Researchers identify gene variations linked to male and female infertility

Identification of genetic variations in the genes coding for the hormone FSH may provide new treatments for male and female infertility, according to work presented at the European Congress of Endocrinology in Copenhagen. A group of researchers at the University of Muenster has characterised gene variations which may improve treatment for almost half of infertile men, as well as allowing tailored treatment for women undergoing assisted reproduction.

Properly functioning FSH (Follicle Stimulating Hormone) is needed to ensure fertility. FSH is produced by the pituitary gland (at the base of the brain) in both men and women. It is essential for normal functioning of the reproductive system. In adult males, FSH is crucial to maintain normal sperm production. In adult women, FSH regulates egg maturation and oestrogen synthesis by the ovaries.

Pituitary-produced FSH binds to specific receptors which are found on the surface of cells in the ovary, testes, and uterus. For the hormone to have its effect, both the hormone and the receptor must function properly. Recently, the group of researchers at the University of Muenster (Germany) has analysed genetic variants in both the FSH gene and in the FSH receptor, which affect fertility in both males and females.

The group found that a distinct single nucleotide change in the DNA structure of FSHB gene (the FSH molecule has 2 subunits - FSHB is the B subunit) caused significant effects in the functioning of the hormone in both men and women. A single change in the DNA of the FSH receptor (FSHR) also caused changes in fertility. They have also found that if a man has both the FSHB and FSH unfavourable genetic variation, then his fertility levels can drop dramatically.

Note: The changes were single nucleotide polymorphisms. The FSHB gene at position 211 normally has a G nucleotide - in this variation this was changed to a T: so the designation for this variation is FSHB-211 G>T. With the gene for the receptor, the change was from A to G at position 2039, designated FSHR 2039A>G.

Professor Joerg Gromoll's group looked at hormone levels in 1213 males and 365 women who had been attending the Muenster fertility clinic, and associated these with the genetic variations in the FSH hormone and receptor. They found that males with the FSHB variation had significant drops in FSH levels and in testicular volume. If a man had both polymorphisms in FSHB and FSHR (gene variations) then this effect was even more pronounced and a drop of 34% in sperm count could be detected..

In contrast, they found that FSH levels in women with the polymorphisms were increased, while progesterone levels were lowered. However, the number of women with the combined variation so far studied was not high enough to draw significant conclusions.

Professor Gromoll, of the Centre of Reproductive Medicine and Andrology, University of Muenster, presented the complete results to the European Congress of Endocrinology in Copenhagen. He said:

"These genetic variations turned out to have significant effects on male and female reproductive endocrinology, and hence on male and female fertility. Where a man has the variants in both the hormone and its receptor, the drop in fertility is very significant. 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. In the same way, knowing which women carry the variants may enable them to receive tailored ovarian stimulation in the future.

"We are now working to identify infertile patients suitable for FSH treatment to induce fertility".