https://gynecology.gr/userfiles/file/scientific-studies/eshr_asrm_pcos.pdf

Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome

The prevalence of obesity is rapidly increasing globally. Epidemiological studies have associated obesity with a range of cancer types, although the mechanisms by which obesity induces or promotes tumorigenesis vary by cancer site. These include insulin resistance and resultant chronic hyperinsulinaemia, increased bioavailability of steroid hormones and localized inflammation. Gaining a better understanding of the relationship between obesity and cancer can provide new insight into mechanisms of cancer pathogenesis.

/pdf/overweight-obesity-and-cancer-epidemiological-evidence-and-3aap682afc.pdf

Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms

Effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. For this reason, elucidation of mechanisms that confer simultaneous resistance to different drugs with different targets and chemical structures - multidrug resistance - has been a major goal of cancer biologists during the past 35 years. Here, we review the most common of these mechanisms, one that relies on drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters. We describe various approaches to combating multidrug-resistant cancer, including the development of drugs that engage, evade or exploit efflux by ABC transporters.

Targeting multidrug resistance in cancer

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.

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women of reproductive age. The classical symptoms are those of hyperandrogenism (hirsutism, persistant acne, androgen dependent alopecia) together with symptoms of anovulation (infertility, amenorrhoea, irregular dysfunctional uterine bleeding).1In the last 10 to 15 years, the use of high resolution pelvic ultrasonography has greatly facilitated identification of polycystic ovaries in women with hirsutism or menstrual disturbance. It is now clear that the range of presenting symptoms of women with polycystic ovaries includes not only non-hirsute women with oligomenorrhoea or amenorrhoea but also hirsute subjects with regular, ovulatory cycles. PCOS occurs in nearly 75% of cases of anovulatory infertility and over 80% of subjects with hirsutism.1 The typical biochemical features of PCOS include hyperandrogenaemia and an increase of serum luteinising hormone (LH) (with normal follicle stimulating hormone) but PCOS is also associated with a characteristic metabolic syndrome that includes hyperinsulinaemia, insulin resistance, and dyslipidaemia.1-4 These features are linked to a significantly increased risk of type II (non-insulin-dependent) diabetes in later life and women with PCOS may also have a greater chance of developing premature cardiovascular disease.3 5 6 

The presence of polycystic ovaries is necessary for the development of the syndrome but not all women with polycystic ovaries have PCOS. The typical …

Polycystic ovary syndrome.

BACKGROUND: Standard sperm characteristics are poor predictors of the outcome of IVF treatments. On the contrary, sperm genome quality has been emphasized for several years as playing a major role in early embryogenesis, thus in the success of IVF attempt. METHODS: Sperm DNA fragmentation from a selected group of 104 couples undergoing assisted reproductive techniques (ART) (IVF: n = 50; and ICSI: n = 54) was measured by TUNEL assay and correlated with semen and ART outcomes. RESULTS: A negative correlation was found between sperm characteristics and the proportion of sperm showing DNA fragmentation. For fragmentation >10%, a significant decrease of the fertilization rate was observed. No correlation was found between sperm DNA fragmentation and embryo quality. A high proportion of sperm with fragmented DNA was a pejorative factor to obtain pregnancies when ICSI was performed, but there was no relationship when conventional IVF was performed. CONCLUSIONS: The proportion of sperm with DNA fragmentation appears to be potentially useful as a predictor of ICSI outcome, whereas embryo quality based on morphological criteria, appeared unaffected by DNA fragmentation.

Sperm DNA fragmentation decreases the pregnancy rate in an assisted reproductive technique

Evidence suggests that hyperinsulinemic insulin resistance may increase serum levels of ovarian androgens and reduce sex hormone-binding globulin (SHBG) levels in humans. The present study was conducted to assess the effect of administration of the biguanide metformin, a drug commonly used in the treatment of diabetes mellitus, on androgen and insulin levels in 24 hirsute patients. The patients selected for the study were obese, with a body mass index higher than 25 kg/m2 and high fasting insulin (> 90 pmol/L) and low SHBG levels (< 30 nmol/L). All patients were given a low calorie diet (1500 Cal/day) and randomized for either metformin administration at a dose of 850 mg or a placebo, twice daily for 4 months, in a double blind study. In the placebo group, diet resulted in a significant decrease in body mass index (30.8 +/- 1.0 vs. 32.7 +/- 1.5 kg/m2; P < 0.0001), fasting insulin (127 +/- 11 vs. 156 +/- 14 pmol/L; P < 0.01), non-SHBG-bound testosterone (0.19 +/- 0.02 vs. 0.28 +/- 0.03 nmol/L; P < 0.02), androstenedione (5.8 +/- 0.5 vs. 9.0 +/- 1.1 nmol/L; P < 0.03), and 3 alpha-diolglucuronide (8.6 +/- 1.1 vs. 11.7 +/- 1.9; P < 0.005) plasma concentrations and a significant increase in the glucose/insulin ratio (0.047 +/- 0.005 vs. 0.035 +/- 0.003; P < 0.001) and plasma concentrations of SHBG (26.0 +/- 3.3 vs. 19.1 +/- 1.9 nmol/L; P < 0.001) and dehydroepiandrosterone sulfate (8.7 +/- 1.5 vs. 8.4 +/- 1.3; P < 0.05). Beneficial effects of diet were not significantly different in the patients who were given metformin instead of placebo. These results confirm that weight loss induced by a low calorie diet is effective in improving hyperinsulinemia and hyperandrogenism in obese and hirsute women. With our study design, metformin administration had no additional benefit over the effect of diet.

Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women.

Origin, differentiation and regulation of fetal and adult Leydig cells.

https://www.fertstert.org/article/S0015-0282(06)03151-7/pdf

Sperm deoxyribonucleic acid fragmentation as a prognostic indicator of assisted reproductive technology outcome

The osteoblast-derived hormone osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly, Osteocalcin-deficient mice exhibit increased levels of luteinizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. These observations raise the question of whether LH regulates osteocalcin's reproductive effects. Additionally, there is growing evidence that osteocalcin levels are a reliable marker of insulin secretion and sensitivity and circulating levels of testosterone in humans, but the endocrine function of osteocalcin is unclear. Using mouse models, we found that osteocalcin and LH act in 2 parallel pathways and that osteocalcin-stimulated testosterone synthesis is positively regulated by bone resorption and insulin signaling in osteoblasts. To determine the importance of osteocalcin in humans, we analyzed a cohort of patients with primary testicular failure and identified 2 individuals harboring the same heterozygous missense variant in one of the transmembrane domains of GPRC6A, which prevented the receptor from localizing to the cell membrane. This study uncovers the existence of a second endocrine axis that is necessary for optimal male fertility in the mouse and suggests that osteocalcin modulates reproductive function in humans.

/pdf/osteocalcin-regulates-murine-and-human-fertility-through-a-513ex13tr3.pdf

Hervé Lejeune

Papers

Sperm DNA fragmentation decreases the pregnancy rate in an assisted reproductive technique

Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women.

Origin, differentiation and regulation of fetal and adult Leydig cells.

Sperm deoxyribonucleic acid fragmentation as a prognostic indicator of assisted reproductive technology outcome

Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis