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Normal Female Infants Born of Mothers with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency¹

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

Address all correspondence to: Dr. Melvin Grumbach, Department of Pediatrics, University of California, San Francisco, California 94143-0434.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.

	Introduction

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WOMEN 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, 2, 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, 5, 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 salt-wasting 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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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 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

Top Abstract Introduction Subjects and Methods Results Discussion References

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 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 µg/L·h.

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 ambiguous 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 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 pregnane-triol 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 17-hydroxyprogesterone level of 524 ng/dL was obtained in the infant at 24 h of age.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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 maternal 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, 10, 11, 12, 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 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 hormone-binding 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, 33, 34, 35, 36, 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 11ß-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 transferred across the placenta without oxidation of the 11-hydroxyl 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 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 11ß-hydroxysteroid 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.

	Acknowledgments

 
The authors thank Drs. Robert Streeter, Susan Kehm, and Linda Mendoza for their assistance with the endocrinological management of these patients.

	Footnotes

 
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.

¹ 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-DK-07418), the NICHHD (R01-HD-02335), and the NIH Pediatric Clinical Research Center (M01-RR-01271).

² Fellow in Pediatric Endocrinology under a program sponsored by the Hopital Cantonal Universitaire (Geneva, Switzerland), and the Fondazione Litta (Vaduz, Liechtenstein).

Received October 26, 1998.

Revised December 10, 1998.

Accepted December 14, 1998.

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