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Premature Ovarian Failure in Patients with Autoimmune Addison’s Disease: Clinical, Genetic, and Immunological Evaluation

G. Reato, L. Morlin, S. Chen, J. Furmaniak, B. Rees Smith, S. Masiero, M. P. Albergoni, S. Cervato, R. Zanchetta, and C. Betterle

Endocrine Unit (G.R., L.M., S.M., S.Ce., R.Z., C.B.), Department of Medical and Surgical Sciences, Downloaded from https://academic.oup.com/jcem/article/96/8/E1255/2833719 by guest on 25 September 2021 University of Padova, I-35128 Padova, Italy; FIRS Laboratories RSR Ltd. (S.Ch., J.F., B.R.S.), Cardiff CF14 5DU, United Kingdom; and Blood Transfusion Service (M.P.A.), Azienda Ospedaliera-Universitaria di Padova, 35122 Padova, Italy

Design: The design of the study was to investigate the prevalence of the following: 1) premature ovarian failure (POF) in patients with autoimmune Addison’s disease (AD); 2) steroid-producing cell antibodies (StCA) and steroidogenic enzymes (17␣-hydroxylase autoantibodies and P450 side- chain cleavage enzyme autoantibodies) in patients with or without POF; and 3) the value of these autoantibodies to predict POF.

Patients: The study included 258 women: 163 with autoimmune polyendocrine syndrome type 2 (APS-2), 49 with APS-1, 18 with APS-4, and 28 with isolated AD.

Methods: StCA were measured by an immunofluorescence technique and 17␣-hydroxylase auto- antibodies and P450 side-chain cleavage enzyme autoantibodies by immunoprecipitation assays.

Results: Fifty-two of 258 women with AD (20.2%) had POF. POF was diagnosed in 20 of 49 (40.8%) with APS-1, six of 18 (33.3%) with APS-4, 26 of 163 (16%) with APS-2, and none of 28 with isolated AD. In patients with APS-1 and APS-4, POF developed after AD, whereas it preceded AD in patients with APS-2. StCA were detected in 31 of 43 with POF (72%) and 51 of 198 without POF (25.7%). StCA were present in 22 of 38 with APS-1 (57.9%) (11 of 13 with POF); in five of 13 with APS-4 (38.5%) (three of four with POF); in 53 of 162 with APS-2 (32.7%) (17 of 26 with POF), and in one of 28 isolated AD patients (3.6%). Twelve of 13 patients with POF with a duration less than 5 yr (92.3%) and 18 of 25 with duration longer than 5 yr (72%) were StCA positive. Twenty-eight of 31 with POF (90.3%) were positive for at least one steroidogenic antibody. Forty-one women with AD less than 40 yr were fol- lowed up for a mean period of 9 yr. Eight of 21 women (38%) positive or seroconverted for steroid- ogenic autoantibodies developed POF at a mean age of 23 yr (six with APS-1, one with APS-2, and one with APS-4), and none of the 20 patients negative for steroidogenic autoantibodies developed POF.

Conclusions: This study indicates that AD is frequently associated with POF and that steroidogenic antibodies are markers of patients with POF. Steroidogenic autoantibodies are predictive markers of POF in patients with AD. (J Clin Endocrinol Metab 96: E1255–E1261, 2011)

ddison’s disease (AD) is a relatively rare condition 100,000 women), but only 5% of cases are of an autoim- A that affects 6–14 persons per 100,000 population, mune origin (3, 4). and autoimmunity is responsible for approximately 80% POF is defined as for at least 4 months in of cases in the developed world (1, 2). Premature ovarian women before the age of 40 yr, in association with hyper- failure (POF) is more prevalent than AD (1,000 per gonadotropin with no prior history of sur-

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: ACA, Adrenal cortex autoantibodies; AD, Addison’s disease; APS, autoim- Printed in U.S.A. mune polyendocrine syndrome; HLA, human leukocyte antigen; IF, immunofluorescence; Copyright © 2011 by The Endocrine Society IPA, immunoprecipitation assay; 17␣-OH, 17␣-hydroxylase; 17␣-OHAb, 17␣-OH autoan- doi: 10.1210/jc.2011-0414 Received February 15, 2011. Accepted May 25, 2011. tibodies; 21-OHAb, 21-hydroxylase autoantibodies; P450scc, P450 side-chain cleavage First Published Online June 15, 2011 enzyme; P450sccAb, vP450scc autoantibodies; POF, premature ovarian failure; StCA, ste- roid-producing cell autoantibodies.

J Clin Endocrinol Metab, August 2011, 96(8):E1255–E1261 jcem.endojournals.org E1255 E1256 Reato et al. Premature Ovarian Failure in Addison’s Disease J Clin Endocrinol Metab, August 2011, 96(8):E1255–E1261 gery, irradiation, or medication that could have had an patients to APS-1 group when AD was associated with chronic effect on ovarian function (4). Autoimmune POF may be candidiasis and/or chronic , APS-2 when associated with AD or other autoimmune diseases, or it AD was associated with autoimmune diseases and/or type 1 mellitus, APS-4 when AD was associated with any may be isolated (3). other autoimmune diseases excluding the previous associations, Antibodies to steroid-producing cells (StCA) are found and isolated AD when other autoimmune diseases were absent. by immunofluorescence (IF) tests (5) in the majority of One hundred sixty-three women had APS-2, 49 had APS-1, 18 patients with AD and POF (6–9). In contrast, patients had APS-4, and 28 had isolated AD. POF was diagnosed using with isolated POF or POF associated with other autoim- the criteria proposed by Nelson (4). Specifically, POF was diagnosed when the patients had an mune diseases (excluding AD) are rarely StCA positive or hypergonadotropic amenorrhea with serum LH and FSH con- if positive are generally diagnosed with subclinical or po- centrations greater than 15 U/liter and estradiol less than 150 tential AD (10, 11). Furthermore, there is a close correla- pmol/liter on two occasions below the age of 40 yr. Downloaded from https://academic.oup.com/jcem/article/96/8/E1255/2833719 by guest on 25 September 2021 tion between the presence of StCA and a lymphocytic in- Forty-one patients with AD (StCA positive or negative) with- filtration of the ovarian tissue (12). out POF were followed up to assess the risk of developing POF In patients with autoimmune AD who do not have (10 patients under 12 yr and 31 aged between 12 and 39 yr of age at the start of follow-up). POF, StCA positivity was found to be helpful in the The study was approved by the local ethics committee, and all the prediction of development of POF, however, only in patients gave signed written informed consent to the study; the study patients with autoimmune polyendocrine syndrome was performed according to the Helsinki Declaration. (APS) type 1 (13, 14). The main gonadal autoantigens recognized by StCA in Measurements patients with POF associated with AD are steroid 17␣- StCA were measured in 241 women with AD (44 with POF hydroxylase (17␣-OH) and cytochrome P450 side-chain and 197 without POF) using the IF technique on unfixed cryo- static sections of normal human tissue from and cleavage enzyme (P450scc) (15). Measurement of auto- testis, as described elsewhere (9). antibodies to 17␣-hydroxylase (17␣-OHAb) and to 17␣-OHAb and P450sccAb were measured in 159 women P450scc (P450sccAb) by immunoprecipitation assays with AD (31 with and 128 without POF) by IPA using recom- (IPA) (16) in different patient groups confirmed that binant antigens labeled with 35S-methionine as reported previ- 17␣-OH and P450scc are the main targets of StCA in pa- ously (16). tients with POF and AD (9, 10, 11). Genetic evaluation We have studied the prevalence of POF in a cohort of HLA-DRB1 typing was carried out in 29 AD patients diag- Italian females with AD referred to our clinic from 1971 nosed with POF by the PCR sequence-specific primers method at to 2009. Furthermore, we have measured StCA (using an low resolution using commercial kits (Olerup SSP, Sweden) (18). IF test) and 17␣-OHAb and/or P450sccAb (using IPA) in Phenotypic frequencies of the patients were compared with the patients with and without POF. Autoantibody-positive frequencies of 206 sex-matched controls using Fisher exact test. patients without POF were followed up to assess whether the presence of StCA, 17␣-OHAb, and/or p450sccAb was predictive for POF. Results

Prevalence of POF in patients with AD POF was found in 52 of 258 women with AD (20.2%) Materials and Methods (Fig. 1). The duration of POF in the patients included in the Patients study ranged from the onset up to 30 yr after diagnosis, In all, 258 women with autoimmune AD were included in the and the mean values of serum FSH measurements were study. Neufeld’s criteria (1, 17) for APS were used to classify the 60 Ϯ 15 U/liter, serum LH measure- ments 35 Ϯ 10 U/liter, and serum 17␤- estradiol levels 35 Ϯ 10 pmol/liter. In particular, POF was found in 20 of 49 patients who had AD (40.8%) in the context of APS-1 (in two, POF had manifested as primary amenorrhea); in six of 18 women with AD (33.3%) in the context of APS-4; in 26 of 163 pa- tients with AD (16%) in the context of APS-2 (in one, POF developed as pri- FIG. 1. Prevalence of POF in patients with autoimmune AD in the context of APS. mary amenorrhea). None of the 28 J Clin Endocrinol Metab, August 2011, 96(8):E1255–E1261 jcem.endojournals.org E1257

␣ TABLE 1. Mean age at onset of AD and POF in the tive for 17 -OHAb on a subsequent serum sample col- different patient groups lected many years after initial assessment. Of 13 women with APS-4, five (38.5%) were StCA Patients with AD and POF positive; three of four with POF (75%) and two of nine Mean age of Mean age of without POF (22.2%) (Fig. 2C), whereas 53 of 162 APS-2 onset of AD (yr) onset of POF (yr) patients (32.7%) were StCA positive, of whom 17 of 26 Total cases of AD 26.7 (range 3–62) 28.5 (range 16–40) and POF with POF (65.4%) and 36 of 136 without POF (26.5%) (n ϭ 52) (Fig. 2D). One of the patients with APS-2 had primary APS-1 and POF 17 (range 3–39) 24.1 (range 14–39) amenorrhea and was StCA positive. Only one of 28 pa- ϭ (n 20) tients with isolated AD (3.6%) was positive for StCA.

APS-2 and POF 35.5 (range 17–62) 32.3 (range 18–40) Downloaded from https://academic.oup.com/jcem/article/96/8/E1255/2833719 by guest on 25 September 2021 (n ϭ 26) APS-4 and POF 23.2 (range 10–42) 25.8 (range 17–37) StCA in relation to duration of POF (n ϭ 6) StCA measurements were available for 38 women with POF with different disease duration and 12 of 13 patients with POF of less than 5 yr from the diagnosis (92.3%) women with isolated AD had POF (Fig. 1). The mean age at the onset of POF and AD in various groups of AD were positive compared with 18 of 25 patients with more patients is summarized in Table 1. In general, AD preceded than 5 yr POF duration (72%) (Fig. 3). POF in patients with APS-1 and APS-4 and followed POF StCA, 17␣-OHAb, and P450sccAb in patients with in those with APS-2. AD, with and without POF ␣ StCA in patients with AD with or without POF All three autoantibodies (StCA, 17 -OHAb, and Positive StCA were found in 81 of 241 patients with P450sccAb) were tested in 159 women with AD and 31 autoimmune AD (33.6%); in particular, StCA were de- with and 128 without POF. Twenty-eight of the 31 pa- tected in 31 of 43 women with POF (72%), with various tients with POF (90.3%) and 50 of 128 patients without duration of disease, and in 50 of 198 without POF POF (39%) were found to be positive for at least one of the (25.3%) (Fig. 2A). autoantibodies (Fig. 4). StCA tested positive in 22 of 38 women with APS-1 The overall results and the correlation between StCA, (57.9%) of whom 11 of 13 with POF (84.6%) and 11 of 17␣-OHAb, and/or P450sccAb in women with autoim- 25 without POF (44%) (Fig. 2B). Two of the 13 patients mune AD with and without POF are summarized in Fig. 5. with POF and APS-1 had primary amenorrhea and both were StCA negative. Genetic analyses carried out in these Genetic testing two StCA-negative patients showed a karyotype typical of Genetic testing carried out in 29 patients with both AD the Turner’s syndrome in one patient. The other patient and POF showed a significantly increased frequency of had a normal female karyotype but however tested posi- HLA-DRB1*04 (P Ͻ 0.000005) and a significant reduc-

FIG. 2. A, StCA in patients with autoimmune AD, with and without POF. B, StCA in patients with APS-1, with and without POF. C, StCA in patients with APS-4, with and without POF. D, StCA in patients with APS-2, with and without POF. E1258 Reato et al. Premature Ovarian Failure in Addison’s Disease J Clin Endocrinol Metab, August 2011, 96(8):E1255–E1261 Downloaded from https://academic.oup.com/jcem/article/96/8/E1255/2833719 by guest on 25 September 2021 FIG. 3. StCA in relation to duration of POF. FIG. 5. Correlation between StCA and 17␣-OHAb and/or P450sccAb tion of HLA-DRB1*01 (P Ͻ 0,003) in the patients com- in women with autoimmune AD, with and without POF. pared with the controls. contrast, none of the 20 persistently StCA-negative pa- tients developed POF during the period of observation. Follow-up of patients with AD with and without StCA Forty-one women with AD younger than 40 yr of age were followed up for a mean 8.9 yr. The 10 young females Discussion aged younger than 12 yr (nine with APS-1 and 1 with We assessed the prevalence of POF, StCA, and antibodies APS-2) were followed up for a mean 12.2 yr (range 1–30 to steroidogenic enzymes (17␣-OHAb and P450sccAb) in yr) (Fig. 6). Four of these 10 patients were initially positive the largest cohort of women with AD published so far. Of for StCA, and another four seroconverted for StCA during 258 females studied, 20.2% had autoimmune POF, which the follow-up. Five of the eight StCA-positive patients suggests that autoimmune AD is strongly associated with (62.5%) developed POF at a mean age of 21.7 yr, whereas autoimmune POF. the other three are still being followed up (to date one is 22 Autoimmune AD may present as an isolated disease, or yr old and has normal menses, and the other two are 6 and it can occur in association with other autoimmune diseases 11 yr old). Of the six initially StCA-negative patients, two as a component of APS, for example, in association with remained persistently negative for StCA; to date one is 9 yr chronic candidiasis and/or chronic hypoparathyroidism old; the other is 21 yr old and has normal menses. All the (APS-1), in association with autoimmune patients who developed POF in this group had APS-1. and/or mellitus (APS-2) and in association Thirty-one patients aged between 12 and 40 yr (five with other autoimmune diseases (APS-4) (1). with APS-1, 24 with APS-2, and two with APS-4) were In our study we have found that the prevalence of POF followed up for a mean 7.9 yr. Thirteen of these 31 women in patients with different types of APS varied; the highest were positive for StCA at the beginning or seroconverted prevalence was detected in patients with APS-1 (Ͼ40%), during the follow-up and three of 13 StCA-positive pa- lower in patients with APS-4 (30%), and the lowest in tients (23%) developed POF (one with APS-2, one with APS-2 (16%). APS-1, and one with APS-4 after 3, 18, and 9 yr, respec- In patients with both AD and POF, AD tended to de- tively). Overall, during the follow-up, eight of 21 StCA- velop before POF (mean age at onset 27 yr of age and 28.5 positive or seroconverted patients (38%) developed POF yr, respectively). The age at onset of POF in patients with (six with APS-1, one with APS-2, and one with APS-4). In different forms of APS differed and POF presented earlier in life in patients with APS-1 than in patients with the other forms of APS. Women with APS-1 developed POF at approximately 24 yr of age; however, some patients pre- sented with primary amenorrhea. It is likely that in pa- tients who presented with primary amenorrhea an auto- immune attack of the had started and caused significant damage before the patient’s puberty. In women with APS-1, POF usually developed after AD had been diagnosed. Similar sequence of disease onset was observed FIG. 4. Positivity for at least one of the three autoantibodies (StCA, also in patients with APS-4 who developed POF at a mean 17␣-OHAb, P450sccAb) in patients with AD, with and without POF. age of 25.8 yr and AD at a mean age of 23.2 yr. This would J Clin Endocrinol Metab, August 2011, 96(8):E1255–E1261 jcem.endojournals.org E1259 Downloaded from https://academic.oup.com/jcem/article/96/8/E1255/2833719 by guest on 25 September 2021

FIG. 6. Follow-up of 10 patients younger than 12 yr of age with autoimmune AD. The symbol (ϩ)or(Ϫ) or nt indicates positivity or negativity or not tested for autoantibodies in the following order: StCA, 17␣-OHAb, and P450sccAb. POF*, Primary amenorrhea. suggest that women with autoimmune AD in the context We have found StCA positivity in approximately 70% of APS-1 and APS-4 may be at risk of developing POF and of women with AD and POF, and this confirms the strong consequently should be tested for adrenal cortex autoan- relationship between StCA and POF as reported previ- tibodies (ACA) and/or 21-hydroxylase autoantibodies ously (11). Furthermore, StCA were positive in more than (21-OHAb) to confirm adrenal autoimmunity and for 92.3% of patients when tested within 5 yr from the onset StCA and/or steroidogenic enzyme autoantibodies to aid of POF. Overall, these observations indicate that StCA are the prediction of the risk of POF. very good markers of POF in patients with AD. The prev- Women with APS-2 tended to develop POF later in life alence of StCA in AD patients at the onset of POF is similar compared with patients with APS-1 or APS-4 and usually to that reported for thyroid autoantibodies in patients before the onset of AD. In particular, POF was diagnosed with chronic (20), ACA or 21-OHAb in pa- at a mean age of 32.3 yr and AD at 35.5 yr. Consequently, tients with AD (9) or autoantibodies to islet cell antigens patients with POF and autoimmune thyroid diseases or in patients with type 1 diabetes mellitus (21). In our study type 1 diabetes mellitus should be tested for StCA or ste- StCA positivity showed tendency to decrease slowly over roidogenic enzyme autoantibodies to confirm autoim- time and approximately 75% of women with POF dura- mune POF and also for ACA and/or for 21-OHAb to as- tion longer than 5 yr tested positive for StCA. A similar sess a risk of autoimmune AD (potential AD) (1). trend in decreasing autoantibody positivity has been de- In our study the majority of patients with APS-1 and scribed in the majority of the above-mentioned autoim- POF were positive for StCA (11 of 13; 84.6%), suggesting mune diseases. an autoimmune background in development of POF. One Two steroidogenic enzymes (17␣-OH and P450scc) ex- of the two StCA-negative patients with APS-1 and POF pressed in the adrenals and the gonads have been identified who presented with primary amenorrhea had Turner’s to be the major target autoantigens recognized by StCA (1, syndrome. This observation suggests that genetic and 15) and serum 17␣-OHAb and P450sccAb can be mea- karyotyping assessments should be carried out in StCA- sured using sensitive IPAs (16). StCA, 17␣-OHAb, and negative APS-1 patients with primary amenorrhea to clar- P450sccAb were tested in many but not all the patients ify the background cause of ovarian insufficiency. This is included in this study and the relationship between the particularly relevant because most of the component dis- autoantibodies and POF analyzed. Unfortunately, we eases manifest early in life in patients with APS-1 due to the were unable to measure all three types of autoantibodies autoimmune regulator gene mutations that are responsi- (StCA, 17␣-OHAb, and P450sccAb) in all patients be- ble for loss of tolerance to self-antigens (19). cause serum samples were no longer available for some of E1260 Reato et al. Premature Ovarian Failure in Addison’s Disease J Clin Endocrinol Metab, August 2011, 96(8):E1255–E1261 the patients, particularly those referred to our department tients with AD should be helpful in the clinical management, before 17␣-OHAb and P450sccAb tests had become particularly in ovarian function assessment. available. Although there was an overall good correlation be- tween StCA, 17␣-OHAb, and P450sccAb, there were Acknowledgments some discrepancies. These discrepancies may be related to the differences in the methods used to measure these an- Address all correspondence and requests for reprints to: Professor Corrado Betterle, Department of Medical and Surgical Sciences, tibodies. For example, IPA to measure 17␣-OHAb and University of Padua School of , Via Ospedale Civile 105, P450sccAb are likely to be more sensitive than an IF test I-35128, Padua; Italy. E-mail: [email protected]. for StCA, and this could account for some samples tested This work was supported by in part by a grant from the ␣ Downloaded from https://academic.oup.com/jcem/article/96/8/E1255/2833719 by guest on 25 September 2021 positive for 17 -OHAb and/or P450sccAb and negative European Union Sixth Framework Program; the EurAPS project: for StCA. In the case of samples positive for StCA and Autoimmune Polyendocrine Syndrome type I, a rare disorder of negative for 17␣-OHAb and/or P450sccAb, it is possible childhood as a model for autoimmunity, Contract 2005- that serum reactivity to yet-unidentified autoantigen (dif- 005223; and in part by a grant from the European Union Seventh ferent from 17␣-OH or P450scc) was responsible for a Framework Program, the Euradrenal project: Pathophysiology positive signal in the IF test (11). and Natural Course of Autoimmune Adrenal Failure in Europe, Our study showed that autoimmune AD in the context Grant Agreement 2008-201167. of APS is strongly associated with autoimmune POF. Fur- Disclosure Summary: All authors declare there are no con- thermore, the prevalence of autoantibodies to the steroid- flicts of interest. ogenic enzymes is higher in patients with autoimmune AD and APS associated with POF compared with AD patients without POF. 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