| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Reproductive Endocrinology |
Department of Pediatrics (H.S.B., W.L.M.) and the Metabolic Research Unit (W.L.M.), University of California San Francisco, San Francisco, California 94143; The Department of Pediatrics (O.H.P.), Indiana University Medical Center, Indianapolis, Indiana
Address all correspondence and requests for reprints to: Walter L. Miller, M.D., Department of Pediatrics, University of California, San Francisco, 1466 4th Avenue, Bldg MR-IV, Rm 209, San Francisco, California 94143-0978.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-hydroxylation, 22-hydroxylation, and scission of the
cholesterol side-chain, all catalyzed by the cholesterol side-chain
cleavage enzyme, P450scc (for review see 10). This cytochrome P450
enzyme and its electron transfer donors, adrenodoxin reductase and
adrenodoxin, are found in adrenal, gonadal, placental, and brain
mitochondria (11, 12, 13, 14); however, all three of these genes and proteins
are normal in patients with lipoid CAH (15, 16, 17, 18, 19). Furthermore, placental
progesterone synthesis persists in the affected mid-term lipoid CAH
fetus, indicating that the P450scc system functions normally in these
patients and that the factor disordered in lipoid CAH should be
expressed in the adrenals and gonads, but not in the placenta (18). In
hindsight, it is now clear that a mutation in any component of the
P450scc system catalyzing so-called 20,22 desmolase activity would be
incompatible with normal gestation, as the human placenta uses this
system to make the progesterone needed to maintain pregnancy (11, 20). In the absence of lesions in the P450scc enzyme system, attention turned to proteins thought to be involved in the movement of cholesterol into mitochondria. Initial efforts ruled out several factors (16, 21), but the cloning of the rat steroidogenic acute regulatory (StAR) protein (22) provided another candidate. The demonstrations that StAR messenger RNA (mRNA) was abundant in the human adrenal and gonad, but not in the placenta or brain (23) corresponded to the expected tissue distribution for a factor causing lipoid CAH (18), and indeed, StAR mutations have been found in 20 of 21 lipoid CAH patients reported to date (24, 25, 26).
An initial survey of lipoid CAH patients found that 46,XX females and 46,XY genetic males were affected equally (9), as would be expected for the autosomal StAR gene on chromosome 8p11.2 (23, 27). However two preliminary reports from Japan (28, 29) and our recent international survey (26) found a preponderance of 46,XY individuals. The basis for this is not clear. Hormonal replacement therapy in lipoid CAH is compatible with survival to adulthood (9, 30), but the small number of affected 46,XX patients precluded their study until recently. Although lipoid CAH ablates any adrenal and testicular steroidogenesis detectable after infancy, Matsuo et al. (28) reported the surprising finding that five out of five affected 46,XX females patients over the age of 13 yr developed secondary sexual characteristics and vaginal bleeding at the time of puberty and had estradiol levels ranging from 22 to 85 pg/mL. Fujieda et al. (29) mentioned three more affected 46,XX females who developed pubertal changes and vaginal bleeding.
We recently suggested that steroidogenic tissues exhibit both StAR-dependent and StAR-independent steroidogenesis (26). In the fetal adrenal and testis, which make large amounts of steroids in utero, tropic stimulation is increased in the absence of StAR-dependent steroidogenesis, leading to the accumulation of the lipoid deposits for which the disease is named. Through mechanical engorgement of organelles and/or toxic effects of cholesterol auto-oxidation products, the cell’s StAR-independent steroidogenic capacity is subsequently destroyed, leading to the characteristic lipoid CAH phenotype of glucocorticoid and mineralocorticoid deficiency and female genitalia in 46,XY patients (26). However, the fetal ovary is steroidogenically quiescent and does not express steroidogenic enzymes (31), hence the StAR-independent steroidogenic capacity of the ovary should be spared until each ovarian follicle is sequentially recruited by cyclical gonadotropin stimulation (26). However, no adolescent-aged 46,XX females with lipoid CAH have been studied both hormonally and genetically. We now report such a patient with a homozygous StAR frameshift mutation, who spontaneously feminized and experienced cyclical vaginal bleeding beginning at age 13.5 yr.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A 15.5-yr-old female was referred to one of us (O.H.P.) with a diagnosis of congenital lipoid adrenal hyperplasia. At the time of referral, she was being treated with carbamazepine to suppress seizures, glucocorticoid and mineralocorticoid replacement therapy to correct the adrenal insufficiency, and medroxyprogesterone to prevent menses.
