21-HYDROXYLASE DEFICIENT NON- CLASSIC ADRENAL HYPERPLASIA: SCREENING, DIAGNOSIS AND TREATMENT Ricardo Azziz, M.D., M.P.H., M.B.A.

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1 C O N F E R E N C I A S X I I I C O N G R E S O J U E V E S 6 D E N O V I E M B R E D E HYDROXYLASE DEFICIENT NON- CLASSIC ADRENAL HYPERPLASIA: SCREENING, DIAGNOSIS AND TREATMENT Ricardo Azziz, M.D., M.P.H., M.B.A. Dept. of Obstetrics and gynecology, Cedars-Sinai Medical Center, and Depts. of Obstetrics and Gynecology, and medicine, The David Geffen School of Medicine at UCLA, Los Angeles, CA This work was supported by research grants RO1-HD (RA). Prevalence of NCAH Twenty-one hydroxylase (21-OH) deficient nonclassic adrenal hyperplasias (NCAH) is one of the most common genetic disorders known to man. This autosomal recessive disorder results in a defect in adrenocortical 21-OH enzyme function. NCAH affects one of every 1000 to 2000 non-jewish White individuals 1, and between 1% and 10% of hyperandrogenic women, depending on the ethnicity of the population studied In the United States others and we have observed an NCAH prevalence of 1% to 2% among populations of White and Hispanic hyperandrogenic patients 2-5. In contrast, studies in France, Italy and Canada yield frequencies of 4% to 6% 6-8, and other studies originating in Israel, India and Jordan demonstrate prevalences of 6% to 10% In contrast, NCAH due to defects of 11β-hydroxylase and 3βhydroxysteroid dehydrogenase are extremely strange, if existent at all, particularly in patients presenting with postpubertal hyperandrogenism 2, Genetics of NCAH NCAH is a homozygous recessive disorder due to the mutation of CYP21, the gene encoding for the enzyme P450c21. In turn, P450c21 is located exclusively in the zona fasciculata of the adrenal cortex, and demonstrates 21-OH activity, converting 17-HP to 11-deoxycortisol and P4 to deoxycorticosterone 16. The gene encoding for P450c21 (i.e. CYP21) exists in tandem with a pseudogene (i.e. CYP21P). Each gene has 10 exons and 9 introns, although CYP21P has many mutations that render it non-transcribable. These genes are located within the HLA locus on chromosome 6 next to the gene for the fourth component of complement (C4) and a gene for the extracellular matrix protein tenacin-x 17. There are multiple mutations reported to result in NCAH, some defined as "mild" mutations (preserving about 20% of native 21-OH activity) and others as "severe" (preserving 0% to 5% of native 21-OH activity). Most of these mutations are similar to the sequences found in a proximate pseudogene (CYP21P), suggesting that the mechanism for acquiring the mutations is gene conversion. Clinically evident NCAH may result from mild/mild (e.g. V281L/V281L) or from mild/severe allele combinations, the so-called "compound heterozygotes" (e.g. V281L/I172N). We should note that there is a loose association between the severity of the clinical presentation and the severity of the CYP21 mutations carried 18. Because of the autosomal recessive nature of NCAH, the incidence of this disorder among family members is actually lower than that observed among other hyperandrogenic patients, e.g. PCOS patients. For example, full sisters will have a 25% chance of being affected, while few mothers are actually homozygous and clinically affected. This contrasts to our finding that in PCOS approximately 35% of mothers and 40% of sisters of PCOS patients are affected by the disorder 19. Diagnosis of NCAH NCAH results in hyperandrogenic symptoms some time after birth, in contrast to the symptoms of classic adrenal hyperplasia (CAH) that are apparent at or near birth. The endocrine diagnosis of 21-OH deficient NCAH is performed by a basal or acute

2 10 XIII CONGRESO DE SAEM RAEM 2003 Vol 40 No. Supl. ACTH-stimulated 17-hydroxyprogesterone (17-HP) level >10 ng/ml (30.3 nmol/l) 20,21. The diagnosis can be confirmed by genotyping, although it should be noted that not all mutations can be readily identified, either because they are new and unknown, or because they are extremely rare and not generally included in screening assays 18,22. Clinical presentation: Comparison to PCOS Overall, it is generally difficult to distinguish NCAH from PCOS solely on clinical grounds, as both disorders demonstrate varying degrees of hyperandrogenism and ovulatory dysfunction 23. We recently studied 905 consecutive untreated hyperandrogenic patients diagnosed between 1987 and 2001 at the University of Alabama at Birmingham, including 654 patients with endocrinologically diagnosed PCOS and 17 with 21-OH deficient NCAH 24. Thirteen of the NCAH were non-related probands, while four of the patients were sisters of four separate probands. Although the significant discordance in number of subjects reduces the validity of a direct statistical comparison between the two patient populations, we should note that PCOS and NCAH patients had similar mean ages, body mass indices, waist hip ratio, hirsutism score, and prevalence of acne (Table 1). All patients with PCOS, by definition had ovulatory dysfunction. Likewise the majority of NCAH patients in this study had ovulatory dysfunction. This is consistent with the observation by other investigators that not all patients with NCAH have oligo-ovulation 25. In the present study, all patients with NCAH were White while 13% of our PCOS population was non- White, primarily Black, consistent with our referral population (Table 1). The paucity of NCAH among Black patients is not surprising, as this racial trend was also observed in a large international multicenter study 21, and is in agreement with the low prevalence CAH among Black subjects 1. Polycystic ovaries are observed by ultrasonography in about 75% of patients with PCOS 26. Likewise about 40% of patients with NCAH demonstrate this clinical feature 23,25, consistent with the fact that "polycystic ovaries" can be observed in a variety of patients with ovulatory disorders. In conclusion, both PCOS and 21-OH deficient Table 1. Comparison of the clinical features of patients with the polycystic ovary syndrome (PCOS) and 21-hydroxylase deficient non-classic adrenal hyperplasia (NCAH) diagnosed among 905 consecutive untreated hyperandrogenic patients seen at the University of Alabama at Birmingham, Features PCOS (n=654) NCAH (n=17) P value Age (yrs) 27.1± ±10.9 N S Race (% non-white) p<0.05 Ovulatory dysfunctiona 654/654 15/16 NS BMI (kg/m2) 33.2± ±6.5 N S W H R 0.84± ±0.07 N S Acne (%) 92/654 (14.1%) 3/17 (17.6%) N S F-G score 8.1± ±3.8 N S Total T (nmol/l) 3.14± ±2.28 N S Free T (nmol/l) 0.03± ±0.02 N S DHEAS (mmol/l) 6.42± ±4.75 p<0.05 SHBG (nmol/l) 182.2± ±162.7 p<0.05 Abbreviations: BMI is body mass index, F-G score is modified Ferriman-Gallwey hirsutism score, T is testosterone, DHEAS is dehydroepiandrosterone sulfate, SHBG is sex hormone binding globulin a All PCOS patients had ovulatory dysfunction by definition; one eumenorrheic NCAH patient was excluded,

3 CONFERENCIAS 11 NCAH present with similar phenotypes, making it virtually impossible to distinguish between the two disorders solely on clinical grounds. We should note that a relatively unique clinical feature of NCAH is the presence of minimal clitoromegaly, which is in sharp contradistinction to the otherwise relatively mild androgenic symptoms, observable in some children with the disorder 21. Clinical presentation: Biochemical profile An exaggerated luteinizing hormone (LH) to folliclestimulating hormone (FSH) ratio has been a recognized finding in PCOS. However, women with NCAH may have also mildly elevated levels of LH, either basally or in response to GnRH stimulation, although generally to a lesser degree than patients with PCOS 25,27. Mean serum measurements of total and free testosterone (T) also do not differ significantly between patients with PCOS and those with NCAH, either in our study (Table 1) or in the experience of others 6,25. While some investigators have noted that the mean dehydroepiandrosterone sulfate (DHEAS) levels of NCAH patients is similar to that of other hyperandrogenic women 25, we actually observed a lower mean DHEAS level among patients with NCAH compared to women with well-defined PCOS (Table 1). Others have also observed that DHEAS level in NCAH