What Causes Low Rates of Child-Bearing in Congenital Adrenal Hyperplasia?

H. F. L. Meyer-Bahlburg

New York State Psychiatric Institute, Unit 15, and Department of Psychiatry, Columbia University, New York, New York 10032-2695

Address all correspondence and requests for reprints to: Dr. H. F. L. Meyer-Bahlburg, New York State Psychiatric Institute, Unit 15, New York, New York 10032-2695.

Women with classical congenital adrenal hyperplasia (CAH) have relatively low fertility rates (1, 2, 3, 4). The largest clinic population was studied by Mulaikal et al. (2) who conducted a questionnaire survey of the Johns Hopkins Hospital sample of women with classical 21-hydroxylase deficiency and obtained responses from 80 of them (71% of the eligible women; age range, 18–69 yr; mean, 33 yr), evenly split into the simple virilizing (SV) and salt-wasting (SW) forms. Half of the women were not heterosexually active. Those who were heterosexually active nevertheless appeared to have low fertility. Among the 25 SV women who reported both adequate vaginal reconstruction and heterosexual activity, the fertility rate was 60%. Only 15 became pregnant, and 13 of these gave birth (9 by cesarian section because of cephalopelvic disproportion); the other 2 had an abortion, 1 spontaneous and the other induced. Among the 15 SW women with both adequate introitus and heterosexual activity, the fertility rate was 7%. Only 1 reported a pregnancy, and that ended in an elective termination.

Mulaikal et al. suggested three mechanisms underlying the low fertility in CAH women overall: 1) insufficient hormonal control of the hyperandrogenemia by glucocorticoid replacement therapy (and possibly long term effects of prenatal and postnatal androgen excess), 2) insufficient vaginal reconstruction resulting in inability to engage in coitus, and 3) absence of heterosexual activity, which in some women was associated with homosexuality. In an accompanying editorial, Federman (5) suggested potential additional factors that might contribute to the low fertility in CAH: an impaired reproductive self-image related to vaginal inadequacy and "a male psychosexuality" as a consequence of putative masculinization of the fetal brain.

The purpose of the present paper is to revisit the issue, review the status of the empirical evidence, especially the role of behavioral determinants, and suggest additional hormone-related psychological factors that may contribute to the low fertility rates of CAH women.

The most widely recognized cause of the low rate of fertility among CAH women remains nonoptimal hormonal control. Ovulatory failure secondary to steroid excess is an important barrier to conception in many CAH women. There is considerable evidence suggesting that the steroid excess is not just an outcome of ACTH oversecretion (6). Among the other contributing factors appear to be 1) a mild degree of ACTH hyperresponsiveness to CRH; 2) altered enzyme kinetics, namely reduced catalytic efficiency of the mutated 21-hydroxylase with resulting increases in the precursor hormones progesterone and 17-hydroxyprogesterone even in the presence of excess glucocorticoid administration; 3) overactivation of the renin-angiotensin-aldosterone axis with ensuing stimulation of adrenocortical biosynthesis; and 4) alterations of the hypothalamic-pituitary-ovarian axis as indicated by abnormal gonadotropin dynamics, polycystic ovaries, and excess ovarian production of progesterone, 17-hydroxyprogesterone, and androgens (6). Consequently, new combination treatments that go beyond mere ACTH suppression are being developed to improve the overall quality of hormonal control in CAH (7).

Much evidence has accumulated that implicates psychological factors in the overall reduction of fertility in women with classical CAH. Reduced heterosexual activity compared to controls has been documented in a number of studies. During adolescence, women with classical CAH as a group tend to have delayed (or absent) heterosexual milestones, such as dating, sexual initiation, and falling in love (3, 8, 9, 10, 11, 12, 13). In adulthood, fewer are heterosexually active, in steady relationships, or married (2, 9, 10, 11, 12, 13). For all of these behaviors, it is predominantly women with the SW variant who differ from controls, much more so than those with the SV variant (4, 9, 11).

Not only overt sexual activity with a partner is delayed or reduced. The frequency of sexual imagery, such as romantic/erotic fantasies and dreams, the intensity of experienced sexual motivation (drive, libido), and the capacity to fall in love also seem to be markedly lower in CAH women as a group, especially those with the SW condition, than in controls (9, 10, 12, 13), although a few CAH women complain of excessive libido, especially when untreated or when treatment lapses.

The reduction of heterosexual activity is likely to stem from several causes. One is an increased rate of bi- or homosexuality in women with classical CAH, as demonstrated especially in sexual imagery such as erotic/romantic fantasies and dreams, in sexual attractions, and, to a lesser degree, in overt homosexual involvement (2, 9, 11–13, 15, 16; in a cohort of CAH with late onset of glucocorticoid replacement: 14). That several studies had negative findings (10, 17, 18, 19) is probably due to methodological factors such as inadequate assessments of sexual orientation, high proportions of (less androgenized) SV cases in a given sample, and small sample sizes. The increased rate of bi- and homosexuality is usually interpreted from the perspective of the organizing effects of pre- and perinatal sex hormones on the developing brain and subsequent sex dimorphic behavior (20, 21, 22), as demonstrated in numerous mammalian species. This interpretation is also compatible with the fact that it is 46,XX women with SW CAH, associated, on the average, with the more severe enzyme abnormality (23) and more marked genital masculinization (24, 25, 26), who show the strongest increase in bi- or homosexual orientation (2, 9, 11, 12). Similarly, the interpretation is in line with the fact that 46,XX individuals raised as males, thus combining pre/perinatal elevated androgens with postnatal and pubertal elevations of then activating androgens, usually appear to be gynecophilic (27, 28), as are those who change to the male gender in adulthood (29). It is important to keep in mind, however, that the majority of CAH women are heterosexual; thus, the prenatal hormonal milieu does not dictate a bisexual or lesbian outcome, and it is likely that the developmental process leading to a specific sexual orientation is influenced by psychosocial factors as well (21).

Another cause of the relatively reduced sexual activity of women with CAH is the genital status in later adolescence and adulthood. Two aspects are particularly relevant to sexual behavior, the width of the vaginal introitus along with the width and depth of the vagina, and the erotic function of the clitoris along with that of the labia minora. Moderate and severe degrees of prenatal androgenization usually affect the external genitalia markedly. The outcome of corrective surgery and/or dilatation of the vagina varies with the technique chosen, the age at which it is performed, and the adherence to postsurgical maintenance. Consequently, there are many reports of CAH women who find intercourse painful or even impossible or who stay away from heterosexual involvement altogether because of their awareness of having an inadequate vagina (2, 10, 30, 31, 32, 33), whereas some sexually inexperienced women overrate the functionality of their vagina (34).

The second aspect of genital status with marked implications for sexual functioning is the clitoris. Early childhood surgery of the hyperplastic clitoris is usually recommended to facilitate gender-typical rearing and the development of a consistent gender identity (35), although the potential costs in terms of loss of erotic sensitivity were debated from the outset when this policy was developed (36). Diminution or loss of erotic sensitivity and orgasmic capacity and, with it, of sexual satisfaction are probably quite frequent when clitorectomy is applied, although some women appear to retain both to varying degrees (8, 13, 18, 29, 36). As a consequence, clitorectomy has widely been replaced, at least in Western industrialized countries, by various techniques of clitoral reduction and/or recession. Published functional outcomes of these techniques appear promising (33, 37, 38), but certainly not universally so (39), and the performance of genital surgery other than for a life-threatening condition without the child’s fully informed consent is being severely criticized by a consumer organization of persons with intersexuality (40). Clearly, there is a great need for systematic and sophisticated follow-up studies that permit a definitive comparison of the functional outcomes of the various surgical techniques as experienced by the women themselves. Erotic sensitivity may also be reduced in CAH women who lack labia minora because of more severe genital masculinization. To what extent surgically created labia minora support erotic sensitivity is unknown.

It seems likely that the awareness of having a functionally inadequate vagina and of experiencing reduced erotic sensitivity, orgasmic capacity, and sexual satisfaction inhibit courtship and perhaps reduce interest in sexuality altogether. Body image problems have been noted or documented by a number of researchers with regard both to general physical characteristics related to sexual attractiveness, such as short stature, lack of breast development, or hirsutism, as well as to genital status and function (19, 30, 41). Inadequate genital status may, therefore, contribute to the strikingly low sexual motivation seen in a considerable number of women with classical CAH. The fact that women with the SW condition as a group have both more severe genital masculinization and more often reduced sexual activity and motivation than SV women is compatible with this interpretation. However, we do not know whether genital status provides a sufficient explanation of the low sexual motivation. The potential influence of concurrent atypical hormone levels needs to be ruled out. This applies to increased progesterone and 17-hydroxyprogesterone (6), given that progestogens are used to reduce sexual libido in sex offenders (42); to medication-induced hypoandrogenemia (43), in view of the fact that androgens are known to contribute to both male and female libido (44); and possibly even to excess glucocorticoid levels, given their role in major depressive disorder (45) and the fact that depression is often associated with reduced sexual motivation (46). Finally, quite a few patients with intersex conditions are chronically oversensitized by frequent genital examinations (47), especially in teaching hospitals, which in some appears to add to difficulties with courtship and sexual functioning.

