Philippe Touraine

Childhood Craniopharyngioma: Hypothalamus-Sparing Surgery Decreases the Risk of Obesity

CONTEXT Craniopharyngioma is a brain tumor whose high local recurrence rate has for a long time led to a preference for extensive surgery. Limited surgery minimizing hypothalamic damage may decrease the severe obesity rate at the expense of the need for radiotherapy to complete the treatment. OBJECTIVE We compared weight gain and local recurrence rates after extensive resection surgery (ERS) and hypothalamus-sparing surgery (HSS). DESIGN Our observational study compared a historical cohort managed with ERS between 1985 and 2002 to a prospective cohort managed with HSS between 2002 and 2010. SETTING The patients were treated in a pediatric teaching hospital in Paris, France. PATIENTS Thirty-seven boys and 23 girls were managed with ERS (median age, 8 years); 38 boys and 27 girls were managed with HSS (median age, 9.3 years). MAIN OUTCOME MEASURES Data were collected before and 6 months to 7 years after surgery. Body mass index (BMI) Z-score was used to assess obesity and the number of surgical procedures to assess local recurrence rate. RESULTS Mean BMI Z-score before surgery was comparable in the 2 cohorts (0.756 after ERS vs 0.747 after HSS; P = .528). At any time after surgery, mean BMI Z-score was significantly lower after HSS (eg, 1.889 SD vs 2.915 SD, P = .004 at 1 year). At last follow-up, the HSS cohort had a significantly lower prevalence of severe obesity (28% vs 54%, P < .05) and higher prevalence of normal BMI (38% vs 17%, P < .01). Mean number of surgical procedures was not significantly different in the 2 cohorts. CONCLUSIONS Hypothalamus-sparing surgery decreases the occurrence of severe obesity without increasing the local recurrence rate.

Resumption of Ovarian Function and Pregnancies in 358 Patients with Premature Ovarian Failure

CONTEXT 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. OBJECTIVE The aim of the study was to determine both the prevalence of and predictive factors for spontaneous resumption of ovarian function in POF patients. DESIGN AND SETTING A mixed retrospective and prospective study was performed at a referral center for reproductive endocrinology. PATIENTS A total of 358 consecutive POF patients were followed from 1997 to 2010 in our center. MAIN OUTCOMES MEASURES The cumulative incidence of resumption of ovarian function was determined, and predictive factors were identified by univariate and multivariate analysis. RESULTS 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. CONCLUSION 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.

Novel NOBOX loss‐of‐function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort

Primary ovarian insufficiency (POI) is a disorder associated with female infertility, which affects approximately 1% of women under 40 years of age. A genetic component has been suggested as one possible cause of the majority of cases of nonsyndromic forms. Newborn Ovary Homeobox (NOBOX) is an ovary‐specific gene, playing a critical role in ovary in mice, as its absence leads to sterility mimicking a POI. In this study, we sequenced NOBOX in a cohort of 178 women with idiopathic POI. Among 19 identified variations, we described one nonsense (c.907C>T/p.R303X) and four missense (c.271G>T/p.G91W, c.349C>T/p.R117W, c.1025G>C/p.S342T, and c.1048G>T/p.V350L) NOBOX heterozygous mutations in 12 patients. We reproduced each of the five mutations and tested their effects on the signaling activity in transfected cells. We demonstrated that these mutations compromised the ability of the proteins to bind to and transactivate the well‐known growth differentiation factor 9 (GDF9) promoter. The pattern of our findings suggests that the genetic mechanism in humans responsible for POI in women involves haploinsufficiency rather than dominant negative gene action. The identification, characterization, and the very high 6.2% prevalence of these new mutations in POI patients suggest considering NOBOX as the first autosomal candidate gene involved in this syndrome. Hum Mutat 32:1108–1113, 2011. ©2011 Wiley‐Liss, Inc.

Characterization of Two Constitutively Active Prolactin Receptor Variants in a Cohort of 95 Women with Multiple Breast Fibroadenomas

BACKGROUND The role of prolactin (PRL) and its receptor (hPRLR) in promoting breast tumors is debated. We recently identified a gain-of-function hPRLR variant (I146L) in four women with multiple breast fibroadenomas (MFA) and no control subject. OBJECTIVES The specific aims were to describe this cohort of women presenting with MFA to identify and functionally characterize germline variants of hPRL/hPRLR genes and compare phenotypes of all patients. DESIGN Ninety-five patients prospectively underwent clinical examination, breast ultrasonography, magnetic resonance imaging, and hormonal evaluation of gonadal and lactotrope functions. We analyzed hPRL/hPRLR coding sequences and made comparisons with a control population of 194 women. Functional characterization of hPRLR variants was performed. Pathology and immunochemistry were systematically carried out after surgical removal of tumors. RESULTS One third of patients had a family history of breast disease. No hormonal imbalance was observed, except 30.7% of explosive stimulated PRL. Prolactin receptor variants were identified in exon 5 (I76V: 10 patients, eight controls) and exon 10 (one patient, no control). Both I146L and I76V variants exhibited constitutive activity. Pathology showed common fibroadenomas and identified six benign phyllodes tumors. Estrogen and progesterone receptors were detected in 85 and 98% of samples, respectively. Ki-67 median staining was less than 5%. No phenotypic difference was observed between carriers and noncarriers of either hPRLR variant. CONCLUSION We present the largest population with MFA ever described, 15% of which had a hPRLR exhibiting basal activity in vitro. This questions the involvement of the hPRLR in MFA etiology and the potential relevance of therapeutic inhibition of PRLR signaling in patients.

