| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Division of Endocrinology and Metabolism, Department of Medicine, and Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029
Address all correspondence and requests for reprints to: Giuseppe Barbesino, M.D., Mount Sinai Medical Center, Box 1055, 1 Gustave L. Levy Place, New York, New York 10128. E-mail: gb{at}doc.mssm.edu
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
We have studied a total of 45 multiplex families, each containing at
least 2 members affected with either GD (55 patients) or HT (72
patients), and used linkage analysis to target as candidate
susceptibility loci genes involved in estrogen activity, such as the
estrogen receptor 
and ß and the aromatase genes. We then screened
the entire X-chromosome using a set of polymorphic microsatellite
markers spanning the whole chromosome. We found a region of the
X-chromosome (Xq21.33-22) giving positive logarithm of odds
(LOD) scores and then reanalyzed this area with dense markers in
a multipoint analysis.
Our results excluded linkage to the estrogen receptor and aromatase
genes when either the patients with GD only, those with HT only, or
those with any AITD were considered as affected. Linkage to the
estrogen receptor ß could not be totally ruled out, partly due to
incomplete mapping information for the gene itself at this time. The
X-chromosome data revealed consistently positive LOD scores (maximum of
1.88 for marker DXS8020 and GD patients) when either definition of
affectedness was considered. Analysis of the family data using a
multipoint analysis with eight closely linked markers generated LOD
scores suggestive of linkage to GD in a chromosomal area (Xq21.33-22)
extending for about 6 cM and encompassing four markers. The maximum LOD
score (2.5) occurred at DXS8020.
In conclusion, we ruled out a major role for estrogen receptor and
the aromatase genes in the genetic predisposition to AITD. Estrogen
receptor ß remains a candidate locus. We found a locus on Xq21.33-22
linked to GD that may help to explain the female predisposition to GD.
Confirmation of these data in HT may require study of an extended
number of families because of possible heterogeneity.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The purpose of the present work was to determine genetic factors that
may influence the gender-related imbalance in the prevalence of the
AITDs. As a tool, we chose the method of linkage analysis in a large
set of multiplex AITD families. We first analyzed the estrogen receptor
and ß genes and the aromatase gene using microsatellite markers
linked to these genes. Aromatase is a tissue enzyme that mediates the
peripheral conversion of testosterone to estrogen and is an important
determinant of estrogen levels at target organs. Estrogen receptor
and ß [the latter recently described and partially mapped in humans
(17, 18)] are the mediators of estrogen actions at the nuclear level
and represent additional candidates. We performed a two-point linkage
analysis of the entire X-chromosome, using 20 microsatellite markers.
We also used multipoint linkage analysis with a subset of these
markers, selected because they gave positive logarithm of odds
(LOD) scores in the 2-point analyses. Our results excluded
linkage to the estrogen receptor and aromatase genes, whereas a
role for the estrogen receptor ß gene could not be ruled out at this
time. More interestingly, we found a locus on Xq21.33-22 that gave a
LOD score of about 2.5, suggestive of linkage in a multipoint analysis
in families with GD but not in those with HT. Xq21.33-22 contains the
gene for X-linked agammaglobulinemia but is also predicted by partial
physical mapping to contain many additional unidentified genes.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A total of 45 autoimmune thyroid disease multiplex families were analyzed. Forty-three families were of Caucasian descent, collected in New York, Italy, Britain, and Israel; 2 families were of Caribbean origin. Ten families had at least 2 members with GD, and 20 families had at least 2 members with HT. The remaining 16 families had at least 2 affected members, 1 of which had HT and the other had GD (mixed families). Fifty-five patients had GD, whereas 72 patients had HT. The female to male ratio was 4.4 among GD patients and 10.1 among HT patients. Also included were 178 unaffected family members. The diagnosis of GD was determined on the basis of documented clinical and laboratory evidence of present or past hyperthyroidism and the presence of at least 1 of the following: diffuse goiter, positive TSH receptor antibody tests, or presence of exophthalmos. The diagnosis of HT was based on evidence of thyroid hormone-replaced primary hypothyroidism with any of the following findings: diffuse, firm goiter or positive antithyroid peroxidase or antithyroglobulin tests. Blood samples were collected from all available affected and nonaffected members of each family after informed consent was obtained.
Microsatellite markers
Candidate genes. The estrogen receptor microsatellite
marker (ER-1/ER-2, GDB 196364, on chromosome 6q25.1) with a polymorphic
informative content (PIC) of 0.913 and the aromatase marker (CYP19, GDB
156107), on chromosome 15q21 (PIC = 0.913) were employed. At the
present time, fine mapping and linkage data are not available for
estrogen receptor ß. However, the gene has been mapped to chromosome
14q22–24 by fluorescent in situ hybridization analysis
(18). We therefore analyzed two microsatellite markers, D14S63 (GDB
187894; PIC = 0.785) and D14S258 (GDB 199369; PIC = 0.800),
at opposite ends of this region and 14 cM apart.
Chromosome X microsatellite markers. We employed a panel of
20 microsatellite markers, spanning the entire chromosome. Fifteen
markers were part of a screening panel (Applied Biosystems, Foster
City, CA), with intervals of about 10 cM. Five additional markers (see
Fig. 1
) were selected for their high PIC
and their location from available on-line databases to explore in
detail Xq21.33-22.
|
Statistical analyses
Two-point linkage analyses. Family data were analyzed using
LIPED (21). The hypothesis of positive linkage to candidate
genes was tested assuming different models, either a dominant or a
recessive mode of inheritance. For each mode of inheritance different
levels of penetrance (20%, 40%, 50%, 60%, and 80%) were tested.
These penetrances were used in the analyses of both the autosomal and
X-chromosome markers. As both estrogen receptor and the aromatase
markers were close to or within the respective candidate genes, a low
(0.01) recombination fraction (
) was assumed in the model. For the
two chromosome-14 markers and all X-chromosome markers, a range of
values, from 0.01–0.5, was used to maximize the LOD score. The
hypothesis of linkage was rejected when LOD scores were -2.0 or less.
LOD scores were first obtained considering all affected subjects,
i.e. with either GD or HT (AITD affectedness). Subsequently,
to verify whether the studied genes could have a role in determining
the type of AITD, analyses were run with the same parameters as above,
but classifying only subjects with GD as affected or only subjects with
HT disease as affected. In each of these analyses, mixed families were
included and when the GD affectedness was examined; HT patients were
considered as nonaffected and vice versa.
Multipoint linkage analysis. Genotype data for the area of
interest of chromosome Xq21.33-22 (see Fig. 1
) were analyzed in a
multipoint analysis in an attempt to maximize the polymorphic
information of each individual from the eight markers depicted in Fig. 1. Using GeneHunter (22), we set inheritance parameters identical to
those that gave the maximum LOD scores in the two-point analysis.
Mapping information from the Genethon 1996 X-chromosome map was used
(23). All linkage analyses were run assuming a fixed general prevalence
of 1% for both diseases. This is in reasonable accordance with
epidemiological data from the literature (9), although prevalence data
obtained using our strict diagnostic criteria are not available.
Susceptibility allele frequencies for the different inheritance models
were then derived according to the Hardy-Weinberg formula for the
recessive and dominant models.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Negative LOD scores (-3) were obtained for the aromatase and the
estrogen receptor genes, at a of 0.01 and assuming different
models, when all patients with AITD were considered affected. These
results ruled out linkage of these two genes to AITD as a whole.
Similar results were observed when either the affectedness of GD or HT
was considered. In this analysis, LOD scores less than -2 were not
obtained in all models because of decreased sample size. Therefore, we
were not able to formally reject linkage of either GD or HT for these
candidate genes at penetrances less than 40%. However, LOD scores
remained negative, (see Fig. 2 for the
example of GD) in all models, arguing against linkage of either HT or
GD to these two genes), As the exact position of the estrogen receptor
ß gene with respect to the two markers on chromosome 14 was not
known, a wide range of values was examined. Overall, negative LOD
scores were observed in all affectednesses, but some small positive
results were observed for D14S258, with a maximum LOD score of 0.87
when GD patients only were considered affected, at a of 0.1 and
penetrance of 40%, assuming a dominant mode of inheritance. Therefore,
linkage of AITD to the genes in this area (including estrogen receptor
ß) could not be conclusively ruled out, but there was little evidence
in favor of linkage.
|
Two-point analysis. Most of the 20 markers gave negative or low positive LOD scores, not allowing formal rejection of linkage for all markers. However, marker DXS8020, on Xq21.33-22, gave a maximum LOD score of 1.8 in GD in the recessive mode of inheritance, with a penetrance of 40%. The same marker gave positive LOD scores, although at a lower level in both the AITD (1.33) and HT (1.55) categories. However, the latter maximum LOD scores were obtained under a different model (20% penetrance, dominant for both HT and AITD).
Multipoint analysis. Genotype data from the eight markers
depicted in the detail box of Fig. 1, spanning a chromosomal
region of about 41 cM were employed in the multipoint analysis. For
each of the affectedness categories, the analysis was run under the
model that gave the maximum LOD score for DXS8020 in the single point
analysis.
When this approach was applied to all AITD and HT families, we were not
able to confirm the results obtained in the single point analysis. HT
gave a maximum LOD score of 0.56 in this analysis, close to DXS8063,
whereas AITD gave a maximum LOD score of 0.26 at the same location. We
investigated the reason for this discrepancy by looking at single
pedigrees. Two large mixed families were relatively uninformative for
DXS8020, contributing almost zero to the two-point analysis for this
marker. However, these two families were very negative for nearby
markers (such as DXS8063). In this situation the multipoint analysis
drew most of the information from the latter marker(s), markedly
reducing the total LOD score. Therefore, it was possible that
significant heterogeneity existed in our dataset of HT families,
affecting the results of linkage analyses for both HT and AITD. A
heterogeneity LOD score of 1.5 was observed in this area, with =
0.68, indicating possible heterogeneity.
In contrast, when the GD dataset was analyzed in the multipoint
analysis, a maximum LOD score of 2.5 was obtained, coincident with
DXS8020 (Fig. 3). LOD scores above 2.3,
which are suggestive of linkage (24), were observed across a segment of
about 5 cM, encompassing DXS8020. The amount of polymorphic and linkage
information contained in our dataset, as calculated by
GeneHunter, was elevated across the whole area, reaching a
maximum of 0.89 at DXS8020. For this reason additional positional
information could only be obtained by adding more families to the
dataset. When we allowed for heterogeneity, the LOD score was 2.5 and
= 0.99, which excluded the presence of significant
heterogeneity.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
and aromatase genes,
precise mapping data are available in the literature. We could,
therefore, use microsatellite markers tightly linked to the genes
themselves. This strongly enhanced the power to detect linkage by
reducing the chances of recombinations between the marker and the
candidate gene. Our data rule out the estrogen receptor and
aromatase genes as necessary genes for AITD. We also did not find any
evidence of linkage to the chromosomal region containing the estrogen
receptor ß gene. Detailed mapping information for this gene was
lacking, and therefore, our analysis obtained with two markers in the
area of the receptor gene itself, but not tightly linked to it, may not
be powerful enough to detect linkage. The analysis of a panel of X-chromosome markers yielded interesting positive LOD scores for all three affectedness statuses for marker DXS8020, located on Xq21.33-22. Subsequent multipoint analysis with dense markers in this area provided a maximum multipoint LOD score of 2.5 on marker DXS8020 for GD patients. There may be more than one reason why data from the single point analyses were not confirmed for HT and AITD subsets of patients. It seems possible that the genetic predisposition to HT may be heterogeneous, i.e. determined by different genes in different families. It should also be remembered that HT has a later onset and that the spectrum of its clinical manifestations, ranging from microscopic thyroid lymphocytic infiltration with serum autoantibodies to the full-blown picture of goiter and hypothyroidism, is highly variable, making diagnostic criteria somewhat less reliable. In contrast, the diagnosis of GD is readily made based on the clinical picture and the high specificity of TSH receptor antibody as diagnostic markers (27). It is noteworthy that, in fact, the results of the multipoint analysis did not rule out linkage of HT to markers on Xq21.33-22, but only failed to confirm the single point analysis, leaving open the possibility that adding more families or using more restrictive criteria for classifying subtypes of HT may in the future show significant linkage for this disease also. Alternatively, it is possible that the type of autoimmune thyroid response is finally determined by other genes, specific for the single AITD type.
A LOD score of 2.5, as we found in our GD families, has been considered suggestive of linkage (24). When many different models are explored, correction for multiple testing has been suggested, by subtracting 0.3–0.6 from the resulting LOD score (28). Even with this very conservative correction, our data remain suggestive of linkage (24). The X-chromosome was chosen because of the disproportionately high prevalence of AITD in women. The well established increase in the incidence of thyroid autoimmunity in patients with Turner’s syndrome is another indication of a possible involvement of the X-chromosome (15). By large, most X-linked monogenic inherited traits are fully recessive and, therefore, clinically evident in men alone. However, AITD inheritance is complex and does not follow a readily identifiable (Mendelian) pattern. For example, genes on the X-chromosome with a dose-dependent effect and interacting with other genes could explain the female predisposition to AITD. It should be noted that although for mathematical reasons it was necessary to set linkage analyses under certain simple models, these also may not accurately describe the real situation, and that when studying multigenic diseases, the concepts of recessive vs. dominant and of penetrance represent approximations. In principle, when the inheritance model of disease is not known, a nonparametric method is preferable, because it prevents the need for multiple testing, therefore reducing the risks of false positives. However, in classical linkage analysis with complex families, this approach is also less sensitive because it discards the amount of information provided by nonaffected members (29). For this reason we used only parametric data.
Xq21.33-22 has now been physically mapped (30). Genes for several X-linked diseases map to this region, such as Alport’s syndrome, diffuse leiomyomatosis, Fabry’s disease, and the gene for X-linked agammaglobulinemia, or Bruton tyrosine kinase (BTK). BTK encodes for a tyrosine kinase protein of the src protooncogene family (31), expressed in B lymphocytes and important in the development of B lymphocytes. Several mutations have been reported in patients with X-linked agammaglobulinemia, resulting in a nonfunctional protein (31). The mouse homologous to BTK (xid) has been shown to modulate the expression of collagen autoimmunity in a susceptible strain (32) by exerting a permissive effect on the autoimmune genetic background. Physical mapping has shown BTK to map between DXS990 and DXS1106 (30), to a region containing the maximum LOD score obtained in our analysis. BTK, therefore, represents a possible candidate as a susceptibility gene for GD. The region also contains a high number of CpG islands (33), a feature that predicts the presence of many additional genes (34).
In summary, we have shown that the estrogen receptor
and aromatase genes are not susceptibility genes for AITD,
whereas the estrogen receptor ß gene is a possible candidate that
deserves further study. We found suggestive linkage of GD to a
locus on chromosome Xq21.33-22 that contains a susceptibility gene
for the disease. Further study with independent datasets is
warranted to obtain confirmation of our findings.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Additional members of the International Consortium for the Genetics
of Autoimmune Thyroid Disease included Drs. Rhoda Cobin (New York, NY),
Luca Chiovato and Aldo Pinchera (Pisa, Italy), Sandra McLachlan (San
Francisco, CA), Bernard Rees Smith (Cardiff, UK), Fred Clark and Eric
Young (Newcastle upon Tyne, UK), and Meir Berezin (Tel Hashomer,
Israel). These contributors were not responsible for the content of the
present manuscript.
Received March 13, 1998.
Revised May 22, 1998.
Accepted June 2, 1998.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  G. L. Chen and J. T. Prchal X-linked clonality testing: interpretation and limitations Blood, September 1, 2007; 110(5): 1411 - 1419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. Straub The Complex Role of Estrogens in Inflammation Endocr. Rev., August 1, 2007; 28(5): 521 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Hsiao, M.-C. Hsieh, K.-J. Tien, S.-C. Hsu, S.-J. Shin, and S.-R. Lin Association between a C/T Polymorphism in Exon 33 of the Thyroglobulin Gene Is Associated with Relapse of Graves' Hyperthyroidism after Antithyroid Withdrawal in Taiwanese J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3197 - 3201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J Owen, J. A Eden, C. E Jennings, V. Wilson, T. D Cheetham, and S. H S Pearce Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population. J. Mol. Endocrinol., August 1, 2006; 37(1): 97 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Aliesky, P. N. Pichurin, C.