Fertility Issues

Introduction

This page carries excerpts from our journal/newsletter (ALIAS) on advances in reproductive technology that might someday provide an AIS woman with some reproductive options. Please note that although some of us have a scientific/medical background, and we have tried to give informed predictions/comments, we are not experts in this area and many of our comments are speculative.
Brave New World (from ALIAS No. 3, Winter 1995)

At the end of a TV discussion by an expert panel on the issues of surrogacy, IVF, abortion, use of foetal eggs or XNXX, genetic engineering etc., etc. [Ref. 1] the presenter expressed surprise that no-one had brought up the possibility of men becoming pregnant. Prof. Robert Winston of Hammersmith Hospital, a well-known worker in the area of assisted conception, answered:

This is relevant in two main cases. Firstly there are some transexual men who might want to bear children. Amazingly, the human embryo has a propensity to implant in almost any tissue so there is no real reason why men should not carry babies, albeit with trans-abdominal rather than vaginal delivery. Secondly, there are some women who happen to have a Y chromosome and who have no ovaries or uterus and are therefore infertile. Again, there is no reason why we couldn’t make these women pregnant [Ref. 2].The major problem lies in implanting the embryo in tissue that wouldn’t cause a massive haemorrhage.

A recent TV programme examined the emerging science of tissue engineering [Ref. 3]. It showed living human cartilage cells growing, in a laboratory dish, into the form of a human ear, using the physical support of an ear-shaped template made of a fine filament matrix and which later dissolves. The technique is being pioneered by clinicians and engineers at a Boston hospital and MIT, and implantation of the engineered ear is currently being tested in animals. There was talk of eventually extending the technique to internal body parts. Perhaps this holds out some distant hope for an improvement in plastic surgery in AIS?

Ref. 1: ‘Brave New World?’ (After Dark Special) 30 May 1994, Channel 4.

Ref. 2: Presumably with donor egg fertilised by the partner’s sperm.

Ref. 3: Test Tube Bodies, BBC1, 24 October 1995.
A Fertile Future? (from ALIAS No. 4, Spring 1996)

A recent TV/press report (Jan ‘96) described the successful in vitro fertilization of a woman’s egg by sperm material extracted directly from her partner’s testes via a biopsy. [Ref. 1] We understand this to be the technique of ICSI (Inter-Cytoplasmic Sperm Inoculation).

We are not sure whether the testes in AIS contain any viable sperm cells [Ref. 2] but if so it would seem possible, in theory at least, that these might be extracted and used to fertilize an egg donated by, say, the normal XX sister of an AIS woman’s male partner? We are awaiting further clinical input on this possibility so don’t get too excited. If it is feasible then presumably only Y-bearing sperm cells would be used, to avoid passing on the faulty X gene in pornroi.com, so only normal male babies would result (no females). Paradoxically this would mean the ‘mother’ providing the sperm and the ‘father’, as it were, providing the egg (via his close female relative). Dr Richard Stanhope [Ref. 3] suggests that, in view of this, the main problem would be related to ethical matters.

Gonadectomy is usually recommended for AIS patients at some point after puberty in order to avoid a risk of malignant changes. In many cases this is done in infancy or childhood (without informed consent of the patient) but the risk of malignant changes before puberty is extremely low and the risk as a whole seems to be discounted in some quarters (See “Gonadectomy” in ALIAS No. 2, Summer 1995.). If there was even a remote chance that at some time in the next 20-30 years it might be possible for an AIS woman to become the natural parent of a child, then it might be wise to delay gonadectomy in today’s AIS infants? See also “Early Gonadectomy” and “Brave New World” in ALIAS No 3, Winter 1995.

Ref. 1: Prof. Gedis Grudzinskas, Prof. of Obstetrics & Gynaecology, Royal London Hospital Medical College, London E1 2ED. Reported in Sunday Times, 28 January ‘96. Also a clinician in Nottingham doing same/similar work featured in TV news.

Ref. 2: It has been reported that 28% of a group of 43 AIS cases had rare spermatogonia in their testes. Rutgers J.L. and Scully R.E: The androgen insensitivity syndrome (testicular feminization): A clinicopathologic study of 43 cases. Int. J. Gynecol. Pathol. 10:126-144, 1991.

Ref. 3: Consultant Paediatric Endocrinologist and Senior Lecturer, Institute of Child Health/Gt. Ormond St. Children’s Hospital, London WC1N 3JH.
Fertility Advances (from ALIAS No. 7, Spring 1997)

Following on from our coverage in an earlier issue [Ref. 1] of Intra-Cytoplasmic Sperm Injection (ICSI) and its possible relevance to AIS, we report that Dr. Simon Fishel [Ref. 2] has made a further advance in the treatment of male infertility. This involves extracting spermatid – a form of pre-sperm – from the testes and injecting it into a human egg in a laboratory dish before re-implantation in the woman’s uterus [Ref. 3]. Dr. Fishel is awaiting approval from the Human Fertilisation and Embryology Authority to start trials involving more than 100 couples. Scientists at Nuture hope that it will prove as successful as ICSI which in their hands has a 27% success rate. It was reported that within the ensuing 18 months Dr. Fishel and his team hoped to achieve human pregnancies using an even earlier form of pre-sperm, called the spermatocyte.

We asked Dr. Fishel whether an even earlier form of sperm cell than this, the spermatogonium, (which has been reported to be occasionally present in the testes of some AIS individuals [Ref. 4]) might be used, thus holding out some slight future possibility of someone with AIS ‘fathering’ a child via surgical extraction of material from the primitive spermatic cells in their testes? He responded (March 1996) as follows:

We are unsure how early we can go with regard to sperm precursors. There is some work in animals which indicates that we can go back to the spermatocyte. However, to go right back to the original precursor, the spermatogonium, would not be possible at this stage. Currently my team is working on spermatogenesis in vitro, but I can see no immediate breakthroughs in future for the stage as early as spermatogonia. It is something we will be working very hard to attain in the coming decade and, considering the pace of current development, I’d have to say anything is possible! Certainly the next 20-30 years [Ref. 5] that you suggest in your letter is an awful long time in scientific development [we believe he means ‘the pace is fast enough to permit many advances in that time’].

Another area we are working on, is to offer cryopreservation (freezing) [of testicular tissue/cells] for future use. We are trying to raise research funding for this project so that we could compare the effects of freezing pre-pubertal tissue compared to [that of] adults. Should we obtain funding, however, I believe we could make great strides in this area.

Later in the year, a newspaper [Ref. 6] reported that Dr. Fishel had in fact engineered the birth of a baby following the freezing of testicular tissue from a man whose sperm did not mature. Long-term freezing has potential for use in boys with cancer in whom chemotherapy might cause infertility. Parents of AIS infants/children may want to ask about this possibility when discussing early gonadectomy with their specialist?

Dr. Fishel is apparently willing to answer questions via a European Infertility Network (EIN) web site (see Links to Other Sites).

Our US representative told us last year of a news report on the possibility of men [Ref. 7] becoming ‘pregnant’ via an embryo implanted in the abdomen. An intra-abdominal pregnancy (i.e. outside the uterus) in a Canadian woman was successful, leading doctors to conclude that they could do this with men. Dr. Edmond Confino in Chicago maintains that the only thing stopping them from doing this with men is ‘societal reaction.’

Ref. 1: See “A Fertile Future” in in ALIAS No. 4, Spring 1996.

Ref. 2: Scientific director of Nurture (Tel: 01159 709490) Nottingham University’s non profit-making research and treatment unit in reproduction.

Ref. 3: Report in The Times 12 (or 13?) February 1996.

Ref. 4: Dr. Joanne Rutgers (Dept. of Pathology, Harbor-UCLA Medical Center, University of California, Los Angeles), co-author of the study of the 43 cases of AIS which reported this, told us recently that they “had no case in which there was complete spermatogenesis” and that “only a minority of cases had any germ cells whatsoever, and these few completely lacked development.” They concluded that “unfortunately the method you describe [ICSI] would not be applicable to patients with AIS.”

