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Congenital Adrenal Hyperplasia in Adults: A Review of Medical, Surgical and Psychological Issues
Cara Megan Ogilvie, Naomi S. Crouch, Gill Rumsby, Sarah M. Creighton, Lih-Mei Liao, Gerard S. Conway Clin Endocrinol. 2006;64(1):2-11.

Our knowledge of the experience of adults with congenital adrenal hyperplasia (CAH) as they pass through life is only now emerging. In this review we gather medical, surgical and psychological literature pertaining to adults with CAH and consider this alongside practical experience gained from a dedicated adult CAH clinic. There is increasing awareness for the need for multidisciplinary teams who have knowledge of CAH particularly with respect to gynaecological surgery and clinical psychology for women and testicular function in men. Routine management of CAH comprises adjustment of glucocorticoid and mineralocorticoid treatment according to individual needs balancing biochemical markers, compliance and long term risks. Bone density is one such long term concern and is not greatly reduced in most individuals with CAH. More recently, attention has turned to cardiovascular risk factors and catecholamine deficiency in adults with CAH. Women with CAH require access to an experienced gynaecologist, specialised pregnancy care and psychosexual support. The very low fertility rates for women with CAH previously reported appear to be improving with time. Men with CAH are often lost to follow up and therefore miss out on surveillance for hypogonadism either through the effect of adrenal rests of from suppression of gonadotrophins resulting in a high prevalence of oligospermia. Fifty years have passed since the introduction of glucocorticoids for the treatment of congenital adrenal hyperplasia (CAH). Over this time, considerable expertise has developed in the paediatric context, but much less is known about long-term outcomes for adults with CAH. Most cohorts are still relatively young and more knowledge about the health and well-being of the older age groups needs to be developed. The optimal treatment for CAH continues to be a challenge. Clinical management rests mainly with endocrinologists with episodic input from gynaecologists, such as follow-up relating to genital surgery and menstrual problems. As we learn more from adults with CAH, the benefits from a multidisciplinary team becomes clear. Endocrinologists, gynaecologists specializing in reconstructive surgery, urologists, fertility specialists, dieticians, sex therapists, biochemists, geneticists, psychologists and clinical nurse specialists all have a role to play and need to be in close communication. Important long-term health issues for adults with CAH affect both men and women. For instance, an early focus was on bone density, and more recently, questions have arisen regarding cardiovascular risk. The literature is unclear with regards to female fertility and optimal management for pregnant women who have CAH. Female sexual function has been largely neglected, with availability of gynaecological services for women with CAH variable at best. Many women do not routinely see a gynaecologist at any stage as an adult, despite having undergone reconstructive surgery to the clitoris and vagina as a child. Finally, men with CAH are often lost from follow-up so we have little information on fertility, health and well-being in this group. The pathophysiology, diagnosis and genetics of CAH as well as glucocorticoid and mineralocorticoid treatments in childhood have been extensively covered in recent reviews.[1-3] Here we aim to cover key clinical issues for adults with CAH based on the experience gained from a multidisciplinary centre of referral for adults. The Middlesex Hospital in London follows a cohort of 111 adults (80 female) with classical CAH, comprising 105 with 21-hydroxylase deficiency, four with 11-hydroxylase deficiency, one with 3hydroxysteroid dehydrogenase deficiency, one with 17-hydroxylase deficiency and one with StAR protein deficiency. The median (range) of the cohort was 33 years (1864), with a median (range) follow-up of 4 years (021). Of the 105 with 21-hydroxylase deficiency, 76 had salt-wasting presenting within the first year of life and 29 were nonsaltwasting or classic simple virilizing presenting by the age of 9 years. The median (range) body mass index (BMI) was 254 kg/m2 (18399) for women and 249 kg/m2 (194312) for men. Median (range) height was 155 m (144171) for women and 165 m (157182) for men.

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Glucocorticoid treatment in adults has to be adjusted according to individual goals; there is no 'perfect regimen'. For instance, in the Middlesex series, of those with salt-wasting CAH 37% use hydrocortisone (median 30 mg, range 1540), 53% use prednisolone (median 7 mg, range 410), 4% dexamethasone and 5% a mix of glucocorticoid replacement. All use fludrocortisone (median 175 g, range 50400). Of those with simple virilizing CAH, 12% receive no treatment, 42% use hydrocortisone (median 20 mg, range 1530), 31% use prednisolone (median 5 mg, range 375), 3% use dexamethasone, 12% use a mix of glucocorticoid replacement and 38% also use fludrocortisone (median 100 g,range 0200). Sixteen women also use the oral contraceptive pill and three receive antiandrogen therapy. In contrast to the paediatric agenda of optimizing final height, the adult concerns relate to long-term consequences of glucocorticoid use. Therefore, one common strategy is to find the minimum effective dose of glucocorticoid for adult maintenance determined by a combination of clinical and biochemical markers. By analogy to the management of type I diabetes, 17-hydroxyprogesterone is often considered equivalent to random glucose measurements and so is not a perfect biochemical marker. Moreover, complete suppression often results in side-effects of glucocorticoid excess so the usefulness of this parameter is to signal the need for dose reduction. Serum testosterone and androstenedione concentrations behave similarly to glycated haemoglobin in type I diabetes, moving on a longer time-scale and indicating too low a dose of glucocorticoid when raised. Thus, we have found the optimal dose of glucocorticoid is that which fails to fully suppress 17-hydroxyprogesterone and maintains androgens in the mid-normal range. In transition from paediatric care, compliance can be very variable but often improves in the third decade of life, allowing reduction of 'prescribed' doses in early adult life. Mineralocorticoid treatment requires precise monitoring in adulthood. The childhood sensitivity to salt loss diminishes over the teenage years, and in adults, salt-wasting disorders are far less precarious.[4] In addition, the tendency to acquire hypertension with age means that many adults are better off on progressively lower doses of fludrocortisone. Balanced against this strategy is the notion that angiotensin II might mediate end-organ damage[5] so that markedly raised renin activity should be avoided. The clinical markers of hypertension and hypokalaemia are late events in the natural history of mineralocorticoid excess compared to suppression of plasma renin activity or total renin concentrations. This sensitivity of renin as a guide to the adjustment of the dose of fludrocortisone is essential if hypertension is to be avoided and our clinic protocol aims to maintain plasma renin activity in the upper normal range or to be slightly raised (up to twofold). Osteoporosis has been an understandable concern for adults with CAH who are glucocorticoid dependent.[6] Corticosteroid therapy inhibits osteoblastic activity, which potentially leads to decreased bone density. Similarly, markers of bone formation,[6] especially osteocalcin, are reported to be low in adult CAH.[7] There are no data regarding fracture risk in subjects with CAH. summarizes eight papers measuring surrogate markers of bone integrity in subjects with CAH. Five studies show normal bone mineral density (BMD) with the expected decline with age. Several studies suggested that low BMD in CAH reflects overtreatment with glucocorticoid, resulting in an increased steroid effect on bone and, to a lesser degree, to an oversuppression of androgens, which can be bone protective. However, other studies[7,8] found no association between BMD and duration of steroid treatment. In the 36 individuals attending the Middlesex Clinic who have had BMD measurements, we found mean t-scores for the lumbar spine and hip (055 and 048, respectively) were not significantly lower than a normal comparison group and that BMI and glucocorticoid dose were not significantly associated with the measurement.
Summary of Literature Involving Adult Bone Studies

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The overall conclusion is that, despite lower serum concentrations of bone turnover markers, bone density is normal in most individuals with CAH. Preservation of bone integrity despite glucocorticoid use may have several explanations. The raised BMI common in CAH may be protective for bone.[9,10] Furthermore, episodes of androgen excess may have an anabolic effect on bone.[11] However, it is important to note that, when measured,[7] androgen levels were generally lower in both men and women with CAH than that found in control groups. It is likely that current treatment strategies provide close to physiological replacement of glucocorticoid, therefore avoiding the effects of supraphysiological doses of these medications on bone.[6] In summary, unless there is a clinical suspicion of previous over-treatment with glucocorticoids, routine bone density measurements are not necessary in the young adult with CAH. If there is evidence of significant glucocorticoid overtreatment, one baseline BMD measurement is probably justified. Currently there is insufficient information on older subjects with CAH; one study included three older female subjects[7] and another two,[12] while none included older male subjects. Until we have more data in this age group, it seems prudent to consider bone density measurements in those subjects over the age of 40. Glucocorticoid treatment has only been used clinically since the 1950s. Therefore, people with CAH are only now reaching an age where risk of cardiovascular disease generally becomes more of a concern. Theoretically, individuals with CAH may be at an increased risk of cardiovascular disease and so far only a few preliminary studies have addressed this specific health issue. Hyperandrogenism in women has been associated with insulin resistance and, in turn, increased cardiovascular risk in other more common conditions such as polycystic ovarian syndrome.[13] People with CAH are known to have higher body fat percentage for BMI.[12,14] In addition, glucocorticoid therapy has been linked with dyslipidaemia[15] and decreased insulin sensitivity in other conditions.[16] A search of the literature reveals one adult study in this area. Speiser et al .[17] found a lower than expected insulin sensitivity for BMI in six nonclassical CAH women compared with a control group assessed by tolbutamide infusion and frequent glucose sampling. However, baseline insulin was not reported, the sample was small, and the degree to which this relates to classical CAH is unclear. In children with CAH receiving prednisone, a significant elevation in triglyceride levels has been reported.[18] The authors attribute this result to glucocorticoid replacement, although the degree to which this finding might be related to difficulties in