The patient was Twin B of a 35-week uncomplicated pregnancy to a
33-yr-old Indian female. She was thought to be well until four months
of age, when she presented with developmental delay, failure to thrive,
vomiting, and severe electrolyte disturbances including Na 109 mEq/L; K
5.9 mEq/L; Cl 74 mEq/L; CO2 15 mEq/L; and glucose 28 mg/dl.
She was a phenotypically normal female with a 46,XX karyotype. An ACTH
stimulation test (Table 1
) indicated a diagnosis of
congenital lipoid adrenal hyperplasia. The child received
mineralocorticoid and glucocorticoid replacement therapy, but
subsequently manifested cerebral atrophy, spastic cerebral palsy,
seizures, severe mental retardation, lymphoplasma cellular gastritis,
and acute neutrophilic esophagitis.
|
Family history
Her sister, Twin A, was well until 4 days of age, when she
developed necrotizing enterocolitis and severe shock. At that time, she
was diagnosed as having hypothyroidism, patent ductus arteriosus, and a
preductal coarctation of the aorta, which were repaired at 17 days of
age. At 50 days of age, she had a duodeno-duodenostomy for duodenal
atresia, followed by several episodes of severe hyponatremia,
hyperkalemia and hypoglycemia. At 13 days of age a serum cortisol level
was 13 µg/dl. At 5 months of age, a metyrapone test had a baseline
11-deoxycortisol level of 1 µg/dL, and after metyrapone, the ACTH
level was 600 pg/mL but the 11-deoxycortisol level did not rise above
0.1 µg/dL. ACTH testing showed adrenal insufficiency (Table 1
). A karyotype was 46,XX. A CT scan showed bilateral
cerebrocortical atrophy. At 15 months of age, she died of a presumed
heart condition; autopsy findings included severe coarctatiation of the
aorta, cardiomegaly, hemiatrophy of the right cerebral hemisphere, left
pleural adhesion, and multiple atelectases. The adrenal glands were 5
gm each with lipoid infiltration, focal calcification, and loss of
adrenal zone demarcation of the cortex. The ovaries had multiple small
follicular cysts with focal lipid deposition noted in the cortical
stromal cells. A preliminary clinical report of these twins appeared in
1983 (32). Unfortunately we found that the slides and tissue blocks had
been discarded, precluding further study of the affected tissues in
Twin A.
The parents were born and raised in India and were not known to be
related. Two brothers of the twins are in good health. A paternal uncle
died with cyanosis at 15 days of age and a paternal aunt had a daughter
who died in infancy of unknown causes, both in India. The twin sisters
and the older brother all had the same histocompatibility leucocyte
antigen (HLA) type:
 |
Preparation of DNA
Blood samples obtained in EDTA were diluted 10:1 with 10 mmol/L sucrose, 2 mmol/L MgCl2, 3 mmol/L Tris HCl, pH 7.5, 0.35% Triton X-100, and the leukocyte nuclei were harvested by centrifugation at 750g for 30 min. The pellet was resuspended and protein digested in 10 mL 20 mmol/L EDTA, 50 mmol/L Tris HCl, pH 8.0, 1% NaDodSO4, 100 µg/mL proteinase K for 30 min at 37 C, then for 10 min at 75 C, following which RNase A was added to 100 µg/mL, and the incubation continued for 30 min at 37 C. Protein was salted out at 4 C with 4 mL supersaturated NaCl, and after centrifugation at 750g for 30 min, the DNA was harvested from the supernatant by ethanol precipitation.
Oligonucleotides and PCR
Oligonucleotides were synthesized by phosphoramidite chemistry in an Applied Biosystems 391 and detritylated in the synthesizer. The oligonucleotides were deprotected by transferring the CPG-support to a 4 mL vial containing 2 mL of 15 mol/L NH4OH, incubated 4 h at 60 C and harvested by vacuum evaporation. DNA corresponding to exons 1–4 of the StAR gene were amplified individually using the oligonucleotide primer pairs Ex1S/Ex1AS, Ex2S/Ex2AS, Ex3S/Ex3AS, and Ex4S/Ex4AS (26), and exons 5–7 were amplified as a single 2.1 kb fragment using primers S3/AS1 (24). The 50 µL polymerase chain reactions (PCR), which used 10–15 ng genomic DNA, 200 µmol/L dNTP, 1.5 mmol/L MgCl2, 20 pmol of each primer, and either Pfu or Taq polymerase, were initiated by denaturation at 95 C for 2 min and terminated by a final extension at 72 C for 15 min. Program 1 (94 C, 50 sec; 64 C, 30 sec; 72 C, 90 sec; 34 cycles) was used for S3/AS1; Program 2 (94 C, 45 sec; 57 C, 45 sec; 72 C, 90 sec; 34 cycles) was used for Ex2S/Ex2AS, Ex3S/Ex3AS, and Ex4S/Ex4AS; Program 3 (94 C, 50 sec; 60 C, 45 sec; 72 C, 90 sec; 30 cycles) was used for Ex1S/Ex1AS.
