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Original Studies |
Reproductive Endocrine Unit, Massachusetts General Hospital (S.B.S., W.F.C.), Boston, Massachusetts 02114; the Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School (J.C.A., J.L.J.), Chicago, Illinois 60611; and the Section of Pediatric Endocrinology, Yale University School of Medicine (M.G.), New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Stephanie B. Seminara, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 505, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114. E-mail: seminara.stephanie{at}mgh.harvard.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Baseline patterns of pulsatile gonadotropin secretion and gonadotropin
responsiveness to exogenous pulsatile GnRH were examined in the
affected males. LH, FSH, and free 
-subunit were determined during
12.5–24 h of frequent blood sampling (every 10 min). Both
patients then received pulsatile GnRH (25 ng/kg) sc every 2 h for
6–7 days. Gonadotropin responses to a single GnRH pulse iv were
monitored daily to assess the pituitary responsiveness to exogenous
GnRH. In the proband, FSH and LH levels demonstrated a subtle, but
significant, response to GnRH over the week of pulsatile GnRH therapy.
Free -subunit levels demonstrated an erratic pattern of secretion at
baseline and no significant response to pulsatile GnRH.
We conclude that 1) affected males with AHC/HH may have an intrinsic defect in spermatogenesis that is not responsive to gonadotropin therapy; 2) female carriers of DAX1 mutations may express the phenotype of delayed puberty; and 3) although affected individuals display minimal responses to pulsatile GnRH, as observed in other AHC kindreds, subtle differences in gonadotropin patterns may nevertheless exist between affected individuals within a kindred.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Long term data on gonadal function in patients with AHC/HH is lacking. No cases of true fertility have yet been reported in men with this condition. It is unclear whether fertility can be induced in these patients by using exogenous gonadotropins, as Dax-1 is also expressed in Sertoli cells, and the recently reported Ahch (Dax1) knockout mouse demonstrates markedly disordered spermatogenesis (7). In addition, little information has been available regarding the phenotypic status of female carriers of DAX1 gene mutations. However, recently, a female with isolated HH was found to be homozygous for a DAX1 nonsense mutation, demonstrating a unique molecular etiology for this disorder (8).
Much of the early clinical data on AHC patients examined whether the
hypogonadism of these individuals was due to defects at the
hypothalamus or pituitary. Attempts to stimulate gonadotropin secretion
were conducted using pulsatile GnRH. Although these cases predated the
discovery of DAX1 (and, by extension, do not represent
confirmed DAX1 mutations), investigators were unable to
resolve whether the hypogonadism of AHC was of hypothalamic or
pituitary origin (9, 10, 11, 12, 13). However, by 1) conducting frequent (every
10–20 min) blood sampling for LH, FSH, and free -subunit (FAS) to
examine the baseline pulsatile activity of the
hypothalamic-pituitary-gonadal (HPG) axis and 2) administering
exogenous pulsatile GnRH at physiological doses to two patients with
different DAX-1 mutations, we have been able to demonstrate that DAX-1
can impair gonadotropin production by acting at both hypothalamic and
pituitary levels (14).
This study presents an extended kindred with AHC/HH. The proband of this family failed to develop spermatogenesis despite 3 yr of exogenous gonadotropin therapy, suggesting the presence of an independent gonadal defect in AHC/HH. In addition, this family demonstrates the novel finding that delayed puberty can be a manifestation of DAX1 mutations in females. The results of detailed hypothalamic-pituitary-gonadal investigations in two members of this kindred are also presented.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The proband, III-9 (Fig. 1
), was
the product of a full-term, normal, spontaneous delivery. He presented
at 11 days of life with poor intake, drowsiness, and weight loss and
presented again at 4 weeks with malnutrition and dehydration. At that
time, examination revealed mottled skin with poor turgor, but the
abdomen, genitalia, and extremities were normal. Electrolyte
determinations consistently showed low sodium and chloride and elevated
potassium levels. Serum cortisol levels were subnormal, with only a 2-
to 3-fold increase after ACTH administration. The patient remained
hospitalized for the next 2.5 months and received cortisone treatment.
