Two landmark fertility studies give hope to young male cancer patients

In one study Japanese fertility experts report two world 'firsts' -- mice born from frozen immature testicular tissue taken from one set of mice and matured in others, and a rabbit born after maturing testicular tissue in a host mouse.

In the second study UK researchers have shown that it is feasible to obtain semen from boys as young as 12 and they are calling for sperm banking to be offered to all cancer patients from the age of 12.

The Japanese study
The Japanese researchers are looking for ways to help babies and young boys whose testicles do not contain mature sperm and for whom there is no effective way as yet to preserve fertility after cancer treatment.

They froze and thawed pieces of immature mouse testes and transplanted them into the testes of host mice whose own sperm had been destroyed by an injection of a cancer drug to mimic damage done by cancer treatment. The transplanted tissue grew in the host mice, spermatogenesis (the process of sperm making) was restored and the tissue produced mature sperm. The researchers recovered spermatogenic cells from this tissue, refroze them and later injected the mature sperm into mouse eggs, transferring the resulting embryos into surrogate mice. A total of 62 mice were born from 123 embryos that successfully implanted. The donor origin of the mice could be confirmed by ultra-violet light as the donor parents were 'green' mice -- a breed containing jellyfish genes that glows green under ultra violet light.

In another experiment frozen pieces of rabbit testicle were transplanted into immunodeficient mice. Again spermatogenesis was restored in a high percentage and yielded mature rabbit sperm. The researchers injected sperm that developed from freshly transplanted tissue samples into rabbit eggs and transferred embryos into two surrogate rabbits. One became pregnant and gave birth to one baby, the donor origin being confirmed by coat colour.

Senior author Dr Atsuo Ogura from the Institute of Physical and Chemical Research Bioresource Center in Ibaraki, said: "Fertility protection is an urgent clinical problem for very young male cancer patients who undergo chemotherapy or radiotherapy. What this research has shown is that immature testicular tissue transplanted into hosts can develop, that we can obtain mature sperm and achieve live births. This gives hope that in the future we will be able to restore fertility even to pre-pubertal boys and babies by taking testicular tissue from them, freezing and later transplanting it back into them by autotransplant -- grafting the tissue onto a site in the body in a similar way that ovarian tissue is beginning to be transplanted to preserve fertility in women. The sperm can then be retrieved from the transplant and ICSI[2] used to fertilise their partner's egg."

The researchers do not envisage using animal hosts for transplanting tissue directly into men. Said team leader Dr Takashi Shinohara, assistant professor at Kyoto University Graduate School of Medicine: "The risk of cross species infection is almost certainly high. The importance of this advance for people is that, although we cannot yet be 100% sure that human testicular transplants will mature in mice, we have, potentially, a new way of testing for feasibility of maturing immature human testicular tissue and producing mature sperm. When testicular tissue is taken from a young cancer patient before treatment we can transplant some of it into mice and thereby check whether the tissue is cancer free and producing mature sperm before proceeding with an autotransplant to the patient from the frozen tissue."

Dr Shinohara said that he thinks that it could be less than a decade before the technique is feasible for boys aged from new born to about age 12, although it was vital to establish ethical guidelines because of issues of consent and the possible side effects from intrusive biopsies on developing testes.

The UK study
A uniquely large study examining the prospects for preserving the fertility of adolescents[3] treated for cancer found that more than 85 per cent of the boys aged from 12 onwards were able to produce a semen sample with a sperm count and quality good enough to make it suitable for freezing.

The research team at University College Hospital, London, which has a specialist adolescent cancer unit, and at the Middlesex Hospital, London, included 238 pre-treatment adolescents in the study plus a group of 71 healthy young donor men to serve as illustration against semen quality and volume.

Lead researcher Dr Gulam Bahadur, consultant clinical scientist at University College Hospital, said: "This is an important and heartening finding. Adult patients are routinely offered pre-treatment sperm cryopreservation. But, this facility has only recently begun to be offered to adolescents and not much is known about the quality of the semen in this age group and its feasibility for freezing."

He said that the mean age of the adolescents able to produce a sample was sixteen and half and of those unable (about 14% of the group) just under fifteen and a half. But, there were perfectly good samples from 12 year olds. In total, 86.1 per cent of boys and youths from 12 to just under 20 were able to produce specimens. The patients had a variety of cancers and sperm from all the cancer groups analysed was suitable for storing.

"This high level of success should reassure doctors, parents and, in particular, patients. These young people are having to embark on chemotherapy or radiotherapy that is probably going to damage or even destroy their ability to father children. Now we can provide them with some positive news that will give a much needed psychological boost at a difficult time in their lives."

Dr Bahadur said that interest was gaining momentum in helping this group of young people and many clinics may have banked sperm for one or two adolescent patients. The new findings should provide an impetus for the service to be offered.

"We believe that every boy from 12 upwards who is being treated for cancer should be offered sperm banking -- there may even be a case for considering boys from 10 upwards, provided they have understood the basic issues."

However, Dr Bahadur said it was vital that the service was offered in the context of adequate and appropriate support and counselling. He felt that the service to cancer patients ought to be offered freely over the long term, to avoid patients being under pressure and to avoid discarding preciously frozen semen samples.

This was a highly sensitive group of patients because of the major biological changes taking place in adolescence and there was the potential for embarrassment when they were faced with adults who were talking to them about such private and personal issues. This sensitivity -- to the use of chaperones for example -- had been shown in the team's previous research to be over 3.5 fold counterproductive.

"These are young people barely coming to terms with their own sexuality, let alone taking on board the issues of having children with a stable partner," said Dr Bahadur. They are being fast tracked into maturity and this poses enormous challenges to those who care for them -- consultants, nurses, counsellors, scientists, regulators -- even lawyers -- as this is a complex legal area."

However, he said, doctors should not shy away from offering sperm freezing because of these difficulties. Previous research had shown that young men who remained childless after treatment were distressed about their infertility. It also showed that the majority of younger cancer patients thought that their cancer experience would potentially make them better parents.

Dr Bahadur added that freezing testicular tissue was also a future possibility for younger boys and in a previous research paper his team had described how they have stored tissue for an eight-year-old boy with cancer.

[1] Birth of offspring following transplantation of cryopreserved immature testicular pieces and in-vitro microinsemination. Human Reproduction. Vol. 17, No 12, pp 3039-3045.
Semen quality and cryopreservation in adolescent cancer patients. Human Reproduction. Vol. 17, No 12, pp 3157-3161.
[2] ICSI -- intracytoplasmic sperm injection: process by which the egg is fertilised by injecting a single sperm.
[3] Adolescence: defined in this paper as being adjudged by certain physical development characteristics to have undergone puberty and to be no older than 19 years and 11.9 months. Estimation of numbers of cancer cases among adolescent boys in the UK is difficult because of differing definitions of adolescence but, using the definition in the research paper, the figure was likely to be between 250 and 500 a year.

Notes:
1 PDF version of this press release and full embargoed text of the paper with complete results can be found from 18.00hrs GMT Monday 25 November: http://www3.oup.co.uk/eshre/press-release/nov02.pdf or from Margaret Willson
2 Human Reproduction is a monthly journal of the European Society of Human Reproduction and Embryology (ESHRE). Please acknowledge Human Reproduction as a source. Dr Helen Beard, Managing Editor. Tel: 44-195-421-2404 Email: [email protected]
3 ESHRE's website is: http://www.eshre.com
4 Abstracts of other papers in ESHRE's three journals: Human Reproduction, Molecular Human Reproduction & Human Reproduction Update can be accessed post embargo from http://www3.oup.co.uk/eshre/ Full text of papers available on request from Margaret Willson.