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Mitochondrial disorders are collectively common, genetically heterogeneous disorders in both pediatric and adult populations. They are caused by molecular defects in oxidative phosphorylation, failure of essential bioenergetic supply to mitochondria, and apoptosis. Here, we present three affected individuals from a consanguineous family of Pakistani origin with variable seizures and intellectual disability. Both females display primary ovarian insufficiency (POI), while the male shows abnormal sex hormone levels. We performed whole exome sequencing and identified a recessive missense variant c.694C > T, p.Arg232Cys in TFAM that segregates with disease. TFAM (mitochondrial transcription factor A) is a component of the mitochondrial replisome machinery that maintains mtDNA transcription and replication. In primary dermal fibroblasts, we show depletion of mtDNA and significantly altered mitochondrial function and morphology. Moreover, we observed reduced nucleoid numbers with significant changes in nucleoid size or shape in fibroblasts from an affected individual compared to controls. We also investigated the effect of tfam impairment in zebrafish; homozygous tfam mutants carrying an in-frame c.141_149 deletion recapitulate the mtDNA depletion and ovarian dysgenesis phenotypes observed in affected humans. Together, our genetic and functional data confirm that TFAM plays a pivotal role in gonad development and expands the repertoire of mitochondrial disease phenotypes.

Background Idiopathic central precocious puberty (ICPP) is supposed to be non-existent in a context of testicular destruction that is typically present in Klinefelter syndrome (KS). Herein, we describe a rare case of ICPP in a Klinefelter patient (47,XXY) with 2 maternal X chromosomes. Moreover, we highlight the differences in gonadotropin levels in comparison to males with ICPP and a normal karyotype. Case presentation An 8 years old boy with a history of cryptorchidism was evaluated for precocious puberty (Tanner staging: P2/G3). Both testes measured 25x35mm. His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml), luteinizing hormone [LH (3.5 UI/l)] and follicle stimulating hormone [FSH (7.7 UI/l)] levels. Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively. Brain magnetic resonance imaging (MRI) was normal. No MKRN3 mutation was detected. He was treated for ICPP for two years. During puberty, he suffered from hypergonadotropic hypogonadism leading to the diagnosis of KS (47,XXY karyotype). Chromosomal analysis by fluorescent multiplex polymerase chain reaction (PCR) using X chromosome microsatellite markers identified 2 maternal X chromosomes. Analysing 8 cases of KS developing ICPP (our reported case and 7 other published cases) revealed that these KS patients with ICPP have higher LH and FSH levels during ICPP episode than in ICPP patients with a normal karyotype (ICPP with KS vs ICPP with a normal karyotype: LH levels 9.4 ± 12 vs 1.1 ± 0.6 UI/l; FSH levels 23.1 ± 38.5 vs 2.7 ± 1.5 UI/l). Furthermore, their response to gonadotropin-releasing hormone (GnRH) stimulation is characterized by excessive LH and FSH secretion (LH levels post-GnRH: 58 ± 48 vs 15.5 ± 0.8 UI/l; FSH levels post-GnRH: 49.1 ± 62.1 vs 5.7 ± 3.9 UI/l). Conclusions ICPP in boys is extremely rare. The pathophysiology of ICPP in KS is unknown. However, maternal X supplementary chromosome and early testicular destruction may play a significant role in the initiation of ICPP, in part explaining the relative “overrepresentation of ICPP in KS. Thus, karyotype analysis could be considered for boys suffering from ICPP, especially if testicular size is smaller or gonadotropins are significantly elevated.

Craniopharyngiomas are rare cerebral tumors associated with severe obesity after hypothalamic surgery. A meta-analysis showed significant weight loss at 1 year after bariatric surgery in these patients even though more modest than in common causes of obesity. We hypothesized that this discrepancy could be partly explained by differences in GLP-1 secretion after surgery since patients with craniopharyngioma present a significantly higher degree of insulin resistance and hyperinsulinism than common obese control. We report three cases of bariatric surgery in patients presenting with hypothalamique obesity related to craniopharyngiomas. At 18 months, the mean weight loss was 20 kg with expected insulin resistance decrease. Before surgery, standardized test meal shows abolition of postprandial GLP-1 secretion in all patients with a progressive restoration in the patients with gastric bypass (GBP) surgery.