patients are similar to that of controls, and lower than that of patients with PCOS 6. That a commonly used marker of adrenal androgen excess should be similar or even lower than that of PCOS women is not entirely unexpected. Firstly, about 25-50% of PCOS women have frankly supranormal DHEAS levels 26,28. Secondly, adrenocortical enzyme kinetics primarily favors the production of cortisol, such that little of excess 17-HP produced in NCAH is actually back-converted to 17-hydroxypregnenolone and then to dehydroepiandrosterone and its metabolite DHEAS. We observed a similar finding when studying other markers of adrenocortical androgen secretion, including 11β-hydroxyandrostenedione 29. Finally, although Δ 4 -androstenedione (A4) levels are frequently supranormal in patients with NCAH 30, the overlap between women with NCAH and other hyperandrogenic patients is significant 6. This not unexpected, considering the relatively little Δ 4 17,20- lyase activity that human P450c17α demonstrates 31 which effectively preventing the direct conversion of the excess 17-HP to A4. Screening for NCAH An important biochemical marker of NCAH is the presence of supranormal levels of the immediate 17- hydroxylated precursor to P450c17α, 17-HP. In a prospective study in 266 hyperandrogenic women, we observed that 15.4% had one time 17-HP levels > 6.0 nmol/l (2 ng/ml) 20. Of these about 60% had a repeat 17-HP that was below this value, while in another 30% the acute ACTH stimulation test was normal 20. The remaining patients had NCAH diagnosed upon the performance of their ACTH stimulation test. Hence, 10-15% of patients with a basal level of 17-HP above 6.0 nmol/l (2 ng/ml) will eventually prove to have NCAH 20, while practically 100% of hyperandrogenic women with a basal 17-HP below this cutoff will not have the disorder 5. It should be noted that about 10% of patients with NCAH will not have a basal 17-HP level above 6.0 nmol/l; and that the level of this steroid will be decreased in the evening, as it follows the adrenocortical circadian rhythm, and will be spuriously increased in the follicular phase to levels greater than 6.0 nmol/l in about 50% of ovulatory controls 20. Hence, to use a basal 17-HP to screen for NCAH, it is necessary to preferable to obtain this measurement in the morning, and shortly after the completion of a spontaneous or induced-vaginal bleed. In conclusion, a higher mean basal follicular phase 17-HP level serves as a useful screening marker for NCAH. About 90% of NCAH patients have a basal 17-HP > 6.0. nmol/l, which is observable in only about 15% of PCOS. Mechanisms of Adrenocortical Excess in NCAH An understanding of the mechanisms underlying the excessive secretion of androgens and progestogens by the adrenal cortex of patients with NCAH is important to appropriately understand and design therapeutic regimens. Firstly, over-activation of the hypothalamic-pituitary-adrenal (HPA) axis and an increased ACTH secretion appears to be an important mechanism resulting in steroid excess in untreated patients, at least in the classic forms of the disorder. However, most NCAH patients do not demonstrate over-activity of the HPA axis. Nonetheless, a few of these patients may demonstrate a mild degree of ACTH hyper-responsiveness to CRH stimulation, and up to 40% have radiologic evidence of adrenocortical hyperplasia and/or isolated adenomas, suggesting

4 12 XIII CONGRESO DE SAEM RAEM 2003 Vol 40 No. Supl. that some degree of chronic ACTH excess is present. Another mechanism resulting in adrenocortical excess in adrenal hyperplasia, and primarily NCAH, results from altered enzyme kinetics in the abnormal 21-OH. The mutated enzyme product is less efficient than the wild type, resulting in an increased precursor to product ratio, independent of ACTH levels. Hence progesterone (P4) and 17-HP levels in these patients may remain above normal even in the presence of excess glucocorticoid administration 31. Finally, alterations in ovarian and gonadotropic function, with the appearance of a polycystic ovary syndrome-like picture, also contribute to the androgen excess of these patients. Functional ovarian abnormalities in patients with the classic and non-classic forms of adrenal hyperplasia may be secomdary to a number of differences mechanisms, including prenatal masculinization of the hypothalamic-pituitary-ovarian (HPO) axis by adrenal androgens; continued disruption of the HPO axis by persistently elevated progesterone or androgen levels; and/or to a direct glucocorticoid effect. Finally, these data would suggest that the measurement of P4 or 17-HP may not be the most accurate marker of therapeutic efficacy, and suppression of both ovaries and adrenals may be necessary for optimum steroidogenic control. Treatment of NCAH Little is known regarding the long-term outcome and optimum treatment of patients with NCAH. As in other androgen excess disorders, therapy should be tailored to patient goals and presenting findings. Contrary to CAH, glucocorticoid administration is only one of the available therapies for the treatment of NCAH that should be considered. Our experience indicates that younger patients (usually < 20 years old) clinically respond well to lower doses of glucocorticoids, while older patients newly diagnosed with the disorder generally fail to respond fully to this therapy. When using glucocorticoids we prefer to use oral dexamethasone (DEX), to improve compliance, although the use of prednisone is certainly an acceptable option. We begin at a dose of DEX 0.5 mg/day for the first days, and then decrease the dose to 0.25 mg/day or 0.5 mg qod, according to patient preference. In the long-term we titrate the dose according to the improvement in clinical features and hormonal profile. Rarely, we encounter patients who require doses of DEX of 0.5 to 0.75 mg/day, although frequently these patients develop Cushingoid features. Adrenocortical suppression generally improves hirsutism, acne, alopecia, and oligo-ovulation, and the final height of affected children. It is a matter of debate whether patients with NCAH are at risk for adrenal insufficiency. Although we have never observed either acute or chronic hypocortisolism in our patients, and many of them have undergone surgery or pregnancy deliveries without having required glucocorticoid supplementation, this possibility cannot be discarded. Therefore, we inform patients of this theoretical risk, and counsel them and their families regarding the presenting symptoms of adrenal insufficiency, particularly in the event of trauma, accidents or surgery. To monitor the adequacy of treatment, we measure the circulating androstenedione (A4) and free testosterone levels at three and six months of therapy, and yearly thereafter, aiming to maintain these levels are or slightly above the upper normal limit. Alternatively, physicians should not aim to normalize the morning 17-HP circulating levels, since adrenal androgens are more sensitive to the suppressive effects of glucocorticoid administration than are C-21 steroids. As noted above, the 17-HP level may remain elevated in spite of adequate androgen and ACTH suppression 32. Alternatively, DHEAS is very sensitive to glucocorticoid administration, and is rapidly and dramatically suppressed, even when the level of other androgens (e.g. A4) remains elevated. While we have found that the A4 levels represent an adequate marker for monitoring therapy, it extremely important to keep in mind that these measures simply serve as a guideline and that clinical response is of greater value in determining the adequacy of therapy. In fact, androgen measures are primarily useful when clinical improvement is not evident, suggesting the possibility of persistent hyperandrogenemia (see below). The principal marker for monitoring the adequacy of therapy is the improvement in clinical features. Acne improves relatively quickly in these patients. Alternatively, glucocorticoid suppression alone has a limited impact on established hirsutism in NCAH, similar to the response seen to oral contraceptives (OCPs) in patients with PCOS. In a randomized study, Spritzer and colleagues observed that treatment with the anti-androgen cyproterone acetate and percutaneous estradiol elicited a more rapid and sustained

