Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused
          by an inborn defect in the 21-hydroxylase gene (CYP21), leading to
          virilization of female patients and causing ambiguous genitals in the
          majority of female infants. Adult women may suffer from loss of libido,
          irregular or absent cycles, and reduced fertility, despite intensive
          medical treatment. These problems have stimulated the search for
          alternative treatment modalities. We present an adult female patient, who
          was difficult to treat medically and whose clinical situation markedly
          improved after laparoscopic bilateral adrenalectomy. The procedure was
          well tolerated and without side effects. Postoperatively the elevated
          serum progesterone and 17-hydroxyprogesterone levels, as well as the
          undetectable LH levels, normalized. The procedure resulted in marked
          clinical improvement. Within 12 months after surgery she lost 11 kg in
          weight. This weight loss consisted mainly of adipose tissue. Acne
          disappeared, and she had a regular 4-week menstrual cycle, with
          progesterone levels that are compatible with a luteal phase. The
          introduction of laparoscopic techniques may give an impulse to the
          application of surgical therapy at a larger scale in patients with
          21-hydroxylase deficiency who are difficult to treat with adrenal
          suppression therapy

Bonjer, H.J. (Jaap)

Bootsma, A.H. (Aart)

Bruining, H.A. (Hajo)

Jong, F.H. (Frank) de

Koper, J.W. (Jan)

Lamberts, S.W.J. (Steven)

Erasmus University Digital Repository

CLINICAL CASE SEMINARFertility and Body Composition after LaparoscopicBilateral Adrenalectomy in a 30-Year-Old Female withCongenital Adrenal HyperplasiaHILGO BRUINING, ATTE H. BOOTSMA, JAN W. KOPER, JAAP BONJER,FRANK H. DE JONG, AND STEVEN W. J. LAMBERTSDepartments of Medicine (H.B., A.H.B., J.W.K.) and Surgery (J.B.), University Hospital Rotterdam,3000 CA Rotterdam; and Department of Medicine (F.H.d.J., S.W.J.L.), Erasmus University Rotterdam,3000 DR Rotterdam, The NetherlandsABSTRACTCongenital adrenal hyperplasia due to 21-hydroxylase deficiency iscaused by an inborn defect in the 21-hydroxylase gene (CYP21), lead-ing to virilization of female patients and causing ambiguous genitalsin the majority of female infants. Adult women may suffer from lossof libido, irregular or absent cycles, and reduced fertility, despiteintensive medical treatment. These problems have stimulated thesearch for alternative treatment modalities. We present an adultfemale patient, who was difficult to treat medically and whose clinicalsituation markedly improved after laparoscopic bilateral adrenalec-tomy. The procedure was well tolerated and without side effects.Postoperatively the elevated serum progesterone and 17-hydroxypro-gesterone levels, as well as the undetectable LH levels, normalized.The procedure resulted in marked clinical improvement. Within 12months after surgery she lost 11 kg in weight. This weight loss con-sisted mainly of adipose tissue. Acne disappeared, and she had aregular 4-week menstrual cycle, with progesterone levels that arecompatible with a luteal phase. The introduction of laparoscopic tech-niques may give an impulse to the application of surgical therapy ata larger scale in patients with 21-hydroxylase deficiency who aredifficult to treat with adrenal suppression therapy. (J Clin EndocrinolMetab 86: 482–484, 2001)CONGENITAL ADRENAL hyperplasia (CAH) due to21-hydroxylase deficiency is caused by an inborn de-fect in the 21-hydroxylase gene (CYP21; Refs. 1–3). This geneis normally expressed in the adrenal glands. The geneticdefect causes a deficit in functionally active enzyme, leadingto the inability to synthesize mineralo- and glucocorticoste-roids. Depending on the type of defect, the level of residualenzyme can range from a subtle reduction to complete ab-sence. The decreased synthesis of cortisol results in increasedsecretion of ACTH from the pituitary, with subsequent ad-renal hyperplasia and overproduction of 21-hydroxylasesubstrates, which can be further metabolized to androgenicsteroids, leading to virilization of female patients and caus-ing ambiguous genitals in the majority of female infants.Growth is initially accelerated, followed by early epiphysialclosure and short stature in both sexes (4–6). Hyperandro-genism of adrenal origin can induce precocious puberty inboys. The medical treatment of 21-hydroxylase deficiencyhas not been substantially altered since 1950 (7).Glucocorticoid replacement aims to reduce virilization bysuppression of ACTH stimulation. The reported prescribeddosages frequently exceed 15 mg cortisol/m2/day, whereas thenormal daily secretion rate is about 7–8 mg/m2 (8, 9). Despitefrequent monitoring and dose adjustments these supraphysi-ological dosages have been shown to lead to adverse effects likeattenuation of growth, obesity, and decreased bone mineraldensity (10–13). In adult life sexual functioning is often im-paired, both biologically and psychologically (14). Women stillsuffer from loss of libido, irregular or absent cycles, and reducedfertility (6, 15–17). In males suppression of gonadotrophic hor-mones may induce poor spermatogenesis (4).These problems have stimulated the search for alternativetreatment modalities (9, 18). It is now possible to carry outprenatal fetal genotyping in women known to be at risk ofhaving offspring with 21-hydroxylase deficiency, and affectedfemale fetuses can be treated in utero to prevent virilization.Also, bilateral adrenalectomy has been used in patients wheremedical suppression of adrenal precursors was difficult toachieve or was accompanied by serious side effects (19–22).Patients without any remaining enzyme activity, the so-calleddouble null mutation carriers, are supposed to be the mosteligible candidates for this approach (9). This invasive treatmenthas become more accessible because the patients can be iden-tified easily by genotyping of the CYP21 gene, and also by theintroduction of laparoscopic adrenalectomy. This procedure issafe, less mutilating, and well tolerated (23–25). We present