DNA sequencing
PCR-amplified DNA was purified by agarose gel electrophoresis,
cloned into pCRII (Invitrogen, Carlsbad, CA), transformed into
Escherichia coli DH5, and analyzed by sequencing multiple
clones on both strands. The identified mutation was confirmed by
digestion of PCR products with Bfa I (New England Biolabs,
Beverly, MA) and analysis of the DNA fragments by electrophoresis on
7% acrylamide gel.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The data in Table 1, obtained during the subject’s infancy,
indicate a severe defect at a very early step in steroidogenesis before
the synthesis of pregnenolone, consistent with lipoid CAH. Estrogens
and gonadotropins were not measured when she was first seen by us at
the age of 15.5 yr as she had been receiving medroxyprogesterone depot
for 2 yr. However, her pubertal development, especially Tanner V
breats, indicated substantial endogenous production of estrogen by her
ovaries. The pelvic ultrasonography also showed an estrogenic effect on
the uterus and a modest-sized ovarian cyst, showing good suppression by
medroxyprogesterone. Although we cannot be certain that the patient and
her twin were monozygotic twins, their identical HLA types and the
presence of lipoid CAH in both make this highly likely, as lipoid CAH,
being due to mutations in the StAR gene on chromosome 8p11.2 (23) is
unlinked to HLA. It is likely that the two infants who died in India
also had lipoid CAH.
Detection of a StAR frameshift mutation
Most StAR mutations causing lipoid CAH are found in exons 5–7 of
the StAR gene (24, 25, 26). Therefore, we initially amplified, cloned, and
sequenced a 2.1 kb fragment encompassing this region using the same
S3/AS1 oligonucleotide pair used previously (24, 25, 26); however, sequence
analysis of four clones revealed no mutations. Therefore, we amplified,
cloned, and sequenced exons 1–4 individually. All clones of exons 1,
3, and 4 had normal sequences, but all clones of exon 2 showed the
deletion of the thymidine at position 261 as numbered in the cDNA
sequence (Genbank U17284) (23) (Fig. 1) suggesting that
the patient was homozygous for this mutation. The deletion of this
thymidine changes the sequence context from CCCCTAGCAG to
CCCCAGCAG, thus destroying the C
TAG
recognition site for the restriction enzyme BfaI. To confirm
that the patient was indeed homozygous for 261delT, we amplified Exon 2
from the patient, both parents, and a normal control. PCR with the
Ex2S/Ex2AS oligonucleotide pair yields a 342 bp fragment. Digestion
with BfaI cuts the normal DNA into 126, 118, and 98 bp
fragments. However the patient’s DNA yielded fragments of 224 and 118
bp, and both parents were heterozygous, having 224, 126, 118, and 98 bp
fragments (Fig. 2). Thus the patient is homozygous for
the 261delT mutation, and both parents are heterozygous, as
expected.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
), permitting survival for weeks to months. Second, the spontaneous feminization and development of vaginal bleeding at the normal time of puberty, as described in other 46,XX patients with presumed lipoid CAH (28) indicates that the ovaries retain steroidogenic capacity. The physiology of ovarian steroidogenesis in lipoid CAH is not analogous to the retained placental steroidogenesis in lipoid CAH (18), as the placenta does not express StAR, while the ovary does (23). This ovarian steroidogenesis presumably is analogous to that described above for adrenal mineralocorticoid biosynthesis. The ovary is steroidogenically inactive and does not even produce the mRNAs for the steroidogenic enzymes during fetal life (31), thus these cells should remain undamaged by accumulated cholesterol esters until they first undergo gonadotropin stimulation at the time of puberty. These cells retain StAR-independent steroidogenic capacity and hence make estrogens, albeit in subnormal amounts, resulting in high gonadotropins. However, only the cells in the individually recruited follicles undergo stimulation, and hence only these cells accumulate cholesterol esters and lose steroidogenic capacity. Thus regular monthly cycles are possible, as the patient’s ovaries retain large numbers of follicles that remain relatively undamaged before recruitment. Such monthly cycles, which may persist for years, are probably anovulatory. However, these cycles can produce extremely large ovarian cysts, which can undergo torsion and present as a life-threatening acute abdomen condition (J.F. Strauss III, personal communication). Our patient had only a 3.1 x 1.6 cm left ovarian cyst, probably due to suppression by the medroxyprogesterone. Such treatment should be instituted prophylactically in post-pubertal 46,XX patients with lipoid CAH to prevent ovarian cysts and torsion.
Present data indicate that all or virtually all patients with lipoid CAH have mutations in the StAR gene. Including the present case, we have analyzed 22 cases of lipoid CAH (24, 25, 26) and have failed to find StAR gene mutations on both alleles in only one patient (patient 14 in ref. 26). The observation that rabbits homozygous for a P450scc gene deletion are normal at birth, then die with a syndrome very similar to lipoid CAH (33), has suggested to some that P450scc lesions could cause lipoid CAH. However, in the rabbit the progesterone needed to maintain pregnancy is provided by the maternal corpus luteum throughout pregnancy, whereas in human pregnancy the corpus luteum produces adequate progesterone only to the end of the second month, after which placental progesterone is needed: maternal ovariectomy during pregnancy causes spontaneous abortion in the rabbit but not in human women after the second month. Thus homozygous mutation of P450scc is not compatible with human term gestation even though it is in the rabbit.
The mutation 261delT causes a shift in the amino acid reading frame of the StAR mRNA, resulting in a protein whose first 45 amino acids correspond to those of normal StAR, followed by a sequence of 63 amino acids whose sequence is unrelated to StAR, before a premature translational termination codon is reached. As the first 62 amino acids of the StAR sequence are not involved in StAR activity (34), and retention of the first 268 amino acids does not confer StAR activity (24, 26, 34), the retention of only 45 amino acids of the StAR sequence cannot confer any StAR activity on the resulting protein. Thus the patient has a severe genetic lesion in the StAR gene that is incompatible with any StAR activity.
Our previous genetic analyses of 21 cases of lipoid CAH, representing 33 unique StAR alleles (24, 25, 26), have identified a wide variety of StAR gene mutations, including amino acid replacements (missense mutations), premature translational terminations (nonsense mutations), frameshifts, and gene deletion or DNA insertion. The mutation identified in this case, 261delT, has not been reported previously. Furthermore, the affected patient is, to our knowledge, the first reported patient of Indian heritage. Although there was no known history of consanguinity, both parents came from the same caste in the Gujarat state of India, suggesting that the 261delT mutation may represent a founder effect among Indians from this group and area, similar to the Q258X and R182L mutations in the Japanese and Palestinians, respectively (26).
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received December 13, 1996.
Accepted February 18, 1997.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
cholesterol hydroxylase activity
in adrenal tissue of a patient with lipoid adrenal hyperplasia. Acta
Endocrinol (Copenh). 71:512–518.
A transversion 11 bp from a splice acceptor site in the gene for
steroidogenic acute regulatory protein causes congenital lipoid adrenal
hyperplasia. Hum Mol Genet. 4:2299–2305.-hydroxylase/17, 20 lyase) and P450c21
(21-hydroxylase) in the human fetus. J Clin Endocrinol Metab. 63:1145–1150.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  W. L. Miller StAR Search--What We Know about How the Steroidogenic Acute Regulatory Protein Mediates Mitochondrial Cholesterol Import Mol. Endocrinol., March 1, 2007; 21(3): 589 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Y. Baker, L. Lin, C. J. Kim, J. Raza, C. P. Smith, W. L. Miller, and J. C. Achermann Nonclassic Congenital Lipoid Adrenal Hyperplasia: A New Disorder of the Steroidogenic Acute Regulatory Protein with Very Late Presentation and Normal Male Genitalia J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 4781 - 4785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Nakatani, E. Hattori, T. Ohnishi, B. Dean, Y. Iwayama, I. Matsumoto, T. Kato, N. Osumi, T. Higuchi, S.-I. Niwa, et al. Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation Hum. Mol. Genet., June 15, 2006; 15(12): 1949 - 1962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bhangoo, W.