Switching Gender: A Surprising Finding About the Lack of Permanency of Gender-Specific Structure & Functioning of Cells Within Adult Sex Organs Once a Genetic Switch That Promotes a Distinctly Female Identity is Turned Off

Recent papers in the prestigious journal Cell (see Sinclair & Smith, 2009; Uhlenhaut et al., 2009) have uncovered a startling phenomenon: The clear differentiation of  most mammalian sexual organ cells into either distinctly male (testicles) or female (ovaries) organs might not be determined once and for all during embryonic development.

It has become a doctrine of faith that except in extremely rare cases of intersex (now preferentially termed as Disorders of Sex Development),  having XX chromosomes led the developing embryo turned fetus  turned newborn baby along a path that led to her having functional ovaries and ova and not testes and sperm. 

This differentiation in the fate of the unspecialized “go-either-way” gonad  was thought to be a self-reinforcing phenomenon. XX chromosomes produced proteins that accelerated early either-one-way-or-the other-way  development towards an irreversibly female mix of circulating hormones, that in turn influenced the formation of distinctly female  sexual  organs  and in most cases, seem to influence the development of  sex differences in the brain in terms of structure and  gender self-identity.  Once the gonads became distinctly female they would be secreting a hormonal mix that was so predominantly  estrogen based that the “pre-ovaries”  not only became mature ovaries, but stayed that way,  and particularly with the onset of puberty, produced  even greater amounts of estrogens which further feminized appearance and function throughout adulthood.

The reverse was also thought to be true: XY chromosomes drove the production of androgens which essentially masculinized the either-or gonads towards maleness. Once the gonads became testicles they would doubtlessly produce male traits that would become even stronger after puberty.

BLAMING MOM FOR CASES OF AMBIGUOUS GENDER

There were a number of  rare exceptions to the rule. Most concerned XY male children with anatomically ambiguous genitalia, and occasionally the reverse: XX females with male-like genitals.   

It was thought that the prenatal level of circulating sex hormones might have an influence  on the  developing embryo   that   blurred distinctions in terms of the absolutely either-or anatomy, physiology and gender identity.  

While gender identity is thought to be far more complex that just having certain chromosomes  and being born with either male or female anatomy,   one of the first strategies in persons born with discordant gender identity , is in fact, hormone manipulation that aims towards the desired gender.

In a sense,  if the  maternal-fetal hormonal environment “made a mistake” then one of the first steps was to reverse it by   tilting the circulating hormone levels. Males who wish to have their bodies match their female identity would be given female hormones, and vice-versa.

At some point in time, the ovaries, testicles, and external sex organs would be removed or surgically repurposed, even as the transgender hormones had to be continued because it was seen as dogma that the gonads could not switch which hormones they were making.

THE PROBLEM OF MENOPAUSE FOR THE CONSENSUS THEORY OF THE IRREVERSIBILITY  OF GONAD DEVELOPMENT & FUNCTION

One other major problem with the theory that gonads were irreversible in gender structure and function is the masculinazation  of post-menopausal females. It was generally thought that the ovaries simply aged out of being efficient producers of female hormones, and the tiny amount of male hormones remaining simply began to circulate and influence the body more towards some masculine traits like hirsutism in particular. But there was no thought that the ovaries could actually become testicles, although in extreme cases of masculinization of secondary sex characteristics, it sometimes appeared that way.

THE INTERPLAY OF SRY, Sox 9, & FOXL2

IN SERTOLI, LEYDIG, GRANULOSA & THECA CELLS

While mice used in the lab are not, of course, human, their sexual anatomy, especially the development of the gonads towards one sex or the other  is highly comparable.

The team of of Uhlenhaut et al.  looked at the intermediate biochemical compounds and pathways that, within both mice and humans,   regulate  two general categories of sexual organ cells  specific to their gender.  These regulated cells are the Sertoli and  Leydig cells for the testicles and the granulosa and theca cells for the development and function of ovaries and ova.

The team   started with a focus on gene-produced complexes known in molecular biology shorthand as  SRY and Sox9.

SRY is basically an initiator of  sexual specialization. Without its action, there is neither female nor male sex cell development. The key is maintaining a certain balance.

When  SRY is uninhibited,  it appears to favor maleness by stimulating Sox9.  SRY’s action is modulated in females before birth by a trio of  other gene-produced complexes acting in concert:  beta-catenin, WNT4, and RSPO1. They  keep down the production of Sox9, leading to femaleness.  

After birth, another complex, known by in molecular biology shorthand as FOXL2, picks up where the trio left off in downregulating Sox9.

HOW A CANCER CHEMOTHERAPY AGENT ALLOWED FOR A SELECTIVE SHUTDOWN OF FOXL2

The team hypothesized that FOXL2 interacts with the classic female hormone estrogen and its receptors in a synergistic way.  More importantly, they  hoped that if they could find an agent that would silence the pro-female FOXL2 complex, they might witness the cessation of at least some female hormone production at the cellular level.  They looked to a drug famous for silencing estrogen receptors in cases of estrogen-driven cancers, particularly breast cancer: Tamoxifen.

The injected  tamoxifen had the desired effect.  Ovaries began to shut down estrogen production, and in particular, they appeared to do so by interfering with FOXL2, just as predicted.

What was unpredicted was that once FOXL2 was blocked, these mature  ovaries cells began to change sex. The female theca cells within them began to morph into male  Leydig cells. The female granulosa cells inside were becoming  male Sertoli cells.  In other words, well past the age of embryos, where maternal environments are thought able to influence gender anatomy, function and identity,  these important sex-specific cells were transgendering long after such a thing was thought possible.

It turns out that without FOXL2, it is conceivable that even mature adult ovaries can essentially become and perhaps act like testicles, and that FOXL2 has to fight off Sox9 throughout the lifespan of the ovary in order for it  to stay an ovary.  

WHY THIS MATTERS

This matters because it gives us an insight how we might better handle   persons with gender identity discordance. It might one day be possible to switch the nature of their gonads by selectively turning off a critical pathway, so that the post-birth ovary can indeed become a testicle and start producing male hormones on its own, as opposed to supplying male hormones and surgically removing ovaries, or vice-versa perhaps for males wishing to become females.  Some surgery and some injected hormone manipulation might still be necessary, but some of it could likely be avoided or minimized.

Perhaps even more importantly to women undergoing menopause, particularly those undergoing unwanted early menopause, insights from this research might find ways to unblock FOXL2, so that it could continue to counterbalance Sox9, and allow ovaries to continue to act like ovaries, and particularly allow for both those younger women who had unusually premature menopause and for  older professional women who had delayed childbirth, now to have children, or offset unwanted effects of female hormone loss without ingested or injected hormones.

Tony Stankus, FSLA tstankus@uark.edu Life Sciences Librarian, Science Coordinator & Professor

University of Arkansas Libraries MULN-223E

Fayetteville, AR 72701

Voice 479-575-4031

Fax: 479-575-4592.

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Parker, Jim L., Deborah L. Ekman, and Lawrence J. Hayden. 2009. Hysterectomy in a phenotypic male with advanced gonadal malignancy and intersex. The Medical Journal of Australia 190, (11) (06/01): 644-6.

Sinclair, Andrew & Craig Smith. 2009. Females battle to suppress their inner male. Cell 139 : 1051-1053.

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