PCOS Review

PCOS

Polycystic Ovarian Syndrome (PCOS) is an ovarian dysfunction syndrome with a combination of heterogeneous signs and symptoms. It is considered the most prevalent endocrinopathy resulting in anovulation in up to 10% of women of reproductive age. 

PCOS pathogenesis is not yet entirely clear, although, in recent years, many researchers have focused their attention on the role of glucose tolerance and insulin resistance. They have placed these mechanisms among the most responsible for the existence of this complex syndrome. Insulin resistance is found in 30 to 40% of women with PCOS, and it is characterized by resistance to the effects of insulin and in the uptake of glucose in the metabolism with subsequent reduction of the body’s ability to eliminate glucose from the bloodstream.

A rise in the serum levels of androgen, insulin, and Luteinizing Hormone (LH), menstrual dysfunction, hirsutism, infertility, and obesity are some of the complications that are associated with PCOS. In addition, endometrial hyperplasia, cancer, type II diabetes, hypertension, and dyslipidemia are considered long-term consequences of PCOS.

Myo-inositol

Myoinositol is an isoform of inositol, belonging to the vitamin B complex, with insulin-like action in vivo and functions as a mediator of insulin. It plays an important role in cellular morphogenesis and cytogenicity, in the synthesis of lipids, and in the structure of cell membranes and cell growth. Data in the literature have shown that there is a correlation between insulin resistance and reduction of myoinositol in some tissues. Some authors suggest that a deficiency in the availability or use of myoinositol may be responsible for a mechanism of insulin resistance with consequent effects on ovarian function. In particular, it seems that in the theca cells of PCOS patients who are sensitive to insulin, the imbalance of inositol goes in the opposite direction to that observed in cells of insulin-resistant women. Supplementation of inositol, therefore, would seem to improve the ovarian response to gonadotropin-induced compensatory hyperinsulinemia, in addition to improving oocyte quality.

N-acetyl- cysteine (NAC)

Recent data has shown that NAC, a mucolytic drug acting as an insulin sensitizer, represents an effective and safe strategy in the treatment of PCOS patients. This molecule appears to exert its beneficial effect both by increasing the insulin secretion by the beta cells of the pancreas and by inducing an increased sensitivity to the organism itself. In particular, some data shows that a moderate increase in plasma thiols improves the consumption of glucose during the hyperglycemic clamp. Other studies suggest a role of NAC, in the regulation of the insulin receptor in human erythrocytes. It has been shown, in fact, that high doses of NAC increase the cellular levels of reduced glutathione (GSH), which is a powerful antioxidant that seems to exert a certain influence on the activity of the insulin receptor in vivo.

In vitro data also shows that cysteine and its analogs are able to potentiate insulin secretion induced by glucose. This observation suggests the presence of a specific molecular portion in the cysteine that is necessary for its insulinotropic effect.

Observing the molecular structure of NAC (N-acetyl-cysteine) highlighted the presence of a disulfide bridge that should facilitate the processing of proinsulin into insulin, a critical step to reduce insulin resistance.

In humans, oral administration of NAC has also been proposed for the prevention of endothelial damage by oxidizing agents in adult insulin-dependent diabetics. Therefore, administration of NAC in PCOS patients could have important long-term effects on insulin secretion, on metabolism, and on peripheral insulin sensitivity.

Alpha Lipoic Acid (ALA)

Alpha Lipoic Acid (ALA) is synthesized in the liver and other tissues and is a key component of several mitochondrial enzyme complexes responsible for oxidative glucose metabolism and cellular energy production. When used pharmacologically, ALA functions as a safe and effective antioxidant, recycling vitamins C and E, elevating glutathione levels, and lowering reactive oxygen species ROS. Cell culture studies reveal that ALA reverses the effects of oxidative stress thus, improving insulin action.

Alpha lipoic acid is a powerful Reactive Oxygen Species (ROS) scavenger. ALA helps the body use glucose, hence, their potential role in improving blood sugar control and benefits those with diabetes.

