Lipoid congenital adrenal hyperplasia (LCAH) is the most

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1 ORIGINAL ARTICLE Endocrine Care Brief Report Gonadal Function, First Cases of Pregnancy, and Child Delivery in a Woman with Lipoid Congenital Adrenal Hyperplasia Khalil Khoury, Elie Barbar, Youssef Ainmelk, Annie Ouellet, and Jean-Guy LeHoux Departments of Pediatrics (K.K.), of Obstetrics and Gynecology (Y.A., A.O.), and of Biochemistry (E.B., J.-G.L.), Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4 Context: Mutations in the steroidogenic acute regulatory protein (StAR) gene often cause lipoid congenital adrenal hyperplasia (LCAH). In this disorder an impairment of steroid synthesis leads to adrenal and gonadal insufficiencies with a particular female genital phenotype in both human karyotypes. Pregnancy in LCAH has not been yet reported. Objective: We describe the first cases of pregnancy in a LCAH female patient bearing the L275P mutation in the StAR gene. Design: We studied the gonadal function, pubertal development, and apply the appropriate hormonal therapy to support pregnancies. Patient: A 46,xx patient of French Canadian descent was diagnosed with LCAH at the age of 4.5 months. Substitution therapy with glucocorticoids and mineralocorticoids led to normal growth and development. Progressive pubertal development started at the age of 11 7/12 yr. Menarche occurred at 14 2/12 yr with normal regular menstruations thereafter but without ovulation. Results: Clomiphene stimulation induced the first pregnancy at 25 4/12 yr of age. Spontaneous abortion occurred after 6 wk gestation. The second pregnancy (with clomiphene stimulation) was induced at the age of 26 yr. Progesterone (Prog) therapy was added at the 17th day of the cycle to protect pregnancy. Vaginal delivery of dichorionic-diamniotic twin pregnancy occurred at 30 wk gestation (two normal weight male babies). Two years later, again under clomiphene stimulation, she underwent another successful singleton pregnancy and delivered a normal weight female baby at 36 wk. The pregnancies were almost uncomplicated. Conclusion: Despite the dysfunctional StAR, pregnancy is possible under the proper therapeutic strategy. (J Clin Endocrinol Metab 94: , 2009) ISSN Print X ISSN Online Printed in U.S.A. Copyright 2009 by The Endocrine Society doi: /jc Received August 4, Accepted January 14, First Published Online January 21, 2009 Lipoid congenital adrenal hyperplasia (LCAH) is the most severe form of congenital adrenal hyperplasia leading to impaired production of glucocorticoids, mineralocorticoids, and sex steroids (1). In this disorder the basal levels of ACTH and plasma renin activity are high with no steroidal response to ACTH or human chorionic gonadotropin (hcg) administration. LCAH is inherited as an autosomal recessive disease. Signs of adrenal insufficiency and hyperpigmentation occur in phenotypical female infants, regardless of the karyotype (2). Affected individuals are all phenotypically female with a severe salt-wasting crisis and hyperpigmentation; they can die shortly after birth unless treated with steroid-replacement therapy (3). The Leydig cells of a 46,xy subject with LCAH are destroyed early in fetal life, thereby eliminating testosterone biosynthesis and normal virilization, resulting in the development of a female phenotype (4). On the other hand, 46,xx subjects with LCAH, when adequately treated, may undergo spontaneous puberty, feminization, and even cyclical vaginal bleeding, but of an anovulatory nature (5, 6). Abbreviations: Andro, Androstenedione; BB, baby; bid, daily; DHEA, dehydroepiandrosterone; E2, 17 -estradiol; GA, gestational age; hcg, human chorionic gonadotropin; 17 OH-Preg, 17 hydroxy-pregnenolone; 17 OH-Prog, 17 hydroxy-progesterone; LCAH, lipoid congenital adrenal hyperplasia; Prog, progesterone; StAR, steroidogenic acute regulatory protein. J Clin Endocrinol Metab, April 2009, 94(4): jcem.endojournals.org 1333