-R. Chen, R. W. Williams, B. Rapoport, and S. M. McLachlan Probing the Genetic Basis for Thyrotropin Receptor Antibodies and Hyperthyroidism in Immunized CXB Recombinant Inbred Mice Endocrinology, June 1, 2006; 147(6): 2789 - 2800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Invernizzi, M. Miozzo, C. Selmi, L. Persani, P. M. Battezzati, M. Zuin, S. Lucchi, P. L. Meroni, B. Marasini, S. Zeni, et al. X Chromosome Monosomy: A Common Mechanism for Autoimmune Diseases J. Immunol., July 1, 2005; 175(1): 575 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tomer and T. F. Davies Searching for the Autoimmune Thyroid Disease Susceptibility Genes: From Gene Mapping to Gene Function Endocr. Rev., October 1, 2003; 24(5): 694 - 717. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. H. Kacem, A. Rebai, N. Kaffel, S. Masmoudi, M. Abid, and H. Ayadi PDS Is a New Susceptibility Gene to Autoimmune Thyroid Diseases: Association and Linkage Study J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2274 - 2280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Adarichev, J. C. Valdez, T. Bardos, A. Finnegan, K. Mikecz, and T. T. Glant Combined Autoimmune Models of Arthritis Reveal Shared and Independent Qualitative (Binary) and Quantitative Trait Loci J. Immunol., March 1, 2003; 170(5): 2283 - 2292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Vaidya, P. Kendall-Taylor, and S. H. S. Pearce The Genetics of Autoimmune Thyroid Disease J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5385 - 5397. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sakai, S. Shirasawa, N. Ishikawa, K. Ito, H. Tamai, K. Kuma, T. Akamizu, M. Tanimura, K. Furugaki, K. Yamamoto, et al. Identification of susceptibility loci for autoimmune thyroid disease to 5q31-q33 and Hashimoto's thyroiditis to 8q23-q24 by multipoint affected sib-pair linkage analysis in Japanese Hum. Mol. Genet., June 1, 2001; 10(13): 1379 - 1386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Imrie, B. Vaidya, P. Perros, W. F. Kelly, A. D. Toft, E. T. Young, P. Kendall-Taylor, and S. H. S. Pearce Evidence for a Graves' Disease Susceptibility Locus at Chromosome Xp11 in a United Kingdom Population J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 626 - 630. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Ban, M. Taniyama, and Y. Ban Vitamin D Receptor Gene Polymorphism Is Associated with Graves' Disease in the Japanese Population J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4639 - 4643. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. P. Weetman Graves' Disease N. Engl. J. Med., October 26, 2000; 343(17): 1236 - 1248. [Full Text] [PDF]
|
|
|
|
|
|
T. Furuya, J. L. Salstrom, S. McCall-Vining, G. W. Cannon, B. Joe, E. F. Remmers, M. M. Griffiths, and R. L. Wilder Genetic dissection of a rat model for rheumatoid arthritis: significant gender influences on autosomal modifier loci Hum. Mol. Genet., September 1, 2000; 9(15): 2241 - 2250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Hunt, S. E. Marshall, A. P. Weetman, J. I. Bell, J. A. H. Wass, and K. I. Welsh Cytokine Gene Polymorphisms in Autoimmune Thyroid Disease J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1984 - 1988. [Abstract] [Full Text]
|
|
|
|
|
|
R. Nithiyananthan, J. M. Heward, A. Allahabadia, A. H. Barnett, J. A. Franklyn, and S. C. L. Gough A Heterozygous Deletion of the Autoimmune Regulator (AIRE1) Gene, Autoimmune Thyroid Disease, and Type 1 Diabetes: No Evidence for Association J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1320 - 1322. [Abstract] [Full Text]
|
|
|
|
|
|
Mapping the Major Susceptibility Loci for Familial Graves' and Hashimoto's Diseases: Evidence for Genetic Heterogeneity and Gene Interactions J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4656 - 4664. [Abstract] [Full Text]
|
|
|
|
|
|
B. Vaidya, H. Imrie, P. Perros, E. T. Young, W. F. Kelly, D. Carr, D. M. Large, A. D. Toft, M. I. McCarthy, P. Kendall-Taylor, et al. The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus Hum. Mol. Genet., July 1, 1999; 8(7): 1195 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Heward, A. Allahabadia, M. Armitage, A. Hattersley, P. M. Dodson, K. Macleod, J. Carr-Smith, J. Daykin, A. Daly, M. C. Sheppard, et al. The Development of Graves' Disease and the CTLA-4 Gene on Chromosome 2q33 J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2398 - 2401. [Abstract] [Full Text]
|
|
|
|
|
|
J. C. Jaume, J. Guo, D. L. Pauls, M. Zakarija, J. M. McKenzie, J. A. Egeland, C. L. Burek, N. R. Rose, W. H. Hoffman, B. Rapoport, et al. Evidence for Genetic Transmission of Thyroid Peroxidase Autoantibody Epitopic "Fingerprints" J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1424 - 1431. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Tomer, G. Barbesino, D. A. Greenberg, E. Concepcion, and T. F. Davies Linkage Analysis of Candidate Genes in Autoimmune Thyroid Disease. III. Detailed Analysis of Chromosome 14 Localizes Graves' Disease-1 (GD-1) Close to Multinodular Goiter-1 (MNG-1) J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4321 - 4327. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology |
