Mental health meets computational neuroscience: A predictive Bayesian account of the relationship between interoception and multisensory bodily illusions in anorexia nervosa

Mental health disorders pose a significant challenge to society. The Bayesian perspective on the mind offers unique insights and tools that may help address a variety of mental health conditions. Psychopathological dysfunctions are often connected to altered predictive and active inference processes, in which cognitive and physiological pathogenic beliefs shape the clinical condition and its symptoms. However, there is a lack of general empirical models that integrate cognitive beliefs, physiological experience, and symptoms in healthy and clinical populations. In this study, we examined the relationship between altered predictive mechanisms, interoception, and pathological bodily distortions in healty individuals and in individuals suffering from anorexia nervosa (AN). AN patients (N=15) completed a Virtual Reality Full-Body Illusion along with interoceptive tasks twice: at hospital admission during an acute symptomatological phase (Time 1) and after a 12-week outpatient clinical weight-restoring rehabilitative program (Time 2). Results were compared to a healthy control group. Our findings indicated that higher levels of interoceptive metacognitive awareness were associated with a greater embodiment. However, unlike in healthy participants, AN patients' interoceptive metacognition was linked to embodiment even in multisensory mismatching (asynchronous) conditions. In addition, unlike in healthy participants, higher interoceptive metacognition in AN patients was related to prior abnormal bodily distortions during the acute symptomatology phase. Prediction errors in bodily estimates predicted posterior bodily estimate distortions after the illusion, but while this relationship was only significant in the synchronous condition in healthy participants, there was no significant difference between synchronous and asynchronous conditions in AN patients. (AU)

Impact of Current Technology in Laparoscopic Adrenalectomy: 20 Years of Experience in the Treatment of 254 Consecutive Clinical Cases.

BACKGROUND: Laparoscopic adrenalectomy (LA), which avoids large abdomen incisions, is considered the gold standard technique for the treatment of benign small- and medium-size adrenal masses (<6 cm) and weighing < 100 g. A trascurable mortality and morbidity rate, short hospitalization and patient rapid recovery are the main advantages compared to traditional surgery. During the past decade, a new surgical technology has been developed that expedites a "clipless" adrenalectomy. Here, the authors analyze a clinical series of 254 consecutive patients who were affected by adrenal gland neoplasms and underwent LA by the transabdominal lateral approach over the two last decades. A literature review is also presented. METHODS: Preoperative, intraoperative and postoperative data from 254 patients who underwent LA between January 2003 and December 2022 were retrospectively collected and reviewed. Diagnosis was obtained on the basis of clinical examination, laboratory values and imaging techniques. Doxazosin was preoperatively administered in the case of pheochromocytoma (PCC) while spironolactone and potassium were employed to treat Conn's disease. The same surgeon (CG) performed all the LA and utilized the same laparoscopic transabdominal lateral approach. Different dissection tools-ultrasonic, bipolar or mixed scissors-and hemostatic agents were used during this period. The following results were obtained: 254 patients were included in the study; functioning tumors were diagnosed in 155 patients, 52 patients were affected by PCCs, 55 by Conn's disease, 48 by Cushing's disease. Surgery mean operative time was 137.33 min (range 100-180 min) during the learning curve adrenalectomies and 98.5 min (range 70-180) in subsequent procedures. Mean blood loss was respectively 160.2 mL (range 60-280) and 96.98 mL (range 50-280) in the first 30 procedures and the subsequent ones. Only three conversions (1.18%) to open surgery occurred. No mortality or postoperative major complications were observed, while minor complications occurred in 19 patients (3.54%). In 153 out of 155 functioning neoplasms, LA was effective in the normalization of the endocrine profile. According to our experience, a learning curve consisting of 30 cases was identified. In fact, a lower operative time and a lower complication rate was reported following 30 LA. CONCLUSIONS: LA is a safe procedure, even for masses larger than 6 cm and PCCs. Undoubtedly, the development of surgical technology has made it possible reducing operative times, performing a "clipless" adrenalectomy and extending the indications in the treatment of more complex patients. A multidisciplinary team, in referral high-volume centers, is recommended in the management of adrenal pathology. A 30-procedure learning curve is necessary to improve surgical outcomes.

Short- and long-term outcomes of sphincteroplasty for anal incontinence related to obstetric injury: a systematic review.

Anal incontinence is a frequent pathological condition with devastating impact on quality of life. The prevalence is approximately 15% of the population, with higher incidence reported in the elderly and multiparous women, and several factors have a major role in its pathogenesis, such as anatomical sphincter defects (Glasgow and Lowry in Dis Colon Rectum 55(4): 482-490, 2012), delivery injuries, and colorectal, uro-gynecological, and perineal surgery. The direct surgical approach is the gold standard treatment for fecal incontinence, especially through anterior sphincteroplasty, although a permanent defect of continence persists over time. The aim of our study is to evaluate, throughout a systematic review of the literature, the short- and long-term outcomes of sphincteroplasty performed for obstetric injuries anal incontinence. A systematic review of the studies published in the literature from January 2000 to December 2021 was performed in accordance with the PRISMA guidelines. Of the 2543 studies extrapolated, only eight fulfilled the inclusion criteria and were admitted represented by retrospective and prospective studies. The data analyzed from the included studies were number and mean age of the female population, and incontinence improvement with preoperative and postoperative short- and long-term outcomes, as reported by QoL questionaries and incontinence scores. Overall 355 patients with obstetric sphincter damage underwent sphincteroplasty with an anterior external sphincter overlapping procedure. A consistent improvement in fecal incontinence at short-term follow-up with relative improvement in QoL was reported. In 7 of 8 studies, the authors found a progressive worsening of the incontinence symptoms on the long-term follow-up. However, it is not clear whether the decrease in long-term continence results is parallel to a simultaneous decrease in QoL scores. Nevertheless, compared to the preoperative findings, the improvement was maintained in the long-term follow-up. Despite the limited data in the literature, a properly performed sphincteroplasty can guarantee a consistent improvement of the continence in short term with encouraging outcomes, especially for solid stool continence, in long time. We believe that anterior sphincteroplasty, as a low cost, feasible, and safe procedure, still has a role in the treatment of fecal incontinence for obstetric injury. Further large cohort randomized clinical trials are necessary to validate these results.

Mental health meets computational neuroscience: A predictive Bayesian account of the relationship between interoception and multisensory bodily illusions in anorexia nervosa.

Mental health disorders pose a significant challenge to society. The Bayesian perspective on the mind offers unique insights and tools that may help address a variety of mental health conditions. Psychopathological dysfunctions are often connected to altered predictive and active inference processes, in which cognitive and physiological pathogenic beliefs shape the clinical condition and its symptoms. However, there is a lack of general empirical models that integrate cognitive beliefs, physiological experience, and symptoms in healthy and clinical populations. In this study, we examined the relationship between altered predictive mechanisms, interoception, and pathological bodily distortions in healty individuals and in individuals suffering from anorexia nervosa (AN). AN patients (N=15) completed a Virtual Reality Full-Body Illusion along with interoceptive tasks twice: at hospital admission during an acute symptomatological phase (Time 1) and after a 12-week outpatient clinical weight-restoring rehabilitative program (Time 2). Results were compared to a healthy control group. Our findings indicated that higher levels of interoceptive metacognitive awareness were associated with a greater embodiment. However, unlike in healthy participants, AN patients' interoceptive metacognition was linked to embodiment even in multisensory mismatching (asynchronous) conditions. In addition, unlike in healthy participants, higher interoceptive metacognition in AN patients was related to prior abnormal bodily distortions during the acute symptomatology phase. Prediction errors in bodily estimates predicted posterior bodily estimate distortions after the illusion, but while this relationship was only significant in the synchronous condition in healthy participants, there was no significant difference between synchronous and asynchronous conditions in AN patients. Despite the success of the rehabilitation program in restoring some dysfunctional patterns in the AN group, prediction errors and posterior estimate distortions were present at hospital discharge. Our findings suggest that individuals with AN prioritize interoceptive metacognitive processes (i.e., confidence in their own perceived sensations rather than their actual perceptions), disregarding bottom-up bodily inputs in favour of their prior altered top-down beliefs. Moreover, even if the rehabilitative program partially mitigated these alterations, the pathological condition impaired the patients' ability to coherently update their prior erroneous expectations with real-time multisensory bottom-up bodily information, possibly locking the patients in the experience of a distorted prior top-down belief. These results suggest new therapeutic perspectives and introduce the framework of regenerative virtual therapy (RVT), which aims at utilizing technology-based somatic modification techniques to restructure the maladaptive priors underlying a pathological condition.

Management of Low-Risk Thyroid Cancers: Is Active Surveillance a Valid Option? A Systematic Review of the Literature.

Thyroid cancer is the most common endocrine malignancy, representing 2.9% of all new cancers in the United States. It has an excellent prognosis, with a five-year relative survival rate of 98.3%.Differentiated Thyroid Carcinomas (DTCs) are the most diagnosed thyroid tumors and are characterized by a slow growth rate and indolent course. For years, the only approach to treatment was thyroidectomy. Active surveillance (AS) has recently emerged as an alternative approach; it involves regular observation aimed at recognizing the minority of patients who will clinically progress and would likely benefit from rescue surgery. To better clarify the indications for active surveillance for low-risk thyroid cancers, we reviewed the current management of low-risk DTCs with a systematic search performed according to a PRISMA flowchart in electronic databases (PubMed, Web of Science, Scopus, and EMBASE) for studies published before May 2021. Fourteen publications were included for final analysis, with a total number of 4830 patients under AS. A total of 451/4830 (9.4%) patients experienced an increase in maximum diameter by >3 mm; 609/4830 (12.6%) patients underwent delayed surgery after AS; metastatic spread to cervical lymph nodes was present in 88/4213 (2.1%) patients; 4/3589 (0.1%) patients had metastatic disease outside of cervical lymph nodes. Finally, no subject had a documented mortality due to thyroid cancer during AS. Currently, the American Thyroid Association guidelines do not support AS as the first-line treatment in patients with PMC; however, they consider AS to be an effective alternative, particularly in patients with high surgical risk or poor life expectancy due to comorbid conditions. Thus, AS could be an alternative to immediate surgery for patients with very-low-risk tumors showing no cytologic evidence of aggressive disease, for high-risk surgical candidates, for those with concurrent comorbidities requiring urgent intervention, and for patients with a relatively short life expectancy.

The Differential Diagnosis of Discrepant Thyroid Function Tests: Insistent Pitfalls and Updated Flow-Chart Based on a Long-Standing Experience.

Background: Discrepant thyroid function tests (TFTs) are typical of inappropriate secretion of TSH (IST), a rare entity encompassing TSH-secreting adenomas (TSHoma) and Resistance to Thyroid Hormone (RTHß) due to THRB mutations. The differential diagnosis remains a clinical challenge in most of the cases. The objective of this study was to share our experience with patients presenting with discrepant TFTs outlining the main pitfalls in the differential diagnosis. Methods: medical records of 100 subjects with discrepant TFTs referred to Thyroid Endocrine Centers at the University of Milan were analyzed, retrospectively. Patients were studied by dynamic testing (TRH test, T3-suppression test, or a short course of long-acting somatostatin analog, when appropriate), THRB sequencing, and pituitary imaging. Results: 88 patients were correctly diagnosed as RTHß with (n = 59; 16 men, 43 women) or without THRB variants (n = 6; 2 men, 4 female) or TSHoma (n = 23; 9 men, 14 women). We identified 14 representative subjects with an atypical presentation or who were misdiagnosed. Seven patients, with spurious hyperthyroxinemia due to assays interference were erroneously classified as RTHß (n = 4) or TSHoma (n = 3). Three patients with genuine TSHomas were classified as laboratory artifact (n = 2) or RTHß (n = 1). Two TSHomas presented atypically due to coexistent primary thyroid diseases. In one RTHß a drug-induced thyroid dysfunction was primarily assumed. These patients experienced a mean diagnostic delay of 26 ± 14 months. Analysis of the investigations which can differentiate between TSHoma and RTHß showed highest accuracy for the T3-suppression test (100% specificity with a cut-off of TSH <0.11 µUI/ml). Pituitary MRI was negative in 6/26 TSHomas, while 11/45 RTHß patients had small pituitary lesions, leading to unnecessary surgery in one case. Conclusions: Diagnostic delay and inappropriate treatments still occur in too many cases with discrepant TFTs suggestive of central hyperthyroidism. The insistent pitfalls lead to a significant waste of resources. We propose a revised flow-chart for the differential diagnosis.

Native Nephrectomy in Patients With Autosomal Dominant Polycystic Kidney Disease Evaluated for Kidney Transplantation.