5 CONFERENCIAS 13 improvement of hirsutism, than hydrocortisone alone, despite increased levels of androgens 33. Our experience confirms this report, and we currently recommend the combination of an anti-androgen (generally spironolactone mg/day) and an OCP, with or without DEX, for the treatment of hirsutism associated with NCAH. Anecdotally over 50% of patients with NCAH, particularly those whose disorder has remained untreated beyond the age of 20 years, may develop a PCOS-like picture. In these women glucocorticoid administration alone may not be sufficient to normalize ovulatory function. Furthermore, these patients may remain somewhat hyperandrogenic, due to excessive ovarian androgen secretion. If after six months of adequate DEX administration (at no more than 0.75 mg/day) NCAH patients remain hyperandrogenic, they may benefit from the addition of an oral contraceptive pill. Likewise if fertility is an issue and ovulatory function is not regulated by glucocorticoid alone, we will proceed to initiate clomiphene citrate or human menopausal gonadotropin (hmg) therapy. The principal cause of the reduced fertility in patients with NCAH is probably ovulatory dysfunction, secondary to hyperandrogenism. However, chronic elevations in circulating P4 and 17-HP levels may also result in an inadequate cervical mucus, and/or a persistently atrophic endometrium. Nonetheless, while NCAH patients may be subfertile, it should be stressed that many of these women become pregnant without requiring treatment 34, and often prior to diagnosis. Assuming that other infertility factors have been ruled out, we first initiate glucocorticoid therapy to improve ovulatory function. If the patient fails to demonstrate adequate or satisfactory ovulation after four months of adrenocortical suppression, we then proceed to ovulation induction with clomiphene citrate, and hmg if necessary. As noted previously, it is possible that long-term chronic hyperandrogenemia results in the disruption of the HPO axis and the development of a PCOS-like phenotype. Overall prognosis for fertility in oligo-ovulatory NCAH patients is good, and should not be any different from that of other hyperandrogenic women seeking ovulation induction. Bibliografía 1. Speiser, P.W.; Dupont, B.; Rubinstein, P.; Piazza, A.; Kastelan, A.; New, M.I. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 1985;37: Azziz, R.; Boots, L.R.; Parker Jr., C.R.; Bradley Jr., E.; Zacur, H.A. 11β-hydroxylase deficiency in hyperandrogenism. Fertil Steril 1991;55: Romaguera, J.; Moran, C.; Diaz-Montes, T.P.; Hines, G.A.; Cruz, R.I.; Azziz, R. Prevalence of 21- hydroxylase-deficient nonclassic adrenal hyperplasia and insulin resistance among hirsute women from Puerto Rico. Fertil Steril 2000;74: Chetkowski, R.J.; DeFazio, J.; Shamonki, I.; Judd, H.L.; Chang, R.J. The incidence of late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency among hirsute women. J Clin Endocrinol Metab 1984;58: Azziz, R.; Zacur, H.A. 21-Hydroxylase deficiency in female hyperandrogenism: screening and diagnosis. J Clin Endocrinol Metab 1989;69: Kuttenn, F.; Couillin, P.; Girard, F.; Billaud, L.; Vincens, M.; Boucekkine, C. et al. Late-onset adrenal hyperplasia in hirsutism. N Engl J Med 1985;313: Motta, P.; Catania, A.; Airaghi, L.; Mangone, I.; Cantalamessa, L.; Zanussi, C. Prevalence of lateonset adrenal hyperplasia in postmenarchal hirsutism. J Endocrinol Invest 1988;11: Innanen, V.T.; Vale, J.M. Assessment of the one hour adrenocorticotrophic hormone test in the diagnosis of attenuated 21-hydroxylase deficiency. J Clin Pathol 1990;43: Mithal, A.; Ammini, A.C.; Godbole, M.M.; Khurana, M.L.; Raj, D.; Karmarkar, M.G. et al. Late-onset adrenal hyperplasia in north Indian hirsute women. Horm Res 1988;30: Eldar-Geva, T.; Hurwitz, A.; Vecsei, P.; Palti, Z.; Milwidsky, A.; Roslër, A. Secondary biosynthetic defects in women with late-onset congenital adrenal hyperplasia. N Engl J Med 1990;323: Khandekar, S.; Lata, V.; Dash, R.J. Screening for late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Indian J Med Res 1990;92:79-82.

