Insulin-sensitizing agents for infertility treatment in woman with polycystic ovary syndrome: a narrative review of current clinical practice.

PURPOSE: Polycystic ovary syndrome (PCOS) is an endocrine, metabolic, and reproductive disorder which, according to the Rotterdam criteria, affects up to 24% of women of childbearing age. Although the prevalence of infertility in this subpopulation of women is high, the optimal treatment has not been fully established yet. Insulin resistance is considered to be an important mechanism involved in the development of PCOS; hence, the aim of this narrative review is to present an overview of the current pharmacological insulin-sensitizing treatment modalities for infertile women with PCOS. METHODS: A MEDLINE and PubMed search for the years 1990-2023 was performed using a combination of keywords. Clinical trials with insulin sensitizers used for infertility treatment as well as analyses of systematic reviews and meta-analyses were evaluated. When deemed necessary, additional articles referenced in the retrieved papers were included in this narrative review. RESULTS: Several insulin-sensitizing compounds and various therapeutical protocols are available for infertility treatment of women with PCOS. Metformin is the most common adjuvant medication to induce ovulation in infertile women with PCOS and is more frequently administered in combination with clomiphene citrate than on its own. Recently, inositol and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as possible options for infertility treatment in PCOS. CONCLUSION: The future of medical treatment of PCOS women with infertility lies in a personalized pharmacological approach, which involves various compounds with different mechanisms of action that could modify ovarian function and endometrial receptivity, ultimately leading to better overall reproductive outcomes in these women.

Treatment of alopecia totalis/universalis/focalis with vitamin D and analogs: Three case reports and a literature review.

BACKGROUND: Alopecia areata (AA) is an inflammatory disease with autoimmune, environmental, and inherited components directed at the hair follicle, either limited to patchy hair loss over the scalp (Focalis, AF), total loss of scalp hair (Totalis, AT), or total loss of both scalp and body hair (Universalis, AU). Despite multiple treatment modalities, no therapy exists. Vitamin D deficiency in patients with AA/AT/AF influences disease severity and duration, inversely correlating with inflammation histologically. CASE SUMMARY: Three girls presented with AT (P1), AU (P2), and AF (P3) at the ages of 1, 5, and 5 years, respectively. For P1-P2, all available treatments implemented for 2 years had failed. We started an initial 6-mo repletion with oral cholecalciferol 2000/4000 IU/d, with no apparent effect. Then we attempted immunomodulation using oral calcitriol and its analog paricalcitol. On calcitriol, 0.5 mcg/d P1 regrew hair within 6 mo. After 4 years, a relapse with loss of eyebrow hair was resolved after doubling the calcitriol dose to 0.5 mcg × 2/d; the results have been maintained for 6 years to date. On calcitriol, 0.25 mcg × 3/d P2 led to the development of asymptomatic hypercalcemia-hypercalciuria, which was immediately resolved by switching to paricalcitol 2 mcg × 3/d; mild tolerable hypercalciuria was maintained. Hair regrowth was observed at 6 mo, stabilizing only as fur at 12 mo. AF in P3 was resolved completely within 3 mo on a daily high dose (8000 IU) of cholecalciferol. CONCLUSION: Vitamin D may have immunomodulating therapeutic impact on AT/AU/AF, which needs to be explored with further pilot clinical trials.

Effects of Hormone Therapy and Flavonoids Capable on Reversal of Menopausal Immune Senescence.

Menopause, probably the most important natural change in a woman's life and a major component of female senescence, is characterized, inter alia, by cessation of ovarian estrogen and progesterone production, resulting in a gradual deterioration of the female immune system. Hormone replacement therapy (HRT) is used in postmenopausal women to relieve some of the peri- and postmenopausal symptoms, while there is also evidence that the therapy may additionally partially reverse menopausal immune senescence. Flavonoids, and especially isoflavones, are widely used for the treatment of menopausal symptoms, although it is not at present clear whether they can reverse or alleviate other menopausal changes. HRT reverses the menopausal CD4/CD8 ratio and also limits the general peri- and postmenopausal inflammatory state. Moreover, the increased levels of interleukins (IL)-1ß, IL-6, and IL-8, as well as of tumor necrosis factor-α (TNF-α) are decreased after the initiation of HRT. However, some reports show no effect of HRT on IL-4, IL-10, and IL-12. It is thus evident that the molecular pathways connecting HRT and female immune senescence need to be clarified. Interestingly, recent studies have suggested that the anti-inflammatory properties of isoflavones possibly interact with inflammatory cytokines when applied in menopause treatments, thereby potentially reversing immune senescence. This narrative review presents the latest data on the effect of menopausal therapies, including administration of flavonoid-rich products, on age-associated immune senescence reversal with the aim of revealing possible directions for future research and treatment development.

