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Philippe Bouchard and Bart C J M Fauser

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Gérard Karsenty, Philippe Bouchard, André Ulmann and Gilbert Schaison

Abstract. Metabolic clearance rate (MCR) and daily production rate (DPR) of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) were measured in 7 hyperthyroid patients and 8 control subjects after a single injection of tritiated 1,25(OH)2D3. Using a bicompartmental analysis, MCR of 1,25(OH)2D3 was found to be significantly higher in hyperthyroid than in control subjects (11.5 ± 4.4 vs 5.9 ± 2.4 ml/min (sd), P < 0.01). No significant difference in plasma 1,25(OH)2D and DPR of 1,25(OH)2D3 was demonstrated. MCR was again measured 1 month after initiation of treatment in 4 hyperthyroid patients and remained elevated. In 2 of these patients, MCR was once more determined 6 months later and had declined towards normal. No correlation was found between MCR and DPR and either plasma calcium, phosphate, immunoreactive PTH, 1,25(OH)D and T3 values. In conclusion, MCR of 1,25(OH)2D3 is elevated in hyperthyroidism, but this finding is probably unrelated to the effect of thyroid hormones on bone metabolism.

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Lise Duranteau, Philippe Chanson, Joelle Blumberg-Tick, Guy Thomas, Sylvie Brailly, Jean Lubetzki, Gilbert Schaison and Philippe Bouchard

We investigated the potential pituitary origin of gonadal insufficiency in hemochromatosis. Gonadotropin secretion was studied in seven patients with hemochromatosis and hypogonadism, before and after chronic pulsatile GnRH therapy. Pulsatile LH secretion was studied before (sampling every 10 min for 6 h) and after 15-30 days of chronic pulsatile GnRH therapy (10-12 μg per pulse). Prior to GnRH therapy, all the patients had low serum testosterone, FSH and LH levels. LH secretion was non-pulsatile in four patients, while a single pulse was detected in the remaining three. Chronic pulsatile GnRH administration did not increase serum testosterone levels; similarly, serum LH levels remained low: neither pulse frequency nor pulse amplitude was modified. We conclude that hypogonadism in hemochromatosis is due to pituitary lesions.

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Philippe Bouchard, Frederique Kuttenn, Irene Mowszowicz, Gilbert Schaison, Marie-Charles Raux-Eurin and Pierre Mauvais-Jarvis

Abstract.

Five women with post pubertal hirsutism due to a partial 21-hydroxylase deficiency were studied. These patients had no abnormalities of the external genitalia. They were compared to 3 adult women with a complete defect in 21-hydroxylase. The diagnosis of 21-hydroxylase deficiency was substantiated by the dramatic increase in 17-hydroxyprogesterone (17-OHP) after im injection of 250 μg synthetic ACTH (22 ± 12 nmol/l to 349 ± 153 nmol/l). However, in adult women with 21-hydroxylase deficiency recognized at birth and presenting abnormalities of the external genitalia, plasma 17-OHP was elevated in basal conditions (512 ± 106 nmol/l) and only slightly increased after ACTH administration (657 ± 133 nmol/l). Plasma cortisol levels determinated at 08.00 h were lower than normal in both groups but only slightly in groups with partial 21-hydroxylase deficiency. After ACTH stimulation, plasma cortisol levels remained lower than normal in all patients but with a noticeable increase in patients with partial defect. The differences noted between precocious and delayed onset virilization gave an indication of the importance of the enzyme defect. Plasma testosterone (T) and androstenedione (Δ4) levels were elevated both in basal conditions and after ACTH administration. However, in patients with delayed onset of hirsutism most circulating T seems to originate from peripheral conversion of Δ4 to T. Plasma ACTH values were strongly elevated in patients with a complete defect in 21-hydroxylase (260 ± 50 pg/ml) but normal in patients with partial deficiency (< 40 pg/ml).

In vitro testosterone 5α-reductase activity was determined in pubic skin homogenates from 4 patients with partial 21-hydroxylase deficiency. The amount of dihydrotestosterone + androstanediols formed from incubated [3H]testosterone was in the normal range for women. Virilization of patients with partial 21-hydroxylase deficiency therefore seems to be essentially due to an increase in active androgen production and not to exaggerated skin 'utilization' of pre-androgens as observed in idiopathic hirsutism.

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Vincent Lavoué, Karine Morcel, Philippe Bouchard, Charles Sultan, Catherine Massart, Jean-Yves Grall, Serge Lumbroso and Marie-Christine Laurent

Introduction

McCune–Albright syndrome (MAS) is characterized by peripheral precocious puberty, caf é -au-lait spots, and polyostotic fibrous dysplasia. This syndrome is due to a post-zygotic mutation of the GNAS1 gene with mosaic distribution and unilateral predominance. Clinical manifestations depend on the tissues carrying the mutation. We describe the ovarian function before and after unilateral ovariectomy in a woman with MAS and bilateral distribution of the GNAS1 gene mutation.

Case report

A 33-year-old patient, previously diagnosed as having MAS, presented irregular menstrual cycles (30–180 days) and monophasic temperature curves. Transvaginal ultrasound and blood tests were repeated at 3-day intervals over 3 months. Findings included a persistent quiescent left ovary, a persistent polycystic right ovary, constantly high estradiol-17β (E2) levels, and very low FSH and LH levels. She also presented severe persistent pelvic pain. Because of unilateral ovarian activity, a unilateral right ovariectomy was performed as well as biopsy of the remaining left ovary. A GNAS1 gene mutation was identified in both ovaries. A regular monthly menstrual cycle was immediately restored. On day 3 of the menstrual cycle, E2 level was 30 pg/ml, FSH level was 7.5 mIU/ml, and LH level was 6.4 mIU/ml. On day 17, pelvic ultrasound showed one follicle of 25 mm in the left ovary. On day 21, the progesterone level was 13.1 ng/ml.

Discussion

This is the first report of ovulation being restored following unilateral ovariectomy in an adult patient suffering from severe MAS with GNAS1 gene mutation identified in both ovaries.

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Georg Brabant, Robin P Peeters, Shiao Y Chan, Juan Bernal, Philippe Bouchard, Domenico Salvatore, Kristien Boelaert and Peter Laurberg

Guideline advice of many societies on the management of subclinical hypothyroidism in pregnancy suggests treatment when TSH serum levels exceed 2.5 mU/l. Justification of this procedure is based on limited experience, mainly from studies carried out in patients with positive thyroid-specific antibodies and higher TSH levels that classically define the condition in the non-pregnant state. Taking into account a lack of clear understanding of the regulation of thyroid hormone transport through the utero-placental unit and in the absence of foetal markers to monitor the adequacy of thyroxine treatment, this review attempts to discuss currently available data and suggests a more cautious approach.

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Magali Svrcek, Emmanuelle Jeannot, Lionel Arrivé, Raoul Poupon, Gaëlle Fromont, Jean-François Fléjou, Jessica Zucman-Rossi, Philippe Bouchard and Dominique Wendum

Objective: The relationship between sex hormones and hepatocellular adenoma development is well established. On the contrary, their contribution to liver adenomatosis (LA) development is still a debatable issue. Recently, inactivating mutations of hepatocyte nuclear factor-1α (HNF-1α) transcription factor gene or activating mutations of β-catenin have been demonstrated in some liver adenomas, and a possible link between HNF-1α gene mutations and oral contraceptives has been suggested. Only two cases of regressive LA after hormone withdrawal therapy have been described so far but without any information concerning the molecular characteristics of the tumours.

Case: We report the case of a 48-year-old woman with LA, who had been taking an androgenic progestin therapy (lynestrenol) for 10 years. A major regression in the number and size of the lesions was observed 6 months after complete withdrawal of this therapy.

Methods: Hepatocellular adenomas were studied by immunohistochemistry for oestrogen, progesterone and androgen receptors (ER, PR and AR respectively), and for β-catenin. Direct sequencing of the HNF-1α gene was also performed.

Results: For the first time, we demonstrate significant immunostaining of AR in the hepatocellular adenomas. This staining was negative in the partially regressive adenoma. Immunostainings for ER and PR were negative. HNF-1α and the β-catenin pathways were not involved in tumour pathogenesis.

Conclusions: Our case suggests a role of androgenic progestin therapy in some cases of LA. Hormone therapy withdrawal may induce a significant regression in lesions.

