Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during reproductive age, characterized by oligo-ovulation or anovulation, hyper-androgenism, and the presence of polycystic ovaries. It is associated with an increased prevalence of metabolic syndrome, cardiovascular disease, and type 2 diabetes. The onset of PCOS has been associated with several hereditary and environmental factors, but insulin resistance plays a key pathogenetic role. Women with PCOS often seek care for menstrual disturbances (oligomenorrhea, amenorrhea, prolonged irregular menstrual bleeding), clinical manifestations of hyperandrogenism, and infertility.
Understanding PCOS
PCOS is considered the most common endocrine disorder in women in the reproductive age, with an estimated prevalence ranging from 6 to 15%, depending on the diagnostic criteria used. PCOS, in fact, is a heterogeneous condition with variable phenotypic expression leading to significant controversy on the diagnostic criteria. Common signs of PCOS not included in diagnostic criteria are represented by insulin resistance, reversal of the FSH/LH ratio, and obesity, which is an important clinical feature of PCOS. Women with PCOS have increased visceral and subcutaneous body fat due to higher androgen levels. