. De Sutter P, Kira K, Verschoor A, Hotimsky A. The Desire to Have Children and the Preservation of Fertility in Transsexual Women: a Survey. International Journal of …; 2002.
  3. Coleman E, Bockting W, Botzer M, et al. Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7. International Journal of Transgenderism. 2012;13(4):165-232. doi:10.1080/15532739.2011.700873.
  4. Schneider F, Neuhaus N, Wistuba J, et al. Testicular Functions and Clinical Characterization of Patients with Gender Dysphoria (GD) Undergoing Sex Reassignment Surgery (SRS). The journal of sexual medicine. 2015;12(11):2190-2200. doi:10.1111/jsm.13022.
  5. Jones CA, Reiter L, Greenblatt E. Fertility preservation in transgender patients. International Journal of Transgenderism. 2016;17(2):76-82. doi:10.1080/15532739.2016.1153992.
  6. HUNGER S. Commentary: Transgender People Are Not That Different after All. Cambridge Quarterly of Healthcare Ethics. 2012;21(2):287-289. doi:10.1017/S0963180111000818.

 

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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com

Fertility and the Male Cancer Patient: The Imperative to Sperm Bank

Many people facing cancer know about some of the side effects of common treatment options. Chemotherapy can cause you to lose your hair and change the way food tastes to you. It can make you nauseous and fatigued. These are symptoms that cancer patients expect to face during treatment. But one side effect you may not have thought about is infertility. For both men and women, treatments can affect the ability to conceive children1. If you are planning on starting or expanding your family, this may be a concern you should talk about with your doctor. A medical professional can help you understand your risk for infertility due to cancer and treatments.

Sperm production can be temporarily reduced by certain cancers and treatments2. Some treatments, however, permanently alter your ability to reproduce. Cancer cells are fast-growing. Cancer treatments are designed to target and eliminate fast-growing cells in the body. This is intended to eradicate cancer cells, but other fast-growing cells, like hair and sperm, are destroyed in the process3. Both radiation and chemotherapy treatments can slow or stop sperm production, and the effects can be permanent3. Additionally, chemotherapy and radiation therapy may alter the DNA of sperm, and it is recommended that a cancer survivor waits for 1 to 2 years before trying to conceive a child for this effect to dissipate4.

If you have been diagnosed with cancer and are worried that treatment may interfere with your plans to have a family, there are options you can pursue to preserve your fertility before you begin treatment. Cryogenic sperm freezing is a simple process that can save your viable genetic material for years, in case you need it to aid in intrauterine insemination or in vitro fertilization. Sperm must be collected and banked before your cancer treatment begins4 to ensure the best possible sample of undamaged cells.  These frozen samples of genetic material preserve your ability to grow your family, whether due to permanent side effects of infertility, or whether you just don’t want to wait a few years after treatment to have a baby.

References

  1. American Society of Clinical Oncology. Side effects of chemotherapy. Retrieved from http://www.cancer.net/all-about-cancer/cancernet-feature-articles/treatments-tests-and-procedures/side-effects-chemotherapy
  2. Livestrong Foundation. Male fertility preservation. Retrieved from http://www.livestrong.org/we-can-help/just-diagnosed/male-fertility-preservation/
  3. Roswell Park Cancer Institute. Cancer and male infertility. Retrieved from https://www.roswellpark.org/patients/fertility-guide/male-infertility
  4. New York Cryo. FAQs: 3. When does one bank sperm? Retrieved from https://nycryo.com/faqs/

 

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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com

Low-Intensity Shockwave Therapy for Treatment of Erectile Dysfunction – Does it work?

20% of all men have erectile dysfunction (ED) with men of increasing age being disproportionally affected. The incidence of ED can be as high as 60% in men with Diabetes or cardiovascular disease. Although previously considered a quality of life issue, the presence of erectile dysfunction in an otherwise healthy man is now considered a harbinger of cardiovascular disease. Vascular factors are the leading cause of ED. A multitude of treatment options exists for those men with minimal or moderate erectile dysfunction, including pills, injections, and external devices. Unfortunately, these don’t work for every man and may interact with medications or underlying diseases. Also, they treat the symptoms and not the underlying cause of ED. Besides, most man would like not to have to take drugs to function sexually.

What is LI-SWT?

Low intensity extracorporeal (i.e., outside the body) shockwave therapy (LI-SWT) is a treatment that has been in use since 2010. Patients are usually treated in the office setting once or twice a week for 4 to 6 weeks. The device applies a low-intensity shockwave to the surface of the penis using an ultrasound gel as the coupling agent.  LI-SWT appears to have minimal side effects and is well-tolerated without any anesthesia. However, it has not received FDA approval for treatment of erectile dysfunction as of the date of this writing. It has been approved for the treatment of plantar fasciitis. Most of the current research has been directed towards erectile dysfunction. A few studies have evaluated the use of LI-SWT in Peyronie’s disease. This article will address the use of LI-SWT in the treatment of erectile dysfunction.

How Does LI-SWT Work?

It is not definitively known how LI-SWT works. However, the current theory is that the shockwave produced by the device causes stress on cell-membranes and release of growth factors and recruitment of stem cells that promote the development of new penile arteries and reducing inflammatory and cellular stress. In animal studies, there is also evidence to suggest nerve regeneration (Fode et al., Nat. Rev. Urolo. 14:593, 2017). LI-SWT is unique in that it could provide a treatment option that corrects the underlying problem instead of just treating the symptoms of erectile dysfunction.

Literature Reviews of LI-SWT?

Several reviews of studies evaluating the use of LI-SWT have been published this year. The first was an analysis of ten randomized controlled studies completed over the past two years by Sokolakis and Hatzichristodoulou (Int Jour Impot Res, 31:177-194, 2019) has concluded that LI-SWT significantly improved erectile function in patients with vascular ED. All ten studies used a validated questionnaire as the assessment tool and included men with moderate to severe ED. Their analysis also contained only 873 studies followed for less than one year. Three studies also measured penile hemodynamics.

A second systematic review by Brunckhorst et al. (Int Urol Neph, 51:773-781, 2019) reviewed eleven studies with 799 patients. Nine studies found an improvement in ED at six months after treatment with the improvement remaining above baseline out to 12 months.

A third review included seven randomized controlled studies evaluating the effect of LI-SWT on erectile function (Dong et al., Am J Men’s Health, March-April:1-14, 2019). Evaluating outcomes by validated questionnaires (ie., International Index of Erectile Function – erectile function domain [IIEF-EF] and the Erectile Hardness Score [EHS]) they found improvement in erectile function after treatment with LI-SWT.

Although the results have been encouraging, there are still many questions to be answered. What patients will respond to LI-SWT? Will the patients with worse erectile dysfunction, Diabetes and/or heart disease respond better or worse? Does patient age or use of oral or injectable medications used to treat erectile dysfunction affect the results of LI-SWT? What are the contraindications for the use of LI-SWT? Should we be treating men on blood thinners? How does the frequency and length of treatments affect the results? Is it better to use fewer treatments/week over a longer period of time? How does the intensity and number of shocks affect the outcome? Does the type of device matter (linear vs. focused shockwaves)? Focused shockwaves have shown their effectiveness while the results of linear shockwaves are still conflicting. When do the effects of LI-SWT occur and how long does the improvement last? These, among other questions, will need to be answered

Current literature demonstrates an improvement of erectile dysfunction with LI-SWT. However, large, multicentered, randomized controlled studies which include not only qualitative (e.g. validated questionnaires) but also quantitative data (e.g. spectral ultrasound vascular data) are needed before LI-SWT becomes the standard of care. For additional information, please contact us.

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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com

Testosterone replacement and the aging male

I recently read the following about testosterone and testosterone replacement  “Last 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.”

The Vet’s findings are similar to what we find in men. 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. We need to consider the balance between the risks and benefits.  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 a 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 who 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.

 

 

 

 

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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com

Zika virus found inside spermatozoa

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Spermatozoa infected by Zika virus (green; arrowhead)

The Zika virus has been shown to be present in semen for as long as 6 months. However, recent work by Martin-Blondel et al  of the Infectious and Tropical Diseases Department of Toulouse University Hospital are the first to demonstrate the presence of the Zika virus in sperm. What is facinating is that in their index case the “ Zika virus was found to be present in all sperm samples only up to the 37th day. Beyond that point, the virus was found only in the semen, where it persisted for over 130 days.”

 

Implications of this does not change the recommendations for use of a barrier contraceptive however does support the use of washed sperm in in vitro fertilization sooner than 6 months after male exposure to the Zika virus. It also gives more impetus to test sperm donations for the Zika virus in fertility clinics. http://bit.ly/2cYlhrF

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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com

ZIKA Alert: Should Men be Banking Sperm?

A Liquid Nitrogen refrigerator containing sperm and eggs samples. High tech lab equipment used in the in vitro fertilization process.

A Liquid Nitrogen refrigerator containing sperm and eggs samples. High tech lab equipment used in the in vitro fertilization process.

As a specialist in male fertility and owner/director of a sperm bank (http://NYCryo.com) , I have been increasingly asked this question by my colleagues and patients over the past several weeks. Interest in the Zika has been ignited recently by news coverage of celebrities including Pau Gasol of the Chicago Bulls talking about freezing his sperm in the Washington post (http://wapo.st/293BkUP) ….if he even decides to go to the Olympic games. In fact, golf greats like Jason Day, Dustin Johnson, Shane Lowry and Rory McIlroy together with Basketball legends LeBron James and Stephen Curry have pulled out of the  games entirely (http://wapo.st/293Cob5, http://wapo.st/29g036u) while others like Jordan Spieth are weighing their options (http://wapo.st/293DG5U). To add to this concern, the Center for Disease Control (CDC) had issued warnings earlier this year on travel for pregnant women and continue to monitor/update their recommendations (http://bit.ly/29ewocX) . In this brief blog I will try to provide a well referenced overview of what is known about the Zika virus to help you decide what is best for you and your future family. A great review article on Zika virus in pregnancy can be found at http://bit.ly/29dWhfn .

 

First the facts provided by the CDC (http://1.usa.gov/294JyZ0) .

  • A man with Zika virus can pass it to his female or male sex partners through their semen….even if they have never had symptoms. In addition, Zika viral RNA level were higher in semen samples then in blood urine or saliva (http://bit.ly/29dkujA) .
  • Using condoms or delaying sex can reduce the risk of getting Zika from sex…however it is not known where saliva or vaginal fluids can pass the virus on.
  • Zika virus RNA has been detected in semen up to 62 days after the onset of symptoms (http://bit.ly/299BJBd) . CDC therefore recommends that men who have been diagnosed with Zika should consider using condoms or not having sex for at least 6 months.

 

It is clear from these statements that we need to know much more about how the Zika virus. In particular, how the virus is transmitted and even more about the longevity of the virus in the human host. So how should men interested in their future fertility protect themselves? Should they bank their sperm as Pau Gasol believes one should? That question is not a simple one to answer given the paucity of data presently available on the Zika virus. Many questions remain before a definitive answer can be given. In fact, there are more questions then there are answers.

  1. Should all pregnant couples be screened for the Zika virus and what exactly should be tested? One problem is that not also tests are as sensitive and many correctly performed tests yield incorrect results (http://n.pr/299L93j) .
  2. What are the best methods to test for the ZiKa virus (http://bit.ly/29kyR9s) ? There are most sensitive test is the Reverse Transcription-Polymerase Chain Reaction which tests for the presence of a piece of the virus. However, it is only positive for 1 to at most 4 weeks after the virus is in the host. The Zika MAC-ELISA is a better test which detects the virus for up to 12 weeks after exposure. However, the possibility still exists that the virus is present after this time but just not detectable.
  3. Should pregnant women have screening during pregnancy and if so at what frequency? Although there are recommendations for screening during pregnancy (http://bit.ly/29kyyeT) who to handle positive results is still evolving.
  4. Does screening guarantee the absence of virus RNA (http://bit.ly/29kyR9s) ? The answer is no. In addition, since screening is usually done on symptomatic individuals and the Zika virus can be asymptomatic in a large number of men, we would need to screen all men considering conceiving with their partner…which is not practical or even possible.
  5. What fluid type should be screened? Cerebrospinal fluid, blood, urine, saliva and semen all seem to have the virus in them…however, which is the best to test is not yet known.
  6. Does the virus directly affect the sperm or egg cell or the genetic material in these cells is also not yet known. However the FDA has imposed restrictions (http://bit.ly/29p4fAF)  on the freezing of sperm and eggs (oocytes) from men and/or women that have had:
    1. A diagnosis of Zika in the past 6 months
    2. A residence, in or travel to, an area with active Zika transmission within the past 6 months
    3. Sex within the past 6 months with a partner who is known to have lived, traveled, or has been diagnosed with Zika in the past 6 months?

 

Men have been banking sperm prior to therapy that might affect their fertility as well as a protection form hazards to their reproductive health from their occupation. It is therefore entirely appropriate for them to bank sperm prior to travel to an area known to have the Zika virus. However, as discussed above, even if they undergo testing for the Zika virus prior to freezing sperm there is no guarantee that the specimen stored is free of the virus from possible prior exposure. In addition, sexual relations with their partner anytime during the 6 months after their return from an area endemic for the Zika virus might predispose their partner to the infection. No easy answers at this time…..just more questions.

 

 

 

 

 

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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com

Zika Virus and Sperm Banking: What you need to know

The Aedes aegypti mosquito in action.

The Aedes aegypti mosquito in action.

In May 2015 the Pan American Health Organization issued an alert regarding the first confirmed Zika virus infection in Brazil.   In less than a year, the World Health Organization declared the Zika virus a public health emergency of international concern.

Although the first human cases of Zika virus were detected in 1947, the outbreaks were limited to tropical Africa, Southeast Asia, and the Pacific Islands. Currently there is renewed concern about this disease due to its recent association with birth defects, with reports of Zika transmission through sexual activity, as well as with the spread of Zika virus to the US.  In addition, the potential for this disease to be transmitted through blood and semen has resulted in the FDA’s recent guidance to the Blood and tissue banking industry.

In this post we present an overview of what we know and the recommendations that have been made by the FDA.

What is Zika?

Zika is a virus that is transmitted to humans by a mosquito (Aedes Aegypti/Aedes Albopictus). The time between exposure to the Zika virus and infection is not known but is thought to be a few days to a week or so. Most people that have the disease don’t have symptoms. In those that do, the most common symptoms of the Zika virus infection are fever, joint pain, rash, headache, and conjunctivitis. Less frequently observed symptoms include digestive problems, abdominal pain, diarrhea and constipation, mucous membrane ulcerations, and itchiness.  Some cases of Guillain-Barré Syndrome (ascending paralysis) have been associated with Zika virus.

It is important to emphasize that 80% of the patients infected with Zika are asymptomatic (without symptoms) and may not be aware that they carry the disease. Once a person has been infected, he or she is likely to be protected from future infections.

Babies born from mothers infected with Zika virus appear to have a risk of being born with smaller sized heads (Microcephaly).

Transmission

The following is a list of the reported means of transmission:

  • Mosquito bites – The risks of being infected by a mosquito bite includes traveling to areas where the virus is known to exist. Please refer to the CDC website for a complete list of these countries. http://www.cdc.gov/zika/geo/index.html
  • Sexual transmission – There have been reported cases where the virus has been sexually transmitted by an infected partner (by a man to his sex partners).
  • Transfusion-transmission – There are possible cases that have been described in Brazil. These reports are currently being investigated.
  • Mother to child – Infected pregnant women can pass on the virus to their fetus during the pregnancy and during delivery to their newborn.

Zika virus has been found in semen at least 2 weeks and possibly up to 10 weeks after the illness onset. The virus is present in semen longer than in blood, but the persistence of Zika in the semen remains unknown.

There is therefore a risk for transmission of Zika Virus by HCT/Ps (Humans Cells, Tissues, and Cellular and Tissue-Based Products), which include, among others, corneas, bone, skin, heart valves, hematopoietic stem/progenitor cells (HPCs) from cord blood and peripheral blood, and reproductive tissues such as semen and oocytes. However, this is presently based on limited information.

What are the FDA recommendations for Sperm and Blood donors including mothers who donate their umbilical cord blood to public banks?

FDA’s guidance suggest that donors should be considered ineligible if they have any of the following risk factors:

  1. Medical Diagnosis of Zika virus infection in the past 6 months.
  2. Residence in, or travel to, an area with active Zika virus transmission within the past 6 months.
  3. Sex within the past 6 months with a male who is known to have either the risk factors listed in the items 1 or 2 above.

Additionally, donors of umbilical cord blood, placenta, or other gestational tissues should be considered ineligible if the birth mother who seeks to donate gestational tissues has any of the following risk factors:

  1. Medical diagnosis of Zika infection at any point during that pregnancy.
  2. Residence in, or travel to, an area with active Zika transmission at any point during that pregnancy.
  3. Sex at any point during that pregnancy with a male who is known to have either of the risk factors listed in items 1 or 2, above.

What should I do if I think I have symptoms of Zika Virus?

Contact your healthcare provider if you develop the symptoms described above and have visited an area where Zika is found. If you have recently traveled, tell your healthcare provider when and where you traveled.

Can I be tested for the Zika virus?

Your healthcare provider my order a blood tests to look for Zika virus infection.

FDA has issued an Emergency Use Authorization (EUA) for a diagnostic tool for Zika virus that will be distributed to qualified laboratories and, in the United States, those that are certified to perform high-complexity tests.

http://www.cdc.gov/zika/hc-providers/diagnostic.html

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Bruce Gilbert

I am a Urologist/Andrologist practicing in Great Neck, New York for the past 30 years. I am also the Medical and Laboratory Director of New York Cryo, an andrology laboratory and long-term reproductive tissue bank on Long Island. Please send ideas and comments to me at bgilbert@nycryo.com