0021-972X/99/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 1999 by The Endocrine Society
Vol. 84, No. 3 Printed in U.S.A.
Normal Female Infants Born of Mothers with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency* JOAN C. LO, VALERIE M. SCHWITZGEBEL†, J. BLAKE TYRRELL, PAUL A. FITZGERALD, SELNA L. KAPLAN, FELIX A. CONTE, AND MELVIN M. GRUMBACH Division of Endocrinology, Departments of Medicine (J.C.L., J.B.T., P.A.F.) and Pediatrics (V.M.S., S.L.K., F.A.C., M.M.G.), University of California, San Francisco, California 94143 ABSTRACT Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, especially those patients with the salt-losing form, have decreased fertility rates. Pregnancy experience in this population is limited. We report the pregnancy outcomes and serial measurements of maternal serum steroid levels in four women with classic 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites with the salt-losing form. These glucocorticoid-treated women gave birth to four healthy female newborns with normal female external genitalia, none of whom were affected with 21-hydroxylase deficiency. In three women, circulating androgen levels increased during gestation, but remained within the normal range for pregnancy during glucocorticoid therapy. In the fourth patient, androgen levels were strikingly elevated during gestation despite increasing
the dose of oral prednisone from 5 to 15 mg/day (two divided doses). Notwithstanding the high maternal serum concentration of androgens, however, placental aromatase activity was sufficient to prevent masculinization of the external genitalia of the female fetus and quite likely the fetal brain, consistent with the idea that placental aromatization of androgens to estrogens is the principal mechanism that protects the female fetus from the masculinizing effects of maternal hyperandrogenism. These four patients highlight key issues in the management of pregnancy in women with 21-hydroxylase deficiency, particularly the use of endocrine monitoring to assess adrenal androgen suppression in the mother, especially when the fetus is female. Recommendations for the management of pregnancy and delivery in these patients are discussed. (J Clin Endocrinol Metab 84: 930 –936, 1999)
W
OMEN WITH congenital adrenal hyperplasia due to 21-hydroxylase deficiency have decreased fertility rates, particularly patients with the salt-wasting variant of this syndrome (1). Contributing factors include an inadequate introitus as a result of poor surgical repair and/or restenosis, lack of heterosexual activity, and anovulation secondary to elevated androgen levels (1–3). It has also been suggested that increased levels of progestational steroids, which may occur even with adequate adrenal androgen suppression, may contribute to reduced fertility (4 – 6). Although fertility rates have improved with early detection and treatment of 21-hydroxylase deficiency and surgical advances in genital reconstruction (7), pregnancy experience remains
very limited in these patients. For example, there is one case report of a woman with untreated 21-hydroxylase deficiency who gave birth to a female infant with androgen-induced, but nonadrenal, female pseudohermaphrodism (8). We describe the pregnancy management and birth outcomes in four women with 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites and manifested the saltwasting form of this disorder. These patients illustrate several important issues in the therapy of pregnant women with congenital adrenal hyperplasia, including the regulation of adrenal androgen production and the role of placental aromatase activity in protecting the female fetus from high circulating maternal androgens and androgen precursors. Subjects and Methods
Received October 26, 1998. Revision received December 10, 1998. Accepted December 14, 1998. Address requests for reprints to: Dr. Joan Lo, Division of Endocrinology, Department of Medicine, University of California, San Francisco General Hospital, Building 100, Room 321, San Francisco, California 94110. E-mail:
[email protected]. Address all correspondence to: Dr. Melvin Grumbach, Department of Pediatrics, University of California, San Francisco, California 94143-0434. * Presented in part at the Fifth Joint Meeting of the European Society for Pediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society, Stockholm, Sweden, June 1997. This work was supported in part by NIH Grants from the NIDDK (5T32-DK-07161 and 5T32-DK07418), the NICHHD (R01-HD-02335), and the NIH Pediatric Clinical Research Center (M01-RR-01271). † Fellow in Pediatric Endocrinology under a program sponsored by the Hopital Cantonal Universitaire (Geneva, Switzerland), and the Fondazione Litta (Vaduz, Liechtenstein).