Native nephrectomy (NN) in patients with autosomal dominant polycystic kidney disease (ADPKD) is indicated in cases of recurrent urinary tract infections and hematuria, neoplastic degeneration, and encumbrance. Timing, indication, and surgical approach of NN depends on the symptoms or policy of the center. The aim of our study is to evaluate our experience. In our retrospective study, we included 130 patients with a diagnosis of ADPKD from 530 patients evaluated for renal transplantation from 2011 to 2017. We analyzed the etiologic indication, the timing, and the complications of NN. In our cohort, 53 patients underwent open NN, 85% pre-kidney transplantation (KT), 13% post-KT, and only 1 case simultaneous with KT. In the pre-KT group, indications included: major indication was encumbrance in the. In the post-KT group, the major indication was infection followed by encumbrance, which developed after KT. Complications were: 3 cases of bleeding (1 required relaparotomy, 2 evolved into hematoma and radiological derange); 1 iatrogenic iliac artery injury, which was contextually repaired, and 5 cases of incisional hernia. At 35 ± 7.2 months follow-up, patients' survival was 96%; 1 patient died at the induction of anesthesia and 1 patient from sepsis after double NN and removal of nonfunctional transplanted kidney. NN is not without complications and should be performed when clearly indicated. In our experience, we preferred to perform NN before KT.

Prostate Cancer Recurrence in Kidney Transplant Recipient 15 Years After Radical Prostatectomy: A Case Report.

Incidence of malignant tumors in kidney transplant recipients is higher than nontransplanted population due to many factors, such as immunosuppression therapy and complex donor-recipient interaction. Genitourinary malignancies have been reported as the second most common malignancy in kidney transplant recipients. In this regard, prostate cancer is the most common neoplasm. Herein, we describe a rare case of prostate cancer recurrence after 15 years in a patient who underwent kidney transplant after radical prostatectomy.

Interoceptive Axes Dissociation in Anorexia Nervosa: A Single Case Study With Follow Up Post-recovery Assessment.

Anorexia nervosa (AN) is a disorder characterized by alterations in body perception. Recent literature suggested that AN can also impair the processing of stimuli from inside the body (i.e., interoceptive) however, very few studies performed a complete interoceptive assessment exploring the evolution of the interoceptive dimensions before and after the subject's recovery. To address this gap in knowledge, this study presented the case of Diana, a 25 years old woman affected by AN. At hospital admission, Diana performed a complete interoceptive assessment for accuracy (IAc), metacognitive awareness (IAw), sensibility (IAs), and interoceptive buffer saturation (IBs) - a new index that behaviourally evaluated the amount of interoceptive processing. Measures were repeated at the end of an outpatients rehabilitative hospital program, after Diana's recovery. Results were confronted with a control (N = 4) of healthy female subjects. Analyses indicated severe deficits in accuracy, buffer saturation, and sensibility compared to control group. Conversely, metacognitive awareness was pathologically enhanced. After the rehabilitative hospital program, Diana's clinical condition was largely improved and this reflected back on the interoceptive patterns that appeared restored, with no difference in interoceptive accuracy and metacognition compared to the control group. In conclusion, results indicated a very specific dissociation between interoceptive axes in AN with pervasive deficits in perception and processing that were accompanied by a pathologically enhanced confidence in the wrong perceptions. This case study reported an interesting and unique clinical pattern with a severe dissociation between interoceptive perceptions that nonetheless appeared restored after the subject's recovery, highlighting the role of interoceptive assessment in the clinical evolution of AN.

The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders.