Primary Adrenal Insufficiency Due to Bilateral Adrenal Hemorrhage-Adrenal Infarction in the Antiphospholipid Syndrome: Long-Term Outcome of 16 Patients

CONTEXT Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction is a rare and life-threatening manifestation of the antiphospholipid syndrome (APLS). Data on the long-term outcome are scarce. OBJECTIVE The aims of the present study were to analyze the long-term outcome related to APLS per se and to characterize the course of adrenal involvement. DESIGN We conducted a retrospective study of patients with bilateral adrenal hemorrhage-adrenal infarction secondary to APLS seen in the Department of Internal Medicine of Pitié-Salpêtrière Hospital in Paris (France) between January 1990 and July 2010. RESULTS Three patients died during the acute phase related to APLS manifestations. Sixteen patients (7 males; 9 females) were followed up during a median period of 3.5 years (range 0.3-28.1 years). Three episodes of recurrent thrombosis were noted. One patient died from cerebral hemorrhage 3 months after the onset of adrenal insufficiency. Repeated Synacthen tests showed complete absence of response in 8 of the 10 patients assessed; cortisol and aldosterone increased appropriately in one patient and to some extent in another one. Dehydroepiandrosterone levels and 24-hour urinary epinephrine levels remained abnormally low in all evaluated patients. Adrenal imaging performed more than 1 year after the initial event revealed completely atrophic glands in 9 of 11 patients. CONCLUSIONS This particular subset of APLS patients who survive the acute phase has a rather favorable long-term outcome. Although adrenal dysfunction is generally irreversible, adrenocortical function may, at least partially, recover in rare cases. In this view, measurement of early morning cortisol during follow-up is indicated to detect these patients.

Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia

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.

Novel anti-mullerian hormone mutation revealed by haematospermia in a 60-year-old patient.

A 60-year-old Algerian man presented with haematospermia, which he had noticed after each ejaculation for a year. There was no history of haematuria or testicular dysfunction. Puberty had been delayed until around 18 years of age. He had been unable to have children, and there was no history of sexual developmental abnormalities or infertility in his siblings. On examination, he was not obese, nonsmoker, had a normal male phenotype with a normal sized penis, but there were no palpable testes, and in addition, gynaecomastia without galactorrhoea was present (Fig. 1a). He had never complained about his voluminous gynaecomastia despite the fact that he had used bandages to conceal it since late puberty. Initial investigations ruled out urogenital malignancy or infectious disease. An ultrasound revealed surprisingly, a pelvic mass. A pelvic MRI showed a 69 · 45 · 49 mm uterus with a distended fluid-filled cavity (Fig. 1b). Furthermore, a cervical canal was present but without vaginal development and a 42 · 21 · 23 mm prostate closely abutted the uterus, but without seminal vesicles. External male genitalia consisted of a penis and empty scrotum, with two intra-abdominal testes identified but no ovarian tissue. Urethrocystography failed to establish a fistula. In keeping with this phenotype, his karyotype was 46XY. Laboratory data displayed testicular insufficiency: low testosterone = 3Æ8 nmol/l (11Æ4–34Æ7) and androstenedione4-dione = 3Æ1 nmol/l (0Æ7–10Æ1) levels; normal oestradiol level 92 pmol/l (<128), progesterone 0Æ23 pmol/l; and high level of gonadotrophins (FSH = 51Æ7 mUI/ml, LH = 18Æ5 mUI/ml); Prolactin levels and other pituitary function were normal. Anti-mullerian hormone (AMH) and inhibin B were undetectable. Seminal analysis demonstrated azoospermia. Based on these results, a diagnosis of persistent Mullerian duct syndrome (PMDS) was made. Pelvic surgery was performed and a 10-cm uterus with two adnexae was removed, confirming the diagnosis of PMDS. Bilateral mastectomy was also performed. Histological findings demonstrated a cystic and hyperplasic endometrium. Ovarian material was absent. The adnexae were comprised of fibrinous tissue without any tubal structures. Given the low risk of gonadoblastoma at this age and the small benefit of a trifling amount of testosterone secretion, gonadectomy was not performed. Testicular biopsy and histology showed cryptorchidism

Sequence variation analysis of the prolactin receptor C-terminal region in women with premature ovarian failure

Using a mouse model expressing only the PRL receptor short isoform mimicking premature ovarian failure, signaling pathways induced by PRL were analyzed in mouse ovaries. Sequencing of the coding portion of exons 10 and 11, specific to the long and short receptor isoform, respectively, did not revealed any mutation in 101 women with premature ovarian failure.

Poor Compliance to Hormone Therapy and Decreased Bone Mineral Density in Women with Premature Ovarian Insufficiency

Premature ovarian insufficiency leads to through infertility and estrogen deficiency. Optimal management encompasses estrogen replacement therapy. Long-term outcome of women with POI is not known. We design a study to evaluate the medical care, hormone replacement therapy compliance and bone mineral density (BMD) in POI women with at least a five-year follow-up after the first evaluation. One hundred and sixty-two patients (37.3±8.0 years) were evaluated (follow-up 7.9±2.8 years). Sixty-nine patients (42.6%) had stopped their hormone replacement therapy (HRT) for at least one year during the follow up period. BMD determination at initial evaluation and at follow-up visit was completed in 92 patients. At first evaluation, 28 patients (30%) had osteopenia and 7 (8%) had osteoporosis. At follow up, 31 women (34%) had BMD impairment with osteopenia in 61% and osteoporosis in 5%. In univariate analysis and multivariate analysis, there was a significant loss of femoral BMD in women who had stopped their HRT for over a year. In conclusion, this first study concerning long-term follow-up of POI patients shows the poor compliance to their HRT, despite its importance in the prevention of bone demineralization. This study reinforces the need for follow up and specific care for POI women.