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matching the control group is unclear. Daytime systolic blood pressure is higher in children with CAH and absence of the nocturnal blood pressure dip has also been noted.[19] Elevated leptin and insulin levels have been found in prepubertal children with classical CAH,[20] and it was hypothesized that low serum adrenaline levels secondary to chronic adrenomedullary hypofunction leads to loss of inhibition of leptin and insulin secretion through -adrenergic receptors. The resulting hyperinsulinaemia may constitute an increased long-term cardiovascular risk. The prophylactic use of dexamethasone in pregnancy for women at risk of having a child with CAH to prevent possible virilization of a female foetus has been the subject of several reviews[21-23] and will not be addressed in this paper. Fertility in women who themselves have CAH is reduced, especially in those with the salt-wasting form,[24,25] the reasons for which are many. Early papers were very pessimistic with regard to female fertility, especially with classical salt-wasting CAH, with Mulaikai et al. [24] reporting no live births in 40 women. More recently this figure has improved, with Kuhnle et al .[26] reporting two births in 20 women and Hoepffner et al. [27] reporting nine births in six women. In the Middlesex series we have had 12 women seek fertility, of whom 11 (92%) have succeeded, with conception being spontaneous in five, induced with clomiphene citrate or gonadotrophins in four and only occurring after adrenalectomy in two. The single unsuccessful case declined adrenalectomy for progesterone hypersecretion. Fecundity rates in simple virilizing CAH have been reported to be around 50%,[28] with the current figure from the our own centre showing 6/7 (86%) success with three being spontaneous and three induced conceptions. A common problem in the fertility studies reviewed here is a failure to quantify the number of women attempting fertility, so precise ovulation and pregnancy rates can only be estimated. Reported reasons for reduced fertility in CAH include inadequate vaginal introitus and therefore unsatisfactory intercourse,[24] poor adrenal suppression,[27] a high prevalence of polycystic ovaries leading to ovulatory dysfunction,[29] and elevated follicular phase progesterone levels [30,31] causing failure of implantation. Biological and psychological factors may intertwine to cause decreased levels of heterosexual sexual activity and increased levels of homosexuality[24] and low maternalism.[32] It is possible that early exposure of the brain to hyperandrogenism may be responsible for many of the psychological outcomes noted.[33,34] Progesterone levels that are abnormally elevated in the follicular phase of the cycle have been reported by several units. [27,30,31,35] The underlying physiology of this phenomenon is not yet known, but it has been noted that some women with CAH consistently hyper-secrete progesterone within the follicular phase of the menstrual cycle and this can be associated with either anovulatory cycles[29] or developing follicles but thin endometrium and subsequent lack of conception.[30] Even good suppression of 17-hydroxyprogesterone does not always affect progesterone elevation.[30] Two women in the Middlesex series have undergone bilateral adrenalectomy to overcome this problem. Postprocedure progesterone levels dropped, indicating that the progesterone was adrenal in origin, and both patients conceived spontaneously after many years of prior infertility. Once a woman with CAH has become pregnant then several new management issues arise. Glucocorticoid replacement should consist of either prednisolone or hydrocortisone because dexamethasone is not inactivated by placental 11-hydroxysteroid dehydrogenase and therefore can cause suppression of the foetal adrenals and low birthweight.[36] There are two main management strategies. The first is to maintain glucocorticoid replacement at prepregnancy doses, increasing doses of hydrocortisone and mineralocorticoid as indicated by maternal symptoms alone, bearing mind that clearance of glucocortcoids is altered in pregnancy.[1] The second is to monitor testosterone and 17-hydroxyprogesterone and aim to suppress these markers to the top of the normal pregnancy range.[37] The former strategy raises concerns about possible virilization of a female foetus when maternal androgen levels are not well controlled. The foetus is protected from 'seeing' maternal androgens by the placental aromatase enzyme, which converts maternal androgens into oestradiol and oestrone.[38] When maternal androgen levels rise because of luteoma or thecal luteal cysts, then foetal virilization is very uncommon, despite extremely high maternal androgen levels due to the capacity the of aromatase enzyme, which consequently protects the foetus.[38] Female virilization (Prader type V) has been reported in maternal luteoma with maternal testosterone of 2000 ng/dl (50300) and androstenedione of 6500 ng/dl (100250) at 20 weeks.[39] It is therefore important to be aware that placental aromatization can be saturated and that other factors may play a role in determining foetal virilization.

