Relation of SIRT1 and subfertility

Sirtuins (NAD-dependent deacylases) are involved in deacetylation of histone and transcriptional factors affecting the protein and regulating the cell cycle. They play an important role in providing resistance to oxidation stress and regulating metabolism not only in the nucleus but also in the cytoplasm and mitochondria. SIRT1 is a sensor and guardian of the redox state in female reproductive cells. SIRT1 prevents damage to ovarian cells by the deacetylation of transcription factors such as forkhead-box (FOXO), which is accountable for the expression of superoxides. The mitochondrial biogenesis raises the mitochondrial mass and controls glutathione peroxide, catalase, and manganese SOD by stimulating the peroxisome proliferator-activated receptor coactivator 1-α (PGc1a).

SIRT1 catalyzes the enzymatic reaction between nicotinamide and the acetyl group of the substrate to form a metabolite O-acetyl ADP ribose by NAD cleavage, which positively affects ovarian cell growth. The SIRT1 genotype regulates normal embryogenesis by controlling the proliferation and apoptosis of granulosa cells. In sirtuin-deficit mice, the phenotype is small with a congenital defect with postnatal death early in life. SIRT1 increases ovarian hormones by maintaining the oxidative milieu in favor of the growth and maturation of the oocytes.

Glucose homeostasis and insulin secretion are also regulated by SIRT1, as its function is to deacetylate PGC-1a, which is a main transcriptional coactivator regulating the hepatic glucose metabolism by gene transcription. Animal studies show that SIRT1 upregulates insulin secretion in response to glucose stimulation, assisting glucose tolerance. Furthermore, it reduces fat deposits in adipose tissues by suppressing PPARg and also aids in resolving obesity, indirectly lowering the intensity of insulin resistance and type 2 diabetes.

PCOS patients are obese and display insulin resistance. As postulated by some researchers, metformin helps reduce OS in PCOS patients by disturbing SIRT1. Adipose tissue possesses a secretory capacity of angiotensin II, indirectly stimulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and increasing ROS production in adipocytes.

SIRT1 is an efficient antioxidant found in the oocyte, where it regulates energy production by the mitochondria. Mitochondrial enzymes, including manganese superoxide dismutase (MnSOD), acting as antioxidants within the oocytes are deacylated by SIRT1.

MnSOD plays a vital role in battling OS within an oocyte, probably by its posttranslational, posttranscriptional alteration. SIRT1 activity also prevents an oxidant environment by dietary antioxidant approaches, perhaps by modifying the energy expense and production. MnSOD counterbalances negatively charged ions (O ^{2 −} ) and finally converts them into soluble water (H ₂ O) inside the mitochondrial substance.

SIRT1 mutations disturb the production of MnSOD in various tissues, including the granulosa cells and the oocytes, thus developing OS. Alteration in MnSOD levels is subject to SIRT1 genetic modification. SIRT1 chiefly contributes in the course of oogenesis with its expression in the oocytes extending to the metaphase II phase (MII), as compared to the SIRT3, which takes part in fertilization and primary embryonic growth. Thus, SIRT1 has a conventional participation in positively regulating the release of ovarian steroids. Resveratrol acts as a broad-spectrum stimulator of SIRT1, which can be used to reduce OS and hence correct luteal defects in subfertile patients.

Metformin is a hypoglycemic drug inhibiting the hepatic gluconeogenesis. In a dose-dependent fashion, it has the capability to inhibit cellular respiration within the mitochondria of hepatic cells by increasing the NAD ⁺ /NADH ratio and SIRT1 activities. Metformin regulates glutathione content by employing cell-signaling mechanisms for mitochondrial regulation, hence improving OS (see Fig. 11.1 ). Metformin regulates SIRT1 by producing the cytokine visfatin, which takes part in NAD production, immune functions, and metabolic disorders ( Fig. 11.2 ).

A hypothetical interpretation of the probable mechanisms metformin adapts to maintain the microenvironment of the human granulosa cells. Advancing age induces oxidative stress in the oocytes, thus increasing lipid peroxidation and concurrently decreasing the expression of SIRT1 via a decreased NAD/NADPH ratio (STEP1). This causes a disturbance in the mitochondrial function by direct damage to the mitochondrial DNA (STEP2), reducing ATP synthesis by the electron transport chain (STEP3). Consequently, oocyte maturation failure, chromosomal segregation disorders, and oocyte/embryo fragmentation occur (STEP4), resulting in infertility. Metformin regulates the NAD/NADPH ratio indirectly and the expression of SIRT1 directly. ATP, adenosine-5-triphosphate; MAPKs, mitogen-activated protein kinase; mtDNA, mitochondrial DNA; NAD(P)H, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; SIRT, sirtuin.

Hypothetical illustration of SIRT1 and oocyte aging mechanism affecting the microenvironment. Advancing age induces oxidative stress in the oocytes, thus increasing lipid peroxidation and concurrently decreasing the expression of SIRT1 via a decreased NAD/NADPH ratio (STEP1). This causes a disturbance in the mitochondrial function by direct damage to the mitochondrial DNA (STEP2), reducing ATP synthesis by the electron transport chain (STEP3). Stress instigates the release of cortisol due to the HPO and HPA axis dysfunction. Consequently, oocyte maturation failure, chromosomal segregation disorders, and oocyte/embryo fragmentation occur (STEP4), resulting in infertility.

Glutathione is another antioxidant within the oocyte and the embryo, where it functions as a reducing agent linked to the glucose metabolism. Reduced NADH produced in the pentose phosphate pathway is imperative to keep glutathione in the reduced state. The exhaustion of glutathione reductase can possibly increase hydrogen peroxide (H ₂ O ₂ ) levels, which can potentially damage the DNA. This effect of a decrease in glutathione levels can cause chromosomal aberrations and maturation failures of an oocyte. Cortisol levels increase with persistent psychological stress and with a combination of decreased GR, it is impossible to combat OS. Physical stress together with emotional stress can cause corticotropin-releasing hormone secretion, resulting in higher plasma cortisol levels. Chronic stress also inhibits natural killer cell action along with the activity of T lymphocytes causing immunosuppression, which may lead to endometriosis and hormonal alterations compromising the formation of gamete and impairment of embryo development and implantation.

The expression of visfatin in human ovarian follicles, follicular fluid, and granulosa-like tumor cell line (KGN) cells is regulated by metformin through SIRT1 signaling pathways. Metformin induces a rise in the NAD ⁺ /NADH ratio by activating the amplified appearance of visfatin, resulting in enhanced SIRT1 expression. Visfatin positively effects the insulin-like growth factor-1-induced steroidogenesis in obese individuals. Visfatin revolves around SIRT1 expression and promotes steroidogenesis in the granulosa cells. Visfatin increases in response to low-level antioxidants in obese individuals and its expression is negatively associated with the antioxidants produced. Thus, visfatin is connected with the genes related to OS and the inflammatory responses, which makes it a powerful contender among OS biomarkers, especially in newborns, for a better choice of treatment.

Visfatin is synthesized in visceral adipose tissue and the ovarian follicles, the myometrium, and the placenta of mammals. It plays a role in many metabolic reactions, inflammatory processes, and cellular energy production. SIRT1, being NAD-dependent deacetylase, requires visfatin to accomplish its metabolic goals. Visfatin increases the insulin-like growth factor-induced steroidogenesis in the granulosa cells of humans as well as gonadotropin production. The literature supports the presence of increased levels of visfatin in type 2 diabetes and PCOS.

Adrenaline

Adrenaline is a catecholamine neurotransmitter produced by the sympathetic nervous system and the adrenal medulla. Pertaining to its connection with the oxidative environment, two potential consequences can be predicted. It can be involved in OS production as well as protection from OS. High levels of adrenaline and dopamine have been documented in the follicular fluid of PCOS. Prolonged stress increases adrenaline production, which crosses the blood–brain barrier and disturbs the HPA axis with an increase in cortisol production due to an increase in the cortisol releasing factor. An increased level of adrenaline is an attribute of obesity, as increased adipose tissues trigger sympathetic activity in females.

Stress hormones, follicular size, and endometrial thickness

Conservation of the oxidative setting seems to indeed be required for the maturation of the follicles and endothelium; however, oxidants hamper the follicular maturity. Levels of oxidants and antioxidants are fairly different between individuals with an endometrial thickness cut-off of 0.8 mm and among those with a follicular size of 2 cm, more or less.