He was discharged with a diagnosis of transient hypoadrenalism of
infancy. Although he did not require any steroid supplementation during
childhood, III-9 recollects a childhood preference for salty foods. He
presented at age 12 yr with anorexia, weight loss, poor growth, and
hyponatremia (Na, 118 mEq/L). Physical examination was notable for
hyperpigmentation, and he was begun on hydrocortisone and
fludrocortisone treatment.
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).
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The patient had five siblings, three of whom died prematurely. A 14-yr-old sister had homocystinuria (III-8), a 2.5-yr-old sister died of nephritis (III-3), and a boy born 2 months prematurely died at 2.5 days of age (III-2). The proband’s brother underwent normal puberty and development. The proband’s father had a history of thyrotoxicosis. His mother (II-4) had a history of delayed puberty, with menarche at age 17 yr.
The patient III-9’s surviving sister (III-4), similar to her mother, also underwent a delayed menarche at age 17–18 yr. However, after completion of puberty, she maintained regular menstrual cycles and conceived two children. In 1981, she had a healthy daughter (IV-1), who had normal growth and development, but did not undergo menarche until age 17 yr. Although the history is vague, both III-4 and IV-1 underwent pubarche and thelarche in their early teens. All three women in this lineage had no history of eating disorder, marked weight loss, major life stressors, or competitive athletics, with the exception of IV-1, who ran on her high school track team.
In 1983, III-4 bore a son (IV-2) who was an 8-lb 5-oz product of an
uncomplicated full-term pregnancy. He presented at 4 weeks of age with
irritability, dehydration, hyponatremia, and hyperkalemia. Physical
examination revealed a slightly thin but well developed male infant
with normally descended testes. During hospital admission, IV-2 was
treated with hydrocortisone and iv sodium chloride; fludrocortisone and
deoxycorticosterone acetate were added to his regimen. Work-up revealed
an elevated serum renin, low serum aldosterone, and normal serum
testosterone (209 ng/dL), LH (6 mIU/mL), FSH (2 mIU/mL), and
17-hydroxyprogesterone (352 ng/dL). Patient IV-2 was switched to
dexamethasone and readmitted at 7.5 weeks for confirmation of his
diagnosis with ACTH stimulation testing. A 3-day ACTH stimulation test
yielded no cortisol elevation, and he was restarted on hydrocortisone
and fludrocortisone, with intermittent injections of
deoxycorticosterone.
Patient IV-2 remained well below the fifth percentile on his growth curve throughout infancy and childhood, with a height age equivalent to 4 yr at age 6 yr. He had two episodes of adrenal insufficiency, presenting primarily with hypoglycemia, once at 15 months during gastroenteritis and otitis media, and once at 7 yr, with gastroenteritis, vomiting, and fever. At 9 2/12 yr, IV-2 underwent dynamic anterior pituitary testing. In response to 0.10 U/kg insulin, his GH level rose from 14 to 33 ng/mL (normal, >10). His cortisol level showed no response, with a baseline level of 11 µg/dL that failed to increase during testing. In response to 400 µg TRH, his TSH levels rose from a baseline of 1.3 µIU/mL to a peak TSH of 5.0 µIU/mL, an inadequate response (normal, increase of 10–30). His PRL rose from a baseline of 6 ng/mL to a peak level of 52 ng/mL (normal, >20 or 3 times baseline). In response to 100 µg GnRH, LH remained less than 0.5 µIU/mL and FSH less than 1.0 µIU/mL at all time points. At a chronological age of 9 2/12 yr, IV-2’s bone age was 6 yr.
At 12 3/12 yr, patient IV-2 continued to be well below the fifth percentile on the normal growth curves (height, 51 in.; height age, 8 6/12 yr; predicted height using Bayley prediction tables, 68 in.). Physical examination revealed no pubic or axillary hair and prepubertal testes. Bone age remained markedly delayed at 6 6/12 to 8 yr. On repeat GnRH stimulation testing, testosterone levels at 1 and 120 min were less than 3 ng/100 mg. FSH levels rose from 2.4 µIU/mL to a peak of 4.6 µIU/mL at 120 min. LH levels rose from 0.16 µIU/mL to a peak of 1.1 µIU/mL at 60 min.
Clinical studies
After obtaining written informed consent, both patients were admitted to the General Clinical Research Center at the Massachusetts General Hospital, patient III-9 in 1980 (age 22 yr) and patient IV-2 in 1998 (age 15 yr). Patient III-9 discontinued his hCG for 8 weeks before the study, and patient IV-2 was not taking any hormone replacement therapy. Frequent blood sampling every 10–20 min was performed for 12.5–24 h for measurement of LH, FSH, and FAS. FSH levels were measured from hourly pools, and testosterone levels were measured from 6-h pools of serum. After completion of frequent sampling, each patient received pulsatile GnRH (25 ng/kg) sc via pulsatile pump every 2 h for 6–7 days. Each morning while using the GnRH pump, gonadotropin responses to a single iv GnRH bolus were monitored. LH, FSH, and FAS levels were determined every 15 min for 2 h after the GnRH pulse.
Assays
Serum LH and FSH concentrations were determined by immunoassays
calibrated against the Second International Reference Preparation of
human menopausal gonadotropin (hMG; WHO 71/223) (15, 16, 17). For patient
III-9, the minimum detectable dose was 0.8 mIU hMG (WHO 71/223)/mL; for
patient IV-2, the minimum detectable dose was 1.6 mIU hMG (WHO
71/223)/mL. Inter- and intraassay coefficients of variation were less
than 10%. FAS was measured using a monoclonal antibody RIA, with a
highly purified -subunit of hCG as the standard (18, 19).
Testosterone levels were also measured by RIA (20). Secretory patterns
were analyzed for pulses using a modified version of the Santen and
Bardin method (21). Statistical analysis was performed using a
Newman-Keuls ANOVA.
Direct sequencing of DAX1
After obtaining informed consent, blood samples were taken from individuals II-4, III-4, III-9, IV-1, and IV-2, and leukocyte DNA was extracted. Exons 1 and 2 of DAX1 were amplified by PCR using primers and conditions described previously (5). Direct sequencing of PCR products was performed using the dRhodamine terminator cycle sequencing kit (Perkin-Elmer Corp., Palo Alto, CA) and automated sequencer (model 377, PE Applied Biosystems, Foster City, CA). After detection of a mutation, additional primers were used to PCR amplify the region of interest (forward, 5'-GCTCAAAGCAAACGCACGTGGCTC-3'; reverse, 5'-GACGAAGCGCAGCGTCTTCAACAG-3'). Restriction enzyme analysis of this DNA fragment was performed using MspI (Promega Corp., Madison, WI).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Direct sequencing of DAX1 revealed a hemizygous 501delA
mutation in both the proband (III-9) and his affected nephew [IV-2;
Fig. 3A; A of the ATG start codon
designated +1; 501delA of IV-2 previously reported (22)]. This single
nucleotide deletion results in a frame shift and premature stop codon
at position 263. Three women (II-4, III-4, and IV-1) from different
generations of this kindred, each with markedly delayed puberty, were
all heterozygous for this 501delA mutation (Fig. 3A). Deletion of this
nucleotide creates a novel MspI restriction site.
Restriction enzyme analysis confirmed the hemizygous status of affected
males and the heterozygous carrier status of females (Fig. 3B).