BACKGROUND: A large number of studies have contributed to understanding the general mechanisms driving ovarian folliculogenesis in humans and show a complex endocrine dialog between the central nervous system, the pituitary and the ovary, integrated by various intraovarian paracrine messages. The role of intraovarian paracrine regulation has acquired more relevance in the recent years owing to the discovery of previously unknown factors, such as the oocyte-derived bone morphogenetic protein (BMP)15. METHODS: A thorough literature search was carried out in order to summarize what has been reported so far on the role of BMP15, and the BMP15 paralog, growth and differentiation factor 9 (GDF9), in ovarian function and female fertility. Research articles published in English until March 2014 were included. RESULTS: The biological actions of BMP15 include: (i) the promotion of follicle growth and maturation starting from the primary gonadotrophin-independent phases of folliculogenesis; (ii) the regulation of follicular granulosa cell (GC) sensitivity to FSH action and the determination of ovulation quota; (iii) the prevention of GC apoptosis and (iv) the promotion of oocyte developmental competence. The existence of biologically active heterodimers with GDF9, and/or the synergistic co-operation of BMP15 and GDF9 homodimers are indeed relevant in this context. Experimental disruption of the bmp15 gene in mice resulted in a mild fertility defect limited to females, whereas natural missense mutations in ewes cause variable phenotypes (ranging from hyperprolificacy to complete sterility) depending on a fine gene dosage mechanism also involving GDF9. Strong evidence supports the concept that such a mechanism plays an important role in the regulation of ovulation rate across mammalian and non-mammalian species. Following the discovery of sheep fecundity genes, several research groups have focused on alterations in human BMP15 associated with primary ovarian insufficiency (POI) or polycystic ovary syndrome. Several variants of BMP15 are significantly associated with POI supporting their pathogenic role, but the underlying biological mechanism is still under investigation and of great interest in medicine. BMP15 maps to the Xp locus involved in the determination of the ovarian defect in Turner syndrome and significantly contributes to the determination of ovarian reserve. Pioneering studies in women undergoing controlled ovarian stimulation indicate that BMP15 may represent a marker of ovarian response or oocyte quality. CONCLUSIONS: BMP15, an oocyte-derived growth and differentiation factor, is a critical regulator of folliculogenesis and GC activities. Variations in BMP15 gene dosage have a relevant influence on ovarian function and can account for several defects of female fertility. The modulation of BMP15 action may have interesting pharmacological perspectives and the analysis of BMP15 may become a useful marker in IVF procedures. Recent outcomes indicate that the close interactions of BMP15/GDF9 have a critical biological impact that should be taken into account in future studies.

Refining calcium test for the diagnosis of medullary thyroid cancer: cutoffs, procedures, and safety.

CONTEXT: Calcitonin (CT) measurement is crucial to the early diagnosis and the follow-up of medullary thyroid cancer (MTC). If the evaluation of stimulated CT levels is required, a provocative test can be performed, being the high-dose Ca test recently reintroduced in clinical practice. OBJECTIVE: Our objective was to identify gender-specific thresholds for MTC diagnosis in a large series of patients who underwent the Ca test. PATIENTS AND METHODS: A total of 91 patients (49 females and 42 males) underwent the Ca test (calcium gluconate, 25 mg/kg) before thyroidectomy and both basal CT (bCT) and stimulated CT (sCT) were compared with histological results by receiver operating characteristic plot analyses. To evaluate possible side effects of Ca administration, cardiac function has been extensively studied. RESULTS: bCT levels were found to harbor the same accuracy as sCT in the preoperative diagnosis of MTC. The best Ca thresholds for the identification of MTC were >26 and >68 for bCT and >79 and >544 pg/mL for sCT in females and males, respectively. The high tolerability and safety of the Ca test was demonstrated and advice offered to be followed before and during the test. CONCLUSIONS: Gender-specific bCT and sCT cutoffs for the identification of C-cell hyperplasia and/or MTC have been defined. The bCT and sCT were found to have a similar accuracy, indicating that serum CT assays with improved functional sensitivity may likely decrease the relevance of the stimulation test in several conditions. Finally, systematic cardiac monitoring confirms the safety of the Ca test.

Gene dosage as a relevant mechanism contributing to the determination of ovarian function in Turner syndrome.