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In cases of maternal CAH, however, foetal virilization is extremely rare. Cliteromegaly in the female newborn has been reported in a CAH mother who stopped glucocorticoid treatment prepregnancy.[40] No comment about pregnancy androgen levels was made and the baby did not have CAH. In all other reports, no case of newborn virilization has emerged. Hoepffner et al .[27] report on nine pregnancies in salt-wasting CAH and medical treatment remained unchanged from prepregnancy regimes throughout all pregnancies. Androgen levels are not commented on, but 17-hydroxyprogesterone values were between 241 and 4164 ng/dl. Lo et al .[41] present four pregnancies in which gluococorticoid doses were increased, one of which was complicated by pre-eclampsia that required inducement of labour and urgent Caesarean section, and another had Caesarean section for arrest of descent. Krone et al .[25] achieved pregnancies with increasing glucocorticoid dosing and managed pregnancy by aiming for androgen levels to be in the upper normal pregnancy ranges for local laboratories. Birth complications included small-for-gestational age, although this was not related to steroid dosing regimens. Follow-up of the children in this study up to 17 years demonstrates development within normal ranges, although one child has nonclassical CAH and another had premature pubarche. It is our experience that glucocorticoid rarely needs adjustment in pregnancy but that fludrocortisone doses may need to be increased, especially in the last trimester. These fludrocortisone increases were based on symptoms of postural hypotension. Throughout labour, parenteral hydrocortisone should be used, our regimen prescribes 50 mg 8-hourly until oral medications are resumed. Caesarean section is more likely to be necessary in women who have experienced significant genital virilization and surgeries, although the criteria for trial of vaginal delivery have not been defined.[25] In summary, the reasons for reduced fertility in women with CAH are multifaceted biological, psychological, social and sexual factors could all contribute to fertility and parenthood outcomes in CAH (see below). Input from a multidisciplinary team is required. As our medical, surgical and psychological approach to treatment improves, we should expect consequent improvements in fecundity, especially in women with salt-wasting CAH. The best method to assist fertility in women with CAH has to be made on an individual basis. Once pregnant, hydrocortisone or prednisolone should be the glucocorticoid of choice and it is unlikely that doses will need to be adjusted throughout pregnancy. While it may seem prudent to measure routine CAH bloods through pregnancy to ensure some control of androgen levels, in the absence of a documented risk of androgen exposure to the foetus, aggressive suppression of maternal androgens in pregnancy is probably not warranted. The effect of in utero exposure of androgens on genital tract development is the major focus of gynaecological care. The degree of virilization of the genitals in CAH can vary from mild clitoromegaly to complete fusion of the labial folds with a prominent phallus and an absence of a vaginal orifice. Over the past 50 years and especially over the past decade, the agenda driving intersex surgery has changed rapidly. In the 1950s John Money, an American psychologist, proposed a case management protocol in which he coined the 'optimal-gender policy' for ambiguous genitalia.[42] Since then, surgery has been routinely performed in infancy and childhood to align the genitalia to the sex of rearing, allegedly to minimize gender uncertainty. Dissent gathered momentum in the 1990s and it has since become increasingly apparent that many individuals were unhappy with their childhood genitoplasty.[43,44] The Intersex Society of North America[45] has issued guidelines for the management of intersex children and states that: 'All children should be assigned as boy or girl without early surgery' (www.isna.org). Adult women with CAH will have had corrective clitoral and vaginal surgery in infancy and childhood. A feminizing genitoplasty procedure consists of clitoral, vaginal and labial surgery, with the aims being to reduce the size of the prominent clitoris, to open the vaginal introitus and achieve a more feminine appearance. It continues to be common practice for surgical procedures to be carried out in infancy as a 'one-stage' operation. In fact the idea of a 'one-stage procedure' is erroneous. Studies assessing long-term outcomes of feminizing genitoplasty are summarized in . Notably, a large proportion of these studies fail to report outcomes in terms of sexual function. Two studies have shown that over 90% of women with CAH require revision surgery to allow tampon use or intercourse. [46] Cosmesis outcome has also been noted to be poor.[44] In interpretation of such studies it must be accepted that surgical techniques change with time and many are reporting on surgery performed up to 80 years ago. Similarly, analysis of current techniques take time emerge. In response to new information and debates, recent guidelines published by the British Association of Paediatric Surgeons[47] recommend early referral to regional centres with paediatric surgeons or urologists, endocrinologists, gynaecologists and psychologists who are experienced in caring for babies and children with CAH (http://www.baps.org.uk). They also recommend deferral of vaginoplasty until after puberty, and avoidance of surgery in cases of mild or moderate clitoromegaly.