Ref. 5: i.e. the point at which today’s AIS infants might want a family of their own and wish their testes had not been removed, without their consent, in childhood.

Ref. 6: The Sunday Times, 10 Nov 1996.

Ref. 7: And presumably women with AIS?
Fertility Update (from ALIAS No. 8, Summer 1997)

In previous issues [Ref. 1] we speculated on the possibility of AIS individuals being able to ‘father’ children via the extraction of immature spermatic cell material from their intact (or frozen) testicular tissue.

An article [Ref. 2] described the freezing of ovarian tissue, in an attempt to secure future fertility, by Paul Serhal, a gynaecologist who heads the assisted conception unit at University College Hospital, London. Another consultant, Mr. Lower at St. Bartholomew’s Hospital, also featured. Peter Brinsden, medical director at Bourne Hall, Cambridge, a private fertility clinic [Ref. 3], said that they had stored tissue from patients with lymphatic cancers as young as six years-old. He said “We hope that by the time they want children we will have the technology to help them”.

Dr. Charmian Quigley, in her review of AIS [Ref. 4], makes the following points:

Testicular development occurs normally in the AIS fetus, and immature spermatogonia (germ cells) are present in the testes at birth and during childhood. However, histological studies [Ref. 5] of testes of older AIS individuals reveal the presence of only occasional spermatogonia in testes removed during the peri-pubertal years, and no germ cells are present in the testes of affected adults, suggesting a progressive decline of germ cell numbers with increasing age. Spermatocytes and more mature germ cells are absent at all ages.

Although we understand that the use of cells as immature as spermatogonia for in vitro fertilization is not on the immediate horizon, early gonadectomy in AIS with cryopreservation (freezing) of testicular tissue might increase the chances of success, should this become possible in say 15-20 years time?

Ref. 1: See “A Fertile Future?” in ALIAS No. 4, Spring 1996 and “Fertility Advances” in ALIAS No. 7, Spring 1997.

Ref. 2: ‘Putting a Future on Ice’ by Lulu Appleton, Daily Telegraph, 18 February 1997.

Ref. 3: Http://www.bourn-hall-clinic.co.uk/

Ref. 4: Quigley et al: Androgen Receptor Defects: Historical, Clinical and Molecular Perspectives. Endocrine Reviews, Vol. 16, No. 3, pp271-321 (1995).

Ref. 5: Microscopic examination of tissue samples.
Men Becoming Pregnant (from ALIAS No. 14, Spring 1999)

The UK Sunday Times (14 March ‘99) published another of those articles speculating about the possibility of men carrying a foetus. The technique would involve attaching the foetus to the muscles inside the abdomen or even fashioning an artificial womb from abdominal tissue. Female hormone treatment would be vital for encouraging the placenta to attach. The child would be born by caesarian section. The medical experts quoted – Lord Robert Winston [Ref. 1], UK IVF expert, and Dr. Simon Fishel [Ref. 2] (who has worked on the ICSI method) – were sceptical of its likely success (because of the possibility of massive internal bleeding and abnormal foetal development) although both have been approached by heterosexual couples seeking a male pregnancy.

The article says that the problem of the female hormones causing dramatic changes in physique in men would mean that transsexuals would probably be among the first to undergo the procedure because such changes would have already been induced by the drugs used to help them change sex. A male-to-female transsexual is quoted as saying she’d be willing to try it.

Why is it that transsexuals, and others with a normal reproductive system for their genetic sex (in this case, men) are always the first to be considered and given press coverage regarding ‘advances’ such as these? Why not increase awareness of the need for some basic reproductive choices in population groups like XY women with AIS, who were born without either ovaries or uterus? Please write to the authors of such articles, and to the people quoted therein, to ask that our case be put forward before that of people who already have reproductive options.

Ref. 1: Hammersmith Hospital, London.

Ref. 2: Centre for Assisted Reproduction, Nottingham. See “Fertility Advances in ALIAS No. 7, Spring 1997.
One Woman’s Meat…. (from ALIAS No. 15, Summer 1999)

A new parent subscriber (Mum of CAIS 12 year-old) wrote:

Thank you for sending the documentation on your group. Enclosed you will find our [subscription] forms and cheque. We read with interest your Internet information. I passed along the website no. [address] to our pediatric endocrinologist and he informed me he has since visited it. We were all pleased with the open, lucid presentation. One small suggestion. Both my daughter and I found rather freakish the factsheet’s suggestion of primitive sperm extraction from AIS testes to fertilize a donor egg. It was the only questionable notion in an otherwise serious, professional document. We look forward to receiving the AISSG information, and wish you very continued success.

Ed’s Note: Our speculation on this possible future fertility option for AIS women (see “Fertility Update” in ALIAS No. 8, Summer 1997) was a serious one. Since they have no ovaries, the only germ cells that could produce a child that is genetically related to an AIS woman would have to come from her testes. The recently-developed methodology (ICSI), for helping men with immature sperm cells, cannot as yet cope with the even more primitive cells in AIS testes, but with the current pace of genetic advances it might well be available within the next 20 years. At that time, many of today’s AIS infants might jump at the chance (especially if they had a male partner whose sister, say, might donate an egg; and perhaps carry the child). They might well be thankful that their parents had resisted pressure to have their child’s testes removed before an age when they could give informed consent.
Fertility Possibility? (from ALIAS No. 15, Summer 1999)

We asked an andrological surgeon Mr. Anthony Hirsch [Ref. 1], (who featured in a recent UK TV documentary on advances in male infertility treatments) about the possibility of these techniques being applied to the testicular material of AIS women. He replied (July 1999):

Many thanks for your note of 25 May. I apologize for the delay in replying to you, partly due to pressure of work, but also because an answer demanded some thought and consideration.

It is certainly true that immature sperm material has been found in the testes of patients with complete androgen insensitivity. If the diagnosis is made before they are operated on, the gonads are probably better not removed immediately so that the patient may mature in response to her own internal natural hormones rather than prescribed synthetic hormone. Since CAIS patients are usually well shaped “females” [Ref. 2], who would usually attract a male partner, it is difficult to envisage why a patient would consider having their own immature sperm cells frozen and stored for the future. The obvious exception would be those complete AIS patients who have female sexual partners, who might one day wish to bear children created by assisted conception from their own joint genetic material [Ref. 3]. I have no information on how many CAIS patients have lesbian partners, but you may be aware of this.

Within the testicular tissue in CAIS, the sperm material is usually immature, with no formed spermatozoa. Within the next 5 years it is probable that immature spermatogenic material could be successfully cultured in the laboratory with the creation of spermatozoa that could be used for intracytoplasmic sperm injection (ICSI). ICSI has a success rate of 22% in terms of a baby per treatment cycle commenced, provided the female partner is under 35 years of age.

The AIS Support Group might therefore consider whether it should advise the parents of CAIS girls about freezing testicular tissue. I think you should also ‘sound out’ the views of 1 or 2 IVF gynaecologists or centres (e.g. Bourn Hall) about the acceptability of freezing gonadal tissue in this way. Assisted conception units would probably need to seek the advice of their Ethical Committees. I am not sure how the present law stands, but presume the HFEA [Ref. 4] would have no objections to IVF or ICSI in this situation, as there appears to be no problem concerning donor sperm for lesbian couples.

It would be very difficult for parents to say “no” to something that may be feasible in the near future, provided it is not illegal or socially completely unacceptable. Therefore, on balance, your proposal is probably something you could advise parents of CAIS girls to consider rather than making a formal recommendation.

I hope this letter has contributed something and will help you. With kind regards and best wishes.

Ref. 1: 113 Harley Street, London W1N 1DG. Tel: 0171 935 6588. Also at Bourn Hall Clinic, Cambridgeshire. Http://www.bourn-hall-clinic.co.uk/

Ref. 2: His quotation marks.

Ref. 3: Our suggestion was that a male partner’s sister, for example, might help. See previous article.