The Effect of Dietary Supplements on Oxidative Stress in Pregnant Women with Gestational Diabetes Mellitus: A Network Meta-Analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) exacerbates the oxidative stress status of the pregnant women. Τo improve the oxidative stress status, several therapeutic interventions have been suggested. The aim of this network meta-analysis is to assess the effect of different dietary supplements on the oxidative stress status in pregnant women with GDM. METHODS: A network meta-analysis of randomized control trials was performed comparing the changes delta (Δ) in total antioxidant capacity (TAC) and concentration of malondialdehyde (MDA) as primary outcomes, following different therapeutic interventions with dietary supplements in pregnant women with GDM. Four electronic databases and grey literature sources were searched. The secondary outcomes were other markers of oxidative stress. RESULTS: The meta-analysis included 16 studies of 1173 women with GDM. Regarding ΔTAC: probiotics and omega-3 with vitamin E were superior to placebo/no intervention. Regarding ΔMDA: vitamin D with calcium, omega-3, vitamin D, omega-3 with vitamin E, magnesium with zinc and calcium, and probiotics were superior to placebo/no intervention. CONCLUSIONS: Administration of dietary supplements in women with GDM can be helpful in limiting the oxidative stress which develop in these pregnancies.

Hypothalamic Inflammation as a Potential Pathophysiologic Basis for the Heterogeneity of Clinical, Hormonal, and Metabolic Presentation in PCOS.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. It is a heterogeneous condition characterized by reproductive, endocrine, metabolic, and psychiatric abnormalities. More than one pathogenic mechanism is involved in its development. On the other hand, the hypothalamus plays a crucial role in many important functions of the body, including weight balance, food intake, and reproduction. A high-fat diet with a large amount of long-chain saturated fatty acids can induce inflammation in the hypothalamus. Hypothalamic neurons can sense extracellular glucose concentrations and participate, with a feedback mechanism, in the regulation of whole-body glucose homeostasis. When consumed nutrients are rich in fat and sugar, and these regulatory mechanisms can trigger inflammatory pathways resulting in hypothalamic inflammation. The latter has been correlated with metabolic diseases, obesity, and depression. In this review, we explore whether the pattern and the expansion of hypothalamic inflammation, as a result of a high-fat and -sugar diet, may contribute to the heterogeneity of the clinical, hormonal, and metabolic presentation in PCOS via pathophysiologic mechanisms affecting specific areas of the hypothalamus. These mechanisms could be potential targets for the development of effective therapies for the treatment of PCOS.

Fibroblast Growth Factor 23 (FGF23) and Klotho Protein in Beta-Thalassemia.

Derangements in phosphate and calcium homeostasis are common in patients with beta-thalassemia. Fibroblast growth factor 23 (FGF23) is among the main hormones regulating phosphate levels, while several studies underline an interplay between iron (Fe) and FGF23. Herein, we investigated, for the first time, the serum intact molecule (iFGF23) and the carboxyl-terminal fragment (C-FGF23) and Klotho levels simultaneously in patients with beta-thalassemia major receiving iron chelation regimens in comparison to healthy control subjects. We also correlated them with the body iron burden. The observational case-control study included 81 subjects (40 thalassemic patients and 41 healthy controls). Serum iFGF23, C-FGF23 and Κlotho were measured by ELISA. Parathormone, 25-hydroxycholecalciferol, calcium, and phosphorus were measured in blood and/or urine. The degree of hemosiderosis was evaluated by assessing the serum ferritin levels and performing T2* MRI measurements. Serum C-FGF23 levels were significantly lower in patients compared to control subjects (p=0.04), while iFGF23 and Klotho levels did not differ. Serum C-FGF23 levels were negatively correlated with ferritin (r=-0,421, p=0.018), whereas there were no significant correlations of each of the three factors with the iron chelation therapy. Decreased serum C-FGF23 levels were found in ßTh patients which may be attributed to inhibition of proteolytic cleavage of iFGF23. Further studies in a greater number of patients will shed more light on the disturbances of the iFGF23, Klotho and C-FGF23 in thalassemia and their possible role in bone disease of such patients.

Successful Treatment of Severe Atopic Dermatitis with Calcitriol and Paricalcitol in an 8-Year-Old Girl.

Atopic dermatitis (AD) is a chronic inflammatory disease affecting children and adolescence. The traditional therapeutic options for AD, including emollients topically and immune modulatory agents systemically focusing on reducing skin inflammation and restoring the function of the epidermal barrier, are proven ineffective in many cases. Several studies have linked vitamin D supplementation with either a decreased risk to develop AD or a clinical improvement of the symptoms of AD patients. In this report, we present a girl with severe AD who under adequate supplementation with cholecalciferol was treated with calcitriol and subsequently with paricalcitol. She had significant improvement-almost healing of her skin lesions within 2 months, a result sustained for more than 3 years now. Because of hypercalciuria as a side effect from calcitriol therapy, treatment was continued with paricalcitol, a vitamin D analogue used in secondary hyperparathyroidism in chronic kidney disease. Calcitriol therapy may be considered as a safe and efficacious treatment option for patients with severe AD, particularly for those with refractory AD, under monitoring for possible side effects. Treatment with paricalcitol resolves hypercalciuria, is safe, and should be further investigated as an alternative treatment of atopic dermatitis and possibly other diseases of autoimmune origin.

Vitamin D and aspects of female fertility.

The role of vitamin D in female reproduction has been intensively examined over the last few decades. A large body of evidence suggests that vitamin D might have beneficial effects on metabolic/hormonal parameters of PCOS and endometriosis, while it appears to be associated with IVF outcomes. However, due to the heterogeneity among observational and interventional studies, no cause-effect relationship has yet been established. The aim of this review is to analyze recent in vitro animal and human studies which examined the association of vitamin D with disease entities affecting female fertility potential. Recent research data strongly imply that vitamin D is implicated in female reproduction and might represent a beneficial and inexpensive therapeutic approach, in combination with first-line medical treatments, to female infertility.

Exercise and the stress system.

Exercise represents a physical stress that challenges homeostasis. In response to this stressor, autonomic nervous system and the hypothalamic-pituitary-adrenal axis are known to react and to participate in the maintenance of homeostasis. This includes elevation of cortisol and cathecholamines in plasma. However, sustained physical conditioning in highly trained athletes is associated with a decreased hypothalamic-pituitary-adrenal response to exercise. On the other hand, highly trained athletes exhibit a chronic mild hypercortisolism at baseline that may be an adaptive change to chronic exercise. In addition the proinflammatory cytokine IL-6 is also activated. Moreover, exercise stimulates the secretion of GH and prolactin, and may influence the type of immunity by stimulating TH2 response profile. Besides, the stress of exercise inhibits the gonadal function, through the production of glucocorticoids and cathecholamines, as well as through activation of the CRH neurons. Nowadays, apart from the beneficial effects of exercise, there is increasing incidence of exercise-related short- and long- term consequences, especially concerning the female athlete that many authors describe as the so-called "exercise-related female reproductive dysfunction". These consequences include amenorrhea, infertility, eating disorders, osteoporosis, coronary heart disease and euthyroid "sick" syndrome. The mechanisms involved in the pathogenesis of the above disorders are discussed in this review.

The hypothalamic-pituitary-adrenal axis in the neuroendocrine regulation of food intake and obesity: the role of corticotropin releasing hormone.

The aim of this paper is to review the present knowledge on the role of the hypothalamic-pituitary-adrenal axis in the control of food intake and the pathogenesis of obesity and to discuss, on the basis of available literature, the interactions between other neurosystems and this hormonal axis. Food intake is influenced by a system of physiologic signals and behavioral controls consisting of positive and negative sensory feedback mechanisms. It is regulated by a complex neuroendocrine system consisting of peripheral signals (cortisol, leptin) in constant interplay with central neurosystems such as the cocaine-amfetamine-regulated transcript system. In these neurosystems, corticotropin-releasing hormone, pro-opiomelanocortin, melanin-concentrating hormone and neuropeptide Y are actively involved. The corticotropin-releasing hormone system is widely distributed throughout the brain, but it is particularly abundant in the medial parvocellular division of the paraventricular nucleus. Within the brain corticotropin-releasing hormone with its two receptor types, its binding protein and its closely related peptide urocortin forms a network of neuronal pathways capable of interacting with other circuitries controlling food intake and sympathetically-mediated thermogenesis. A defect in the synthesis and release of corticotropin-releasing hormone has been implicated in the development of obesity in laboratory animals. This condition is alleviated by exogenous corticotropin-releasing hormone treatment. The relationship between the neuropeptide Y system and the hypothalamic-pituitary-adrenal axis is complex and seems to include positive feedback between neuropeptide Y and corticosteroids and negative feedback between corticotropin-releasing hormone and neuropeptide Y. Leptin is involved in the regulation of energy balance by interacting with the hypothalamic-pituitary-adrenal axis. In the past, we have shown by cross-correlation analysis, that under physiological conditions cortisol and plasma leptin levels are related to each other in a time-related negative and positive fashion over 24h.