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Summary of Literature Involving Physical Outcomes of Feminizing Genitoplasty in Women With Congenital Adrenal Hyperplasis

Clitoral reduction involves removal of part of the erectile tissue with preservation of the glans and dorsal neurovascular bundle. The aim is minimize the loss of sensitivity. Previous procedures included clitoral recession, which involved setting the clitoris back under the pubic bone, without removal of any tissue. This has fallen out of favour, as it tends to trap the corporal bodies and cause pain during arousal. Clitorectomy, the complete removal of the paired corpora and the glans, is now no longer performed in the UK, although may have been carried out as recently as 10 years ago. If steroid suppression therapy is poor, the clitoris may regrow despite surgical reduction. In one study regrowth occurred in 39% of patients.[48] Vaginal surgery varies depending upon the degree of virilization. In mild cases where mainly labial fusion is present, a simple inverted-U-shaped incision is made over the perineal body, and the underlying tissue divided. The skin may then be laid down to refashion the posterior forchette. Flap vaginoplasties may be performed where the vagina joins the urethra in an intermediate position. Perineal skin is used to reconstruct the posterior forchette but the anterior vagina is not repositioned. In more severe cases, where the vagina joins the urethra in a higher position, a 'pull-through' procedure is performed. The upper vagina is mobilized and brought down to meet the newly created introitus. A common late complication of vaginoplasty is introital stenosis with the formation of scar tissue. Vaginal dilator therapy has previously been used following surgery to try to prevent such scarring but is clearly not appropriate in young children. Further surgery is therefore often required around the time of puberty to allow menstrual flow, the use of tampons and sexual intercourse. There is no standard way of classifying outcomes, which can make surgical results difficult to assess and compare. In a paper looking at surgical correction of vaginal anomalies, outcomes are classified as 'excellent' if the vagina is suitable for intercourse, and 'satisfactory' if the vaginal orifice is suitable for menstrual flow but needs further surgery for intercourse.[49] This may appear logical from a surgical perspective but women may not perceive being unable to have penetrative intercourse as a 'satisfactory' outcome. Other authors advise that functional results cannot be fully evaluated until after the woman is sexually active.[50] Few objective data are available in the literature regarding sexual function in females with CAH. It has been argued that the

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burden of a chronic disease may significantly affect social functioning and relationships, and any condition that affects the genitalia may heighten anxiety regarding sexual relationships. In a study looking at sexual experiences, women with CAH were compared with women with diabetes.[51] Both conditions involve regular medications and hospital visits, but diabetes does not directly affect the genital area. The CAH group were less sexually experienced, more reluctant to establish intimate relationships, and less satisfied with the frequency of sexual opportunities. The CAH women also reported higher levels of penetration difficulties and persistent pain during intercourse, and lower attainment of orgasm. Poor surgical outcome, though important, may not account for all sexual difficulties reported by women with CAH.[52] In a retrospective study of adolescents who underwent feminizing surgery in childhood, a poor result was found in 41% of women and a good result in only 8%.[44] Only 18% of these women had an adequate vaginal introitus and 59% a normal clitoris. Alizai et al .[46] found inadequate vaginas in all 13 girls and unsatisfactory clitoral anatomy in six girls who had undergone feminizing genitoplasty. An initial pilot study[53] of six CAH women showed that all women had markedly abnormal clitoral sensation and penetration difficulties after feminizing genitoplasty in childhood. Masculine development in women whose brain has been 'hardwired by male hormones' during critical periods could prove once and for all that gender attributes are controlled by sex steroids. The importance of CAH to psychologists and sexologists is thus obvious. Three main areas of gender development in women with CAH have been examined: juvenile play style, sexual partner orientation and core gender identity (see Hines[34] for a detailed review). As far as gender identity is concerned, it is now generally thought that, with few exceptions, women with CAH tend to self-identify as female. In fact, when gender identity in girls with CAH is compared to a younger group of physically healthy 'tomboys', the tomboys have higher male identity scores.[54] As for sexual orientation, reported rates of homosexuality and bisexuality are less consistent and vary as widely as 5%[24] and 37%.[55] It has been argued that different findings reflect methodological differences such as age of participants, timing of 'feminizing' treatments, and severity of illness. How homosexuality is defined, if it were indeed a tight and stable category, would of course also influence results. What seems to provide more consistent evidence for the effects of androgens is gendered play activity of young children. Girls exposed to high levels of prenatal androgens are more likely to engage in stereotypically masculine play, including a greater preference for 'boy toys' such cars and guns, and a lesser preference for 'girl toys' such as dolls and kitchen equipment.[34] Girls with CAH have also been reported to be more likely than other girls to accept boys as playmates and engage in rough-and-tumble play. It is important to bear in mind that many social, familial, educational and emotional factors also influence gender development. It will always be difficult to account for adult social, psychological and sexual outcomes in CAH women because it is impossible to separate androgenic factors from the impact of the stigma of ambiguous genitalia, the (often repeated) surgical sexing, the potential parental doubt over the sex of the child, inadequate provision of information and psychological support, and the presence of a chronic disease and attendant lifelong interventions. In other words, women with CAH have been subjected to major developmental interference and it is well to bear this in mind when interpreting psychological reports. Because of the almost exclusive theoretical focus on the supposed capacity of women with CAH to elucidate the relative contributions of nature (androgenized brain) and nurture (sex of rearing) in gender development, little authoritative information exists on the social and emotional well-being of women and men with CAH. Relatively positive 'personality functioning' has been reported, based on case work with female adolescents who have received early and adequate medical and psychological care.[56] Another study, however, reported reduced social competence and poorer body image but also a lesser tendency towards 'depressive coping' compared with a control group. [57] The paucity of information on multiple aspects of psychological well-being and quality of life for adults with CAH should concern all health professionals. Furthermore, although some suggestions for psychological service providers working with women with ambiguous genitalia have been put forward,[58] the general lack of articulation of sound applied psychology in clinical management for adults with CAH would need to be tackled, alongside effort to overhaul clinical management, on the basis of lessons from adults. Until recently, treatment of adult males with CAH has often been limited to mineralocorticoid and glucocorticoid replacement in severe cases to alleviate obvious deficiencies. Indeed, glucocorticoid treatment for nonsalt-wasting CAH men was often stopped after final height had been achieved. However, it is now apparent that long-term control of CAH in men is required to preserve fertility. Jaaskelainen et al .[79] considered fecundity rates in men with CAH. In Finland, the men with CAH have a child rate of 007, significantly less than the average for the Finnish male population of 034. The authors suggest that psychological support for

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men with CAH is as important as for their female counterparts. There have been a series of anecdotal reports of testicular abnormalities in male patients with CAH.[59] Recently, these abnormalities have been correlated with fertility and glucocorticoid suppression ( ). Cabrera et al .[60] found semen analysis abnormalities in CAH men with normal testes. This report included two men who had successfully fathered pregnancies but subsequently became infertile after developing nodular testes. There was no significance difference in androgen levels in the men with testicular abnormalities and those without.
Comparison of the Two Studies Correlating Male Fertility With Testicular Abnormalities

