'MIF Matters' Discussion

This email dialogue is between three AIS women (one in the UK, two in the US) on the role of Mullerian Inhibitory Factor (MIF) [Ref 1] in AIS, at the time that one of them was drafting an article (see “Y Gonads” in ALIAS No. 7, Spring 1997):

Ref 1: Also known as Mullerian Inhibitory Hormone (MIH), Mullerian Inhibitory Substance (MIS) or Anti Mullerian Hormone (AMH).

Correspondent 1 wrote:
I've got this theory that it's actually the other way round from what the gynaecologist said and that, in AIS, it is chromosomes that “make us what we are” (faulty X --> androgen insensitivity --> Eve principle) in the sense intended by the gynaecologist (i.e. externally female, at birth and beyond) and that it’s hormones that are the bad guys (normal Y --> testes --> MIF --> suppression of internal female organs). I'm classing MIF as a 'male' hormone here.

Correspondent 2 replied:
That's a good point. Without MIF, someone with AIS would have a complete set of internal female organs but with internal testes instead of ovaries.

Correspondent 1 wrote:
Yes, I'm suggesting that a) oestrogenic hormones have been grossly over-rated by medics in talking to parents/patients (they can't cause internal or external female genital structures to develop, only external body features – body shape and breasts – and there’s more to being a woman than that) and that b) the notion of a Y chromosome in a female body has been the cause of unnecessary panic by doctors.

Correspondent 2 replied:
Yes, and maybe that's why medics have somewhat mythologized the syndrome, overemphasizing the physical and psychological femininity of AIS women. You suggest that “... [all this] leaves the patient with no chance of exploring and resolving her feelings about her internal deficiencies and their sequelae (no menstruation, infertility, vaginal hypoplasia etc.).” This is another good point.

Correspondent 3 now joins in:
I am trying to sort out the ‘faulty hormone/chromosomes that make us what we are’ conundrum. I really like this but need to sort it all out in my own mind. I guess it's hard to separate the chromosomes from the hormones because it’s the Y chromosome (rather than the faulty X) which causes testes-->testosterone-->MIF. You’re saying we're not ‘hurt’ by the testosterone, but rather by the MIF which results from the production of the testosterone?

Correspondent 1 replied:
Right, except that MIF doesn't strictly “result from the production of testosterone”. It's another substance produced by the foetal testes, from the Sertoli cells (testosterone being produced by the Leydig cells). I’m not sure whether they are produced at the same time or not. We are insensitive to the testosterone, but I'm also going on to say that we need not even consider ourselves 'hurt' by the Y chromosome.

Correspondent 3 asked:
If we were still androgen-insensitive but didn't produce MIF from our testes, we'd have a uterus etc. – right?

Correspondent 1 replied:
In theory, yes. But this doesn't happen in AIS [Ref 2]. However, it does happen in XY gonadal dysgenesis because here the testes never develop properly in the first place and are just ‘streaks’ [Ref 3]. This could be M_____'s situation. Unlike us, she never produced MIF because she has no testes; and so her uterus, cervix and vagina were allowed to form. She has XY chromosomes and yet menstruated for the first time recently under hormone treatment. These facts show that a Y chromosome need not be a threat to internal femaleness – whereas a hormone (MIF) can! I then advance the parallel notion that the ‘faulty’ X chromosome can be considered a ‘goodie’ as far as femaleness in AIS is concerned because by rendering the tissues androgen-insensitive it has allowed the external genitalia to develop as female instead of male; and that oestrogenic hormones (which are plugged so hard by medics) are no big deal – they only provide some additional superficial female attributes.

Ref 2: Apart from fragments of uterus, tubes etc. seen in some AIS patients.
Ref 3: See “Swyer Syndrome” in ALIAS No. 8.

Is my 'conceptual framework' or 'paradigm' (as ‘Correspondent 2’ so splendidly termed it – thanks, ‘Correspondent 2’!) a load of cobblers? It may well be. Actually, I don't really care if it is, because I think that medics' rhetoric on this subject is just as suspect. Maybe no one has hit on the most useful concept yet.

Correspondent 3 wrote:
But in the chicken and egg game, the MIF is only produced after the body produces testes, not before the gonads are differentiated, right? Sorry, I don't know enough about biology to know this. If you can help me with these technical questions, it would allow me to analyse your new theory more completely. I do think it sounds great and I am pleased at most efforts to confound the medics – maybe it will divert their attention so they won't have time to lie to their patients (: !!

Correspondent 1 replied:
Yes, I agree with your analysis – on all counts!

Correspondent 3 wrote: So at the point when MIF is produced, it's already too late [to change direction, from testes to ovaries] even if science could prevent the MIF from being released in AIS? We would wind up with a uterus, cervix and upper third of the vagina (the bits which are missing in AIS) – but still no ovaries?

Correspondent 1 replied:
Yes. We'd be in a similar situation to M_____, but with internal testes rather than just the streak gonads that she has. And if the recent work on using primitive sperm precursor cells to fertilize eggs [Ref 4] were to progress, then, in this hypothetical future situation (testes with uterus), I guess an AIS woman could potentially carry a child conceived from her own testicular material and a donor egg (from her male partner's XX sister or mother?)! Pure speculation on my part, but it might happen? And even if viable ‘sperm’ couldn't be harvested from her testes, I guess a donor egg could be fertilized with a partner's sperm and be implanted.

Ref 4: See “Fertility Advances” in ALIAS No. 7, Spring 1997.