6 14 XIII CONGRESO DE SAEM RAEM 2003 Vol 40 No. Supl. 12. Arnaout, M.A. Late-onset congenital adrenal hyperplasia in women with hirsutism. Eur J Clin Invest 1992;22: Azziz, R.; Bradley Jr., E.L.; Potter, H.D.; Boots, L.R. 3β-Hydroxysteroid dehydrogenase deficiency in hyperandrogenism. Am J Obstet Gynecol 1993; 168: Joehrer, K.; Geley, S.; Strasser-Wozak, E.M.C.; Azziz, R.; Wollmann, H.A.; Schmitt, K. et al. CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11β-hydroxylase deficiency. Hum Mol Genet 1997;6: Moran, C.; Potter, H.D.; Reyna, R.; Boots, L.R.; Azziz, R. Prevalence of 3β-hydroxysteroid dehydrogenase deficient nonclassic adrenal hyperplasia in hyperandrogenic women with adrenal androgen excess. Am J Obstet Gynecol 1999;181: Miller, W.L. Molecular biology of steroid hormone synthesis. Endocr Rev 1988;9: Miller, W.L. Genetics, diagnosis and management of 21-hydroxylase deficiency. J Clin Endocrinol Metab 1994;78: Speiser, P.W.; Knochenhauer, E.S.; Dewailly, D.; Fruzzetti, F.; Marcondes, J.A.M.; Azziz, R. A. multicenter study of women with nonclassical congenital adrenal hyperplasia: relationship between genotype and phenotype. Mol Genet Metab 2000;71: Kahsar-Miller, M.D.; Nixon, C.; Boots, L.R.; Go, R.C.; Azziz, R. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil Steril 2001;75: Azziz, R.; Hincapie, L.A.; Knochenhauer, E.S.; Dewailly, D.; Fox, L.; Boots, L.R. Screening for 21-hydroxylase deficient non-classic adrenal hyperplasia among hyperandrogenic women: a prospective study. Fertil Steril 1999;72: Moran, C.; Azziz, R.; Carmina, E.; Dewailly, D.; Fruzzetti, F.; Ibañez, L. et al. 21-Hydroxylasedeficient nonclassic adrenal hyperplasia is a progressive disorder. Am J Obstet Gynecol 2000;183: Bachega, T.A.S.S.; Billerbeck, A.E.C.; Marcondes, J.A.M.; Madureira, G.; Arnhold, I.J.P.; Mendonça, B.B. Influence of different genotypes on 17- hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21- hydroxylase deficiency. Clin Endocrinol (Oxf) 2000; 52: Azziz, R.; Dewailly, D.; Owerbach, D. Nonclassic adrenal hyperplasia: current concepts. J Clin Endocrinol Metab 1994;78: Moran, C.; Azziz, R. 21-Hydroxylase deficient nonclassic adrenal hyperplasia: the great pretender. Sem Reprod Med (in press). 25. Dewailly, D.; Vantyghem-Haudiquet, M.C.; Sainsard, C.; Buvat, J.; Cappoen, J.P.; Ardaens, K. et al. Clinical and biological phenotypes in late-onset 21 hydroxylase deficiency. J Clin Endocrinol Metab 1986;63: Carmina, E.; Koyama, T.; Chang, L.; Stanczyk, F.Z.; Lobo, R.A. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 1992;167: Levin, J.H.; Carmina, E.; Lobo, R.A. Is the inappropriate gonadotropin secretion of patients with the polycystic ovary syndrome similar to that of patients with adult-onset congenital adrenal hyperplasia? Fertil Steril 1991;56: Moran, C.; Knochenhauer, E.; Boots, L.R.; Azziz, R. Adrenal androgen excess in hyperandrogenism: relation to age and body mass. Fertil Steril 1999;71: Huerta, R.; Dewailly, D.; Decanter, C.; Knochenhauer, E.S.; Boots, L.R.; Azziz, R. 11β- Hydroxyandrostenedione and Δ 5 -androstenediol as markers of adrenal androgen production in patients with 21-hydroxylase deficient nonclassic adrenal hyperplasia. Fertil Steril 1999;72: New, M.I.; Lorenzen, F.; Lerner, A.J.; Kohn, B.; Oberfield, S.E.; Pollack, M.S. et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab. 1983;57: Auchus, R.J.; Lee, T.C.; Miller, W.L. Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. J Biol Chem 1998;273: Sánchez, L.A.; Morán, C.; Reyna, R.; Ochoa, T.; Boots, L.R.; Azziz, R. Adrenal progestogen and androgen production in 21-hydroxylase deficient non-classic adrenal hyperplasia is partially independent of ACTH stimulation. Fertil Steril 2002; 77: Spritzer, P.; Billaud, L.; Thalabard, J.C.; Birman, P.; Mowszowicz, I.; Raux-Demay, M.C.; Clair, F.; Kuttenn, F.; Mauvais-Jarvis, P. Cyproterone acetate