atypical adult female patient with CAH as a result of completeloss of 21-hydroxylase activity, who was difficult to treat med-ically and whose clinical situation was markedly improved bylaparoscopic bilateral adrenalectomy.Received April 4, 2000. Revision received October 4, 2000. AcceptedOctober 26, 2000.Address correspondence and requests for reprints to: Dr. Atte H.Bootsma, Department of Medicine, Room D430, University HospitalRotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail:bootsma@inw3.azr.nl.0021-972X/01/$03.00/0 Vol. 86, No. 2The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.Copyright © 2001 by The Endocrine Society482 at Medical Library Erasmus MC on November 28, 2006 jcem.endojournals.orgDownloaded from The patientThe patient, now a 31-yr-old female, from nonconsanguin-eous parents, was born with ambiguous genitalia. She wentthrough a salt-losing crisis shortly after birth and was diag-nosed as having classical CAH on clinical grounds. At 2 yrof age a nephropyelotomy and a meatotomy of the urethrawere performed to relieve her from recurrent urinary tractproblems. When she was 4 yr old a clitoral reduction andcorrection of the labia were performed, followed by an in-troitusplasty and vaginoplasty at age 13 and 16, respectively.She visited the hospital three to four times each year, and onthese occasions circulating hormone levels were checked.The results were used to adjust the glucocorticoid dose tokeep androstenedione and 17-hydroxyprogesterone levelswithin in the normal range using as little medication aspossible. Despite this frequent monitoring and frequent doseadjustments, she experienced many problems that can ac-company the treatment of these patients: she did not feelfeminine, had a masculine build, was obese, had irregularmenses with long amenorrhoic periods, and a seborrhoicskin with acne. Her weight was 79 kg, and her height was 168cm, whereas her mother and father measured 174 and 180cm, respectively. She was normotensive (110/70 mm Hg).Using allele-specific PCR (26) it was determined that thepatient was homozygous for a splice-site mutation in intron2, which by itself would have resulted in a very low residualactivity of 21-hydroxylase activity (27). In addition, however,the patient was heterozygous for the five most C-terminalmutations in the protein: V281 L, Ins T, Q318 ter, R356 W, andP453 S. At the age of 29 she used dexamethasone at a dosevarying between 0.5 and 1 mg per day in two divided dosestaken at 0900 and 2100 h and 0.0625 mg/day fludrocortisone.With those treatment regimens serum progesterone and 17-hydroxyprogesterone concentrations remained well abovethe reference levels in our laboratory, whereas serum ACTHlevels were normal. A representative hormonal profile isshown in Table 1. Furthermore, the LH was suppressed,which might contribute to the disturbance of her menstrualcycle (Table 1). A computed tomography scan showed bi-lateral hyperplasia of both the adrenals.Laparoscopic biadrenalectomy was offered as alternativetreatment, with the objective to restore the menstrual cycle,reduce masculinization, and make medical (supplementa-tion) therapy easier and less intensive.Adrenalectomy was performed using a standard laparo-scopic procedure (22–24). The operation and postoperativerecovery were uncomplicated, and discharge from hospitalfollowed after 3 days. Replacement therapy was started with10 mg hydrocortisone three times daily and 0.0625 mgfludrocortisone once daily. Hydrocortisone replacement waslater tapered to 20 mg daily without adverse effects. How-ever, early morning serum ACTH levels turned out to beincreased. Therefore, hydrocortisone replacement therapywas increased to 25 mg/day, after which ACTH levels nor-malized (data not shown). Postoperative laboratory data (Ta-ble 1) revealed that the serum progesterone and 17-hydroxyprogesterone levels had normalized and that LHlevels became measurable again. The procedure resulted inmarked clinical improvement. Within 12 months after sur-gery she had lost 11 kg in weight, her acne had disappeared,and she had a regular 4-week menstrual cycle, with proges-terone levels that are compatible with a luteal phase. Thisstrongly suggests that she ovulated during her menstrualcycles. Subjective improvement was reported in terms ofincreased feeling of well being and femininity. Her physicalactivity and capacity were unaltered, subjectively. Bodycomposition and bone mineral density were assessed bydual-energy x-ray absorptiometry using a Lunar DPX-L den-sitometer (Lunar Corp., Madison, WI) before and after sur-gery (Table 2). The results show that loss of fat completelyaccounted for her weight loss. Lean body mass and bonemineral density did not change.DiscussionHere, we report the excellent clinical effect of bilaterallaparoscopic adrenalectomy in an adult female with classicalCAH. The patient, like many of her fellow patients, hadexperienced virilizing and masculinizing effects from birth toadulthood, despite intensive follow-up and variable doses ofmedical treatment. Recently, laparoscopic adrenalectomyTABLE 1. Laboratory resultsReference values Preoperativea 3 monthspostoperative6 monthspostoperative12 monthspostoperativeFSH (IU/L) 1–7 5.2 8.0 8.9 1.7LH (IU/L) 1–8 ,0.1 2.5 2.3 0.67Progesteroneb (nmol/L) F: 0.5–3 109 0.6 0.9 18Oestradiol (pmol/L) F: 50–400 52 117 85 280L: 200–80017-OH-progesterone (nmol/L) F: 0.5–2 28.6 0.3 0.1 0.1L: 1.5–10Serum ACTH (ng/L) 15–65 11–26 950Medicationmg/day Dexamethasone 0.75mg/day Hydrocortisone 30 30 20mg/day Fludrocortisone 0.0625 0.0625 0.0625 0.0625F, Follicular phase of the menstrual cycle; L, luteal phase of the menstrual cycle.a One hormonal profile is presented preoperatively, which is representative of many measurements over a period of 6 yr under variable dosesof dexamethasone (0.5–1 mg/day).b Serum LH, FSH, progesterone, and oestradiol concentrations measured preoperatively, as well as 3 and 6 months after operation, werenot related to the menstrual cycle, which was abnormal. However, menstrual cycles had normalized 12 months after bilateral adrenalectomy,and the serum gonadotropin and steroid hormone concentrations at that time were drawn on day 24 of the menstrual cycle.CLINICAL CASE SEMINAR 483 at Medical Library Erasmus MC on November 28, 2006 jcem.endojournals.orgDownloaded from was introduced as a new modality for surgical treatment. Theavailability of ample local expertise with this procedure fordifferent indications (24) helped us with the decision to offerour patient bilateral adrenalectomy as the alternative for themedical treatment of the sequelae of her CAH. This proce-dure would completely deprive her of all adrenal steroidhormone precursors and their (masculinizing) effects. Earlierstudies have shown that the hyperplastic adrenal is not help-ful in times of stress. It has been demonstrated that adrenalsteroid precursors promote salt wasting under stress condi-tions in both patients and healthy volunteers (28). On theother hand, clinically beneficial effects of steroid precursorshave recently been reported for dehydroepiandrosterone(DHEA): suppletion of DHEA restored libido in DHEA-deficient women (29, 30). These findings necessitate carefulfollow-up of adrenalectomized women to determine whethersuppletion to physiological dosages of steroid precursors isindicated to further improve their quality of life. Follow-up isalso required because failure of surgical therapy with recur-rence of virilization several years later has been reported (20).Virilization in those patients was driven by either ovarian ste-roidogenesis or hormone production in ectopic adrenal tissue(20, 21). To date, the frequency and clinical importance of thesefailures in adrenalectomized patients have not been deter-mined. Procedure-related complications are impressively lowin experienced hands (23, 24).In our patient, a good short-term result was obtained. Allpreoperative goals were met, without any complications ei-ther related to the procedure or to the hormonal replacementtherapy afterward. This is in line with the data reported onpatients with classic adrenal hyperplasia who were treatedby biadrenalectomy by different techniques or earlier in theirlives (9, 18–21). The introduction of laparoscopic techniquesmay give an impulse to the application of surgical therapyat a larger scale in cases that are difficult to treat with adrenalsuppression therapy.References1. Wedell A, Thilen A, Ritzen EM, Strengler B, Luthman L. 1994 Mutationalspectrum of the steroid 21-hydroxylase gene in Sweden: implications for ge-netic diagnosis and association with disease manifestation. J Clin EndocrinolMetab.78:1145–1152.2. Strachan T. 1994 Molecular pathology of 21-hydroxylase deficiency. J InheritMetab Dis. 17:430–441.3. Miller W. 1994 Clinical review 54: genetics, diagnosis, and management of21-hydroxylase deficiency. J Clin Endocrinol Metab. 78:241–246.4. Urban MD, Lee PA, Urban Migeon CJ. 1978 Adult height and fertility in menwith congenital virilizing adrenal hyperplasia. N Eng J Med. 299:1392–1396.5. Premawardhana LDKE, Hughes IA, Read GF, Scanlon MF. 1997 Longer termoutcome in females with congenital adrenal hyperplasia (CAH): the Cardiffexperience. Clin Endocrinol. 