Myo-inositol also improves peripheral insulin sensitivity by enhancing the activity of insulin receptor substrate-1 (IRS-1) pathways. Additionally, hyperglycemia-induced inflammation further deteriorates β cell function in women with PCOS (Malin et al., 2015). First, acute testosterone exposure produces insulin hypersecretion in an AR-dependent manner in cultured female mouse and human islets incubated in high glucose. To explore this hypothesis, we generated female mice with testosterone excess and conditional AR deletion in β-cells (βARKO) (Navarro et al., 2018).
Oocyte quality improvements, relevant for women undergoing IVF, are assessed after a full follicular cycle of supplementation, approximately 90 days. Insulin and testosterone markers improve earlier, typically within 6 to 8 weeks. Powder formulations generally offer better dose flexibility than capsules for women who need to adjust based on cycle response. The two forms of inositol are chemically similar enough that manufacturing quality matters — impurities or mislabeling of the ratio affects outcomes. This is also the formulation to use when estrogen is low or borderline — because high d-chiro-inositol will lower it further through aromatase inhibition. The researchers concluded that d-chiro-inositol at supraphysiological concentrations induces "inositol paradox" in the ovaries, impeding the very follicular development it is meant to support.
Smaller RCTs have not consistently reported that testosterone therapy improved glycemic control in hypogonadal men with T2D (Grossmann et al., 2015). In the Rancho Bernardo study, an observational study of the association between endogenous sex hormones and the prospective development of T2D, the authors also concluded that low testosterone concentrations predicted incident T2D in older men (Oh et al., 2002). It is well established that testosterone deficiency predisposes men to visceral obesity, metabolic syndrome and T2D (Navarro et al., 2015, Zitzmann, 2009, Stellato et al., 2000, Oh et al., 2002). Correlation between insulin sensitivity (M)… Positive correlation between insulin sensitivity… Our data suggesting that testosterone is not unequivocally sensitizing, and that sex or other characteristics may influence the response of glucose metabolism to testosterone, underscore the need for further investigations in this area.
The effects of T onto I-related signal transduction pathways were investigated in undifferentiated Hfsmc cells treated with T for 15 min, 30 min, 2, 6 and 12 h vs. T0 (time before stimuli addition); 15 min I treatment was used as positive control. T insulin-like effects on human skeletal muscle cells has been not yet fully investigated. We know that acute physical exercise induces a rapid increase in the human serum endogenous levels of several circulating factors such as T 4–6, but the related short-term effects on T-targeted cells, such as skeletal muscle cells, have been not yet characterized. All together our data indicate that testosterone through the activation of non-genomic pathways, participates in skeletal muscle glucose metabolism by inducing insulin-related effects. GLUT4 cell expression, localization and the phosphorylation/activation of AKT, ERK, mTOR and GSK3β insulin-related pathways at different time points after treatment with testosterone were analyzed..|If you don’t do the testing under appropriate conditions and with the right assays, it’s easy to misclassify somebody as being hypogonadal. Are there psychological or weird market mechanisms at play that share a feature with what happened with opioids and what is now happening with this testosterone prescription that is not matched anywhere else in the world? In thinking about psychological mechanisms that led to this disaster, how about the handing out of testosterone mostly to men who don’t have hypogonadism? The decision to prescribe should be guided by severity of testosterone deficiency, burden of symptoms, and presence of comorbid illness. Recent clinical trials highlight that testosterone replacement in older men has both benefits and risks. Similarly, use of androgen deprivation in men with prostate cancer significantly increases the risk of T2DM with a hazard ratio (HR) of 1.4 (19). The most striking benefits were seen for libido, body composition, and correction of anemia.|Furthermore, testosterone treatment modulated the insulin-dependent signal transduction pathways inducing a rapid and persistent activation of AKT, ERK and mTOR, and a transient inhibition of GSK3β. The high d-chiro group showed worsened oocyte quality, elevated androgen levels in follicular fluid, and reduced estradiol — the opposite outcomes of the myo-inositol group. Ovarian granulosa cells require aromatase to convert testosterone to estradiol, which drives follicle maturation and endometrial development. In muscle and fat tissue, d-chiro-inositol mediates insulin’s effect on glycogen synthesis.}
The onset of the millennium was accompanied by a significant surge in both testosterone testing and initiation of testosterone replacement, especially in men without clear indications (1). By dissecting the hypothalamic-pituitary-gonadal axis, we demonstrated that the cause of low testosterone was a decrease in testicular responsiveness to luteinizing hormone (LH).
In females, excess testosterone action via AR in β cells promotes insulin hypersecretion leading to oxidative injury, which in turn predisposes to T2D. In summary, the hormonal, metabolic, and body composition changes following correction of extreme hyperandrogenism in this patient indicate that testosterone may improve insulin sensitivity both directly and through changes in body composition. In conclusion, testosterone exerts a series of potent metabolic effects, which include insulin sensitization, maintenance and growth of the skeletal muscle, suppression of adipose tissue growth and maintenance of erythropoiesis and haematocrit.
A third of these genes code for proteins involved in inflammation and cellular stress, demonstrating that islets lacking AR are adapting to injury. This is consistent with the observation that male βARKO mice exhibit blunted GSIS and glucose intolerance in response to parenteral glucose, which does not activate gut GLP-1 secretion. Rather, testosterone enhances GSIS from cultured islets by increasing cAMP accumulation (Navarro et al., 2016).
In the Massachusetts Male Aging Study, a population-based prospective study that followed over a thousand men aged for almost 10 years, the authors reported that low serum testosterone concentrations play a role in the development of T2D (Stellato et al., 2000). This effect was subsequently overshadowed by profound changes in body composition that occurred 9 months postoperatively and led to the development of overt diabetes. Luteinizing hormone and follicle-stimulating hormone were low preoperatively and increased postoperatively, reaching values close to the postmenopausal normal range after 9 months, possibly due to a slow recovery of the gonadotrophs from the 10-year suppression by testosterone. Dehydroepiandrosterone-S and 17-OH-progesterone were low before and after surgery, suggesting a normal adrenal androgen production.
In the ovaries, it down-regulates aromatase activity — the enzyme responsible for converting androgens to estrogen. This is the most replicated finding in the inositol and PCOS literature. When FSH binds its receptor, myo-inositol mediates the downstream cascade that drives follicle maturation, estrogen synthesis, and oocyte development. This discrepancy is likely related to tissue-specific AR mRNA instability (Yeap et al., 1999, Krongrad et al., 1991, Yeap et al., 2004) or the high glucose-induced AR mRNA degradation under islet culture conditions (Harada et al., 2018).