7 CONFERENCIAS 15 versus hydrocortisone treatment in late-onset adrenal hyperplasia. J Clin Endocrinol Metab. 1990; 70: Feldman, S.; Billaud, L.; Thalabard, J.C.; Raux- Demay, M.C.; Mowszowicz, I.; Kuttenn, F.; Mauvais-Jarvis, P. Fertility in women with lateonset adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1992; 74: GRAVES OPHTHALMOPATHY Armin E. Heufelder Division of Endocrinology, The Eliscourt Clinical Center and Medical Faculty, Technical University of Munich, Germany Graves ophthalmopathy (GO) results from a complex interplay of genetic, immunological, hormonal and environmental factors. Various genes, including those coding for HLA, may determine a patient s susceptibility to the disease and its severity, but in addition, environmental factors such as stress and smoking may determine its course. Once established, the inflammatory process within the orbital tissues takes on a momentum of its own. Based on the current state of knowledge, the following working scheme for the pathogenesis of GO is proposed: Against the background of a permissive immunogenetic milieu, macrophages and dendritic cells appear to initiate the immune process in a nonspecific manner by reacting to an environmental (e.g. microbial) insult. These cells can efficiently take up antigen, travel to regional lymphoid tissues and present antigenic peptides to T cells, thereby sensitizing T and B cells to proliferate, to expand in an antigen-specific manner, and to recirculate, ready to release abundant quantities of chemokines (RANTES) and proinflammatory cytokines (IL-1, TNFalpha, IFNgamma). These compounds facilitate upregulation of various adhesion- and co-stimulatory molecules, which act to prepare the orbital microvascular endothelium for recruitment and efflux of circulating T cells that carry a restricted repertoire of V genes and have been primed to cross-react between intrathyroidal and orbital antigenic epitopes. Infiltration of T cells into orbital connective tissue and extraocular muscle is perpetuated by preadipocytes and fibroblasts, which act as target and effector cells of the orbital immune process. This includes preadipocyte fibroblasts present in the perimysium of extraocular muscles, which do not appear to be immunologically or metabolically different from those located in the orbital connective tissue. Differentiation of preadipocytes into adipocytes is mediated, at least in part, by nuclear transcription factors (PPARs, NFκB) and accompanied by increased expression of the TSH receptor, which appears to facilitate the orbital immune process and its consequences, stimulation of adipogenesis and accumulation of hydrophilic glycosaminoglycans (GAG). Both endogenous (high TSH receptor antibodies) and exogenous factors (e.g. smoking) may act as amplifiers in this process. Once adipogenesis and GAG deposition have exceeded a critical stage, mechanical complications may occur within the confines of the bony orbits, resulting in impairment of arterial blood supply and venous drainage, tissue hypoxia, oxidative tissue injury, extraocular muscle dysfunction and optic nerve compromize. Unless relieved early and efficiently by spontaneous autodecompression or therapeutic interventions such as immunomodulatory measures or surgical decompression, permanent tissue changes will ensue, causing restriction of extraocular muscles, connective tissue fibrosis and optic nerve damage. Clinically, close follow-up in all patients with Graves disease and early recognition of GO are mandatory. Much emphasis should be placed on preventing GO by early identification of patients with Graves disease who are at high risk of GO. Once active progressive GO has been documented, conventional therapy (oral or intravenous glucocorticosteroids, surgical decompression of the orbits, radiotherapy) should be administered early on to arrest orbital inflammation in its earliest stages before irreversible changes have occurred. Novel therapeutic approaches such as long-acting octreotide, antioxidants, methotrexate, biologicals or B-cell directed strategies are now under study to assess their role in the treatment of GO.