Jérome Dulon

Pierre and Marie Curie University - Paris 6, Lutetia Parisorum, Île-de-France, France

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Publications (8)25.9 Total impact

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    ABSTRACT: Context:Primary ovarian insufficiency (POI) is a disorder affecting approximately 1% of women under the age of 40 years. NR5A1 (SF-1) mutations have been recently reported in association with POI.Objective:Our objective was to evaluate the frequency and functional impact of NR5A1 variants in POI.Patients and Methods:One hundred eighty patients diagnosed with idiopathic POI were screened for NR5A1 mutations and functional analysis was performed for the identified variants. The DNA-binding capacity of the variants was evaluated by means of EMSA, while their transcriptional activity was assessed using luciferase reporter assays.Results:Sequencing the NR5A1 gene revealed 4 missense variants in 3 patients. These patients were aged 20, 25, and 33 years at diagnosis and presented with secondary amenorrhea. None of them presented a syndromic form, although 2 had a familial history of POI. The functional analysis carried out for these missense variants showed no significant difference in DNA binding capacity or in transcriptional activity compared to wild-type NR5A1.Conclusions:Our study in a large cohort of patients with POI showed the prevalence of NR5A1 mutations to be low (1.6%, upper 95% confidence interval 3.5%). Moreover, no functional impact was observed. Overall, in contrast with the initial report, our results exclude NR5A1 mutations as a major genetic cause of POI.
    The Journal of clinical endocrinology and metabolism 03/2013; · 6.50 Impact Factor
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    ABSTRACT: OBJECTIVE: Women with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility. DESIGN: Case/control study. METHODS: Sixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28±3 days), were included. LH pulse patterns over 6 h were determined in patients and controls. RESULTS: NO DIFFERENCES WERE OBSERVED BETWEEN PATIENTS AND CONTROLS IN TERMS OF MEAN LH LEVELS, LH PULSE AMPLITUDE, OR LH FREQUENCY. IN CAH PATIENTS, LH PULSATILITY PATTERNS WERE HETEROGENEOUS, LEADING US TO PERFORM A CLUSTERING ANALYSIS OF LH DATA, RESULTING IN A TWO-CLUSTER PARTITION. PATIENTS IN CLUSTER 1 HAD SIMILAR LH PULSATILITY PATTERNS TO THE CONTROLS. PATIENTS IN CLUSTER 2 HAD: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels. CONCLUSIONS: LH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.
    European Journal of Endocrinology 08/2012; 167(4):499-505. · 3.14 Impact Factor
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    ABSTRACT: Resumption of ovarian activity and spontaneous pregnancies are described in patients with premature ovarian failure (POF), but there is a lack of data concerning the prevalence of and predictive factors for these phenomena. The aim of the study was to determine both the prevalence of and predictive factors for spontaneous resumption of ovarian function in POF patients. A mixed retrospective and prospective study was performed at a referral center for reproductive endocrinology. A total of 358 consecutive POF patients were followed from 1997 to 2010 in our center. The cumulative incidence of resumption of ovarian function was determined, and predictive factors were identified by univariate and multivariate analysis. Of 358 patients with idiopathic POF, 86 (24%) patients presented features indicating resumption of ovarian function, and in 77 cases (88%) within 1 yr of diagnosis. Twenty-one spontaneous pregnancies (16 births, five miscarriages) occurred in 15 (4.4%) patients. Multivariate analysis (Cox model) showed that a familial history of POF, secondary amenorrhea, presence of follicles at ultrasound, and inhibin B and estradiol levels were significantly predictive of resumption of ovarian function (P < 0.01), whereas association with an autoimmune disease, anti-mullerian hormone level, the presence of follicles on biopsy, and/or genetic abnormalities did not appear predictive. We created a predictive score for resumption of ovarian function comprising age at diagnosis, presence of follicles at ultrasound, and inhibin B level. Intermittent ovarian activity in patients with POF is not a rare phenomenon. The predictive score described in this study may help us to identify POF patients most likely to recover intermittent ovarian function.
    The Journal of clinical endocrinology and metabolism 12/2011; 96(12):3864-72. · 6.50 Impact Factor
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    ABSTRACT: Osteoporosis has been an understandable concern for children and adult patients with congenital adrenal hyperplasia (CAH) who may receive or have received supraphysiological doses of glucocorticoids. Some previous reports on bone mineral density (BMD) in adult CAH patients showed no significant differences in BMD between patients with CAH and controls, but others have found lower BMD in CAH patients. In reports documenting the BMD reduction, this outcome has been attributed to an accumulated effect of prolonged exposure to excess glucocorticoids during infancy and childhood. We recently conducted a trial to establish the role of the total cumulative glucocorticoid dose on BMD. We established for the first time that there was a negative relationship between total cumulative glucocorticoid dose and lumbar and femoral BMD. Women might benefit from the preserving effect of estrogens compared to men. BMI (Body Mass Index) also appeared to protect patients from bone loss. In light of this, physicians should bear in mind the potential consequences of glucocorticoids on bone and therefore adjust the treatment and improve clinical and biological surveillance from infancy. Furthermore, preventive measures against corticosteroid-induced osteoporosis should be discussed right from the beginning of glucocorticoid therapy.
    International Journal of Pediatric Endocrinology 01/2010; 2010.
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    ABSTRACT: Premature ovarian failure (POF) encompasses a heterogeneous spectrum of conditions, with phenotypic variability among patients. The etiology of POF remains unknown in most cases. We performed a global phenotyping of POF women with the aim of better orienting attempts at an etiological diagnosis. We performed a mixed retrospective and prospective study of clinical, biological, histological, morphological, and genetic data relating to 357 consecutive POF patients between 1997 and 2008. The study was conducted at a reproductive endocrinology referral center. Seventy-six percent of the patients presented with normal puberty and secondary amenorrhea. Family history was present in 14% of the patients, clinical and/or biological autoimmunity in 14.3%. Fifty-six women had a fluctuating form of POF. The presence of follicles was suggested at ultrasonography in 50% of the patients, and observed in 29% at histology; the negative predictive value of the presence of follicles at ultrasonography was 77%. Bone mineral density alterations were found in 58% of the women. Eight patients had X chromosomal abnormalities other than Turner's syndrome, eight other patients evidenced FMR1 pre-mutation. Two other patients had autoimmune polyendocrine syndrome type 2 and 1. A genetic cause of POF was identified in 25 patients, i.e. 7% of the whole cohort. POF etiology remains most often undiscovered. Novel strategies of POF phenotyping are in such content mandatory to improve the rate of POF patients for whom etiology is identified.
    European Journal of Endocrinology 06/2009; 161(1):179-87. · 3.14 Impact Factor
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    ABSTRACT: It remains controversial whether long-term glucocorticoids are charged of bone demineralization in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The aim of this study was to know whether cumulative glucocorticoid dose from the diagnosis in childhood to adulthood in patients with CAH had a negative impact on bone mineral density (BMD). This was a retrospective study. Thirty-eight adult patients with classical and non-classical CAH were included. BMD was measured in the lumbar spine and femoral neck. Total cumulative glucocorticoid (TCG) and total average glucocorticoid (TAG) doses were calculated from pediatric and adult files. We showed a difference between final and target heights (-0.82+/-0.92 s.d. for women and -1.31+/-0.84 s.d. for men; P<0.001). Seventeen patients (44.7%) had bone demineralization (35.7% of women and 70% of men). The 28 women had higher BMD than the 10 men for lumbar (-0.26+/-1.20 vs -1.25+/-1.33 s.d.; P=0.02) and femoral T-scores (0.21+/-1.30 s.d. versus -1.08+/-1.10 s.d.; P=0.007). In the salt-wasting group, women were almost significantly endowed with a better BMD than men (P=0.053). We found negative effects of TCG, TAG on lumbar (P<0.001, P=0.002) and femoral T-scores (P=0.006, P<0.001), predominantly during puberty. BMI was protective on BMD (P=0.006). The TCG is an important factor especially during puberty for a bone demineralization in patients with 21-hydroxylase deficiency. The glucocorticoid treatment should be adapted particularly at this life period and preventive measures should be discussed in order to limit this effect.
    European Journal of Endocrinology 06/2008; 158(6):879-87. · 3.14 Impact Factor
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    ABSTRACT: During childhood, the main aims of the medical treatment of congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase are to prevent salt loss and virilization and to attain normal stature and normal puberty. As such, there is a narrow therapeutic window through which the intended results can be achieved. In adulthood, the clinical management has received little attention, but recent studies have shown the relevance of long-term follow-up of these patients. The aims here are to review the multiple clinical, hormonal and metabolic abnormalities that could be found in adult CAH patients as such a decrease in bone mineral density, overweight and disturbed reproductive functions. In women with classic CAH, a low fertility rate is reported, and is probably the consequence of multiple factors including neuroendocrine and hormonal factors, feminizing surgery, and psychological factors. Men with CAH may present hypogonadism either through the effect of adrenal rests or from suppression of gonadotropins resulting in infertility. Therefore a multidisciplinary team with knowledge of CAH should carefully follow up these patients, from childhood through to adulthood, to avoid these complications and to ensure treatment compliance and tight control of the adrenal androgens.
    Hormone Research 01/2008; 69(4):203-211. · 2.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: During childhood, the main aims of the medical treatment of congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency, are to prevent salt loss and virilization and to achieve normal stature and normal puberty. As such, there is a narrow therapeutic window through which the intended results can be achieved. In adulthood, the clinical management has received little attention, but recent studies have shown the relevance of long-term follow-up of these patients. Indeed, long-term evaluation of adult CAH patients enables the identification of multiple clinical, hormonal and metabolic abnormalities as bone mineral density alteration, overweight and disturbed reproductive functions. In women with classic CAH, low fertility rate is reported, and is probably the consequence of multiple factors, including neuroendocrine and hormonal factors, feminizing surgery, and psychological factors. Men with CAH may present hypogonadism either through the effect of adrenal rests or from suppression of gonadotropins resulting in infertility. These patients should therefore be carefully followed-up, from childhood through to adulthood, to avoid these complications and to ensure treatment compliance and tight control of the adrenal androgens, by multidisciplinary teams who have knowledge of CAH.
    Annales d Endocrinologie 10/2007; 68(4):274-80. · 1.02 Impact Factor