COPENHAGEN, Denmark Pinpointing men with 2 specific variations in genes encoding for follicle-stimulating hormone (FSH) and its

s receptor (FSHR) may lead to targeted therapy of male infertility with FSH, say German researchers. Reporting the findings at the 2013 European Congress on Endocrinology last week, Joerg Gromoll, PhD, from the Center for Reproductive Medicine, Muenster, Germany, said the combinatory effect of these variants in the hormone and its receptor is "an unparalleled example in endocrinology." "Where a man has the variants in both the hormone and its receptor, the drop in fertility is very significant," said Dr. Gromoll, explaining that such men have significantly lower-than-average sperm counts. "We estimate that around 45% of infertile men would respond to FSH therapy, and this work may enable us to identify exactly who will benefit and to what extent," he observed. Asked to comment on the findings, chair of the British Fertility Society, Allan Pacey, PhD, from the University of Sheffield, United Kingdom, said although more work is needed to iron out the details, "This is exactly what we need in male fertility, because we just don't have a lot of things we can do. We've got very few tests that can be done in blood and that we could have a therapy for." FSH is already widely used in female infertility treatment, Dr. Pacey noted, and exactly the same preparations could be used in men. However, randomized controlled trials (RCTs) would be needed first, to determine the amount and length of FSH therapy required in men and to demonstrate that it actually works to improve sperm count, he cautioned. This is vital in a field where "people tend to jump on things," Dr. Pacey observed, adding, "There are too few good RCTs in fertility." For example, in men "it could take many, many months" to get sperm counts up with FSH, he explained, "so these are the issues an RCT would help to sort out: Whom do you offer it to? For how long? And can you give a daily dose of FSH, or less often?"

Both Variants in Men Meant 34% Drop in Sperm Count FSH, produced by the pituitary gland, is essential for normal functioning of the reproductive system in both men and women, Dr. Gromoll explained in Copenhagen. In men, the hormone is crucial for sperm production, and in women it regulates egg maturation and estrogen synthesis by the ovaries. FSH binds to specific receptors that are found on the surface of cells in the ovary, testes, and uterus. For the FSH to have its effect, both the hormone itself and the receptor must function properly. Recent research has shown that a genetic variation a single nucleotide polymorphism (SNP) in one of the subunits of the FSH molecule, where the G nucleotide is substituted for the T nucleotide (FSHB-211 G>T), is associated with lower serum FSH levels and low sperm count in males, Dr. Gromoll said. Also, a SNP in the FSH-receptor gene (FSHR 2039 A>G) has previously been shown to be associated with FSH levels in women. Dr. Gromoll's group examined 1213 male partners in infertile couples without known causes for male infertility who had been attending the Muenster fertility clinic and genotyped them all for both of these SNPs. They found that men with the variant coding for FSH had significant drops in FSH (-0.51 U/L per T allele) and luteinizing hormone (LH) levels and in bitesticular volume (-3.2 mL). When both variants, for FSH and its receptor, were present, the effect was even more pronounced, and a 34% drop in sperm count was detected. "Oligozoospermic patients carrying unfavorable variants affecting FSH action may benefit from FSH treatment," Dr. Gromoll concluded. Too Few Women to Draw Any Firm Conclusions Dr. Gromoll and colleagues also examined 365 women with normal menstrual cycles and proven ovulation and found that the SNP in FSH was associated

with higher FSH (0.99 U/L) and LH levels (1.30 U/L) and with reduced progesterone (-1.96 ng/mL). The variation in the FSHR gene was also associated with higher FSH levels, but the number of women was too small to calculate the effect of the combination of the 2. "Knowing which women carry the variants may enable them to receive tailored ovarian stimulation in the future," Dr. Gromoll observed. The work in both men and women was published recently (J Clin Endocrinol Metab. 2012;97:3639-3647;J Clin Endocrinol Metab. 2013;98:E82-6). The authors and Dr. Pacey have reported no relevant financial relationships. 2013 European Congress on Endocrinology. Abstract OC5.4, presented April 30, 2103.