46:327–332.6. Mulaikal RM, Migeon CJ, Rock JA. 1987 Fertility rates in female patients withcongenital adrenal hyperplasia due to 21-hydroxylase deficiency. N EnglJ Med. 316:178–182.7. Wilkins L, Lewis RA, Klein R, Rosemberg E. 1950 The suppression of an-drogen secretion by cortisone in a case of congenital adrenal hyperplasia. BullJohns Hopkins Hosp. 86:249.8. Sandrini R, Jospe N, Migeon CJ. 1993 Temporal and individual variations inthe dose of glucocorticoid used for the treatment of salt-losing congenitalvirilizing adrenal hyperplasia due to 21-hydroxylase deficiency. Acta PaediatrSuppl. 388:56–80.9. Ritzen EM, Wedell A. 1996 Adrenals of patients with severe forms of CAHdo more harm than good. J Clin Endocrinol Metab. 81:3182–3184.10. Pang S, Kenny F, Foley T, Drash A. 1977 Growth and sexual maturation intreated congenital adrenal hyperplasia. In: Lee P, Plotnick L, Kowarski AA,Migeon C, eds. Congenital adrenal hyperplasia. Baltimore: University Press;233–246.11. Helleday J, Siwers B, Ritzen EM, Carlstrom K. 1993 Subnormal androgen andelevated progesterone levels in women treated for congenital virilizing 21-hydroxylase deficiency. J Clin Endocrinol Metab. 76:933–936.12. Knorr D, Hinrichsen de Lienau SCG. 1988 Persistent obesity and short finalheight after corticoid overtreatment for congenital adrenal hyperplasia (CAH)in infancy. Acta Pediatr Jpn. 30:89–92.13. Ja¨a¨skela¨inen J, Voutilainen R. 1996 Bone mineral density in relation to glu-cocorticoid substitution therapy in adult patients with 21-hydroxylase defi-ciency. Clin Endocrinol. 45:707–713.14. Kuhnle U, Bullinger M, Schwarz HP, Knorr D. 1993 Partnership and sexualityin adult female patients with congenital adrenal hyperplasia. First result of across-sectional quality of life evaluation. J Steroid Biochem Mol Biol.45:123–126.15. Klingensmith GJ, Wentz AC, Meyer III WJ, Migeon CJ. 1976 Gonadotropinoutput in congenital adrenal hyperplasia: effects in congenital hyperplasiabefore and after adrenal suppression. J Clin Endocrinol Metab. 43:993–996.16. Klingensmith GJ, Garcia SC, Jones Jr HW, Migeon CJ, Blizzard RM. 1977Glucocorticoid treatment of girls with congenital adrenal hyperplasia: effect onheight, sexual maturation and fertility. J Pediatr. 90:966–1004.17. Holmes-Walker DJ, Conway GS, Honour JW, Rumsby G, Jacobs HS. 1995Menstrual disturbance and hypersecretion of progesterone in women withcongenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endo-crinol (Oxf). 43:291–296.18. 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Guazzoni G, Montorsi F, Bergamaschi F, et al. 1994 Effectiveness and safetyof laparoscopic adrenalectomy. J Urol. 152:1375–1378.24. Bonjer HJ, Lange JF, Kazemier G, de Herder WW, Steyerberg EW, BruiningHA. 1997 Comparison of three techniques for adrenalectomy. Br J Surg.84:679–682.25. Wells SA, Merke DP, Cutler Jr GB, Norton JA, Lacroix A. 1998 Therapeuticcontroversy: the role of laparoscopic surgery in adrenal disease. J Clin Endo-crinol Metab. 83:3041–3049.26. Wilson RC, Wei JQ, Cheng KC, Mercado AB, New MI. 1995 Rapid DNAanalysis by allele-specific PCR for detection of mutations in the steroid 21-hydroxylase gene. J Clin Endocrinol Metab. 80:1635–1640.27. Nikoshkov A, Lajic S, Holst M, Wedell A, Luthman H. 1997 Synergistic effectof partially inactivating mutations in steroid 21-hydroxylase deficiency. J ClinEndocrinol Metab. 82:194–199.28. Janowski A. 1977 Naturally occurring adrenal steroids with salt losing prop-erties: relationship to congenital adrenal hyperplasia. In: Lee P, Plotnick L,Kowarski AA, Migeon C, eds. Congenital adrenal hyperplasia. Baltimore:University Press; 99–112.29. Arlt W, Callies F, Christoph van Vlijmen J, et al. 1999 Dehydroepiandros-terone replacement in women with adrenal insufficiency. N Engl J Med.341:1013–1020.30. Oelkers W. 1999 Dehydroepiandrosterone for adrenal insufficiency. N EnglJ Med. 341:1073–1074.TABLE 2. Body composition measured by dual emission x-rayabsorptiometryPreoperative 6 monthspostoperative12 monthspostoperativeFat mass (kg) 31.8 (41%) 24.1 (35%) 21.0 (31%)Lean body mass (kg) 43.8 44.0 43.0Bone mineral content(g/cm2)1.21 1.19 1.19Z-score (SD) 0.4 0.6 0.7Total body mass (kg) 79 71 68484 BRUINING ET AL. JCE & M † 2001Vol. 86 † No. 2 at Medical Library Erasmus MC on November 28, 2006 jcem.endojournals.orgDownloaded from 

Fertility and body composition after laparoscopic bilateral adrenalectomy in a 30-year-old female with congenital adrenal hyperplasia

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