Ref. 4: Human Fertilization and Embryology Authority, Paxton House, 30 Artillery Lane, London E1 7LS. Tel: 0171 377 5077. Website: http://www.hfea.org.uk
Fertility Advance (from ALIAS No. 16, Spring 2000)

Tammy, a 27 year-old woman with 5 alpha reductase deficiency emailed to a group of women with AIS and related conditions (Oct. 1999):

I was reading the Johns Hopkins [Hospital] site on 5-AR and noticed it said that in 5-AR the testes will contain sperm. I had them removed at 13 but was wondering…. might I have been able to ‘have’ my own children if they had taken the sperm out [and preserved them]. Or would the sperm be dead because of ‘cooking’ in my abdomen. I know for normal men sperm will die if it is too hot, and part of infertility treatments include wearing boxers to provide adequate air circulation. I know it doesn’t matter at this point for me personally, because my testes and any sperm I may have had are probably either sitting in a jar of formaldehyde or have long ago been thrown out with the rest of the medical waste. BUT if there is a possibility that our little orchid sisters may have reproductive options, I’d like to know and consider the possibilities…

I wish I had the option… and think I would do it (talk about crossing gender barriers!)… mommy No. 1 donates the sperm so mommy No. 2 could carry the baby… I think it sounds wonderful. Another barrier… if two women are able to procreate a child together how can they be denied marital rights? And would society have to accept an ‘I’ for those of us who want it? [Ref. 1] OK, maybe the kid would have issues about it but we prove here that anything can be overcome. Besides, lesbians merge families all the time and raise healthy happy children…. it’s all about love in my opinion. If any of you know if the sperm would be viable, please respond.

We directed her to “ICSI” in ALIAS No. 15, Autumn 1999, about which she commented:

Dr. Hirsch wrote (in letter in No. 15):

“…Since CAIS patients are usually well shaped females, who would usually attract a male partner, it is difficult to envisage why a patient would consider having their own immature sperm cells frozen and stored for the future….”

Why indeed would a well shaped CAIS woman, capable of attracting a male partner want to have reproductive choices? I wonder sometimes if people who make statements like this realize they are talking about real people. Yeah….it’s kind of a weird concept to, in essence, ‘father’ your child but it’s the only option we have, and it shouldn’t be so easily dismissed… especially by a doc. It’s a personal choice for the affected XY woman to make. How much trouble would it be to freeze the tissue and let her decide later what to do with it? I think I’ll write my old doc just to be sure they threw mine out 🙂

Ref. 1: Some group members (CAIS as well as PAIS) have said they would like the option to enter ‘I’ (intersexed) instead of ‘M’ or ‘F’ on official forms.
Half-Cloning (from ALIAS No. 16, Spring 2000)

On 5th Sept 1999 the UK’s Sunday Times [Ref. 1] reported on a medical advance pioneered by a team headed by Zev Rosenwaks at the Cornell Medical Center, New York. They had been able to take immature egg cells from the ovaries of a donor, remove the nucleus (containing the donor’s genetic material) and replace it with genetic material taken from an ordinary body cell of another animal. The researchers have found they can reprogramme the DNA genetic blueprint from any living cell to make it behave like an unfertilized egg. Once the reconstituted egg cell is mature, it is fertilized in the laboratory and then incubated in the womb of a surrogate mother. The donor egg cell thus acts as an ‘envelope’ for the prospective genetic mother’s genetic material.

They are primarily working on animals (of 35 mice eggs, almost half matured) but the work is being pursued in humans (in Rosenwaks’ first batch of 10 reconstituted human eggs, six were capable of maturing). They have no human pregnancies yet.

The UK’s Human Fertilisation and Embryology Authority [Ref. 2], which regulates infertility treatment in Britain, said the research would be unlikely to receive approval. Other specialists believe that pressure from childless women will lead to its acceptance. The technology, which would sweep away the queue of more than 1,000 childless women waiting for donor eggs, has been welcomed by British infertility experts. Peter Brinsden, director of Bourn Hall, Cambridgeshire [Ref. 3], one of Britain’s largest infertility clinics said: “Egg donation does not give women their own genetic child; this technology does. I would have no problem using it once it is established.”

Although babies born from the technique would be only ‘half-cloned’ (the maternal cloned genetic material is fertilized by normal sperm as in regular IVF treatments), there is concern that using ‘old’ DNA from cells in the mother’s body could mean that a newborn baby was the genetic age of the mother. Early studies of Dolly the sheep, the first animal to be wholly cloned, suggest that her cells are much older than her chronological age.

The announcement, at a conference in France, has also raised anxiety about the gathering pace of cloning technology before regulatory frameworks. Said Philip Hammond, the [UK] Conservative [Party] health spokesman, “We need legislation. If nature intended post-menopausal women to have babies, it would not have created the menopause.”

Ed’s Note: As usual, a male political spokesman pontificates about women’s reproductive choices, and needless to say, women who’ve never had any reproductive options, at any time of their lives (e.g. those with AIS) get missed out of the discussion altogether.

Ref. 1: Egg Cloning May Let 70-year-olds Become Mothers” by Lois Rogers.

Ref. 2: http://www.hfea.org.uk

Ref. 3: http://www.bourn-hall-clinic.co.uk/
Ectopic Pregnancy (from ALIAS No. 16, Spring 2000)

A CAIS woman emailed to a group of AIS women:

Anyone else feel that great things might be possible for the next generation of ‘orchids’? There was headline news today [10th Sept 1999] of the successful delivery of a baby (by Davor Jurkovic, Obstetrician at King’s College Hosp., London) that developed outside his mother’s womb. He’s a triplet. The other 2 eggs made it to the uterus, the third lodged in the Fallopian tube which then ruptured and the embryo escaped and grew in the abdominal cavity between the mother’s bladder and uterus. All 3 babies are doing fine. Jurkovic said it was a 1 in 60-100 million chance of successful outcome in these circumstances. He’d seen one other case earlier in his career but the mother died during delivery.

It has been known for some time that it is possible for an embryo to implant and grow completely outside of the reproductive tract, i.e. anywhere in the abdominal cavity where it can tap into a rich blood supply (that’s my understanding from what I’ve read). The main problem is that a massive and life-threatening haemorrhage is highly likely at some stage in the maturation or the delivery process. The apparent insurmountability of this problem is the main reason why medics have said that in practice it is not something that can be contemplated as an elective procedure for people who do not have a uterus, e.g. normal men, transsexuals (it’s always these groups that are mentioned in the press when speculating on this; never AIS women, needless to say). See “Men Becoming Pregnant” in ALIAS No. 14.

In the current case, a team of 26 medical staff enabled safe delivery and this birth at King’s proves that it is possible although Dr. Jurkovic said that “I don’t think a surgical attempt to replicate it would be successful because the surgery involved would have to be so delicate it would not be possible.”

I’m excited about the possible options opening up for future ‘orchids’, but at the same time sad that it’s too late for most of us, but that’s always the way with medical advances.

A CAIS 40 yr-old commented:

This is interesting. I think I may have shown you the article theorizing male pregnancies by Edmund Confino, M.D. (as I recall) of Northwestern University [Ref. 1]. I contacted him with my comment that while it was nice to conjecture about men (read “XY with functioning androgen receptors”) becoming pregnant it would certainly behove medical science to attempt such procedures with AIS women. Never got a response.

While perhaps I might have considered having children if such techniques had been available ten or twenty years ago, the truth is that at this point I’d damn well settle for ‘normal’ vaginal length. And it bugs me that teams of doctors could be assembled at a cost of thousands of pounds to treat this woman and zero dollars seems to be spent perfecting vaginoplasty options… It is so @#$%^&* frustrating to still not have this resolved!!

OK, I’m off my soap box. I guess it’s just that advances in fertility treatments kinda frost me when we didn’t get so much as the truth from our doctors, never mind an ounce of psychological or emotional support.