2 1334 Khoury et al. Pregnancy and Child Delivery in Lipoid CAH J Clin Endocrinol Metab, April 2009, 94(4): The most common cause of LCAH is attributed to mutations in the steroidogenic acute regulatory protein (StAR) (7). StAR is mainly expressed under acute tropic hormone stimulation (8). It is produced in the cytoplasm and mediates the biosynthesis of steroid hormones by controlling the transfer of cholesterol from the outer to the inner mitochondrial membrane where cytochrome P450 side chain cleavage is located (9, 10). Without StAR, steroidogenesis proceeds, for a temporary period, at about 14% of the StAR-induced level (2, 11). To understand the pathogenesis of different manifestations of LCAH, the concept of a StAR-dependent and a StAR-independent step of steroidogenesis was proposed: 1) the loss of StAR activity leading to a decrease of more than 80% of adrenal and gonad steroidogenesis; and 2) the impairment of the steroidogenic capacity by the accumulation of cholesterol, cholesterol esters, and oxidation products, engorging the cells and damaging its cytoarchitecture. We have previously reported the cases of two children with LCAH (46,xy and 46,xx) in a French Canadian family due to a homozygous StAR mutation, L275P (12). Here, we report the gonadal function, pubertal development, and the first cases of pregnancy in the 46,xx. Patients and Methods Patient history The patient was born in 1979 after 42 wk gestation and spontaneous delivery, without complications (12). At the age of 1.5 months, physical examination was normal, with discrete skin hyperpigmentation. Blood glucose and electrolytes were normal. She was admitted to hospital at the age of 4.5 months for a history of fever, anorexia, fatigue, and weight loss. She was treated with antibiotics (pharyngitis) for 10 d. However, by the end of treatment, she was lethargic with somnolence, vomiting, dehydration with hyponatremia, and hyperkaliemia. Serum sodium and potassium levels were and 5.7 mmol/liter, respectively, blood glucose was 6.3 mmol/liter, and urinary sodium was 71 mmol/liter. Her blood pressure and cardiac pulse were /60 and 130 per minute, respectively. Her respiratory rate was 28 per minute. Her physical examination showed also a generalized hyperpigmentation, hypertrichosis on her arms and the lower part of her back. External genitalia were completely normal female. She had low levels of cortisol and aldosterone, with no response to an ACTH stimulation test. She suffered three episodes of hypoglycemia (12). During all the following years, she had normal growth and development with glucocorticoid and mineralocorticoid substitution therapy. Results Gonadal function An abdominal and pelvic echography performed at the age of 2 5/12 yr revealed a normal uterus and ovaries. This examination was repeated at 11 1/12 and 12 3/12 yr, and showed a prepubertal uterus and normal ovaries with small follicles. The serum gonadotropin levels were normal between the age of 2 and 12 yr (FSH IU/liter and LH IU/liter). Serum levels of 17 hydroxy-progesterone (17 OH-Prog) ( 1.7 nmol/liter), dehydroepiandrosterone (DHEA) ( 1.7 nmol/liter), androstenedione (Andro) ( 0.3 nmol/liter), and testosterone ( 0.35 nmol/liter) were very low. Plasma ACTH varied from pmol/liter during that period. She started thelarche at the age of 11 7/12 yr, pubarche at the age of 12 yr, and spontaneous menarche at the age of 14 2/12 yr. The menstruations were regular (every d) with no dysmenorrhea. The registered basal temperature indicated a monophasic nonovulatory curve. Table 1 summarizes the hypophyso-gonadal function at the age of 12 2/12 yr, including a hcg stimulation test at that age, and a clomiphene stimulation at 25 yr, showing a significant increase of plasma 17 -estradiol (E2) and Prog levels. Fertility studies and follow-up Between the age of 20 and 25 yr, she was followed in our fertility clinic. However, despite her regular menstruations, there was no spontaneous ovulation. Clomiphene stimulation was started at the age of 25 yr to induce more estrogen secretion and ovulation (Table 2). The starting dose for the first month was 50 mg/d 5 d, then increased to mg/d 5 d. A first pregnancy was confirmed at the age of 25 4/12 yr by a high level of hcg; unfortunately, a spontaneous abortion occurred 6 wk later. Months later, clomiphene stimulation was then restarted, and Prog (Prometrium 200 mg/d; Solvay Pharmaceuticals, Inc., Marietta, GA) was added at the 17th day of the cycle, expecting the eventual corpus luteum insufficiency. At the age of 26 yr, a quadruple pregnancy of approximately 6 wk was confirmed by echography and by a high level of circulating hcg. One fetus was naturally lost at 7 wk gestational age (GA), and one feticide was done wk later. Prometrium (200 mg) was given daily (bid) up to the 25th week of GA. Hypertension was noted at 29 wk, and a premature delivery of two normal boys occurred at 30 wk GA (October 2005, Table 2). At 28 yr of age, the patient consulted again for another ovulation induction. Clomiphene stimulation was started, and Prometrium 200 mg bid was prescribed to be taken from the 17th day of the cycle up to the 17th week of gestation. In October 2008, a normal female child was born after 36 wk GA. Pregnancy outcome The twin male babies, baby A (BB A) and baby B (BB B), of the second pregnancy (diamniotic, dichorionic) were born in cephalic position, weighing 1275 (BB A) and 1370 g (BB B). The catch-up of growth was relatively appropriate for BB A and B. However, at the current age of 3 yr old, height is at the 25th and 3rd percentile for BB A and B, respectively, whereas the weight is at the 10th and less than the 3rd percentile, respectively, and the cranial circumference is at the 25th and 15th percentile, respectively. Psychomotor development was normal. The endocrine data including plasma ACTH, cortisol, FSH, LH, and testosterone at the age of 4 d, 2 months, and 5 months, were normal for the two infants. During the neonatal period, both babies had hyalin membrane disease grade II. In addition, until the current age, both infants did not have any specific serious health problems except for recurrent otitis media requiring myringotomy. In addition, infant A had surgery for bilateral inguinal hernia at the age of 2 months, and urinary infection at 11 months associated with urethral valve and lithiasis. The female baby of the third pregnancy was born with a weight of 2930 g and no apparent female phenotype abnormality

3 J Clin Endocrinol Metab, April 2009, 94(4): jcem.endojournals.org 1335 TABLE 1. The hypophyso-gonadal function at the age of 12 2/12 yr, including a hcg stimulation test at that age and a clomiphene stimulation test at 25 yr old FSH LH 17 OH-Preg Prog 17 OH-Prog DHEA Andro E2 (IU/liter) a (IU/liter) b (nmol/liter) c (nmol/liter) d (nmol/liter) e (nmol/liter) f (nmol/liter) g (pmol/liter) h Observations 12 2/12 yr BII/PII/AA B.A 9 6/12 yr IM hcg stimulation 3500 IU/d 5d d d d d yr B IV/P III/A menarche 17 yr B V/P V/A B.A 15 yr 24 yr Regular menstruations, basal T o anovulatory 25 yr clomiphene 50 mg/d 5 d , Not determined; IM, intramascular; B, breast development; P, pubic hair; A, auxiliary hair; BA, bone age; T o, temperature. a FSH: prepubertal, IU/liter; puberty Tanner II and III, IU/liter; and Tanner IV and V, UI/liter. b LH: prepubertal, IU/liter; puberty Tanner II, IU/liter; Tanner III, UI/liter; and Tanner IV and V, UI/liter. c 17 OH-Preg: puberty Tanner II and III, nmol/liter; and Tanner IV and V, nmol/liter. d Prog: adult (follicular), nmol/liter; and luteal, nmol/liter. e 17 OH-Prog: puberty Tanner II and III, nmol/liter; and Tanner IV and V, nmol/liter. f DHEA: puberty Tanner II and III, nmol/liter. g Andro: puberty Tanner II and III, nmol/liter. h E2: puberty Tanner II, pmol/liter; Tanner III, pmol/liter; Tanner IV, pmol/liter; Tanner V, pmol/liter; adult (follicular), pmol/liter; and luteal, pmol/liter.

4 1336 Khoury et al. Pregnancy and Child Delivery in Lipoid CAH J Clin Endocrinol Metab, April 2009, 94(4): TABLE 2. Fertility study and follow-up Dates (yr/month/d) Prog (nmol/liter) (follicular phase, ; luteal phase, ) HCG (IU/liter) Observations 2004/08/ Under clomiphene 100 mg/d 5 d/cycle (1st pregnancy) 2004/09/ /09/29 10 Spontaneous abortion at the 6th week of pregnancy 2005/02/23 Clomiphene 150 mg/d 5 d/cycle, Prometrium 200 mg/d starting at the 17th day of the cycle 2005/03/23 Date of last menstruation 2005/04/ nd day of the last cycle 2005/04/ Confirming 2nd pregnancy 2005/06/ Prometrium 200 mg bid up to the 25th week of gestation 2005/10/18 30th week, delivery 2008/01/26 Date of last menstruation 2008/03/ rd pregnancy, Prometrium 200 mg bid up to the 17th week gestation 2008/03/ /05/ E pmol/liter; serum aldo 490 pmol/liter; renin ng/liter sec; sodium 137 mmol/liter, potassium 4.4 mmol/liter; serum creatinine 41 mol/liter 2008/10/04 36th week, delivery Normal values are in parentheses. aldo, Aldosterone. or hyperpigmentation. Abdominal and pelvian echography showed a normal aspect of adrenal gland, ovaries, and uterus. At 4 d old, cortisol and blood electrolytes were normal, but aldosterone was at the upper-normal limit, and plasma renin activity was slightly high. At 1 month old, pregnenolone, 17 hydroxypregnenolone (17 OH-Preg), DHEA, DHEA-sulfate, 17 OH- Prog, 11-deoxycortisol, and cortisol were normal; ACTH was slightly elevated. Blood electrolytes, FSH, LH, and E2 were normal at 4 d and at 1 month. A prolonged physiological jaundice was observed; she is breast feeding, and her thyroid function is normal. Discussion During pubertal age the patient s normal pituitary secretion of FSH and LH stimulated the recruited follicles of her ovaries to produce the appropriate amount of estrogens to induce progressive pubertal feminization and regular menstruations. Interestingly, during her early pubertal development, a hcg stimulation test resulted in a small increase in Andro and a substantial enhancement of E2 secretion (Table 1), indicating a capacity for estrogen production. However, the patient lacked the spontaneous estrogen surge necessary for ovulation. Our observations are in agreement with the report by Matsuo et al. (6), that five of five 46,xx patients with LCAH older than 13 yr expressed a spontaneous development of secondary sex characters and vaginal bleeding at puberty. Later on, it was decided to proceed to a clomiphene stimulation at the age of 25 yr, hoping to induce ovulation by the stimulation of pituitary gonadotropin secretion. The luteinization process was confirmed by the high levels of Prog and E2 during the second half of her menstrual cycle (Table 1). According to Ronen-Fuhrmann et al. (13), this is due to the high StAR expression induced in all ovarian interstitium and the granulosa cells of periovulatory follicles. This may suggest that steroidogenesis in these cells exposed for the first time to acute LH stimulation was not seriously disrupted yet. It may also indicate that the ovulatory peak of LH may have a role of activation of the StAR-independent system via other StAR-like proteins such as MLN64, which is present in human placenta, granulosa, and theca cells, as well as in the fetal adrenal cortex (14). Other elements may also account for the basal level of steroid hormone production, such as the translocator protein, which is able to bind cholesterol and stimulate steroidogenesis in the absence of StAR (15), or by interacting with it (16). Thus, it is possible that without StAR, the translocator protein complex can act as a low-capacity system responsible for basal levels of steroidogenesis, whereas StAR acts in concert with that system during an acute tropic stimulation, transforming it into a high-capacity cholesterol transfer system. A first pregnancy was confirmed at the age of 25 4/12 yr. Unfortunately, a spontaneous abortion occurred 6 wk later. This raised the question about the consequence of this mutated StAR and the integrity of steroid production inside the theca- and granulosa-lutein cells of the corpus luteum. Furthermore, these cells might have been unable to maintain the high-normal production of Prog under the acute and important placental chorionic gonadotropin stimulation to preparing and stabilizing the endometrium while protecting the embryo during the first trimester (17, 18). Clomiphene stimulation was successful in producing a second and third pregnancy. Prog administration since the 17th day of the cycle proved to be the appropriate substitution therapy

5 J Clin Endocrinol Metab, April 2009, 94(4): jcem.endojournals.org 1337 for the expected corpus luteum insufficiency during the first trimester, and preventing abortion (19), as occurred during the first pregnancy. Ovulation induction with clomiphene citrate is associated with 6 8% of cases with multiple pregnancies (which was the case for our patient), mainly twins (20). During her last two pregnancies, the patient developed high blood pressure without preeclampsia. This was classified as gestational hypertension because it first started during pregnancy and returned to normal after delivery. The etiology of this symptom is not clear, however, it is unlikely that the normal dose of administered glucocorticoids and mineralocorticoids had any role. It is possible that the multiple pregnancy status represented a risk factor for the second pregnancy (21). Our patient is probably one of the first cases of LCAH in which a spontaneous pubertal development, menarche, and menstruations were observed; she is the first reported woman to have pregnancy and child delivery, as previously communicated in 2006 (22). Despite the dysfunctional StAR, our understanding of its physiological role during the different phases of follicular development and the corpus luteum formation was essential to develop the appropriate therapeutic strategy. Acknowledgments We thank Dr. Mélanie Arbour-Levert for her assistance with the clinical follow-up of the pregnancies. Address all correspondence and requests for reprints to: Jean-Guy LeHoux, Department of Biochemistry, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4. Jean-Guy. LeHoux@USherbrooke.ca. This work was supported by Grant MT from the Canadian Institutes of Health Research. Disclosure Summary: The authors have nothing to disclose. References 1. 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