The pathogenesis of intensive care unit-acquired paresis (ICUAP), a frequent and severe complication of critical illness, is poorly understood. Since ICUAP has been associated with female gender in some studies, we hypothesized that hormonal dysfunction might contribute to ICUAP.To determine the relationship between hormonal status, ICUAP and mortality in patients with protracted critical illness.Prospective observational study.Four medical and surgical ICUs.ICU patients mechanically ventilated for7 days.None.Plasma levels of insulin growth factor-1 (IgF1), prolactin, thyroid stimulating hormone (TSH), follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and cortisol were measured on the first day patients were awake (day 1). Mean blood glucose from admission to day 1 was calculated. ICUAP was defined as Medical Research Council sum score48/60 on day 7.We studied 102 patients (65 men and 37 women, 29 post-menopausal), of whom 24 (24%) died during hospitalization. Among the 86 patients tested at day 7, 39 (49%) had ICUAP, which was more frequent in women (63% versus men 36%, p = 0.02). Mean blood glucose was higher in patients with ICUAP. Estradiol/testosterone ratio was greater in men with ICUAP.ICUAP 7 days after awakening was associated with increased blood glucose and with biological evidence of hypogonadism in men, while an association with hormonal dysfunction was not detected in women.

Prolactin is a polypeptide hormone whose major biological actions are related to normal lactation and reproduction. Abnormally high prolactin levels, referred to as hyperprolactinemia, can result in various reproductive disorders. Currently, therapeutic management of hyperprolactinemia relies on dopamine agonists, since dopamine is the primary physiological suppressor of pituitary prolactin production. Epidemiologic studies have shown that prolactin levels in the high-normal range, as well as medications that interfere with dopamine action (e.g. certain antipsychotic drugs), might correlate with increased breast cancer risk. In addition to circulating prolactin, it is now well established that prolactin is also produced locally within various tissues, including breast and prostate. Increasing evidence, mainly from animal studies at present, suggests that excess locally produced prolactin may promote the growth of breast and prostate tumors via an autocrine or paracrine mechanism. These findings have renewed the interest in finding alternative strategies to suppress prolactin actions when dopamine agonists are ineffective. Our studies of the relationship between prolactin structure and function have resulted in the development of pure prolactin-receptor antagonists. These molecules prevent endogenous prolactin from exerting its actions via a competitive mechanism for receptor binding. In this review, we discuss the possible future therapeutic utility of this novel class of compounds.

Benign breast diseases have always been neglected in comparison to cancer, despite the fact that there are many more patients with such diseases than patients presenting to a breast clinic for cancer. Like normal breast tissues, benign breast diseases are under a complex system of controls by both systemic hormonal and local factors. In this review, we attempt to present an overview of the latest knowledge concerning the epidemiology, classification, clinical presentation, management, and physiopathology of these disorders.

The involvement of human prolactin (hPRL) in breast cancer has been recently reconsidered based on its autocrine/paracrine proliferative effect described in human mammary tumor epithelial cells. Therefore, there is growing interest in the development of potent hPRL antagonists that may inhibit this effect. We previously designed hPRL analogs displaying antagonistic properties in a human transcriptional bioassay. We now report that the most potent of those analogs, G129R-hPRL, antagonizes all hPRL-induced effects analysed in various breast cancer cell lines, including cell proliferation. The analog per se lacks intrinsic agonistic activity on PRL receptor-activated signaling cascades, cell proliferation and apoptosis, indicating that its mode of action only occurs through competitive inhibition of hPRL. We provide some molecular basis of this antagonistic effect by demonstrating that G129R-hPRL competitively inhibits hPRL-activation of the JAK-STAT and MAPK pathways, two signaling cascades involved in the mitogenic effect of hPRL in mammary epithelial cells. This competitive inhibition persists for at least 48 h, as evidenced by long term analysis of STAT5b activation or of progression through cell cycle. These results are the first demonstration at the molecular level that hPRL antagonists interfering with receptor dimerization disrupt signaling events in breast cancer cells, which prevents hPRL-induced cell proliferation.

Hyperprolactinemia is involved in almost 30% of infertility problems. At the onset of menopause, prolactin levels often decrease; however, no data are available regarding the course of hyperprolactinemia after menopause with hormonal replacement therapy (HRT). A retrospective study was undertaken in our department to evaluate the potential role of estrogens in women with a history of hyperprolactinemia. Twenty-two patients, with hyperprolactinemia before menopause, were followed-up. Group I included 11 patients who withdrew bromocriptine treatment when menopause was confirmed. These patients were placed on HRT with no other medication administered. HRT was a combination of percutaneous estradiol gel and an oral progestin. Group II included 7 women treated by bromocriptine before menopause and after menopause concomitantly with HRT. Group III included 4 patients who did not receive HRT or other treatments once menopause was diagnosed. The mean serum prolactin level was unchanged in Group I (22.8+/-21.7 before and 22.8+/-16.1 ng/ml after HRT) while it increased but not significantly from 8.1+/-5.2 to 16.0+/-11.7 ng/ml in Group II. The mean duration of HRT was 42.8+/-23.8 (7-81) and 37.3+/-31.0 (6-99) months in Group I and II respectively. In Group III patients, PRL levels decreased spontaneously from 61.2+/-39.8 to 33.0+/-34.7 ng/ml. In conclusion, in this population of menopausal patients with a history of moderate hyperprolactinemia, HRT did not seem to affect plasma prolactin levels.