Ref. 1: See “Fertility Advances” in ALIAS No. 7, Spring 1997 where he was said to be in Chicago.
Fertility Breakthrough (from ALIAS No. 17)

A team of French, Spanish and Italian fertility experts reported [Ref. 1] that an infertile woman’s genetic make-up can be introduced into a donated egg so that the resulting child carries her genes rather than the donor’s. [Ref. 2] A woman who is unable to make eggs can thus reprogram donor eggs with the genetic material from any of her own body cells to effectively ‘create her own eggs’. The technique is known as ‘membrane fusion’ and parts of it resemble the methodology used to clone Dolly the sheep. [Ref. 3]

The team’s leader, Dr. Jan Tesarik from Paris, said that no attempt had been made to fertilize the experimentally reconstituted eggs because the creation of human embryos (fertilized eggs) for research is banned in France and Spain, and strictly regulated in Italy. One of the team, Dr. Peter Nagy, is already working in Brazil where ethical guidelines allow such studies and says it would be possible to use the technique on patients there by the end of the year. Use of the method in Europe would probably take longer because of the need to get ethical agreement.

Ref. 1: Tesarik J., Nagy Z.P., Mendoza C., and Greco E: Chemically and mechanically induced membrane fusion: non-activating methods for nuclear transfer in mature human oocytes. Human Reproduction 2000 May; 15(5):1149-54. (Laboratoire d’Eylau, 55 rue Saint-Didier, 75116 Paris, France, MAR & Molecular Assisted Reproduction and Genetics, Granada, Spain, CIVTE, Centre of Insemination In Vitro and Embryo Transfer, Sevilla, Spain, Centre for Reproductive Medicine, European Hos.)

Ref. 1: Reported (with diagrams of the technique) in The Daily Telegraph, Thursday April 27th. Go to http://www.telegraph.co.uk and do a search (at foot of page) on ‘Tesarik’.

Ref. 3: See also “Half-cloning” in ALIAS No. 16, Spring 2000.

[Further coverage of fertility issues can be found in ALIAS Nos, 18, 19, 20, 21 and 22 (not yet summarized here).]
Update (Oct 2010)

Time and resources have not allowed us to keep this page updated as much as we’d like. To quickly summarise the current situation, we reproduce here a section from the 2010 paper by Berra et al:

Coordination of fertility options for women with DSD requires both knowledge of the potential for each individual but also of the provision of unusual fertility services. In the UK the three main choices for starting a family come under different agencies. Adoption comes under the auspices of social services, ovum donation is often provided by private fertility clinics and surrogacy is supported by a voluntary organizations (see Internet Resources [below]).

Preparation for fertility may start with a clinical psychology assessment working through the plans and wishes of each individual. A fertility specialist is required to describe the practicalities of each option. Support groups are [a] very helpful source of user information with forums passing on up to date experiences. Women with no uterus will usually choose between surrogacy and adoption.

Women with gonadal dysgenesis and a normal uterus may consider ovum donation. While ovum donation is available in the UK sometimes as part of the NHS fertility services, the rate limiting step is the availability of donates oocytes. In order to circumvent any delay, many couples choose to enroll with clinics in Europe, India or North America w[h]ere supplies of oocytes are less restricted. Successful pregnancies after egg donation in women with 46XY gonadal dysgenesis are still to[o] few to be certain of success rates (Siddique et al, Plante et al, Kan et al, Selvaraj et al). Although [the] rate of Caesarean Section may be increased (Cornet et al), normal term vaginal delivery has been reported (Siddique et al).

Internet Resources:
– AISSG Androgen Insensitivity Syndrome Support Group
– COTS Childness Overcome Through Surrogacy, Surrogacy UK and HFEA Human Fertilisation Embryology Authority (see Links to Other Sites)
– Daisy Network Premature Menopause Support Group (see Links to Other Sites)

AISSG group meetings continue to discuss issues such as adoption and it is planned to have expert speakers on the topic at future meetings.

Personal stories from people with AIS or a related condition

We use this part of the web site to display people’s stories. If you have AIS or a related condition, or you are the parents of an affected child, we would like to hear from you. The UK group looks after the web site so please send your story to the UK group (see How to Contact Us).
Many people with AIS and related conditions have found it very helpful to tell what happened to them. For many of us, it is very therapeutic to “say” those things that we have never told anyone, and quite cathartic to “get it off your chest” by tossing it out into the wider world, but in a safe way. If you wish, you can supply a pseudonym, although most people opt for us to use their real first name on the site. We understand the importance of safeguarding people’s identity/privacy, so your full name, email address etc. will be completely confidential. Please remember not to mention other people’s names without first obtaining their permission.

It is also a great help to other affected people/families to discover, by reading people’s stories, that in fact a community of XY women exists, when they always thought they were “the only one”.
Tell us how you learned about your, or your child’s condition, what you felt and thought, and where you are with it now. What aspects do you think need further attention? Please give your email a title/subject line that give us some hint that it’s a genuine message, because we sometimes don’t open emails that arrive with a blank subject line or ones that look like spam.

A CAIS woman wrote in 1997:
I remember repeatedly thinking as a teenager “How am I going to get myself out of this?” What I meant was not how would I make it all go away (I knew that was an impossibility). Rather I thought “How am I going to summon up the courage to get the help I need, how am I going to find the strength to talk about it?” (even though I didn’t yet know the truth and know what ‘it’ was), “and how the hell am I ever going to build a normal relationship?” I couldn’t even imagine telling anyone I was unable to have children and didn’t have pubic hair – the two things I actually knew and understood at that age.

The image of being painted into a corner was vivid in my mind since the age of 12 or 13. It haunted me until age 36. I never saw any way out of the corner except by taking my life, until I came across the letter [from another AIS woman, in a medical journal, giving the support group contact details]. The letter wasn’t just a release from a corner, it was a release from the prison that was my mind, a place where everything was locked shut inside and could find no freedom of expression. And when I read the description, in ALIAS No. 1, of “….the process of hearing oneself actually saying out loud those words that you thought would forever remain as circling thoughts in your head”, I convulsed with sobbing (the word convulsing is not an exaggeration; I had never cried from so deep a place, or as intensely as when I read that quote). Nothing I ever read so brilliantly depicted how I felt about my life experience and the ordeal of keeping it all locked inside my mind.

We received the following email in March 2004:
A kind hello from Giorgia, I mail you from Belgium. I don’t have an AIS diagnosis nor dealt with the medical issues mentioned on your site. I just want to mail to express how much impressed I am from reading the personal порно stories. I’m also very shocked at the medical discourses, terms and attitudes towards women with AIS.

Having an educational background and work experience in both anthropology and psychotherapy, I feel that the degree of primitiveness expressed by our culture to accomodate “variations” is very high: we live in a sex, gender and sexual primitive society. On the psychological side, I feel hurt to read the effects of the knowledge women have on theirselves. The way that this knowledge has been transmitted and expressed, strikes me as very painfull. Since I too don’t bleed and don’t have a womb but appear female, I can sympatise very strongly with the stories of these women.

Warm regards, Giorgia.

What is AIS?

Androgen Insensitivity Syndrome (AIS) is one of a number of biological intersex conditions. Intersex results from a variation in the embryological development of the reproductive tract, often determined by a known genetic mutation.
Index to this Page

What is Intersex?

The usual pattern of human foetal development results in a 3-part alignment, as follows

Either:

1) sex chromosomes = XY, leading to
2) gonads = testes, leading to
3) external genitalia = male

or:

1) sex chromosomes = XXX, leading to
2) gonads = ovaries, leading to
3) external genitalia = female

So what happens in intersex?
Very rare…

… is a type of intersex condition in which the person actually has a male/female mix at the genetic (chromosome) level and at the gonadal level (the ‘1’ and ‘2’ above). This is extremely rare and only one or two members of our group are in this situation. The old term used in medicine for this situation is a hermaphrodite. Note, however, that a hermaphrodite, in the sense understood by most of society, is a purely mythical creature from ancient literature, one that supposedly has a complete working set of both male and female internal and external organs (such that the individual can, in theory, impregnate itself). This is not humanly possible. Unfortunately medicine took over this literary term in the days before genetics was understood and used it as a medical term, to refer to these individuals who have both ovarian and testicular tissue internally (an ovo-testis) and who, as a result, can have ambiguous external genitalia.
Not quite so rare…

… is the type of intersex condition in which the sex chromosomes are either XY or XX (i.e. not a mixture) and the gonads are either testes or ovaries (i.e. not a mixture) – as in the majority of the population – but there is a mismatch or distortion in the usual alignment of these two elements (the ‘1’ and ‘2’ above) with the external genitalia (the ‘3’ above).

This means that you can, for example, have an XY individual with testes but with an external appearance that is essentially female (i.e. an XY female: either completely female in appearance as in Complete AIS, or partly female in appearence as in Partial AIS) or an XX individual with ovaries but with some degree of male genital appearance (e.g. a woman with congenital adrenal hyperplasia or CAH).

Note that the term ‘intersex’ relates to the elements of this entire axis or alignment (the sex chromosomes, the gonads and the genitalia), and not just to the appearance of the external genitalia. A patient with the complete form of AIS (CAIS), or with Swyers Syndrome (XY gonadal dysgenesis), will always appear female externally (no ambiguity) but she is still intersexed, because she has XY chromosomes and internal testes (testicular streak gonads in the case of Swyers) that are considered at odds with her external femaleness.

Terminology (and Media Confusion)

Before we get into a basic introduction to what AIS is, in medical terms, a brief but important diversion to the subject of bad/confusing terminology and how the media can make things worse.

First off, please note that it is nonsense to talk, in relation to sport for example, of ‘gender testing’ because gender is to a large extent a social construct, describing the way people present themselves to the world and so cannot usefully be subjected to ‘verification’. Rather, it is the notion of sex that Olympic committees and the like are seeking to police.
‘Trans’ Terms

Intersexuality is not the same as a transsexuality (gender dysphoria) and is not a transgender state. Neither of the latter terms is one that we recognise as belonging in any general discussion of intersex. We are not happy with the recent tendency of some trans groups/people to promote transgender as an umbrella term to encompass, for example, transsexuality, transvestitism and intersex. We object to other organisations/individuals putting us in categories without consulting us, especially categories that imply that interexed people, of necessity, have gender identity issues. See the paper by Mazur et al cited at foot of this page.

The problems this causes…

We are constantly trying to get away from the idea that intersex is necessarily to do with gender identity, a notion that others (including the press/media) like to impose on us. Moreover, the prefix trans- infers a “moving across”, and although a few people with intersex conditions may choose to change their gender role, the vast majority never “go” anywhere in terms of their sex or their gender, but are happy to stay in the status in which they grew up.

XY females may suffer various problems on finding out their diagnosis. Problems such as:

confusion
anger at secrecy and paternalism (withholding of diagnostic information)
shame and stigma
an existential type of identity crisis
low self-esteem
difficulty grasping how this biological phenomenon can come about
grief at being denied fertility and rites of passage (e.g. lack of menstruation)
a feeling of freakishness and isolation compared to their peers
a fear that others might see them as ‘male’
a concern regarding their ability to function in a relationship (e.g. vaginal hypoplasia)
the burden of keeping a secret, or uncertainty over who to tell and how
a retreat from medical care leading to failure to take HRT with a risk of osteoporosis
etc., etc.

These are the issues that are of major concern to most of our members; and none of these necessarily means that their inner sense of gender identity is compromised.

This trend towards ‘muscling in’ on intersex issues seems to be a initiative on the part of certain politically-minded people in the ‘trans’ community, to bring intersex under their banner (for whatever reason – it lends more credibility to their cause?) or even to actively interfere in clinical issues relating to intersex. See Announcements for an account of the problems we had in 2000 with a gender dysphoria/transsexual organisation trying to interfere in protocols for ‘gender reinforcement’ surgery in intersexed infants with so-called genital ambiguity.
‘Intersex’ vs ‘Ambiguous Genitalia’

Note that the term ‘ambiguous genitalia’ refers to one specific component (the form taken by the external genitalia) in some intersex states. Yet even specialist clinicians will sometimes use the more general term ‘intersex’ when they are actually referring specifically to patients with outwardly observable ‘ambiguous genitalia’. Many intersexed patients have a totally female phenotype (body form), and usually no gender ID conflicts. Yet they are still intersexed because their internal features (e.g. chromosomes, gonads) are seen to be incongruent with their external appearance. Women with the Complete form of AIS or with Swyers syndrome, for example, come into this category.

The problems this causes…

This sloppy use of terminology causes us a lot of problems because the media (magazines, newspapers, TV) pick up on this and assume that ‘intersex = ambiguous genitalia = gender identity problem’, then print/broadcast material that conveys to the general public the idea that gender identity is, of necessity, an issue in intersex… which it absolutely is not.

The vast majority of our members have a secure female gender identity. Yet it has been known for a CAIS group member (with, by definition, no external genital ambiguity) to agree the text of an article based on her story (one that concentrates on secrecy, confusion about her diagnosis, isolation etc.) only to find at publication that the editor has, say, slipped in a picture (in one case, the left half of a man’s photo joined to the right half of a woman’s photo) with a caption that says “[Name] is confused about being a man or a woman”. …. just because they have this fixed idea that if you’re intersexed then you must have a gender identity problem (and no doubt because this notion sells more magazines/newpapers). See AIS in Articles/Books.

Or else an article will discuss the issues quite sensibly, using the non-emotive term ‘androgen insensitivity’, but when the featured group member finally sees it on the newstand she finds that a huge headline has been splashed across the cover page (again, without consulting her… or us, if we have been involved…) saying “[Name] discovers she is a hermaphrodite.”
‘Hermaphrodite’ Terms

When medicine eventually realised that the mis-alignment type of condition described earlier was a somewhat different situation to the very rare one in which the actual chromosomes and gonadal tisue are a male/female mix, the term for the latter situation was adjusted, from ‘hermaphrodite’ to ‘true hermaphrodite’ (see Related Conditions for more information). This meant that a new variant of the term, i.e. ‘pseudo-hermaphrodite’, could be introduced to describe the mis-aligment situation. The particular mis-alignment where you have XY –> testes –> female appearance (sometimes referred to nowadays as an ‘XY female’ condition) was charmingly termed ‘male pseudo-hermaphrodite’ (and there is also a type of condition that comes under the umbrella term ‘female pseudo-hermaphrodite’; Congenital Adrenal Hyperplasia for example).

The problems this causes…

Most of our members detest these hermaphrodite terms, just as those with AIS find the old name (testicular feminisation syndrome) for their specific condition deeply offensive. For many of our members who have not been told the truth by doctors, it is these terms that they come across in medical libraries/bookshops, when searching for information that will allow them to make sense of their situation. This is deeply traumatising for a teenager who in all respects except for her internal organs appears to be female (and who often has only come to medical attention through a failure to menstruate) and we feel these archaic terms should be banned from the medical literature.

Jeffrey Eugenides, in his novel Middlesex, was wrong in referring to his main character Callie as a hermaphrodite – something that the press, needless to say, picked up and propagated in their reviews of the book (see AIS in Books/Articles). If he was going to use these out-of-date and confusing terms then Callie (like the vast majority of our members with AIS, 5-alpha-reductase deficiency, Swyers syndrome etc.) was not a hermaphrodite (i.e a true hermaphrodite) but a ‘male pseudo-hermaphrodite’. As mentioned above, this is an umbrella term for someone with certain male characteristics (XY sex chromosomes, internal testes) yet certain female characteristics (female external genitalia and general body form, breasts etc.). But this is splitting hairs for most people, and rather than use either archaic term, it would have been much better if Eugenides had just used the more up-to-date term, ‘intersex’.
DSD Terminology

There was a proposal, arising out of a conference in 2005 of (mainly paediatric) clinicians to adopt the term Disorders of Sex Development (DSD) as a new term to replace ‘intersex’; with the various ‘hermaphrodite’ terms being replaced with Sex Chromosome DSD (in place of true hermaphrodite), 46,XY DSD (in place of male pseudo-hermaphrodite) and 46,XX DSD (in place of female pseudo-hermaphrodite). The DSD terminology and the way it was introduced has been controversial in some circles. See the Debates/Discussions page.