ALA can specifically activate two important molecules of the insulin signalling pathway: 

• Insulin Receptor Substrate-1 (IRS-1) protein.
• Phosphatidylinositol 3-kinase (PI 3-kinase) with subsequent enhancement of glucose uptake via the glucose transporter system in skeletal muscle and adipocytes.

Serenoa Repens

Serenoa repens is derived from the berry of the dwarf palm tree. A large number of papers have evaluated its efficacy in controlling BPH-related lower urinary tract symptoms. In women, serenoa repens has been shown to have positive effects on the reproductive system such as increasing the size and secreting ability of the mammary glands, decreasing ovarian and uterine irritability, relieving dysmenorrhea, and ameliorating ovarian dysfunction. Several mechanisms of action of Serenoa repens have been proposed, including anti-androgenic action, an anti-inflammatory effect and an anti-proliferative – proapoptotic effect mediated through the inhibition of growth factors. In vitro, Serenoa repens extract significantly inhibited both type I and II isoenzymes of 5α-reductase and inhibited in a dose-dependent inhibition of intracellular binding of dihydrotestosterone (DHT) to its cytosolic and nuclear receptors. 

Infertile woman with PCOS may be offered a number of treatment strategies to achieve conception. Weight loss is the first line of treatment recommended particularly for obese patients. However, if this approach fails, ovulation induction is proposed. Furthermore, in cases in which weight loss and ovulation induction are unsuccessful, the next approach recommended is assisted reproductive technology.

Recently, there has been growing interest in the use of alternative insulin sensitizing drugs, namely myo-Inositol pre-treatment, to improve the quality and safety of fertility management of PCOS women. A systematic review examining the effect of myo-Inositol in women with PCOS established that level “I-a” evidence exists for the effectiveness of myo-Inositol in improving various manifestations of the disorder in this particular female population. By improving insulin sensitivity of target tissues, Myo-Inositol is believed to improve oocyte quality and control clinical and biochemical hyperandrogenism and dyslipidemia.

The addition of NAC, ALA, and Serenoa repens to Myoinositol with their expected synergistic properties, seems to be a good alternative to the already known medical treatment based on improving glucose utilization with metformin and inducing ovulation with Clomiphene citrate. Many clinical trials have studied the efficiency of these ingredients separately in women with PCOS. They have shown good results in improving PCOS symptoms and improving ovulation and pregnancy rates, whether spontaneously or after assisted reproductive technique or in vitro fertilization.

References:

1. Unfer V, Carlomagno G, Dante G, et al. Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials. Gynecol Endocrinol. 2012
2. Ciotta L, Stracquanda M, Pagano I, et al. Effects of Myo-Inositol supplementation on oocyte’s quality in PCOS patients: A double-blind trial. Eur Rev Med Pharmacol Sci. 2011 
3. John C. Marshall and Andrea Dunaif. All Women with PCOS Should Be Treated for Insulin Resistance. Fertil Steril. 2012 Jan; 97(1): 18–22.
4. Angela Sacchinelli, Roberta Venturella, Daniela Lico et al. The Efficacy of Inositol and N-Acetyl Cysteine Administration (Ovaric HP) in Improving the Ovarian Function in Infertile Women with PCOS with or without Insulin Resistance. Obstet Gynecol Int. 2014; 2014: 141020.
5. Vittorio Unfer,Fabio Facchinetti, Beatrice Orrù, et al. Myo-inositol effects in women with PCOS: a meta-analysis of randomized controlled trials. Endocr Connect. 2017 Nov; 6(8): 647–658.
6. 8. Carlomagno G and Unfer V. Inositol safety: clinical evidences. Eur Rev Med Pharmacol Sci. 2011;15(8), 931-936
7. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 Jul;28(7):412-9
8. Enzo Bonora, Gianni Formentini, Francesco Calcaterra, et al. HOMA-Estimated Insulin Resistance Is an Independent Predictor of Cardiovascular Disease in Type 2 Diabetic Subjects: Prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002 Jul; 25(7): 1135-1141