Stikkelbroeck et al .[61] found large palpable tumours were associated with low testosterone and normal LH levels; however, normal FSH levels did not reflect a normal semen analysis. In this report adrenal rest tissue is more likely to be present and to be larger in men who are heterozygous or homozygous for the deletion or conversion of the CYP21 gene. Repeat scanning of the subjects 26 years later showed a quantifiable relationship between glucocorticoid replacement and alteration in tumour size.[62] Ultrasound examination has the same sensitivity for testicular masses as magnetic resonance imaging (MRI).[63] In most centres ultrasound is more accessible than MRI and therefore has become the investigation of choice for possible adrenal rest tissue. Ultrasound findings include hypoechoic lesions with hyperechoic reflections. Masses are often adjacent to the mediastinum testis.[61] Should testis sparing surgery be required, then MRI may be valuable for tissue margin delineation.[64] When men with CAH present with testicular masses, concerns about possible malignancy arise immediately, but neither ultrasound nor MRI can differentiate between adrenal rest tissue and malignancy. [64] In one study, 18% of young males presenting with bilateral testicular masses to urology were found to have undiagnosed CAH.[65] In patients with known CAH, adrenal rest tissue can be clinically differentiated from Leydig cell tumours as it is more often bilateral, occurs in men who show evidence of poor adrenal suppression and the tumour regresses with increased glucocorticoid suppression.[64] If the mass is located near the mediastinum testis and does not show distortion of testicular contour then it is more likely to be an adrenal rest.[63] The differential diagnosis of malignancy needs to be remembered and, if in doubt, a biopsy needs to be considered. A case of Leydig cell malignancy has been reported in a male with salt-wasting CAH.[66] The diagnosis was made on clinical grounds as histology was difficult to differentiate from adrenal rest tissue. Testicular sparing surgery has been suggested as the treatment of nonresponsive adrenal rest tissue,[64] although the effectiveness of this procedure for preservation of spermatogenesis is not clear. Uncontrolled adrenal androgen secretion in men with CAH can result in increased aromatization of androgen to oestrogen. Oestrogen feeds back to the pituitary gland to cause gonadotrophin suppression.[67,68] Some men with CAH have hypogonadotrophic hypogonadism and small testes and this picture reverses with increased glucocorticoid suppression as androgen and oestrogen levels decrease and fertility is restored.[69] An example of oligospermia reversal with glucocorticoid treatment, and related biochemistry, is presented in Fig. 1.

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Testicular response to glucocorticoid in a 26-year-old man with CAH who presented with primary infertility and oligospermia. He had been diagnosed with CAH at 6 months because of his family history of two affected brothers. Glucocorticoid treatment was stopped at age 16 years on achievement of final adult height. On restarting glucocorticoid, androgen and 17-hydroxyprogesterone levels dropped and LH and testicular size improved. The subject's partner conceived 5 months later and then went on to have two further pregnancies. The natural history of fertility in men with CAH is still unclear. However, although such information is lacking it is desirable for all men with CAH for whom future fertility is a concern to have a testicular ultrasound, the timing of which is unknown but should probably begin after puberty and, if normal, be repeated on a 3to 5-yearly basis. Evidence of adrenal rest tissue can be a clinical indication for aggressive glucocorticoid treatment even in simple virilizing CAH; it is likely that such rest tissue causes oligospermia and subfertility and it is possible for adrenal rest tissue and semen abnormalities to respond to such suppression. The absence of adrenal rests with or without normal biochemistry cannot predict normal semen analysis. Therefore, routine semen analysis should be available for men with CAH. If glucocorticoid suppression is unsuccessful then testis sparing surgery should be considered and malignancy ruled out. Until we obtain more information it may be prudent to offer semen preservation to men with CAH. Optimal treatment of adults with CAH requires a multidisciplinary approach. We need to reconsider where our clinical energies should be placed to optimize long-term outcomes for this condition. Bone monitoring is, for the most part, unnecessary. Women with CAH should have early access to gynaecology review and both males and females should have ready access to specialist psychological support for managing the physical demands, social stigma and psychosexual difficulties associated with the disease. We should be continuing to follow-up men with CAH with greater vigilance on their biochemical markers of disease control. It is possible that, as our multidisciplinary treatment improves, more women will desire pregnancy and we will obtain more information about ovulation induction and subsequent pregnancy management.

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References

1. White, P.C. & Speiser, P.W. (2000) Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews, 21, 245291. 2. Merke, D.P. & Camacho, C.A. (2001) Novel basic and clinical aspects of congenital adrenal hyperplasia. Reviews in Endocrine and Metabolic Disorders, 2, 289296. 3. Speiser, P.W. & White, P.C. (2003) Congenital adrenal hyperplasia. New England Journal of Medicine, 349, 776788. 4. Rosler, A. (1984) The natural history of salt-wasting disorders of adrenal and renal origin. Journal of Clinical

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