Subjects Between 1992 and 1997, four women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency were studied during pregnancy at the University of California San Francisco (UCSF). All patients were originally diagnosed with 21-hydroxylase deficiency at the Pediatric Endocrinology Clinic at UCSF and were managed through this clinic until the age of 21 yr.
Laboratory measurements Serum total testosterone, androstenedione, and 17-hydroxyprogesterone measurements were performed by RIA at Nichols Institute Diagnostics (San Juan Capistrano, CA; now Quest Diagnostics, Inc.), Endocrine Sciences, Inc. (Calabasas Hills, CA), SmithKline Beecham Clinical Laboratories (Van Nuys, CA), UCSF Clinical Laboratories, and Unilab (Sacramento, CA). Total testosterone levels were determined by
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PREGNANCY OUTCOMES IN WOMEN WITH CONGENITAL ADRENAL HYPERPLASIA chemiluminescent assay at Meris Laboratories, Inc. (San Jose, CA). Androstenedione levels obtained through Meris Laboratories were measured by RIA at ARUP Laboratories (Salt Lake City, UT). Serum free testosterone was measured by equilibrium dialysis at Nichols Institute Diagnostics and Endocrine Sciences, Inc. and by RIA at Unilab. Serum dihydrotestosterone levels were measured by RIA at Endocrine Sciences, Inc.. Plasma ACTH levels were determined by immunoradiometric assay, performed at UCSF Clinical Laboratories using kits obtained from Nichols Institute Diagnostics. PRA was measured as the rate of angiotensin I generation by SmithKline Beecham Clinical Laboratories. Urinary estriol levels were determined by RIA at Nichols Institute Diagnostics. Normal reference data for serum steroid hormone levels are indicated in Table 1.
Results Case 1
A 35-yr-old woman with the salt-losing form of 21-hydroxylase deficiency conceived successfully after in vitro fertilization. At 8 months of age, she had been diagnosed with female pseudohermaphrodism due to salt-losing congenital adrenal hyperplasia after evaluation for ambiguous genitalia (clitoromegaly and a single urogenital orifice, with fusion of the labioscrotal folds) and poor weight gain. The excretion of urinary pregnanetriol and 17-ketosteroids was greatly elevated for age, and she was treated with im and later oral cortisone acetate and fludrocortisone therapy. The patient underwent successful genital reconstruction after menarche at age 15 yr. At age 16 yr, fludrocortisone was discontinued, with adequate maintenance of blood pressure with a high salt diet. Menstrual cycles were notable for periods of oligomenorrhea and amenorrhea. After 4 yr of infertility, she conceived successfully at age 35 yr after her second trial of in vitro fertilization. She presented for endocrine evaluation at 25 weeks gestation; her regimen consisted of prednisone (5 mg/day) and a high salt diet. Physical examination was notable for facial hirsutism, acne, and clitoromegaly. Androgen levels obtained at 23 weeks gestation were markedly elevated. The serum concentration of androstenedione was 613 ng/dL, that of testosterone was 303 ng/dL, and that of 17-hydroxyprogesterone was 7500 ng/dL. By 25 weeks gestation, the total testosterone level had increased to 390 ng/dL, and a free
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testosterone level was markedly elevated at 29.8 ng/L. Ultrasound examination showed a female fetus with possible prominence of the clitoris, but no scrotal sac or testes. No maternal adnexal abnormalities were noted. Because of the concern for fetal virilization, her prednisone dosage was increased incrementally to 15 mg/day (5 mg every morning, 10 mg every evening) to achieve more effective maternal androgen suppression. However, androgen levels remained elevated despite compliance with medication, and by 34 weeks gestation, her testosterone level measured 621 ng/dL, and free testosterone was 48.4 ng/L (Table 2). The plasma concentration of ACTH measured 47 ng/L, that of 17-hydroxyprogesterone was 1695 ng/dL, and PRA was 3.4 mg/Lzh. At 37 weeks gestation, the patient developed preeclampsia, and labor was induced. An urgent cesarean section was performed for fetal bradycardia, and a 2.7-kg infant girl was delivered. Although initial Apgar scores were low, and temporary mechanical ventilation was required, the infant recovered without sequelae within 24 h. Physical examination revealed normal external female genitalia; a serum 17hydroxyprogesterone level of 384 ng/dL was obtained 2 days after birth, excluding the diagnosis of congenital adrenal hyperplasia in the infant. Maternal hormone levels subsequently fell after delivery, and androgen levels were within the normal range at 6 weeks postpartum on a prednisone dose of 10 mg/day (5 mg, twice daily; Table 2). Her prednisone dose was eventually tapered to her pregestational dose of 5 mg/day; hormone levels determined 19 months later revealed the androstenedione, testosterone, and free testosterone levels to be normal, whereas the 17-hydroxyprogesterone level was elevated (Table 2). Case 2
A 22-yr-old woman with the salt-losing form of 21-hydroxylase deficiency conceived spontaneously and was followed throughout pregnancy. She had been diagnosed with female pseudohermaphrodism and salt-losing congenital adrenal hyperplasia in the first month of life when she presented with dehydration, vomiting, hyperkalemia, and am-
TABLE 1. Reference values for 17-hydroxyprogesterone, testosterone, free testosterone, androstenedione, and dihydrotestosterone levels throughout normal pregnancy and in nonpregnant adult women that pertain to the measurements performed in Patients 1– 4 Clinical laboratory
Nichols Institutea Nonpregnantb 1st trimester 2nd trimester 3rd trimester Endocrine Sciences Nonpregnantb 1st trimester 2nd trimester 3rd trimester SmithKline Beechamb Meris Laboratoriesb Unilabb UCSF Laboratoriesb
17-OHP (ng/dL)
Test (ng/dL)
Testfree (ng/L)
D4A (ng/dL)
DHT (ng/dL)
20–500 228–748 220– 860 700–2400
15–70 34–192 76–181 57–174
1.0– 8.5 3.7–15.6 5.8–12.7 4.2–11.9
50–250 134–507 161–758 161–729
5–30
15–290 180–235 150– 415 230–1200 30–290
10–55
1.1– 6.3
4–22
35–209 35–209 25–95 6– 86 22– 80 30–70
0.8– 6.9 0.8– 6.9
85–275 140–508 190– 482 207–560 65–270 50–270 21–308 80–230
0.1–3.8
These reference values are not intended to guide clinical care in other patients as the normal range will vary with assay methodology and laboratory. 17-OHP, 17-Hydroxyprogesterone; Test, testosterone; D4A, androstenedione; DHT, dihydrotestosterone. a Now known as Quest Diagnostics. b Normal values for nonpregnant premenopausal adult women.
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TABLE 2. Hormone levels obtained in patients 1– 4 throughout pregnancy Gestational week
Patient 1 23 25 27 29 34 6 weeks post 19 months post Patient 2 4 months prior 11 15 19 30 37 4 days post 14 days post Patient 3 7 37 Patient 4 16 19 26 34
17-OHP (ng/dL)
7500a
Test (ng/dL)
Testfree (ng/L)
D4A (ng/dL)
880a 860a 1695 2332b 7040b
303 390 314 374 621 24b 51b
120a 2200d 6900d 930d 2000d 4900d 130d 160d
17a 65d 136d 69d 76d 162d 21d 11d
57a 180d 410d 180d 210d 490d 74d 41d
2100a
40e 112
180e 230
763 390a 1241 8693
29f 49 58 107f
DHT (ng/dL)
613 29.8 24.7 30.7 48.4 1.2b 3.1b
5.6 5.5 2.4f
576 687 638 83b 172b
168 267 590f
51b 93b 5.7b 6.7b
7.3b 12b
Adrenal steroid replacement (total dose per day)
Prednisone 5 mg 5 mg 7.5 mgc 10 mgc 15 mgc 7.5 mgc 5 mg Dexamethasone 0.375 mgc 0.375 mgc 0.375 mgc 0.50 mgc 0.50 mgc 0.50 mgc 0.75 mgc 0.375 mgc Methylprednisolone 6 mgc 10 mgc Cortisone acetate 37.5 mgc 37.5 mgc 37.5 mgc 37.5 mgc
Fludrocortisone 0.1 mg 0.1 mg 0.1 mg 0.1 mg 0.1 mg 0.1 mg 0.1 mg 0.1 mg Fludrocortisone 0.15 mg 0.2 mgc
17-OHP, 17-Hydroxyprogesterone; Test, testosterone; D4A, androstenedione; DHT, dihydrotestosterone. Unless otherwise indicated, hormonal measurements were performed by Nichols Institute (Quest Diagnostics). a UCSF Clinical Laboratories. b Endocrine Sciences. c Divided into two or three doses per day (see text). d SmithKline Beecham Clinical Laboratories. e Meris Laboratories. f Unilab.
biguous external genitalia, characterized by a 2.3-cm clitoris bound in chordee and complete fusion of the labioscrotal folds. Urinary excretion of pregnanetriol and 17-ketosteroids were markedly elevated. She was treated with cortisone acetate and deoxycorticosterone acetate pellet implantation, which was later replaced with oral fludrocortisone therapy. Clitoroplasty was performed at 15 months of age, followed by vaginal exteriorization at age 5 yr. Vaginoplasty was completed successfully at age 16 yr after menarche, and treatment was changed to dexamethasone and fludrocortisone, resulting in suppression of androgen levels to the low normal range. She became pregnant at age 22 yr. Hormonal measurements at 11 weeks gestation showed normal androgen levels (Table 2) on a regimen of 0.375 mg/day dexamethasone (0.25 every morning, 0.125 every evening) and 0.1 mg/day fludrocortisone. A paternal serum 17-hydroxyprogesterone level of 150 ng/dL after cosyntropin stimulation suggested that the father was not a heterozygous carrier of a 21-hydroxylase gene mutation. Because androgen levels were noted to rise during pregnancy, her dexamethasone dose was increased to 0.50 mg/day (0.25 mg, daily) in the second trimester to achieve suppression of adrenal androgens and androgen precursors (Table 2). Further increases in 17-hydroxyprogesterone, testosterone, and androstenedione levels were noted during the last trimester, although values remained within the expected range for pregnancy. Because of extensive prior vaginal reconstruction, the patient underwent elective cesarean section at 40 weeks gestation and
delivered a healthy 3.0-kg female infant with normal external genitalia. Maternal hormone levels fell after delivery, and androgen levels determined 4 and 14 days postpartum were in the normal to low range of values for nonpregnant women (Table 2). Case 3
A 26-yr-old woman with the salt-losing form of 21-hydroxylase deficiency conceived spontaneously and was followed throughout pregnancy. She had been diagnosed with female pseudohermaphrodism at 4 days of age after presenting with salt-wasting, hyperkalemia, and ambiguous genitalia, characterized by clitoromegaly (2 cm), a single urogenital orifice, and labioscrotal fusion. The excretion of urinary pregnanetriol and 17-ketosteroids was strikingly elevated. Treatment was initiated with cortisone acetate and deoxycorticosterone acetate pellet implantation, which was later replaced with oral fludrocortisone therapy. Genital reconstruction and clitoroplasty were performed at age 18 months, with subsequent vaginoplasty at age 14 yr after menarche. She became pregnant at ages 17 and 25 yr, but underwent therapeutic abortions in both instances. During this time, serum androgen levels were normal on a steroid regimen of 6 mg/day methylprednisolone (2 mg, three times daily) and 0.1 mg/day fludrocortisone. Menstrual cycles were regular after the age of 23 yr. She conceived again at age 26 yr and presented for endocrine evaluation at 7 weeks
PREGNANCY OUTCOMES IN WOMEN WITH CONGENITAL ADRENAL HYPERPLASIA
gestation. No signs of virilization were noted on examination, and serum androgen levels were normal (Table 2). However, methylprednisolone was increased to 10 mg/day (three divided doses of 4, 4, and 2 mg), and fludrocortisone was increased to 0.2 mg/day (0.1 mg, twice daily) in the second trimester because of symptoms of weakness, thirst, and salt craving. At 37 weeks gestation, maternal androgen levels were increased, but remained within the expected range for pregnancy (Table 2). Excretion of urinary total estriol was normal at 15 mg/day. At 40 weeks gestation, labor was initiated and augmented with pitocin; however, a cesarean section was eventually performed for prolonged labor and arrest of descent. She delivered a 3.8-kg healthy female infant with normal external genitalia. The infant’s serum 17-hydroxyprogesterone level of 250 ng/dL, determined 24 h after delivery, excluded the diagnosis of 21-hydroxylase deficiency in the newborn. Case 4
A 29-yr-old woman with the simple virilizing form of 21-hydroxylase deficiency conceived spontaneously and was evaluated at 16 weeks gestation. She had been diagnosed at age 4 yr when her identical twin sister presented with premature pubarche and mild virilization of the external genitalia and was diagnosed with 21-hydroxylase deficiency. Our patient had minimally virilized female external genitalia. The excretion of urinary 17-ketosteroids and pregnanetriol was elevated for age; oral cortisone acetate therapy was initiated. She underwent normal pubertal development, with menarche occurring at age 10 yr. Menstrual cycles were irregular. At age 26 yr, she had a spontaneous abortion, but conceived again at age 29 yr. She presented for endocrine follow-up at 19 weeks gestation, at which time her examination was notable for mild hirsutism. Serum androgen levels were normal on a regimen of 37.5 mg/day cortisone acetate (25 mg every morning, 12.5 mg every evening; Table 2). Karyotype analysis of amniotic cells revealed a female fetus, and DNA studies indicated that the father had two normal CYP21 genes. Hormonal measurements obtained at 26 and 34 weeks gestation demonstrated progressive increases in total testosterone and androstenedione levels, which were within the normal range for pregnancy, and minimal change in free testosterone levels (Table 2). Because of borderline oligohydramnios, labor was induced at 37 weeks gestation, and the patient delivered a healthy 3.2-kg female infant with normal external genitalia. A normal 17hydroxyprogesterone level of 524 ng/dL was obtained in the infant at 24 h of age. Discussion
The improved prognosis for fertility in women with female pseudohermaphrodism due to congenital adrenal hyperplasia underscores the need for further attention to the management of pregnancy in these patients. Of the four women affected with 21-hydroxylase deficiency, three spontaneously conceived and had normal pregnancies, and one required in vitro fertilization. All four patients delivered healthy female newborns with nonvirilized external genitalia, including one patient who had strikingly elevated ma-
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ternal androgen levels during pregnancy. None of the female infants had clinical or biochemical evidence of 21-hydroxylase deficiency. Although successful pregnancies have been reported in women with simple virilizing congenital adrenal hyperplasia and more rarely in patients with the salt-wasting variant (Table 3), there have been few reports describing the endocrine management of these patients during gestation (9 –13). To our knowledge, this report represents one of the first series of successful pregnancy outcomes in women with 21-hydroxylase deficiency in which detailed hormonal data during gestation have been documented. Three of these four women manifested classical salt-wasting 21-hydroxylase deficiency. We monitored serum androgen levels during pregnancy, and despite adrenal androgen excess in one patient, all four women gave birth to female infants with normal female external genitalia, which we attribute to the protective effect (within limits) of placental mechanisms on the transfer of natural androgens to the fetus. The differentiation of male external genitalia is induced by testosterone/dihydrotestosterone during the first 12 fetal weeks (14). Hence, maternal androgen excess during the critical period of 7–12 weeks gestation can lead to varying degrees of masculinization of the female fetus; in severe cases, complete labioscrotal fusion and penile urethra formation have been reported (15). Fetal exposure to excess androgens subsequent to this period typically results in labial hypertrophy and clitoromegaly (but not a urogenital sinus), effects comparable to the changes seen with postnatal virilization (15). In addition, high androgen levels in the female fetus can lead, putatively, to masculinization of the female fetal brain (reviewed in Ref. 14). Several mechanisms, however, may protect the female fetus from the masculinizing effects of elevated androgens in the maternal circulation. The principal one is placental aromatization of maternal testosterone and androstenedione to estradiol and estrone, respectively, whereby the placenta serves as a metabolic barrier to reduce fetal exposure to maternal androgens (14). Placental aromatase activity also protects the mother from the virilizing effects of fetal androgen production (16). Indeed, female pseudohermaphrodism has been reported in infants with placental aromatase deficiency, indicating the importance of the feto-placental unit in androgen metabolism as early as the first trimester (16 –19). Moreover, both aromatase concentration and total aromatase activity in human placenta increase substantially during pregnancy (20), thus conferring greater fetal protection during advanced gestational stages. The effectiveness of this conversion may explain the lack of infant virilization in case 1 despite striking elevations in maternal testosterone and androstenedione levels. Protection of the female fetus has also been observed in a few cases of maternal hyperandrogenism due to pregnancy luteoma, hyperreactio luteinalis, and polycystic ovary syndrome (21–23). The risk of masculinization of the external genitalia of the female fetus increases when the capacity of the placental aromatase system to convert C19 steroids to estrogens (20) is exceeded. Synthetic nonaromatizable androgens and progestins escape this protective mechanism and, hence, can produce masculinization of the external genitalia of the female fetus at relatively low maternal plasma concentrations (15, 24, 25). Other maternal factors that may
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TABLE 3. Pregnancy outcomes in women with simple virilizing or salt-losing congenital adrenal hyperplasia Source
Yamashita and Kozakae (1956) de Alvarez and Smith (1957) Wilson and Keating (1958) Gans and Ser (1959) Mason (1961) Swyer and Bonham (1961) Southern et al. (1961) Avin (1962) Vant and Horner (1963) Speroff (1965) Harrison and Lister (1966) Eyton-Jones (1968) Mori and Miyakawa (1970) Lev-Ran (1975) Sotiropoulos et al. (1976) Kai et al. (1979) Porter and de Swiet (1983) Grant et al. (1983) Mulaikal et al. (1987) Costa et al. (1997) Premawardhana et al. (1997) Andersen et al. (1983) Grant et al. (1983) Mulaikal et al. (1987) Blumberg et al. (1988) Yarnell et al. (1994)
No. of women and classification
1 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1
Total no. of pregnancies
Birth outcomes (delivery method)
simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing simple virilizing virilizingb simple virilizing
1 1 2 1 1 1 1 2 2 1 1 2 1 1 1 3
1 1 2 1 1 1 1 1 1 1 1 1 1 1 3 1
1 simple virilizing 1 simple virilizing 15 simple virilizing 2 virilizingb 2 simple virilizing 3 salt-wasting 1 salt-wasting 3 salt-wasting 1 salt-wasting 1 salt-wasting 1 salt-wasting
1 1 25 2
1 1 1 2
{8
5 TAB, 2 normal childrena (V, C)
1 5 1 2 1
1 1 1 1 1
normal male (C) SAB normal female (V, C) normal female (C) normal female (C) normal male (C) SAB ruptured EP, 1 normal female (C) SAB, 1 normal female (C) normal female (V) normal male (V) SAB, 1 normal male (V) normal female (C) normal childa childrena (3C) SAB, 1 normal male (V), 1 pseudohermaphrodite female (V) normal female (C) normal childa (C) SAB, 1 TAB, 20 normal childrena (4V, 9C)c normal childrena (2C) normal female (C) TAB, 4 normal childrena (4V) TAB SAB, 1 normal female (C) normal male (C)
Reference no.
9 43 10 11 44 12 45 46 47 48 49 13 50 51 52 8 53 54 1 55 7 56 54 1 57 58
V, Vaginal delivery; C, cesarean delivery; EP, ectopic pregnancy; SAB, spontaneous abortion; TAB, therapeutic abortion. The majority of patients were female pseudohermaphrodites diagnosed in infancy or early childhood. a Gender unspecified. b Salt-losing status not specified. c Outcome and method of delivery not described in three pregnancies and seven births.
contribute to fetal protection, but to a lesser degree, include a reduction in the fraction of bioavailable testosterone due to increased sex hormone-binding globulin levels (26) and the potential antiandrogenic effects of progesterone (27–29). The gestational changes in C19 and C21 steroid levels may complicate the assessment of adrenal androgen excess in pregnant women with 21-hydroxylase deficiency. Hence, it is important to use reference values for serum androgen concentrations obtained in normal pregnant women. Longitudinal studies indicate that circulating testosterone levels rise during normal pregnancy and can increase up to 1.7-fold from 6 –36 weeks gestation (26, 30). The rise in sex hormonebinding globulin levels, on the other hand, may result in mildly decreased bioavailable testosterone concentrations early in pregnancy, whereas an increase in bioavailable testosterone concentration occurs later in gestation (26, 31). Free testosterone levels, therefore, provide a more accurate measure of functional maternal testosterone concentrations and should be used as the primary method of monitoring androgen status throughout pregnancy. Smaller increases in androstenedione levels of up to 1.2-fold during normal pregnancy have also been reported in longitudinal studies (26, 30), although more substantial increases are suggested by reference laboratory data (Table 1). The serum concentration of 17-hydroxyprogesterone rises more than 3-fold by term pregnancy (30). A rise in serum androgen values during gestation was found in all four women with 21-hydroxylase deficiency. In
three of the women, androgen levels on glucocorticoid therapy remained within the normal range for pregnancy. The high testosterone levels in patient 1 suggest inadequate glucocorticoid suppression of adrenal androgens; this patient was also not on fludrocortisone therapy. Attention to glucocorticoid regulation of excess adrenal androgens and androgen precursors is particularly important if the fetus is female. There is at least one report of an androgen-induced, but nonadrenal, female pseudohermaphrodite born to a mother with the simple virilizing form of 21-hydroxylase deficiency who ceased glucocorticoid treatment before conception (8). Similarly, reports of masculinization of the external genitalia of female fetuses have been described in pregnancies of mothers harboring a virilizing adrenocortical or ovarian tumor, including a luteoma of pregnancy (32–37). In one case, the female child had a developed penis (37). Nevertheless, our data and the reports we evaluated suggest that there is a relatively large margin of safety owing principally to the placental aromatase system in protecting the female fetus from the effects of high circulating maternal aromatizable androgens. In pregnant women with 21-hydroxylase deficiency, we recommend treatment with glucocorticoids that are inactivated by placental 11b-hydroxysteroid dehydrogenase type II (e.g. hydrocortisone, cortisone acetate, prednisone, and methylprednisolone) to minimize fetal adrenal suppression (38). Dexamethasone, which provides longer and more effective suppression of adrenal androgen production (2), is
PREGNANCY OUTCOMES IN WOMEN WITH CONGENITAL ADRENAL HYPERPLASIA TABLE 4. Suggested guidelines for the management of women with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency during pregnancy and delivery Gestational management Adrenal steroid replacement and adrenal androgen suppression Use a glucocorticoid that is metabolized by placental 11bhydroxysteroid dehydrogenase II (e.g. hydrocortisone, cortisone acetate, prednisone, methylprednisolone). Assess clinical status, serum electrolytes, and serum androgen levels regularly to determine the need for increased glucocorticoid and/or mineralocorticoid therapy. Excessive nausea, salt craving, and poor weight gain suggest adrenal steroid insufficiency. In select cases, measurement of PRA may be helpful. Serum testosterone and free testosterone levels should be measured every 6 weeks in the first trimester and every 6 – 8 weeks thereafter. Target free testosterone levels to the high normal range for pregnancy; however, management must be individualized for each patient. Avoid inducing cushingoid effects from too high a dose of glucocorticoids. Fetal gender determination by ultrasonography may be helpful in guiding treatment goals, as maternal androgen excess will have minimal effects on the male fetus. Labor and delivery Stress dose glucocorticoid therapy A soluble hydrocortisone ester (up to 50 –100 mg, iv, every 8 h) should be given at the initiation of active labor and continued until after delivery, followed by a rapid taper to previous maintenance doses. Cesarean vs. vaginal delivery Android pelvic characteristics may increase the risk for cephalopelvic disproportion. Elective cesarean section should be considered in all patients, especially those who have had reconstructive genital surgery. Evaluation of the infant Examine the infant for ambiguous genitalia. Female pseudohermaphrodism may either be a consequence of maternal hyperandrogenism or, if the father is a carrier, of fetal 21-hydroxylase deficiencya (male infants may have enlarged external genitalia). If the external genitalia are ambiguous, appropriate laboratory studies in the infant should be carried out to exclude 21-hydroxylase deficiency. a In an affected mother with 21-hydroxylase deficiency, we estimate the risk of having an affected female infant with fetal congenital adrenal hyperplasia to be approximately 1 in 240. This is based on an estimated 1 in 60 incidence for heterozygous individuals derived from newborn screening data (59) multiplied by a 50% chance of passing on the affected gene and a 50% chance that the affected infant is female. Ideally, genotype studies or a cosyntropin stimulation test to evaluate paternal carrier status may be informative. However, the former is not generally available commercially, and neither procedure is cost effective given the extremely low risk of an affected female infant.
transferred across the placenta without oxidation of the 11hydroxyl group and can suppress the fetal adrenal gland (38, 39). However, treatment considerations are different in pregnancies where the fetus is at risk for congenital adrenal hyperplasia, as suppression of the abnormal fetal adrenal gland is the aim of prenatal therapy (40, 41). Maternal serum testosterone and free testosterone levels should be assessed periodically during pregnancy in all patients with 21-hydroxylase deficiency. Sequential measurements should be obtained in the same laboratory, at the same time of day (preferably in the morning), and at a consistent time after the last glucocorticoid dose. Recommendations for
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the management of pregnancy and delivery in these patients are outlined in more detail in Table 4. Measurement of PRA may also be helpful in optimizing adrenal steroid replacement, although it should be realized that modest increases in PRA may occur during normal pregnancy (42). Glucocorticoid dosages frequently need to be increased to provide adequate steroid coverage during gestation in women with congenital adrenal hyperplasia, analogous to the management of an Addisonian patient during pregnancy. At present, there are no guidelines concerning the extent to which adrenal androgen production should be suppressed during pregnancy, particularly in the latter stage of pregnancy when there is increased capacity for placental aromatization. Our recommendation is to aim for adrenal androgen suppression that approximates the high normal range expected for each trimester of pregnancy; however, therapy for each patient should be individualized and adjusted carefully. In any event, the untoward effects of excessive glucocorticoid therapy must be avoided, especially in light of the low risk of masculinization of the female fetus. High glucocorticoid doses increase the risk of hypertension, fluid overload, excessive weight gain, and Cushingoid features, among other undesirable maternal effects. In patient 1, the high dose of prednisone may have affected the risk of preeclampsia. Although we do not recommend the use of dexamethasone or betamethasone (which are not inactivated by placental 11bhydroxysteroid dehydrogenase type II) during pregnancy in these women, if these steroids are used, measurement of serum or urinary estriol levels during the second and third trimesters is useful in assessing adrenal suppression by these steroids in the fetus. In summary, we report successful pregnancy outcomes in four women with 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites and manifested salt wasting. In all four glucocorticoid-treated mothers, a normal female infant with nonvirilized external genitalia was delivered. These patients highlight key issues in the management of 21-hydroxylase deficiency during gestation, particularly the interplay of maternal androgen excess and the protective role of placental aromatase and other factors to prevent virilization of the female fetus. These protective factors appear to account for the lack of masculinization of the external genitalia despite elevated circulating testosterone levels in the mother. Acknowledgments The authors thank Drs. Robert Streeter, Susan Kehm, and Linda Mendoza for their assistance with the endocrinological management of these patients.
References 1. Mulaikal RM, Migeon CJ, Rock JA. 1987 Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 316:178 –182. 2. Richards GE, Grumbach MM, Kaplan SL, Conte FA. 1978 The effect of long acting glucocorticoids on menstrual abnormalities in patients with virilizing congenital adrenal hyperplasia. J Clin Endocrinol Metab. 47:1208 –1215. 3. Klingensmith GJ, Garcia SC, Jones HW, Migeon CJ, Blizzard RM. 1977 Glucocorticoid treatment of girls with congenital adrenal hyperplasia: effects on height, sexual maturation, and fertility. J Pediatr. 90:996 –1004. 4. Rosenfield RL, Bickel S, Razdan AK. 1980 Amenorrhea related to progestin excess in congenital adrenal hyperplasia. Obstet Gynecol. 56:208 –215. 5. Helleday J, Siwers B, Ritze´n EM, Carlstro¨m K. 1993 Subnormal androgen and
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18. 19.
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