If, for the various reasons outlined above, general sexual motivation and heterosexual courtship and partner activity are reduced or lacking altogether, child-bearing is less likely to happen as a consequence of intercourse. However, the new (noncoital) reproductive techniques that are increasingly being used by women in the U.S., including by those, such as lesbians, who are not heterosexually active, are in principle also available to women with classical CAH. Yet, a barrier to their use may be another psychological characteristic, namely low maternalism. CAH women as a group have a lower interest than controls in getting married and performing the traditional child-care/housewife role (14, 48, 49, 50). As children, they show an unusually low interest in engaging in maternal play with baby dolls (14, 48, 51), and their interest in caring for infants, the frequency of daydreams or fantasies of pregnancy and motherhood, or the expressed wish of experiencing pregnancy and having children of their own appear to be relatively low in all age groups (14, 48, 49, 50, 51, 52). Again, these findings are much more pronounced in women with SW-CAH than in those with SV-CAH (53). In our own study (13), low maternalism was the characteristic that most distinguished SW women from women with nonclassical CAH and non-CAH controls (Meyer-Bahlburg, H. F. L., unpublished data). The phenomenon is well characterized by this quote from a 29-yr-old woman with SW-CAH: "Jim [long-term partner] and I can’t stand children. My sister’s kids drive us up the wall. They’re cute and everything, but I never had any maternal feelings like that, like I wanted to have a baby. ... Most people look at babies and think they’re cute, and they coo over them. I never felt anything. It’s just a baby. I like animals better. I have cats. Those are my babies."

It is unlikely that low maternalism is just a reflection of the CAH women’s awareness of problems with reproductive functioning, because no comparable effects are seen in samples of girls or women with Turner’s syndrome (54, 55). Rather, maternalism appears to be one facet of a broad spectrum of sex dimorphic behaviors that appear masculinized in females with classical CAH (51, 56), in parallel with the findings on prenatal sex hormone influences on sex dimorphic behaviors in other mammals (57). Unfortunately, the existing human research data are too limited in sample sizes, assessment methods, and design to allow us to make definitive statements about the interplay of biological and psychosocial factors in the development of maternalism in CAH girls.

The foregoing caveat applies to all behavioral research reported to date on CAH women. Moreover, it seems likely from our own sampling experience as well as that of others (4) that those patients who are dissatisfied with their experience of medical management and/or the overall outcome are less likely to participate in follow-up studies. As a consequence, the available data may be biased in the direction of relatively good functioning.

Despite these limitations, the evidence clearly indicates that the reduced fertility of CAH women with classical CAH, especially the SW form, has a variety of reasons. The main reason, it seems, is not the dysregulation of ovulation and suppression of conception, but the lower rate of heterosexual involvement combined with the lower rate of interest in having children. The lower rate of heterosexual involvement is probably related to the postoperative status of the genitalia and possibly also to prenatal androgen effects on the brain. The lower interest in having children seems to be part of the overall masculinization of childhood behavior in girls with classical CAH; in adolescent and adult CAH women, the various problems with heterosexuality may further contribute.

There is room for improvement not only in the endocrine management of the menstrual cycle and thereby the capacity to conceive, but also in the surgical management of the genitalia. In addition, it seems clinically obvious that psychosocial guidance by experienced therapists can be helpful, but due to the very limited number of mental health specialists with experience in this area, no systematic outcome data are available on this issue. Yet, there are limits to what one can expect from such medical and psychosocial management, given that childlessness may not just be a problem of conception/hormonal management and genital status/surgery with their body image implications, but also of lessened maternal orientation. In this context, it is important to note that the suppression of excessive fetal androgenization by dexamethasone treatment, as used for pregnancies at risk for CAH offspring, has been documented to effectively reduce the degree of genital masculinization (with all its implications) in female newborns with classical CAH (58). Long term follow-up studies of the behavioral outcome will show whether dexamethasone treatment also prevents the effects of prenatal androgens on brain and behavior and thereby put the psychoendocrine assumptions to a test.

Received January 11, 1999.

Accepted February 24, 1999.

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