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

Disclosures

Clin Endocrinol. 2006;64(1):2-11. 

In This Article

Adult Female Issues

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[21,22,23] 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 17α-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 11β-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 17α-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 (50–300) and androstenedione of 6500 ng/dl (100–250) 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.

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 17α-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 Table 2 . 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.

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 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.

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