-X. Gu, S. Pavlakis, H. Anhalt, L. Heier, S. Ten, and J. L. Jameson Phenotypic Features Associated with Mutations in Steroidogenic Acute Regulatory Protein J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6303 - 6309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Fluck, A. Maret, D. Mallet, S. Portrat-Doyen, J. C. Achermann, B. Leheup, G. E. Theintz, P. E. Mullis, and Y. Morel A Novel Mutation L260P of the Steroidogenic Acute Regulatory Protein Gene in Three Unrelated Patients of Swiss Ancestry with Congenital Lipoid Adrenal Hyperplasia J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5304 - 5308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Chen, B. Y. Baker, M. A. Abduljabbar, and W. L. Miller A Genetic Isolate of Congenital Lipoid Adrenal Hyperplasia with Atypical Clinical Findings J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 835 - 840. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Jo and D. M. Stocco Regulation of Steroidogenesis and Steroidogenic Acute Regulatory Protein in R2C Cells by DAX-1 (Dosage-Sensitive Sex Reversal, Adrenal Hypoplasia Congenita, Critical Region on the X Chromosome, Gene-1) Endocrinology, December 1, 2004; 145(12): 5629 - 5637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Heikkila, H. Peltoketo, J. Leppaluoto, M. Ilves, O. Vuolteenaho, and S. Vainio Wnt-4 Deficiency Alters Mouse Adrenal Cortex Function, Reducing Aldosterone Production Endocrinology, November 1, 2002; 143(11): 4358 - 4365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Coulter, I. C. McMillen, I. M. Bird, and M. D. Salkeld Steroidogenic Acute Regulatory Protein Expression Is Decreased in the Adrenal Gland of the Growth-Restricted Sheep Fetus During Late Gestation Biol Reprod, August 1, 2002; 67(2): 584 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Richmond, C. J. Flickinger, J. A. McDonald, M. A. Lovell, and A. D. Rogol Lipoid Congenital Adrenal Hyperplasia (CAH): Patient Report and a Mini-Review Clinical Pediatrics, July 1, 2001; 40(7): 403 - 407. [PDF]
|
|
|
|
|
|
H. S. Bose, S. Sato, J. Aisenberg, S. A. Shalev, N. Matsuo, and W. L. Miller Mutations in the Steroidogenic Acute Regulatory Protein (StAR) in Six Patients with Congenital Lipoid Adrenal Hyperplasia J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3636 - 3639. [Abstract] [Full Text]
|
|
|
|
|
|
N. Katsumata, Y. Kawada, Y. Yamamoto, M. Noda, A. Nimura, R. Horikawa, and T. Tanaka A Novel Compound Heterozygous Mutation in the Steroidogenic Acute Regulatory Protein Gene in a Patient with Congenital Lipoid Adrenal Hyperplasia J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 3983 - 3987. [Abstract] [Full Text]
|
|
|
|
|
|
J.-G. Lehoux, D. B. Hales, A. Fleury, N. Brière, D. Martel, and L. Ducharme The in Vivo Effects of Adrenocorticotropin and Sodium Restriction on the Formation of Different Species of Steroidogenic Acute Regulatory Protein in Rat Adrenal Endocrinology, November 1, 1999; 140(11): 5154 - 5164. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. S. Bose, R. M. Whittal, M. A. Baldwin, and W. L. Miller The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule PNAS, June 22, 1999; 96(13): 7250 - 7255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Korsch, M. Peter, O. Hiort, W. G. Sippell, B. M. Ure, B. P. Hauffa, and M. Bergmann Gonadal Histology with Testicular Carcinoma in Situ in a 15-Year-Old 46,XY Female Patient with a Premature Termination in the Steroidogenic Acute Regulatory Protein Causing Congenital Lipoid Adrenal Hyperplasia J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1628 - 1632. [Abstract] [Full Text]
|
|
|
|
 |
|
 E. Y. Adashi and J. D. Hennebold Single-Gene Mutations Resulting in Reproductive Dysfunction in Women N. Engl. J. Med., March 4, 1999; 340(9): 709 - 718. [Full Text] [PDF]
|
|
|
|
|
|
J.-G. Lehoux, A. Fleury, and L. Ducharme The Acute and Chronic Effects of Adrenocorticotropin on the Levels of Messenger Ribonucleic Acid and Protein of Steroidogenic Enzymes in Rat Adrenal in Vivo Endocrinology, September 1, 1998; 139(9): 3913 - 3922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. L. Miller Why Nobody Has P450scc (20,22 Desmoslase) Deficiencyg J. Clin. Endocrinol. Metab., April 1, 1998; 83(4): 1399 - 1400. [Full Text]
|
|
|
|
|
|
K. M. Caron, S.-C. Soo, W. C. Wetsel, D. M. Stocco, B. J. Clark, and K. L. Parker Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia PNAS, October 14, 1997; 94(21): 11540 - 11545. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
