Cryptorchidism May be Associated with Genetic Mutations

Cryptorchidism, a common congenital defect of the male genitalia that affects 3-4% of full-term infants and 30% of those born prematurely, poses a risk for infertility and testicular cancer. However, the exact etiology and pathogenesis of cryptorchidism are not clearly known. Now, a recent study published in the Journal of the American Medical Association has identified a potential link between cryptorchidism and genetic alterations such as insulin-like factor 3 (INSL3) receptor gene mutations and Klinefelter syndrome.
Alberto Ferlin from the Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, Italy, and coworkers, conducted the case-control study on 600 male infants in Italy during 2003 to 2005, to investigate the rate of genetic alterations in cryptorchidism. Three hundred noncryptorchid boys between 1 to 4 years were selected as controls. Follow-up of the subjects was done for 2 to 3 years and those with persistent cryptorchidism were treated with orchidopexy.
Study results showed that mutations ranged from low in boys with cryptorchidism (2.8%), to high in those with persistent cryptorchidism (5.3%) and bilateral cryptorchidism (8.3%), compared to controls (0.3%). The calculated odds for having genetic alteration in boys with persistent cryptorchidism were more than 17 times; however, there was lack of mutations in boys with low gestational age or low birth weight and those who had spontaneous descent of the testes. The researchers found that Klinefelter syndrome and INSL3 receptor gene mutations were most frequently associated with cryptorchidism, suggesting a significant relationship between the disease and genetic alterations.
Early studies have indicated that INSL3 plays a key role in testicular descent, with mutations in the gene or its G protein-coupled receptor (leucine-rich repeat, containing G protein-coupled receptor (LGR8)) likely to be associated with cryptorchidism.
Ferlin, et al. (Molecular Human Reproduction, 2006) conducted a study to investigate the hypothesis pertaining to the relationship between INSL3 mutations and the signs of testicular dysgenesis syndrome (TDS), characterized by undescended testis, poor semen quality, testis cancer, and hypospadias. The analysis was performed on 967 subjects with maldescended testes and/or infertility and/or testicular cancer and 450 controls. The researchers also conducted in vitro functional analysis of genetic alterations (R4H, W69R, and R72K) by observing the increase of INSL3-dependent cAMP (cyclic adenosine monophosphate) in cells that express LGR8. It was found that 1.9% of the subjects had 6 INSL3 mutations, with no similar finding in the controls. Based on the findings, it was suggested that a significant link may exist between INSL3 gene alterations and TDS syndrome signs; although, a definite causative role was not established.
Although cryptorchidism or undescended testicle may occur bilaterally, it commonly affects the right testes. A combination of factors such as maternal health, genetics, and environment may play an important role in its development, but the exact cause is unknown. Generally, the condition resolves by itself but sometimes may require orchidopexy to relocate the testis into the scrotum.
Substantiating the current research, which identifies the association between undescended testicles and genetic mutations in INSL3 receptor gene and Klinefelter syndrome, with further larger studies, may help to elucidate the underlying disease mechanism. Further, this may facilitate in developing novel therapeutic strategies for patients with persistent and bilateral cryptorchidism, thereby reducing the burden associated with male infertility.
References
1. Ferlin A, Zuccarello D, Zuccarello B, Chirico MR, Zanon GF, Foresta C. Genetic alterations associated with cryptorchidism. JAMA. 2008 Nov 19;300(19):2271-6.
2. Ferlin A, Bogatcheva NV, Gianesello L, et al. Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization. Mol Hum Reprod. 2006 Jun;12(6):401-6. Epub 2006 May 10.

Perfumed 'risk' to future fertility

A principal investigator for the Human Reproductive Sciences Unit of theUK's Medical Research Council (MRC) has revealed that using certain cosmetics during the early stages of pregnancy could affect fertility in males in later life. Professor Richard Sharpe undertook research on rats, which showed that after exposure to certain chemicals commonly found in cosmetics such as perfume and household fabrics, the actions of male sex hormones were blocked and the animals suffered fertility problems.

Professor Sharpe and his Edinburgh-based team believe that there is a crucial window between eight and 12 weeks of pregnancy when the male reproductive system is established and male sex hormones are activated. It is at this time that if exposed to chemicals in cosmetics, the male fetus 'may not realise its full reproductive potential, including the size of the
penis and testes, undescended testes or sperm count', he said. Professor Sharpe told the Scotland on Sunday newspaper that the 'male programming' window occurs far earlier in fetal development than previously thought, and it is at this time that male sex hormones such as testosterone are most active.

Speaking to BBC Scotland's news website, he said: 'If you are planning to become pregnant you should change your lifestyle... We would recommend you avoid exposure to chemicals that are present in cosmetics, anything that you put on your body that might then get through your body into your developing baby'. He added: 'It is not because we have evidence that these chemicals categorically cause harm to babies, it is only based on experimental studies on animals that suggest it is a possibility'.

Disorders of the male reproductive function can affect up to one in six young males with low sperm counts being the most common dysfunction. Professor Sharpe said that the chemicals he is concerned about may also increase the risk of suffering testicular cancer in later life.

New Method to Diagnose Blockage that Causes Male Infertility

Almost as common as diabetes, male infertility affects 15% of reproductive age men in India. Many cases of infertility are caused by blockages within the male sex organs that result in low sperm counts or no sperm counts. These blockages are often reversible and therefore important to diagnose as couples may be able to conceive naturally afterward. To date, one such type of blockage, termed ejaculatory duct obstruction, has been difficult to diagnose as a cause of infertility. Last month, Dr. Paul Turek, a Professor Emeritus in Urology at UCSF, published a paper in The Journal of Urology that dramatically simplifies this diagnosis. "All prior tests for this diagnosis involve simply looking at the system and trying to guess how it works, but this new test actually 'pokes' at the system and watches how it responds," says Dr. Turek, a nationally recognized microsurgeon and male infertility specialist.

"We simply applied the same principles that have been used to assess urination issues in urology for the past 30 years, termed urodynamics, to the male sex organs, and call it 'vasodynamics.'"

For the study, 2 groups of men were compared: normal fertile men and infertile men suspected of having ejaculatory duct obstruction. In addition to taking ultrasound pictures of the reproductive tract system in both groups, which is the current standard diagnostic test, he did something else. By injecting harmless, colored dye into the system through a fine needle and measuring the pressure and flow characteristics of the dye as it progressed through the ejaculatory ducts, he found large differences between the fertile and infertile groups of men.

In fertile men, it took 33 cm of water pressure to cause flow in the ejaculatory ducts, whereas in the infertile men with suspected obstruction, it took 4 times that pressure or 116 cm water pressure. "With this hydraulic technique, we can actually measure the degree of blockage in the male sex organs, which has never been done before," says Dr. Turek of the new technique. Not only that, after surgery was performed to relieve the obstruction in the blocked men, the injection procedure was repeated and the water pressures fell into the range of the normal fertile men. This response also corresponded well with improvements in semen quality after the treatment.

"For several decades, the diagnosis of ejaculatory duct obstruction has involved a lot of guesswork. Vasodynamics now removes the guessing and replaces it with real information that can be used to reliably improve male fertility potential," says Dr. Turek.