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Patient III-9 (Fig. 4A) exhibited
apulsatile gonadotropin secretion, with LH levels below the limits of
detection of the assay (<0.8 mIU/mL). FSH levels were at the low end
of the normal male range (mean FSH, 1.2 mIU/mL), but FAS levels were
well within the normal range (mean FAS, 126.2 pg/mL). Six FAS pulses
were detected by modified Santen and Bardin analysis. In patient IV-2
(Fig. 4B), LH levels were below the limits of detection (<1.6 mIU/mL)
for every data point in the study. Mean FSH and FAS levels equaled 3.5
mIU/mL and 34.9 pg/mL, respectively. No FAS pulses were detectable.
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Both III-9 and IV-2 received pulsatile GnRH for 7 and 6
days, respectively, to examine their pituitary responsiveness to
exogenous pulsatile GnRH (Fig. 5). There
was no initial gonadotropin pulse for either patient on day 1 of
therapy. For patient III-9, FSH levels tripled from day 1 to day 7 of
GnRH therapy (P < 0.001; Fig. 5A). LH levels remained
at the level of assay sensitivity for the first 4 days of the study,
then increased significantly over the course of the last 3 days
(P < 0.005). Testosterone levels increased from 6 to
141 ng/dL during the week. FAS levels did not change significantly.
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). However, mean FSH
levels increased modestly, but significantly, from day 1 to day 6
(P < 0.001). |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the rat, Dax-1 is expressed in Sertoli cells, with maximal levels present during the first spermatogenic wave (postnatal days 20 and 30) (23). However, Dax-1 expression declines to low basal levels in the 40-day-old, sexually mature animal, demonstrating a pattern of developmental regulation. The mouse model of AHC, created by targeted disruption of the mouse homolog of DAX1 (Ahch), has extended our understanding of the role of this gene mutant in gonadal function (7). Based on observations in the human, it was originally hypothesized that the hypogonadism of AHC in mice would be due to deficient gonadotropin secretion. However, mutant mice had normal levels of LH and FSH; pituitary immunohistochemical staining for LHß and FSHß was also normal. Male mice demonstrated a primary testicular defect with progressive seminiferous tubule epithelial degeneration, leading to a complete loss of germ cells by 14 weeks. Leydig cell hyperplasia was also observed, suggesting either an independent Leydig cell defect due to Ahch disruption or a secondary response to the Sertoli cell defect.
Although the differences between human and mouse phenotypes could be explained by species-specific pathways, there is a paucity of data regarding testicular histology and induction of spermatogenesis in men with AHC. Schwartz et al. reported the case of an affected male who underwent a short course of pulsatile GnRH and produced a semen sample with a few spermatozoa (24). However, further details regarding sperm count, morphology, and motility were not described. In the present report, the proband underwent a testicular biopsy after 7 yr of low dose hCG therapy, revealing essentially Sertoli cell only syndrome with Leydig cell hyperplasia. However, 3 yr of escalating doses of both hCG and Pergonal failed to induce spermatogenesis despite an increase in testicular size from 5 to 10 cc. These findings suggest that even when bypassing the hypothalamic-pituitary axis with exogenous gonadotropins, AHC patients can harbor an intrinsic gonadal defect. The degeneration of large segments of the seminiferous tubules observed in knockout mice suggests that Ahch is necessary for maintenance of epithelial integrity and spermatogenesis. Extending this concept to the human male, restoration of a normal hormonal milieu in AHC/HH appears unable to overcome this defect.
The age of onset of AHC appears to be variable. Most patients present with salt wasting in neonatal life, but a significant fraction are well into their childhood years before presentation (5). Although the hypogonadotropic hypogonadism associated with AHC is conventionally perceived as a congenital disorder, recent data have demonstrated transient postnatal activation of the HPG axis in AHC patients. Normal serum gonadotropin and testosterone levels have been demonstrated in a newborn male with AHC and a confirmed DAX1 mutation (A300V) (25). Hormonal data from four boys with AHC (aged 1–3 months) have also suggested an active HPG axis (26). In the current report, the proband’s nephew demonstrated a neonatal testosterone level of 209 ng/dL in the setting of a LH level of 6 mIU/mL during this same developmental window. These findings suggest that the mechanisms that control neonatal activation of the HPG axis may be distinct from those occurring at puberty or that the hypogonadotropic hypogonadism of AHC worsens over time. Therefore, our understanding of the hypogonadotropic hypogonadism associated with AHC continues to evolve, encompassing defects at the hypothalamus, pituitary, and perhaps even gonad, with congenital and developmental components.
Despite these insights into the age spectrum of AHC in male patients, until recently, little information has been available regarding the adrenal or pubertal phenotype in female carriers of DAX1 gene mutations. Merke et al. reported two boys with AHC/HH and a nonsense mutation in the DNA-binding domain of the DAX1 gene (8). The boys’ maternal aunt, who was homozygous for the nonsense mutation through gene conversion, had the phenotype of isolated hypogonadotropic hypogonadism, demonstrating a surprising range of phenotypes in this one family. In the kindred reported here, three female heterozygotes carrying the del501A mutation all underwent markedly delayed menarche. Delayed puberty in female carriers may thus represent a forme fruste of the hypogonadotropic hypogonadism associated with AHC. Although it is possible that there are other etiologies for the delayed puberty in these women, no commonly implicated physiological or genetic factors could be elicited by history. Although the women in this kindred may have had an incomplete form of central hypogonadism, there is no evidence to suggest that any of them had adrenal dysfunction. The possibility that these women might have had abnormal DHEAS or aldosterone levels or diminished adrenal reserve on formal ACTH testing could not be studied.
Partial expression of X-linked disorders in heterozygous females has been well documented for a number of conditions, including ornithine transcarbamylase deficiency (27, 28), Duchenne muscular dystrophy (29, 30), and fragile X mental retardation (31). Although it is assumed that female somatic cells undergo a 50:50 random X inactivation, this is often not true in a given individual or clonal cell population. Therefore, if a female carrier has a higher proportion of mutant alleles on the active X-chromosome in a relevant cell lineage (i.e. skewing), she may show symptoms similar to those of a hemizygous affected male, as has been observed in hemophilia B (32). Although in the current report, multiple females within a single kindred had delayed menarche, familial nonrandom X inactivation has been described in some rare pedigrees [Duchenne muscular dystrophy (30) and hemophilia B (33)]. Although no direct evidence is presented in the current study to support familial skewing, the possibility of genetic determinants in the randomness of X inactivation remains an important model to consider (34, 35). In addition to extended pedigrees, further studies will be needed to determine whether DAX1 mutations occur in females with delayed puberty who do not have a family history of AHC/HH.
Long term data on hypothalamic-pituitary-gonadal function in patients with AHC/HH are also lacking. Age at diagnosis has been used to assess the severity of AHC (5), but no standardized biochemical testing yet appears available as a marker of reproductive phenotype. Using pulsatile GnRH therapy, investigators have observed patterns consistent with both hypothalamic and pituitary defects (9, 10, 11, 12, 13, 14). In the current study, both the proband and his nephew shared many similarities with respect to their gonadotropin profiles. Neither individual demonstrated LH pulsatility at baseline. During a 1-week exposure to exogenous pulsatile GnRH, both patients demonstrated significant elevations of FSH compared to baseline levels, but the responses were very modest compared to those in patients with Kallmann syndrome, a type of HH due to an isolated hypothalamic defect in GnRH secretion. Our group has shown that Kallmann’s patients given an identical regimen of pulsatile GnRH demonstrate a more robust gonadotropin response, with marked increases in both LH and FSH secretion occurring within 1 week (14).
Despite these gross similarities, there were also some important differences in the gonadotropin profiles between the affected males of this kindred. Although IV-2 had flat FAS levels, III-9 had FAS levels well within the normal male range with evidence of erratic pulsatility, suggesting GnRH-independent stimulation to the gonadotrope. Patient III-9 also had significant elevations of both LH and FSH over the week of GnRH exposure, whereas IV-2 demonstrated a significant change in only FSH. Patient III-9’s rise in LH, although quite subtle, was accompanied by a marked rise in his testosterone level from 6 ng/dL (day 1) to 141 ng/dL (day 7). Prior therapy with hCG may have allowed III-9 to achieve a greater mass of Leydig cells and hence an increase in testosterone compared to his nephew, although both received identical pulsatile GnRH regimens and had similarly meager LH responses. Nonetheless, one might have expected a somewhat more dramatic rise in LH to have accompanied the elevation in testosterone, raising the possibility that FSH itself may induce Leydig cell steroidogenesis or that it stimulates another factor to induce testosterone production. Although recombinant FSH does not appear to have a direct effect on testosterone production in vitro, recent data suggest that FSH may increase the production of a Sertoli cell-secreted factor able to up-regulate testicular steroidogenesis (36). Therefore, although both patients demonstrated atypical responses to GnRH compared to other states of GnRH deficiency, subtle differences between these two patients suggest that the proband has a less severe reproductive phenotype than his nephew.
In addition, the proband of this family survived 12 yr without glucocorticoid or mineralocorticoid replacement, suggesting that he also has a less severe form of adrenal insufficiency. Intrafamilial variability in the temporal expression and degree of adrenal insufficiency has been reported by a number of investigators (5). In a kindred previously reported by our group, the presentation of adrenal insufficiency spanned 1 day to 8 yr among affected individuals (14). The proband’s nephew never had steroid therapy withdrawn after neonatal life, so it is not known whether he could have survived off of therapy. In the future, serial monitoring of ACTH levels in male patients with known DAX1-inactivating mutations may help investigators to more precisely determine the onset of adrenal insufficiency. Although most AHC patients are found to have HH when they reach pubertal age, not all patients have been found to have mutations in the DAX1 gene, suggesting that other gene defects or epigenetic phenomena may lead to the same phenotype (3).
In summary, this study adds to the growing body of information of the hypogonadism of AHC and expands the phenotype of this disorder to include intrinsic defects in spermatogenesis in men and possibly delayed puberty in women. Both members of this kindred demonstrated gonadotropin profiles consistent with a pituitary defect, but subtle differences between the profiles suggest that the reproductive phenotype was less severe in the proband.
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Footnotes |
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Received April 13, 1999.
Revised July 7, 1999.
Accepted August 9, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit as an alternative
neuroendocrine marker of gonadotropin-releasing hormone (GnRH)
stimulation of the gonadotroph in the human: evidence from normal and
GnRH-deficient men. J Clin Endocrinol Metab. 70:1654–1661.-Carboxymethylmercaptotestosterone-bovine serum albumin conjugate:
measurement of testsoterone in male plasma without chromatography. Steroids. 28:101–109.[CrossRef][Medline]
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E. R. B. McCabe Vulnerability within a Robust Complex System--DAX-1 Mutations and Steroidogenic Axis Development J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 41 - 43. [Abstract] [Full Text] [PDF]
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G. Mantovani, G. Ozisik, J. C. Achermann, R. Romoli, G. Borretta, L. Persani, A. Spada, J. L. Jameson, and P. Beck-Peccoz Hypogonadotropic Hypogonadism as a Presenting Feature of Late-Onset X-Linked Adrenal Hypoplasia Congenita J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 44 - 48. [Abstract] [Full Text] [PDF]
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J. Teixeira, S. Maheswaran, and P. K. Donahoe Mullerian Inhibiting Substance: An Instructive Developmental Hormone with Diagnostic and Possible Therapeutic Applications Endocr. Rev., October 1, 2001; 22(5): 657 - 674. [Abstract] [Full Text] [PDF]
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 B. Jeffs, J. J. Meeks, M. Ito, F. A. Martinson, M. M. Matzuk, J. L. Jameson, and L. D. Russell Blockage of the Rete Testis and Efferent Ductules by Ectopic Sertoli and Leydig Cells Causes Infertility in Dax1-Deficient Male Mice Endocrinology, October 1, 2001; 142(10): 4486 - 4495. [Abstract] [Full Text] [PDF]
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S. Domenice, A. C. Latronico, V. N. Brito, I. J. P. Arnhold, F. Kok, and B. B. Mendonca Adrenocorticotropin-Dependent Precocious Puberty of Testicular Origin in a Boy with X-Linked Adrenal Hypoplasia Congenita Due to a Novel Mutation in the DAX1 Gene J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4068 - 4071. [Abstract] [Full Text] [PDF]
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J. C. Achermann, M. Ito, B. L. Silverman, R. L. Habiby, S. Pang, A. Rosler, and J. L. Jameson Missense Mutations Cluster within the Carboxyl-Terminal Region of DAX-1 and Impair Transcriptional Repression J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3171 - 3175. [Abstract] [Full Text] [PDF]
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 Z. J. Wang, B. Jeffs, M. Ito, J. C. Achermann, R. N. Yu, D. B. Hales, and J. L. Jameson Aromatase (Cyp19) expression is up-regulated by targeted disruption of Dax1 PNAS, June 20, 2001; (2001) 141543298. [Abstract] [Full Text] [PDF]
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S. J. B. Aylwin, J. P. Welch, C. L. Davey, J. F. Geddes, D. F. Wood, G. M. Besser, A. B. Grossman, J. P. Monson, and J. M. Burrin The Relationship between Steroidogenic Factor 1 and DAX-1 Expression and in Vitro Gonadotropin Secretion in Human Pituitary Adenomas J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2476 - 2483. [Abstract] [Full Text] [PDF]
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S. B. Seminara and W. F. Crowley Jr. Perspective: The Importance of Genetic Defects in Humans in Elucidating the Complexities of the Hypothalamic-Pituitary-Gonadal Axis Endocrinology, June 1, 2001; 142(6): 2173 - 2177. [Full Text] [PDF]
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L. M. B. Oliveira, S. B. Seminara, M. Beranova, F. J. Hayes, S. B. Valkenburgh, E. Schipani, E. M. F. Costa, A. C. Latronico, W. F. Crowley Jr., and M. Vallejo The Importance of Autosomal Genes in Kallmann Syndrome: Genotype-Phenotype Correlations and Neuroendocrine Characteristics J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1532 - 1538. [Abstract] [Full Text]
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M. Beranova, L. M. B. Oliveira, G. Y. BÉdÉcarrats, E. Schipani, M. Vallejo, A. C. Ammini, J. B. Quintos, J. E. Hall, K. A. Martin, F. J. Hayes, et al. Prevalence, Phenotypic Spectrum, and Modes of Inheritance of Gonadotropin-Releasing Hormone Receptor Mutations in Idiopathic Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1580 - 1588. [Abstract] [Full Text]
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 J. J. Tremblay and R. S. Viger Nuclear Receptor Dax-1 Represses the Transcriptional Cooperation Between GATA-4 and SF-1 in Sertoli Cells Biol Reprod, April 1, 2001; 64(4): 1191 - 1199. [Abstract] [Full Text]
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Mutational Analysis of DAX1 in Patients with Hypogonadotropic Hypogonadism or Pubertal Delay J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4497 - 4500. [Abstract] [Full Text]
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Z. J. Wang, B. Jeffs, M. Ito, J. C. Achermann, R. N. Yu, D. B. Hales, and J. L. Jameson Aromatase (Cyp19) expression is up-regulated by targeted disruption of Dax1 PNAS, July 3, 2001; 98(14): 7988 - 7993. [Abstract] [Full Text] [PDF]
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