Introduction to AIS

So AIS is a condition that affects the development of the reproductive and genital organs.

Male foetuses usually have a Y sex chromosome which initiates the formation of testes (and the suppression of female internal organ development) during gestation. Testes are the site of production of masculinizing hormones (androgens) in large quantities.

Both male and female foetuses usually have at least one X sex chromosome, which contains a gene that gives their body tissues the capacity to recognise and react to androgens. At puberty girls react to the relatively small quantity of androgens (that come mainly from their adrenal glands) by developing pubic/underam hair and darkish pigmentation around the nipples.

People with AIS have a functioning Y sex chromosome (and therefore no female internal organs), but an abnormality on the X sex chromosome that renders the body completely or partially incapable of recognising the androgens produced. In the case of complete androgen insensitivity (CAIS), the external genital development takes a female form. In the case of partial insensitivity (PAIS), the external genital appearance may lie anywhere along the spectrum from male to female. Other related conditions, resulting from changes on different chromosomes, also disrupt the normal pathway of androgen action, resulting again in a feminized phenotype (body form). See Related Conditions.

People with these ‘XY conditions’ may identify as female, intergendered, or male.

How AIS Occurs

Every foetus, whether genetically male (XY) or female (XX), starts life with the capacity to develop either a male or female reproductive system. All foetuses have non-specific genitals for the first 8 weeks or so after conception. After a few weeks, in an XY foetus (without AIS), the non-specific genitals develop into male genitals under the influence of male hormones (androgens).

In AIS, the child is conceived with male (XY) sex chromosomes. Embryonic testes develop inside the body and start to produce androgens. In AIS, these androgens cannot complete the male genital development due to a rare inability to use the androgens that the testes produce so the development of the external genitals continues along female lines. However, another hormone produced by the foetal testes suppresses the development of female internal organs. Thus a person with AIS has external genitals that in Complete AIS (CAIS) are completely female or in Partial AIS (PAIS) are partially female. Internally, however, there are testes instead of a uterus and ovaries.

So in a genetically male (XY) foetus the active intervention of male hormones (androgens) is needed to produce a fully male system. A female body type with female external genitalia is the basic underlying human form.

In about two thirds of all cases, AIS is inherited from the mother. In the other third there is a spontaneous mutation in the egg. The mother of the foetus, who does not have AIS, but has the genetic error for AIS on one of her X chromosomes, is called a carrier.

Forms of AIS (Complete and Partial)

There are two forms of the condition: Complete AIS (CAIS) where the tissues are completely insensitive to androgens, and Partial AIS (PAIS) where the tissues are partially sensitive to varying degrees. The condition is actually represented by a spectrum, with CAIS being a single entity at one end of a range of various PAIS manifestations.

Drs. Charmian Quigley and Frank French (The Laboratories for Reproductive Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7500, USA) proposed a grading system for the phenotypic features (external appearance) in AIS, modelled on the Prader classification for Congenital Adrenal Hyperplasia (CAH). The scale runs from AIS Grade 1 to Grade 7 with increasing severity of androgen resistance – and hence decreasing masculinization with increasing feminization.

At the CAIS end of the spectrum the outward appearance is completely female (AIS Grades 6/7) and the sex of rearing is invariably female. In PAIS the outward genital appearance can lie anywhere from being almost completely female (Grade 5), through mixed male/female, to completely male (Grade 1); it has been suggested that slight androgen insensitivity might contribute to infertility in some otherwise normal men. Some babies with PAIS may be raised as males but many are re-assigned as female.

Grade 1 PAIS Male genitals, infertility
Grade 2 PAIS Male genitals but mildly ‘under-masculinized’, isolated hypospadias
Grade 3 PAIS Predominantly male genitals but more severely ‘under-masculinized’ (perineal hypospadias, small penis, cryptorchidism i.e. undescended testes, and/or bifid scrotum)
Grade 4 PAIS Ambiguous genitals, severely ‘under-masculinized’ (phallic structure that is indeterminate between a penis and a clitoris)
Grade 5 PAIS Essentially female genitals (including separate urethral and vaginal orifices, mild clitoromegaly i.e. enlarged clitoris)
Grade 6 PAIS Female genitals with pubic/underarm hair
Grade 7 CAIS Female genitals with little or no pubic/underam hair

Before puberty, individuals with Grade 6 or 7 are indistinguishable

Note however that in the study of Hannema et al (2004), 70% of ‘CAIS’ patients with substitution mutations in the androgen receptor ligand-binding domain had epididymides and vasa deferentia present. These structures develop from the primitive Wolffian ducts under the influence of androgens, once the testes have formed and started to make testosterone, and were in fact more developed than epididymides and vasa deferentia in ‘normal’ 16 to 20 week-old male fetuses. The researchers suggest that the combination of some slight tissue sensitivity to androgens together with the particularly high levels of testosterone seen in CAIS can stimulate Wolffian duct development/differentiation. They suggest that the classification of androgen insensitivity in such patients should be considered severe [PAIS] rather than complete [CAIS].

The grading scale is described in more detail, with line drawings of the genital appearance, in issue No. 6 of our newsletter which is available as a free sample download file (see Literature).

It is thought not possible to have the complete and partial forms of AIS in the same family unit. In cases where this appears to happen it is probably a case of one sibling having a low grade of partial AIS (e.g. grade 3 in which there will be some masculinization of the genitalia) and the other sibling having a high grade of PAIS (e.g. grade 6 in which the genital appearance will appear female as in the complete form, which is grade 7, but with pubic/underam hair).

The two forms are considered in more detail in Complete AIS and Partial AIS.

Synonyms

Androgen Insensitivity Syndrome, Androgen Resistance Syndrome, Testicular Feminization Syndrome (Testicular Feminisation Syndrome), Feminizing Testes Syndrome (Feminising Testes Syndrome), Male Pseudo-hermaphroditism, Morris’s Syndrome (CAIS), Goldberg-Maxwell Syndrome, Reifenstein Syndrome (PAIS), Gilbert-Dreyfus Syndrome (PAIS), Rosewater Syndrome (PAIS), Lubs Syndrome (PAIS).

Other XY conditions with some similarities to AIS: 5 alpha-reductase deficiency, 17 keto-steroid reductase deficiency, XY gonadal dysgenesis (Swyer Syndrome), leydig cell hypoplasia, Denys-Drash Syndrome, Smith-Lemli-Opitz Syndrome. See Related Conditions.

XX conditions with some similarities to AIS: Mayer Rokitansky Kuster Hauser (MRKH) Syndrome, Mullerian dysgenesis, vaginal atresia.

Genetics – Usual (non-AIS) Situation

In human somatic (body) cells there are normally 46 chromosomes made up of 23 pairs. 44 of the 46 are called autosomes because they are not thought to determine gender. The other two are called sex chromosomes. Non-AIS males have a relatively large X swiss rolex orange and a small Y sex chromosome and normal females have two X sex chromosomes.

When the germ, or generative cells, are formed in the body of the adult, these sex chromosomes become separated, so that a sperm carries either a single X or a single Y chromosome, whilst every egg carries a single X chromosome. At conception the new embryo will be XX or XY, according to whether the egg, which is second hand ultra thin watch always X, was fertilized by an X-bearing sperm or by a Y-bearing sperm. Thus the sperm controls the genetic sex of the child.

Foetal Development – Usual (non-AIS) Situation

Although the sex of the embryo is determined at the time of conception, anatomical differences don’t show until approximately two months later. In this ‘indifferent stage’ every foetus has the primitive structures necessary for either a male or a female system: there are both Wolffian ducts and Mullerian ducts.

Gonad is the term given to the undifferentiated organ that will later become either a testis an ovary. Testes develop earlier than ovaries. In an XY foetus, the gonads develop into testes. The testes then cause the Wolffian ducts to develop into the rest of the internal male system, and the Mullerian ducts to be suppressed. In an XX foetus, the gonads develop into ovaries, the Mullerian ducts then form the rest of the female internal system and the Wolffian ducts are suppressed.

It is important to understand not only that there is a single primitive structure in the indifferent stage from which the male or the female organs develop, but that, each reproductive organ in either sex has a counterpart in the opposite sex. For example, the penis of the male and the much smaller clitoris of the female both come from the embryonic genital tubercle or phallus. Men have a vestigial uterus, the utriculus masculinus in the prostate and women have a homologue prostate in the glands at the lower end of the urethra.

Genetics – AIS

There are a number of abnormalities of the sex chromosomes that can occur. One example is Klinefelter’s Syndrome, in which a man carries an extra X chromosome. Another is Turner Syndrome in which a woman is missing an X chromosome. AIS is not a disorder of the sex chromosomes, because the sex chromosomes in an AIS baby are those of a normal male, XY. The genetic fault lies in the Androgen Receptor (AR) gene on the X chromosome received from the mother. This affects the responsiveness, or sensitivity, of the foetus’s body tissues to androgens.

AIS is inherited by a genetic condition in the family known as an X-linked recessive inheritance pattern, or partly recessive gene or a male-limited autosomal dominant. This means that it is passed on via the female line, so it can affect some or all of a mother’s XY children. For a carrier woman there is a 1 in 4 risk in each pregnancy of that child having AIS (or a 1 in 2 risk if the foetus of such a pregnancy is known to be genetically male, e.g. as a result of an amniocentesis sample taken during pregnancy). The AIS condition does not manifest in embryos of a carrier mother that are genetically female (i.e. XX) but they have a 1 in 2 chance of being carriers themselves and could therefore pass AIS on to their children.

So the possibilities in a given pregnancy, where the mother is a carrier, are…

‘Normal’ XY boy, or
AIS XY baby, or

‘Normal’ XX girl, or
Carrier XX girl

… with a 1 in 4 chance of each situation resulting.

Diagram X-linked recessive inheritance in AIS

The term ‘affected son’ is used in the above diagram because the X-linked recessive inheritance pattern is common to a number of genetic conditions which manifest in sons and not daughters.

If AIS is present in a family, there are tests available to see if an XX woman is a carrier and thus capable of passing the defective gene on to her children (see Obtaining/Facing Diagnosis).

Foetal Development – AIS

In the case of an AIS foetus, a Y-bearing sperm fertilizes the egg (which is always X) and produces an XY embryo. In the early stage of foetal life differentiation is as a male, with testes and the Mullerian ducts regressing. The Mullerian ducts would have formed the internal female organs in an XX girl. Once the testes are formed, they start to produce testosterone, which would normally cause the masculinization of the body.

Masculinization is an active process; it needs the positive or active intervention of the male hormones in order to take place. If these male hormones are either absent, or the tissues do not respond to them (as happens to differing degrees in the various forms of AIS), then the passive tendency is for the external genitals to differentiate into female external organs which, in the complete form of AIS, are indistinguishable from those of normal girls. This female physical development is not due to the presence and influence of oestrogens but to the ineffectiveness of androgens . In other words, the inherent trend is for any foetus to develop female external genitals and general body form, in the absence of the masculinizing effects of male hormones. Or as Money et al express it “Cellular insensitivity to androgen (in AIS) permits the 46,XY foetus not to masculinize.” Shearman is somewhat more dramatic in his declaration that “If the target cells lack this (androgen) receptor, testosterone passes like a stranger in the night and neutral female absolutism reigns supreme.”

Unfortunately, however, by the time the androgen insensitivity in AIS becomes evident, the internal reproductive organs have already progressed partially down the male route, and the Mullerian Inhibitory Factor (MIF) from the testes has already begun its work of destroying the primitive female internal organs. The testes remain in a ‘frozen’ partially-developed male state and the development of the internal female organs cannot be reactivated.

Incidence

Mainly using data on the frequency of inguinal (groin) hernia in presumed females, Jagiello and Atwell estimated the frequency of AIS to be about 1 in 65,000 genetic males. This presumably refers only to the complete form (CAIS), since the infants were assumed to be female until the occurrence of the hernia. DeGroot quotes an incidence of about 1 in 60,000. Hauser gives an incidence of 1 in 2,000. Adams-Smith et al give a figure of 1 in 20,000. The most accurate figure currently available is probably that from an analysis (Bangsboll et al.) of a nationwide Danish patient register, suggesting an incidence of 1 in 20,400 male births (hospitalized cases only, so the true incidence is probably higher). CAIS has been said to rank third as a cause of primary amenorrhoea (lack of menstruation), after gonadal dysgenesis (Turner Syndrome) and congenital absence of the vagina (Mayer-Rokitansky-Kuster-Hauser syndrome).

Complete AIS (CAIS) is sometimes referred to as ‘classical testicular feminization’ (‘classical testicular feminisation’), CAIS may be more common than PAIS (the ‘partial’ form of the condition) but we don’t have incidence figures for PAIS.

Early Knowledge of AIS

A condition that could have been AIS was mentioned in the Talmud (400 BC). A speculation has been made that Joan of Arc (1412) might have had AIS (Wooster 1992?). The same suggestion has been made with regard to Queen Elizabeth I, the ‘Virgin Queen’ (1533 – 1603) (Bakan 1985).

AIS may have been reported as early as 1817, when Steglehner described the case of an apparently normal woman who had undescended testes. The condition has been of relatively long interest to geneticists. Dieffenbach, an American geneticist, first pointed out in 1906 that there is a hereditary pattern to AIS. Petterson and Bonnier (1937) concluded that the affected persons are genetically male. Some early textbooks refer to the syndrome as the Goldberg-Maxwell Syndrome. Morris (1953) first used the term “testicular feminization.” Morris and Mahesh (1963) subsequently described an incomplete form of the condition.

Wilkins (1957) first demonstrated that the basic defect is tissue unresponsiveness to androgens. Hence the newer, and as far as most clinicians are concerned, more correct name of Androgen Insensitivity Syndrome. Netter and colleagues (1958) reported this disorder in a famous photographic model and Marshall and Harder (1958) reported affected twins who worked as airline stewardesses. In 1974 Migeon showed that the condition results from androgen receptor resistance. The androgen receptor gene was cloned and sequenced in 1988.

 

Note: The list below contains references to medical journal articles/papers relevant to the subject matter of this web page. We don’t expend as much effort keeping this list updated as we do for those on other pages (covering topics like facing the daignosis, vaginal hypoplasia, the pros and cons of gonadectomy and genital surgery) because medical articles covering clinical features, genetics etc. are not as useful to patients/parents as those covering practical issues and dilemmas.

General Refs:

See Medical Literature Sites on our ‘Links to Other Sites’ page for ways of accessing journal articles.

Money J., Schwartz M., Lewis V.G: Adult erotosexual status and fetal hormonal masculinization and demasculinization: 46,XX congenital virilizing adrenal hyperplasia and 46,XY androgen-insensitivity syndrome compared. Psychoneuroendocrinology, Vol 9, No 4, pp 405-414, 1984.

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

Jagiello F. and Atwell J.D.: Prevalence of testicular feminization. Lancet I: 329 only, 1962.

DeGroot L.J. (ed): Endocrinology, Vol 2 (Ed 2), Philadelphia PA, Saunders, 1989.

Hauser G. A: Testicular Feminization. In Intersexuality. Edited by C. Overzier. Academic Press, New York, 1963.

Adams-Smith W.N. and Peng M.T: Inductive influence of testosterone upon central sexual maturation in the rat. J. Embryol. Morph., 17: 171, 1967.

Bangsboll S et al: Testicular feminization syndrome and associated tumours in Denmark. Acta Obstet Gynecol Scand 71:63-66, 1992.

Griffin J.E: Wilson J.D: The syndromes of androgen resistance. N. Engl. J. Med. 1980; 302: 198-209.

Wooster N: The Real Joan of Arc?, published by The Book Guild, Lewes, Sussex (1992?). The statement in this book, that Bernard Shaw’s heroine may have had testicular feminization, is discussed in a letter from G. Richeux, Doncaster, to The Guardian on 4 September 1992 and entitled “Oh why can’t a woman be more like an admirable, literary man?”.

