It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.

Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.

Objective: The Androgen Excess Society (AES) charged a task force to review all available data and recommend an evidence-based definition for polycystic ovary syndrome (PCOS), whether already in use or not, to guide clinical diagnosis and future research. Participants: Participants included expert investigators in the field. Evidence: Based on a systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, we tried to identify studies evaluating the epidemiology or phenotypic aspects of PCOS. Consensus Process: The task force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the AES Board of Directors. No section was finalized until all members were satisfied with the contents and minority opinions noted. Statements that were not supported by peer-reviewed evidence were not included. Conclusions: Based on the available data, it is the view of the AES Task Force on the Phenotype of PCOS that...

https://www.ae-society.org/pdf/guidelines/Criteria.pdf

Position statement: Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: An androgen excess society guideline

https://www.fertstert.org/article/S0015-0282(08)01392-7/pdf

The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)61375-1.pdf

Cushing's syndrome

Autophagy is characterized by sequestration of bulk cytoplasm and organelles in double or multimembrane autophagic vesicles, and their delivery to and subsequent degradation by the cell's own lysosomal system. Autophagy has multiple physiological functions in multicellular organisms, including protein degradation and organelle turnover. Genes and proteins that constitute the basic machinery of the autophagic process were first identified in the yeast system and some of their mammalian orthologues have been characterized as well. Increasing lines of evidence indicate that these molecular mechanisms may be recruited by an alternative, caspase-independent form of programmed cell death, named autophagic type II cell death. In some settings, autophagy and apoptosis seem to be interconnected positively or negatively, introducing the concept of 'molecular switches' between them. Additionally, mitochondria may be central organelles integrating the two types of cell death. Malignant transformation is frequently associated with suppression of autophagy. The recent implication of tumor suppressors like Beclin 1, DAP-kinase and PTEN in autophagic pathways indicates a causative role for autophagy deficiencies in cancer formation. Autophagic cell death induction by some anticancer agents underlines the potential utility of its induction as a new cancer treatment modality.

/pdf/autophagy-as-a-cell-death-and-tumor-suppressor-mechanism-3fqqxbk9s6.pdf

Autophagy as a Cell Death and Tumor Suppressor Mechanism

Background/Aims: In a genome-wide investigation we recently identified the EGF-containing fibulin-like extracellular matrix protein 1 gene, EFEMP1</i&

The EFEMP1 gene: a frequent target for epigenetic silencing in multiple human pituitary adenoma subtypes

Summary
In 1992 a 54-year-old man underwent transsphenoidal adenomectomy to remove a clinically nonfunctioning pituitary adenoma during which there was a transient cerebrospinal fluid (CSF) leak. He received radiotherapy to a small residual remnant. Follow-up magnetic resonance imaging (MRI) scan in 1997 showed an increase in the tumour in the pituitary stalk region and an additional intradural lesion at C1 level. In the absence of neurological symptoms and signs, an observational policy was followed. By 1999 the cervical dural lesion had enlarged and laminectomy was performed, during which three intradural lesions were removed. Histology and immunohistochemistry of the metastases were identical to those of the initial pituitary adenoma. Follow-up MRI scan showed extension of the pituitary remnant above the chiasma, requiring transfrontal surgery. Operation was complicated by secondary brain haemorrhage from which the patient died. Autopsy revealed a small amount of residual tumour at the top of the stalk and several small intradural tumour nodules at the level of the foramen magnum. Genetic analysis of the initial pituitary tumour identified significant allelic losses in keeping with its invasive nature, while that of the metastases indicated a separate clone as shown by retention of alleles lost in the primary tumour. The regrown pituitary tumour also appeared to be of a different clone to the initial tumour and the same as two of three of the first metastases (C1 level). The foramen magnum metastasis showed the same loss of heterozygosity (LOH) pattern as one of the original C1 metastases and the pituitary tumour tissue obtained at autopsy. We speculate that at the initial pituitary surgery, cells seeded into the CSF and grew in the dura. These cells were from a different clone, implying that the original pituitary tumour contained at least two clones, possibly three, providing evidence for the contemporaneous oligoclonality of the original pituitary tumour.

Pituitary tumours are multiclonal from the outset: evidence from a case with dural metastases

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenemia, insulin resistance, altered lipid profile, and therefore with subsequently increased risk for metabolic complications such as type 2 diabetes and cardiovascular diseases. It has been reported that sisters of probands with PCOS, who themselves had PCOS or hyperandrogenemia with normal menses, were more insulin resistant than unaffected sisters. We have previously reported that 60% of first-degree relatives (premenopausal mothers and sisters) of PCOS probands had polycystic ovaries (PCO) on ultrascan. Sisters with PCO were more likely to have oligomenorrhea and increased androgen levels than sisters without PCO. The aims of this study were to assess insulin sensitivity status [homeostasis model of assessment, quantitative insulin sensitivity check index, glucose to insulin ratio (G/I)] and lipid profiles in probands with PCOS and their sisters with PCO and without PCO on ultrascan. Mixed model hierarchical regression analysis, to accommodate the nonindependent nature of the subjects (family relationships), with the three groups together did not show significant differences in insulin sensitivity, calculated as quantitative insulin sensitivity check index, homeostasis model of assessment, and G/I for PCOS probands, through sisters with PCO on ultrascan, to sisters without PCO on ultrascan. There was a significant association of measures of insulin sensitivity with body mass index. Lipid parameters did not differ between the groups. These data suggest that presence of PCO on ultrasound scan per se does not predispose to reduced insulin sensitivity in sisters of women with PCOS. Because about 20% of premenopausal women in the general population have PCO on ultrascan, and obesity/overweight is becoming more prevalent, it is important that future studies take full account of the contribution made by obesity to risk factors for metabolic/vascular complications.

Do polycystic ovaries on ultrasound scan indicate decreased insulin sensitivity in sisters of women with polycystic ovary syndrome

Tumour suppressor genes in pituitary tumour formation

While the majority of pituitary tumours will remain benign, a proportion will show invasive behaviour and a still smaller proportion will become malignant. Recent studies at both the biochemical and molecular level are now defining the changes associated with pituitary tumour initiation and progression. In particular, the use of microsatellite analysis in determining regions of gene deletion has considerably advanced our understanding of pituitary tumourigenesis. Bringing together the data of several groups now allows a tentative map to be drawn showing loss of heterozygosity at several chromosomal loci to be associated with the transition to the invasive and malignant phenotype, while changes associated with chromosome 9p and silencing, through methylation, of the tumour suppressor gene p16 appear to occur early in pituitary tumourigenesis. At the biochemical level, immunohistochemical studies have defined changes in key regulatory proteins along this multistep pathway. To determine whether these changes are truly predictive of tumour behaviour awaits carefully designed prospective studies. These future studies may well aid decision-making regarding management in a manner not possible using current histological assessment.

Richard N. Clayton

Papers

The EFEMP1 gene: a frequent target for epigenetic silencing in multiple human pituitary adenoma subtypes

Pituitary tumours are multiclonal from the outset: evidence from a case with dural metastases

Do polycystic ovaries on ultrasound scan indicate decreased insulin sensitivity in sisters of women with polycystic ovary syndrome

Tumour suppressor genes in pituitary tumour formation

Molecular biology of human pituitary adenomas.