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Zeina Chakhtoura, Anne Bachelot, Dinane Samara-Boustani, Jean-Charles Ruiz, Bruno Donadille, Jérôme Dulon, Sophie Christin-Maître, Claire Bouvattier, Marie-Charles Raux-Demay, Philippe Bouchard, Jean-Claude Carel, Juliane Leger, Frédérique Kuttenn, Michel Polak and Philippe Touraine

Objective

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).

Design

This was a retrospective study.

Methods

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.

Results

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).

Conclusion

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.

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Paul Laissue, Sophie Christin-Maitre, Philippe Touraine, Frederique Kuttenn, Olli Ritvos, Kristiina Aittomaki, Nathalie Bourcigaux, Laetitia Jacquesson, Philippe Bouchard, Rene Frydman, Didier Dewailly, Anne-Céline Reyss, Luke Jeffery, Anne Bachelot, Nathalie Massin, Marc Fellous and Reiner A Veitia

Background and objective: Mutations in bone morphogenic protein 15 (BMP15) and growth/differentiation factor 9 (GDF9) lead to altered fertility in animal models. In the human, a heterozygous point mutation of BMP15 has been associated with premature ovarian failure (POF).

Subject and methods: We have directly sequenced both genes in a cohort of 203 POF patients presenting with primary or secondary amenorrhea and high FSH levels and in a control population including 54 women with regular menstrual cycles who had at least one child.

Results: We have identified several heterozygous variants. One alteration in GDF9 (S186Y) and one in BMP15 (L148P) may have pathogenic effects as both positions are conserved in vertebrate species, ranging from the chicken to mammals. These variants were absent in the control samples. We also found synonymous and neutral substitutions.

Conclusions: We propose that although mutations in BMP15 and GDF9 are not a major cause of ovarian insufficiency, they may be involved in POF.

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Delphine Vezzosi, Catherine Cardot-Bauters, Nicolas Bouscaren, Maëlle Lebras, Mireille Bertholon-Grégoire, Patricia Niccoli, Nathalie Levy-Bohbot, Lionel Groussin, Philippe Bouchard, Antoine Tabarin, Philippe Chanson, Pierre Lecomte, Isabelle Guilhem, Nicolas Carrere, Eric Mirallié, François Pattou, Jean Louis Peix, Diane Goere, Françoise Borson-Chazot, Philippe Caron, Vanina Bongard, Bruno Carnaille, Pierre Goudet and Eric Baudin

Objective

Management of insulinomas in the context of MEN1 remains poorly studied. The aim of this study was to evaluate long-term results of various surgical approaches in a large cohort of insulinoma–MEN1 patients.

Design and methods

Consecutive insulinoma–MEN1 patients operated on for a nonmetastatic insulinoma between 1957 and 2010 were retrospectively selected from the MEN1 database of the French Endocrine Tumor Group. The type of surgery was categorized as distal pancreatectomy (DP), total pancreatectomy/cephalic duodenopancreatectomy (TP/CDP), or enucleation (E). Primary endpoint was time until recurrence of hypoglycemia after initial surgery. Secondary endpoints were post-operative complications.

Results

The study included 73 patients (median age=28 years). Surgical procedures were DP (n=46), TP/CDP (n=9), or E (n=18). After a median post-operative follow-up of 9.0 years (inter-quartile range (IQR): 2.5–16.5 years), 60/73 patients (82.2%) remained hypoglycemia free. E and TP/CDP were associated with a higher risk of recurrent hypoglycemia episodes (unadjusted hazard ratio: 6.18 ((95% CI: 1.54–24.8); P=0.010) for E vs DP and 9.51 ((95% CI: 1.85–48.8); P=0.007) for TP/CDP vs DP. After adjustment for International Union against Cancer pTNM classification, enucleation remained significantly associated with a higher probability of recurrence. Long-term complications had occurred in 20 (43.5%) patients with DP, five (55.6%) with TP/CDP, but in none of the patients who have undergone E (P=0.002).

Conclusion

In the French Endocrine database, DP is associated with a lower risk for recurrent hypoglycemia episodes. Due to lower morbidity, E alone might be considered as an alternative.