Bakan R: Queen Elizabeth I: A Case of Testicular Feminization Syndrome? Med. Hypotheses, 1985, 17(3), 277-84.

Steglehner G: De Hermaphroditism Nature. Kunz Bambergae et Lipsias, 1817.

Dieffenbach H.: Familiaerer Hermaphroditismus. Inaugural Dissertation, Stuttgart, 1912.

Petterson G. and Bonner G.: Inherited sex-mosaic in man. Hereditas 23: 49-69, 1937.

Goldberg M.B., Maxwell A.F.: Male pseudohermaphroditism proved by surgical exploration and microscopic examination. A case report with speculations regarding pathogenesis. J. Clin. Endocrinol. 8:367-379, 1948.

Morris J: The syndrome of testicular feminization in male pseudohermaphrodites. Am. J. Obstet. Gynecol, 65: 1192-1211, 1953.

Morris J.M. and Mahesh V. B: Further observations on the syndrome, `testicular feminization’. Am. J. Obstet. Gynec. 87: 731-748, 1963.

Wilkins L: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. Springfield, III: Charles C. Thomas, 1957 (2nd ed.).

Netter A., Lumbrosa P., Yaneva H and Liddle J: Le testicule feminisant. Ann. Endocr. 19: 994-1014, 1958.

Marshall H.K. and Harder H.I: Testicular feminizing syndrome in male pseudohermaphrodite: report of two cases in identical twins. Obstet. Gynec. 12:284-293, 1958.

Migeon et al.: Studies of the locus for androgen receptor:localization on the human X and evidence for homology with the Tfm locus in the mouse. Proc. Nat. Acad. Sci. 78: 6339-6343, 1981.

Williams, J: Androgen insensitivity syndrome: a survey of the terminology, language and information found in medical textbooks, scientific papers and the media. Thesis (M.Sc.) Science Communication, Department of Humanities, Imperial College, London (1996).

Blackless, M. et al: How Sexually Dimorphic Are We? Review and Synthesis. American Journal of Human Biology 12:151æ¶ (2000).

Boehmer A.L. et al: Genotype versus phenotype in families with androgen insensitivity syndrome. J. Clin. Endoc. and Metab.,86: 4151-60 (2001).

Wilson Bruce E: Androgen Insensitivity Syndrome. A useful online monograph covering many aspects of AIS. Dr. Wilson has been mentioned a number of times in our newsletter, ALIAS, and has spoken at AISSG US group meetings.

Hannema S.E., Scott I.S., Hodapp J., Martin H., Coleman N., Schwabe J.W. and Hughes I.A: Residual Activity of Mutant Androgen Receptors Explains Wolffian Duct Development in the Complete Androgen Insensitivity Syndrome. J. Clin. Endoc. and Metab., Vol. 89, No. 11, 5815-5822 (2004).

Minto C. L. et al: XY Females: Revisiting the Diagnosis. BJOG (an International Journal of Obstetrics and Gynaecology), Vol. 112, pp. 1407-1410, October 2005.

Mazur, T., Colsman, M., and Sandberg, D. E: Intersex: Definition, Example, Gender Stability, and the Case Against Merging with Transsexualism. In Ettner, R., Monstrey, S., and Eyler, A. E. (eds), Principles of Transgender Medicine and Surgery. Binghamton, New York: Haworth Press, Inc., 235-259 (2007).

Parker P.M: Androgen Insensitivity Syndrome – A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers (paperback pub. 19 Jul 2007, Icon Group International Inc.). This is one of a number of similarly titled books covering various medical conditions from the same editors and publisher. The publisher’s online catalogue lists it as Testicular Feminization – A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References. In spite of the inclusion of á´©entsíŠ in the newer title it is virtually useless to that readership. The descriptive text portions are heavily oriented towards molecular genetics and the bibliography sections seem based entirely on the highly medical literature databases at the US National Institutes of Health. The book fails to mention the support group for AIS that has been in existence since 1988. The book’s recommended standard search on AIS produces pages and pages of article titles, only one of which relates to psychosocial aspects (the Natarajan paper sanctioning non-disclosure of diagnostic information!). A section describing how to search a complementary medicine database at NIH containing, one is led to believe, material of more interest to patients, gives 13 titles, only two of which are of any relevance. Wikipedia tells us that: 詬ip M. Parker.. ..has patented a method to automatically produce a set of similar books from a template which is filled with data from database and internet searches, and is currently listed as the author of 85,000 books at Amazon.com.” See http://www.nytimes.com/2008/04/14/business/media/14link.html. As Cheryl Chase put it (Personal Communication 31 March 2008): “Human hands (and judgment) never touched the book.쯓MALL>

Mendonca B.B., Domenice S., Arnhold I.J. and Costa E.M: 46,XY disorders of sex development. Clinical Endocrinology, [e-publication ahead of print] 2008.

Warne G.L. and Raza J: Disorders of sex development (DSDs), their presentation and management in different cultures. Reviews in Endocrine and Metabolic Disorders, 9: 227-36, 2008.

Berra, M., Liao, L-M., Creighton, S. and Conway, G.S: Long-term health issues of women with XY karyotype. Maturitas 65(2), 172-178, 2010.

Karkazis, K., Jordan-Young, R., Davis, G. and Camporesi, S: Out of Bounds? A Critique of the New Policies on Hyperandrogenism in Elite Female Athletes. The American Journal of Bioethics, 12(7): 3–16, 2012.

Related Conditios

Introduction

Most of the page is devoted to various XY female intersex conditions other than AIS (AIS having been described in detail elsewhere on the site) and includes a brief mention of the dreaded ‘male-pseudohermaphrodite’ umbrella term!

But firstly we consider some XXX female non-intersex conditions which share common features with some XY female intersex conditions, such as lack of vaginal development. It then looks briefly at true hermaphroditism. The page does not cover XX female intersex conditions such as Congenital Adrenal Hyperplasia (CAH). For information on this type of condition please refer to the web sites of the CAH support groups.

‘XX Female’ Conditions

These will only be considered briefly since the main focus of this site is on ‘XY female’ conditions. However, they do have some features, such as vaginal hypoplasia (underdevelopment), in common with some XY female conditions and we have members of our group who have MRKH. See Overview for a summary of normal female development.

For resources related to XX conditions such as MRKH please refer to our (PDF format) Vaginal Hypoplasia Information Sheet. See also Patricia DeFrain’s Index to Articles, Books etc. on MRKH Syndrome (and Related Issues), a list of publications from Patricia’s (now defunct) website. See also Links to Other Sites.

Note: You need to have a PDF Reader on your PC in order to access PDF files. See About this Site page for more info.

Mayer Rokitansky Kuster Hauser (MRKH) Syndrome

Absent or incomplete vagina, incompletely developed uterus with normal Fallopian tubes and ovaries. Normal breast development and pubic hair. Failure to menstruate.

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The Androgen Insensitivity Syndrome Support Group (AISSG) is a UK-based group which started in 1988 (formalised in 1993).

We provide information and support to young people, adults and families affected by XY-female conditions such as complete and partial Androgen Insensitivity Syndrome or AIS (old name Testicular Feminization Syndrome or Testicular Feminisation Syndrome). We rolex daytona also support those affected by Swyer’s Syndrome (XY Gonadal Dysgenesis), 5-alpha Reductase Deficiency, Leydig Cell Hypoplasia, Mayer-Rokitansky-Kuster-Hauser (MRKH) Syndrome, Mullerian Dysgenesis, Mullerian Duct Aplasia, Vaginal Atresia, and other related conditions.

The group has played a dual role in providing support and comfort to affected adults/families all over the world, as well as fighting for and contributing to a better understanding of the various conditions, and of how they should be ‘treated’ by the medical community.

This site provides access not just to the UK group but to a consortium of worldwide support groups that have grown from the UK group (see How to Contact Us for contact details of the UK and other national groups).
Aims of the Group

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