Correspondent 3 wrote:
So in a sense, we should be encouraging doctors to look at ways to suppress MIF in known carriers who become pregnant [with an AIS child] rather than trying to correct the androgen receptor defect in the unborn foetus (which I believe Prof. Hughes suggested, to our horror, at the Sept ‘96 UK meeting)?

Correspondent 1 replied:
Before suppressing MIF in the foetus of a pregnant carrier, you'd have to determine that the foetus was AIS because if it was ‘non-AIS XY’ then testosterone action with a lack of MIF might theoretically result in male external genitalia with a uterus, cervix and upper vagina? – a kind of mirror image of CAIS! I really know very little about MIF. It may not have been studied much although I have some references [Ref 5]. I didn't hear Prof. Hughes say all this about correcting the receptor defect. I must have still been in shock following the famous ‘uncles, brothers and sons’ statement! [Ref 6] Did he mean correction at the tissue receptor level or in the gene on the X chromosome which encodes the receptor protein?

Ref 5: Josso N. et al: Anti-Mullerian hormone and intersex states. Trends Endocrinol. Metab., 2:227-233, 1991. Harbison M.D. et al: Anti-Mullerian hormone in three intersex states. Ann. Genet., 34:226-232, 1991. Lee M.M and Donahoe P.K: Mullerian inhibiting substance: a gonadal hormone with multiple functions. Endocr. Rev., 14:152-164, 1993. Josso N. et al: Anti-Mullerian hormone and testicular descent: clinical and hormonal aspects. In: Dufau M.L. and Fabbri A. (eds), Cell and Molecular Biology of the Testis. Raven Press, New York,1994.
Ref 6: See “External Emphasis” in ALIAS No. 6, Winter 1996.

Correspondent 3 wrote:
PLEASE correct all faults of logic, information etc., as I am interested in having a deeper understanding of the biology of this. I think that the Y chromosome is largely irrelevant in AIS except for the hormones it facilitates. It is not the chromosome itself that causes any problems other than ‘psychological’ ones. I think it is vital to emphasize that it is not a chromosome per se but rather the MIF from the testes which is the problem because doctors like Prof. Hughes are thinking of trying to ‘fix’ the chromosome (the X chromosome, or maybe the androgen receptor problem stemming from the fault on the X) and would, in my opinion, be performing a far greater service if they would find a way to trick the body to not produce the hormone MIF or to neutralize it effects.

Correspondent 1 replied:
Yes, you're right that the Y chromosome in AIS is only of material relevance by virtue of the hormones it facilitates (or in fact the hormone, singular (i.e. MIF) since in CAIS the other hormone (testosterone) produced by the testes “passes like a ship in the night so that neutral female absolutism reigns supreme” as one author subtly expressed it [Ref 7]. However, I guess you could say that the Y chromosome facilitates this hormone action by virtue of having caused testes to be formed from the gonads in the first place. Also, I remember now that the Y chromosome does have a gene that has a direct influence on height and which is thought could account for the tallness of some AIS women, so it may have some direct relevance there.

Ref 7: Shearman R.P: Intersexuality. In Clinical Reproductive Endocrinology, Churchill Livingstone, p346-361, 1985.

Correspondent 3 wrote:
In so many ways I thank God for my X chromosome which carries the ‘defect’ for androgen resistance. I do not think, therefore, of either chromosome (X or Y) as being ‘faulty’. My ‘AIS’ X chromosome allows me to be Susan rather than Sam or Steven or some other male persona. What I am distressed by is the MIF which ate away our potential upper vagina and uterus, robbing us of the opportunity to have normal relationships and perhaps become pregnant using new technologies for fertilization. Having a uterus etc. would have facilitated menstruation too. So it's that pesky MIF, not a pesky Y (or X) chromosome, that is the real problem.

My personal ‘hierarchy of preference’ would therefore be:

1) XX (not a possibility since I'm XY but you can't kill a girl for dreaming!)

2) XY, Gonadal Dysgenesis (Swyer Syndrome), i.e. with streak gonads that fail to produce MIF, allowing uterus, cervix and upper vagina to develop.

3) XY, CAIS but with MIF suppressed. (Note: the Y chromosome is irrelevant here, it's the resistance to androgens and the MIF suppression that would allow me to be female internally.) But if viable sperm could be obtained from the testes then I would invert preferences 2 and 3.

4) XY, CAIS.

5) XY, PAIS.

6) XY non-AIS. This is a very distant last. I can't bear to call this ‘normal’ as I think non-AIS XY’s (i.e. those ‘male’ creatures) are inherently un-evolved behemoths. In fact, I think I shall privately refer to all such individuals as ‘non-AIS XY's’ so that they are defined by what they don't have (AIS) rather than what they do (normal X chromosomes)!

I am now really fascinated about MIF and will go to the medical school library to get information. Wouldn't it be great if doctors could find a way to suppress or neutralize MIF in pregnant known carriers of AIS? Maybe we should suggest this to Prof. Hughes etc.? I am terrified about what he said at the UK meeting and I think his statement reflected a huge prejudice that it would be better to have the androgen resistance problem corrected. I couldn't disagree more. To paraphrase an old MTV phrase (do you get this mindless gibberish music video station over there?) “I want my AIS.” But I want it with MIF inhibitor (a double inhibition!).

I wish there was a profession where I could live, sleep, eat, drink AIS – I find the various dimensions of this syndrome captivating – from the biology to the psychology. I know I say this often, but working on the support group stuff is so much more meaningful to me than my professional work. To also study the biology and chemistry of it would be frosting on the cake!