STUDY QUESTION: What is the burden of X chromosome mosaicism in the occurrence of spontaneous menarche (SM) in Turner syndrome (TS)? SUMMARY ANSWER: SM was significantly associated with X chromosome mosaicism in the TS patients; a mosaicism with around 10% euploid cell line may predict spontaneous pubertal development when determined by molecular-cytogenetic techniques on uncultivated tissues. WHAT IS KNOWN ALREADY: Spontaneous puberty can be observed in a minority of patients with TS, more frequently, but not exclusively, in those with a high level of 46,XX/45,X mosaicism at standard karyotype. The genetic mechanisms contributing to ovarian function in TS patients are still not determined. However, submicroscopic X-linked and autosomal copy number variations (CNVs) have recently emerged as an important genetic risk category for premature ovarian insufficiency and may be involved in modulating the TS ovarian phenotype. STUDY DESIGN, SIZE, DURATION: A group of 40 patients with a diagnosis of TS at conventional karyotyping participated in the study; 6 patients had SM and 34 patients had primary amenorrhoea (PA). All clinical data and the patients' DNA samples were collected over the years at a single paediatric clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS: The patients' samples were used to perform both genetic (Copy Number Assay) and molecular-cytogenetic (array-CGH and iFISH, interphase-FISH) analyses in order to evaluate the X chromosome mosaicism rate and to detect possible rare CNVs of genes with a known or predicted role in female fertility. MAIN RESULTS AND THE ROLE OF CHANCE: All TS patients showed variable percentages of the 46,XX lineage, but these percentages were higher in the SM group (P < 0.01). A mosaicism around 10% for the euploid cell line may predict spontaneous pubertal development when determined by molecular-cytogenetic techniques performed in uncultivated tissues. A few CNVs involving autosomal and X-linked ovary-related loci were identified by array-CGH analysis and confirmed by real-time quantitative PCR, including a BMP15 gene duplication at Xp11.22, a deletion interrupting the PAPPA gene at 9q33.1, and an intragenic duplication involving the PDE8A gene at 15q25.3. LIMITATIONS, REASONS FOR CAUTION: This is a pilot study on a relatively small sample size and confirmation in larger TS cohorts may be required. The ovarian tissue could not be studied in any patients and in a subgroup of patients, the mosaicism was estimated in tissues of different embryonic origin. WIDER IMPLICATIONS OF THE FINDINGS: The combined determination of X chromosome mosaicism by molecular and molecular-cytogenetic techniques may become useful for the prediction of SM in TS. The detection of CNVs in both X-linked and autosomal ovary-related genes further suggests gene dosage as a relevant mechanism contributing to the ovarian phenotype of TS patients. These CNVs may pinpoint novel candidates relevant to female fertility and generate further insights into the mechanisms contributing to ovarian function. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Telethon Foundation (grant no: GGP09126 to L.P.), the Italian Ministry of the University and Research (grant number: 2006065999 to P.F.) and a Ministry of Health grant 'Ricerca Corrente' to IRCCS Istituto Auxologico Italiano (grant number: 08C704-2006). The authors have no conflict of interest to declare.

Blood cell mitochondrial DNA content and premature ovarian aging.

Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction.

Genes involved in human premature ovarian failure.

Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles before the age of 40 years, representing one major cause of female infertility. POF relevance is continuously growing because women tend to conceive ever more frequently in their thirties and forties. POF can present very early with a pubertal defect. More frequently, it is the end stage of an occult process (primary ovarian insufficiency, POI) affecting ∼ 1-2% of under-40 women. POI is a heterogeneous disease caused by a variety of mechanisms. Though the underlying cause remains unexplained in the majority of cases, various data indicate that POI has a strong genetic component. These data include the existence of several causal genetic defects in humans, experimental and natural models, as well as the frequent familiarity. The variable expressivity of POI defect in women of the same family may indicate that, in addition to some monogenic forms, POI may frequently be considered as a multifactorial defect resulting from the contribution of several predisposing alleles. The X chromosome-linked defects play a major role among the presently known causal defects. Here, we review the principal X-linked and autosomal genes involved in syndromic and nonsyndromic forms of POI with the wish that this list will soon become upgraded because of the discovery of novel contributing mechanisms. A better understanding of POI pathogenesis will indeed allow the construction of tests able to predict the age of menopause in women at higher risk of POI.

Primary Ovarian Insufficiency: X chromosome defects and autoimmunity.

Premature ovarian failure (POF) is a primary ovarian defect characterized by absent menarche or premature depletion of ovarian follicles before the age of 40 years. However, in several instances the distinction between definitive or intermittent POF may be difficult on clinical bases, therefore the more appropriate term Primary Ovarian Insufficiency (POI) has been recently proposed and will be used in this review. POI is a heterogeneous disorder affecting approximately 1% of women <40 years. The most severe forms present with absent pubertal development and primary amenorrhea, whereas forms with post-pubertal onset are characterized by disappearance of menstrual cycles (secondary amenorrhea) associated with a defective folliculogenesis. POI is generally characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (LH and FSH) (hypergonadotropic amenorrhea). Heterogeneity of POI is reflected by the variety of possible causes, including autoimmunity, toxics, drugs, as well as genetic defects. Several data indicate that POI has a strong genetic component. In this manuscript we discuss the X chromosome abnormalities that are associated with POI.