Early menopause linked to increased risk of cerebral aneurysm.

The appearance of occasional masculine features seen in some women after the menopause may be the result of a genetic malfunction complicated by the loss of endogenous estrogen. However, the implications of this suggestion – made in a study reported in the journal Cell in December – stretch before and beyond the menopause and into the whole lifespan of sex determination and gender maintenance. The study found, contrary to what are most people’s expectations, that gender does not depend solely on the arrangement of chromosomes. Its collaborating investigators from the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the Medical Research Council’s National Institute for Medical Research (NIMR) in London, found that, if a certain gene located on a non-sex chromosome is turned off, cells in the ovaries of adult female mice turn into cells typically found in testes. The study thus challenges the long-held assumption that the development of female traits is the default pathway of nature – that is, an embryo’s default route to gender determination would be female unless a transcription factor gene known as SRY was located on the Y chromosome. The gene which appears to be instrumental in this process is known as FOXL2, and this study showed – in the mouse model – that deletion of FOXL2 in adult ovarian follicles leads to the immediate upregulation of testis-specific genes, including the critical SRY gene. Significantly, FOXL2 is located not on the sex chromosomes but on an autosome, and is therefore present in both sexes. When the FOXL2 gene was ablated (switched off) in the mouse ovaries, the investigators were surprised by the results. ‘We expected the mice to stop producing oocytes, but what happened was much more dramatic,’ said EMBL investigator Mathias Trier. ‘Somatic cells which support the developing egg took on the characteristics of the cells which usually support developing sperm, and the gender-specific hormone-producing cells also switched from a female to a male cell type’. However, it was when the EMBL scientists teamed up with the NIMR group of Robin Lovell-Badge in London that an explanation for this battle of the sexes emerged and how FOXL2 plays such a crucial role in keeping female mice female. They showed that FOXL2 and the estrogen receptors actually interact to regulate expression of the testes-promoting gene known as Sox9. Sox9 has for a while been known to function in the embryo to make the early gonads become testes rather than ovaries, but this new study now suggests that Sox9 performs its same duties in the adult as well. Thus, FOXL2 – in its interaction with estrogen – is critical to keep Sox9 turned off in ovaries throughout life, and therefore to prevent any male effects and keep females feminine. Maintenance of the ovarian phenotype is thus an active process throughout life; FOXL2 and Sox9 oppose each other’s action to ensure not just the formation but also the maintenance of the different female and male supporting cell types. And without FOXL2 the estrogen receptor fails to work. It’s interesting that both FOXL2 and Sox9 have already been implicated elsewhere in the causation of premature ovarian failure. Treier suspects that this process, by which FOXL2 is necessary to keep Sox9 switched off in the adult ovary, is what underlies the occasional signs of masculinization seen in some postmenopausal women. ‘When estrogen declines,’ he said, ‘part of the ovary may switch to a testiclelike structure’, which may also be why estrogen replacement therapy was originally claimed to make women feel feminine forever. With HRT now under a safety cloud, agents that modulate FOXL2 activity may be yet another way to preserve that female femininity.