[last updated 17 Aug 2003]
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.
At the end of a TV discussion by an expert panel on the issues of surrogacy, IVF, abortion, use of foetal eggs, 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 couldnt make these women pregnant [Ref. 2].The major problem lies in implanting the embryo in tissue that wouldnt 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 partners sperm.
Ref. 3: Test Tube Bodies, BBC1, 24 October 1995.
A recent TV/press report (Jan 96) described the successful in vitro fertilization of a womans egg by sperm material extracted directly from her partners 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 womans male partner? We are awaiting further clinical input on this possibility so dont 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, 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 todays 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. Childrens Hospital, London WC1N 3JH.
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 womans 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, Id 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 Universitys 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 todays 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?
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. Bartholomews 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.
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 shed 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.
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 factsheets 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.
Eds 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 todays 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 childs testes removed before an age when they could give informed consent.
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 partners 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
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.
On 5th Sept 1999 the UKs 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 donors 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 mothers 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 UKs 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 Britains 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 mothers 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.
Eds Note: As usual, a male political spokesman pontificates about womens reproductive choices, and needless to say, women whove 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/
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 (thats 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 dont 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.
A team of French, Spanish and Italian fertility experts reported [Ref. 1] that an infertile womans genetic make-up can be introduced into a donated egg so that the resulting child carries her genes rather than the donors. [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 teams 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).]