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The surgical removal of the gonads is called a gonadectomy (or, more specifically, an orchidectomy, or orchiectomy in some texts). An orchidectomy is often performed at some point before adulthood in AIS in order to avoid a small risk of cancerous changes.
What sort of changes can be seen in testicular tissue?
(Note: In the case of Partial AIS (PAIS)... as opposed to Complete AIS (CAIS)... a wish to avoid the effects of virilising hormones from the testes at puberty may be an overriding factor in a decision about a gonadectomy. In CAIS, this is not an issue because of the tissue insensitivity to androgens.)
In the 1950s/60s the testes usually remained in place - often they were not discovered. In the 1970s/80s there was a move towards gonadectomy, early in childhood, on the basis that testes would not welcome in a female patient and would cause psychological problems. In the 1990s/00s the emphasis moved towards gonadectomy after puberty based on a perceived risk of tumours.
Removal in early childhood would often be done the time when an inguinal (groin) hernia was investigated surgically. Some clinicians justify this by claiming to spare the patient the ostensible psychological trauma of 'knowing too much' or, where there is a single parent, advising that the possibility of an accident might leave the child to fare for herself not knowing her need for surgery.
Some clinicians recommend that orchidectomy be postponed until after secondary sexual development is completed (Manuel et al and Marshchak et al), due to the low likelihood of tumour development before puberty and the fact that the testes produce enough oestrogen at puberty to stimulate breast development. Other clinicians recommend this strategy because of an alleged 'more natural' female development via gonadal oestrogens as compared to externally administered hormones (HRT). However, Shah et al state that they have not found this to be true. Clinicians at the UK Royal Society of Medicine (RSM) symposium on intersex management (April 1995) did not appear to have a clear view on the matter.
Evidence is emerging that the timing of orchidectomy and the start of HRT could be important in relation to bone mineralization in AIS (see HRT/Osteoporosis).
Some people feel that early gonadectomy undermines the rights of the child to know their own medical history, to give informed consent, and in some cases of PAIS, to decide whether to continue in the gender of rearing. (As mentioned earlier, girls with CAIS cannot be virilised by male hormones from their testes, because of their complete insensitivity to androgens.)
One clinician at the 1995 RSM symposium on intersex management suggested that early orchidectomy was practised more often for the benefit of the clinician than of the patient. Lewis and Money have stated that orchidectomy in AIS should always be only on the basis of truly informed consent of the patient.
We have one or two group members in their 30s/40s who still have their testes intact and are perfectly healthy. An HRT/osteoporosis expert at a 2006 AISSG meeting told how a colleague had recently diagnosed a 72 year-old woman with AIS. She had not undergone a gonadectomy and she'd had no tumours. It was suggested that clinicans really need to take notice of the current challenge to the orthodox practice of removing the gonads in AIS. We also have a very significant number of group members who say that they never felt the same after having their gonadectomy, and that they had great trouble getting used to HRT, finding a suitable preparation etc. Some group members are very angry that they had their testes removed without their permission, and we know of some CAIS women who feel better using testosterone- rather than oestrogen-based HRT.
A support group member (CAIS) emailed:
After my testes were removed I experienced a range of psychological symptoms including: hot sweats, depression, mood swings and a distinct feeling of being generally unwell; even though I was taking oestrogens. My depression was not due to my discovery of having AIS because the doctors had lied to me and I did not know.
Thus began a long search to find an endocrinologist who would listen to me. Eventually I met Prof Jacobs and Dr Conway at the Middlesex [University College London Hospital NHS Trust] and have not looked back. I am still angry that it took me that long angry that a doctor can tell me lies, remove all the testosterone that my body had naturally produced for 21 years, replace it with synthetic oestrogens and then refuse to give me my testosterone back! It doesn't take a genius to work out that this sudden and complete change in my hormones would have some effect, and no-one even bothered to check up on how I was coping.... Although I realise that the testosterone has no effect upon my tissues, there has been no research to see if it is active with regard to the brain and general mood. The team at the Middlesex Hospital have been great, they are the only medics I have met who genuinely want to help and ask me what it is I feel I need....
The risk of malignant changes in AIS testes is thought to be small, with a negligible risk before puberty (see below). The incidence of breast cancer is 1 in 8 females and yet the breasts of young women are not routinely removed just in case they might develop breast cancer.
A speaker at a 2006 AISSG meeting talked of the notion in medical practice known as "max'ing and min'ing" which means that you do the maximum possible in order to minimise the possibility of something bad happening (for example, the use of masses of technology for women giving birth, and the practice of gonadectomy in AIS women because of a very small cancer risk?) But can this strategy in itself actually cause harm?
The 2005 study by Cools et al (see Refs at foot of page) shows promise in developing a methodology for detecting early signs of neoplasia (specifically, differentiating this from delayed maturation of gonadal tissue) and suggests that once larger patient groups have been studied it may be possible to monitor patients via biopsies to evaluate the risk, as an alternative to gonadectomy.
Another possibility that has been suggested is to relocate abdominal testes to the groin area and monitor them using magnetic resonance imaging (MRI) and/or ultrasound, rather than advocating orchidectomy.
Parents often ask if gonadectomy in infancy/childhood is justified in relation to the cancer risk. They must be guided by their clinicians, but many parents want to make a fully-informed decision.
Most of the following is summarised from two reviews of AIS, in which detailed references can be found (Quigley C.A. et al: Androgen Receptor Defects: Historical, Clinical and Molecular Perspectives. Endocrine Reviews, Vol. 16, No. 3, pp271-321 (1995). and Batch J.A. et al: Androgen Insensitivity Syndrome. Reproductive Medicine Review 1992, 1: 131-150).
As a group, patients with AIS show an increased frequency of gonadal malignancy (seminomas). It is not clear whether this predisposition is primarily an intrinsic tendency in the abnormally developed gonads or whether it is due to their abnormal position (e.g. intra-abdominal) with some studies claiming an incidence no higher than seen in simple cryptorchidism (testicular maldescent).
The incidence of testicular tumours in regular XY men is around 1 in 25,000 per year which is equivalent to 1 in 500 men per lifetime. Three percent of boys are born with at least one undescended testicle (UDT). If the testes are undescended then the risk is 10 to 40 times greater, representing a 1 in 10 to 1 in 50 lifetime risk.
Any testicular malignancy in AIS is thought to be preceded by low grade CIS or carcinoma in situ, also called intratubular germ cell neoplasia. Although information about the incidence and spontaneous course of CIS in children is limited, CIS in one 10 year-old boy (not AIS but with bilateral cryptorchidism) was followed by invasive neoplasia 10 years later. Two studies in children and adolescents suggest that CIS is more common in PAIS than CAIS. One of these studies found CIS in 3 of 8 PAIS children (youngest 2 months) but in none of 4 CAIS children, whilst the other study found CIS in 5 of 8 prepubertal PAIS children. In contrast, two other studies found no cases of CIS in a total of 36 children and adolescents with PAIS or CAIS, although it was not clear how the diagnosis was made in the second study. Similarly, no gonadal tumours were found in a series of 14 individuals with AIS (?Lukasa et al). Malignant germ cell tumours (seminomas) have been reported in postpubertal patients, these patients generally being more than 30 years of age. In adult studies, 50% of untreated patients with CIS developed germ cell cancer within five years of diagnosis.
The overall frequency of gonadal neoplasia in AIS is difficult to judge, due to the small size of most series and a variety of sampling biases. An early (1963) study (Morris et al) which we mentioned in "Gonadectomy" in ALIAS No. 2 estimated a risk of 22% but this is most likely an overestimate, since many of the cases were referred primarily because of the malignancy. A 1992 Danish study reported tumours in 4 of 21 patients but a 1976 study had found no tumours in 23 patients of their own and only 7 tumours in 82 cases gleaned from the literature (8.5%). The risk of such tumours increases with age, the 1976 study (Manuel et al) suggesting an age-related risk of 3.6% at age 25 but approaching 33% at age 50. Two reports from one group (1981 and 1991) estimate the overall risk to be 6 to 9%.
Apart from the children with CIS, noted earlier, the youngest age at which a gonadal tumour has been reported is 14 years and all such patients were postpubertal. Other workers, e.g. Dewhurst (1976) estimate an overall rate of malignancy of 5 to 10%. A 1987 study (authors?) estimates the lifetime risk of gonadal carcinoma in AIS to be 2 to 5% (equivalent to between 1 in 50 and 1 in 20 AIS patients from age 25-85+), compared to an overall prevalence of CIS and invasive testicular cancer of less than 1% in the general adult male population. A 1993 paper offers a case report and review of the literature. Testicular cancer has recently been reported in a 17 year-old AIS woman by Chen et al.
A 2000 study by Ahmed et al evaluated 118 subjects from a UK national database. In 65 CAIS patients 91% had normal testicular tissue (3 were atrophic, 2 had fibrous changes and 1 had bilateral hamartoma). In ___? PAIS patients 95% were normal (3 were atrophic and there were no tumours). There was no malignancy found.
The 2005 study by Cools et al looked at 58 samples from 30 patients, 15 of which had CAIS. 10 of these patients had testes in the groin and all were normal. Five had intra-abdominal testes, with one of these showing carcinoma in situ (CIS).
At the 2009 AISSG UK group meeting Dr. Naomi Crouch (gynaecology registrar at the University College Hospital London multi-disciplinary intersex clinic) talked about the cancer/gonadectomy issue, as follows:
Guest speaker Naomi Crouch said that the risk of cancerous changes in CAIS testes is thought to be about 5% by early adulthood and that gonadectomy at age 18 is recommended. The advantage of not doing it in childhood is that the intact testes will facilitate a natural puberty (testosterone from the testes gets converted in the body to oestrogen which promotes breast growth etc.).
A group member asked why then aren't breasts removed from young XX women, when the risk of breast cancer in the general population of women is about 8%? Naomi confirmed that the risk of breast cancer in general is about 1 in 12, but it was easier to monitor breast tissue for changes than it is to monitor intra-abdominal testes in AIS women. Ultrasound technicians, for example, do not have so much expertise in terms of knowing what to look for, since these conditions are rare.
Naomi said that in certain other XY-female conditions like Swyer’s syndrome (XY gonadal dysgenesis or pure gonadal dysgenesis) the testes are dysgenetic, in other words not properly formed but just streaks of tissue, unlike in CAIS where they are reasonably fully formed organs even if their cells are not mature enough to produce proper spermatic material. Such dysgenetic tissue is more prone to cancerous changes (more like a 30% risk) so gonadectomy is recommended at a slightly earlier age, say 15-16, in those conditions.
A 2010 study by Pleskacova et al summarises current knowledge:
The overall prevalence of CIS and invasive type II GCT (seminoma and nonseminoma) in this group is estimated to 5.5%. There is, however, an important difference between patients with complete and partial androgen insensitivity syndrome in whom malignancies occur in 0.8% and 15%, respectively (Cools et al., 2006a).
Other hypovirilization syndromes are very rare. Malignancies in 17% of patients with 17-hydroxysteroid dehydrogenase were mentioned in one small series (Cools et al., 2005), while only one case of seminoma in a patient with 5 alpha--reductase deficiency and no tumors in patients with Leydig cell hypoplasia have been reported so far (Sasaki et al., 2003; Cools et al., 2005). However, this needs confirmation in larger series.
Patients with gonadal dysgenesis (with either a 46,XY or 45,X/46,XY karyotype) seem to be the most endangered subgroup, although the prevalence in different series is rather incoherent, being reported in 15–100% of all cases (Slowikowska-Hilczer et al., 2001; Cools et al., 2006). After the rational interpretation of available data, Cools et al. (2006) rated the total occurrence at 12% and possibly at more than 30% if gonadectomy had not been performed. Particularly in patients with mosaic karyotype the prevalence ranges between 15 and 40%, while in those with 46,XY karyotype it achieves approximately 30%.
See also the 2012 paper by Deans et al (in the Refs list at foot of this page) on the current thinking about gonadectomy in CAIS.
Who knows, maybe in 20 years time it will be possible for primitive sperm material extracted from in situ (or excised and frozen) AIS testes to be used to fertilise a donor egg?
Recent work by Dr. S. Fishel of NURTURE (Nottingham University Research and Treatment Unit in Reproduction, Queen's Medical Centre, Nottingham, NG7 2UH, UK) has made this possible in infertile men, using a sperm cell precursor, the spermatid; but whether an even more primitive precursor cell, the spermatogonium (some of which have been reported in the testes of 28% of a group of 43 AIS cases) might be used is unknown at present. In AIS this would involve the donation of an egg by, say, a sister of the male partner, with the AIS woman in effect being the 'father'. This could have major ethical/societal implications. Dr. Fishel has also successfully engineered a pregnancy using frozen spermatic material, a technique that has applications in the case of young boys with cancer in whom chemotherapy might cause infertility.
Maybe parents of AIS youngsters will also wish to discuss this possibility, when considering early orchidectomy, since huge advances could have been made by the time their child is grown-up and possibly wanting to start a family.
See also (see Fertility Advances).
The following pointers can be offered:
At a symposium on intersex management held in London on 28 Jan 2002 (jointly organised by clinicians and AISSG) there was a general air of anxiety amongst a number of paediatric clinicians. Several where getting quite agitated and saying things like: "Well, I have the parents in front of me... or I'm in the hot seat.... ....and they are asking me what I advise, so I have to tell them something.... so what do I tell them (e.g. about early/late gonadectomy)?.
Support group participants in the audience answered What you do is this.... you tell them that the risk of gonadal cancer, in AIS at least, is very low before puberty/early adulthood... you put them in touch with a clinical psychologist if possible, and you put them in touch with other parents via the support group... so they can discuss things at length, and in their own time, and can explore all the angles. There is no hurry to do surgery unless it's a life-threatening situation. Intersex is largely a psycho-social phemomenon and not a medical emergency, and doctors should not feel they have to be the only people to advise parents.
See Medical Literature Sites on our 'Links to Other Sites' page for ways of accessing journal articles.
Lukasa et al: ___________________________ ?
Morris J.M., Mahesh VB: Further observations on the syndrome, “testicular feminization”. Am J Obstet Gynecol 87:731-748, 1963.
Dewhurst C.J. et al: Gonadal malignancy in XY females. J. Obstet. Gynaecol. Br. Commonw. 1971; 78:1077-83.
Manuel M., Katayama K.P., Jones H.W. Jr: The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol 124:293-300, 1976.
Marshchak C.A., Kletzky O.A., Davajan V., Mishell D.R: Clinical and laboratory evaluation of patients with primary amenorrhea. Obstet. Gynecol. 1982; 57: 715-721.
Lewis V.G., Money J: Gender-identity/role: G-I/R Part A: XY (androgen-insensitivity) syndrome and XX (Rokitansky) syndrome of vaginal atresia compared. In: Handbook of Psychosomatic Obstetrics and Gynaecology; Dennerstein L. and Burrows G.D. (Eds.) Elsevier Biomedical Press, 1983, pp51-67.
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.
Shah R., Woolley M.M., Costin G: Testicular feminization: the androgen insensitivity syndrome. J. Paediatric Surgery, Vol 27, No 6 (June) 1992, pp 757-760.
Groveman S: Medical, Psychological and Legal Issues in the Clinical Management of the Complete Androgen Insensitivity Syndrome Patient into Adulthood. A paper drafted in 1997 by Sherri Groveman who founded our sister group, AISSG US. It covers counselling, the clinical examination, truth disclosure, peer group support, vaginal construction, and gonadectomy and informed consent.
Chen C.P. et al; Androgen receptor gene mutations in 46,XY females with germ cell tumours. Hum Reprod 1999 Mar;14(3):664-70.
Ahmed et al: _______________________ 2000 J. Clin. Endoc. & Metab. 85: 658.
Esegbona G., Cutner A.S., Cuckow P.M., Creighton S.M: Laparoscopic gonadectomy in paediatric and adolescent girls with intersex disorders. BJOG 110(2):210-2, 2003.
Cools M. et al: Morphological and Immunohistochemical Differences between Gonadal Maturation Delay and Early Germ Cell Neoplasia in Patients with Undervirilization Syndromes. J. Clin. Endoc. & Metab. 90 (9): 52955303, Sept 2005.
Cools M. et al: Germ Cell Tumors in the Intersex Gonad: Old Paths, New Directions, Moving Frontiers. Endocr Rev. (2006); 27: 468-484.
Androgen Insensitivity Does Not Mean Immediate Surgery. PDF of web-based report (2 Nov 2007) on paper given by Dr. T. Purves at an American Academy of Pediatrics meeting. See original at http://www.medpagetoday.com/MeetingCoverage/AAPMeeting/tb/7209 for latest letters/comments.
Pleskacova J. et al: Tumor Risk in Disorders of Sex Development. Sexual Development, published online 17 June (2010).
Deans, R., Creighton, S. M., Liao, L. M., & Conway, G. S. Timing of gonadectomy in adult women with complete androgen insensitivity syndrome (CAIS): patient preferences and clinical evidence. Clin Endocrinol (Oxf), 76(6), 894-898 (2012).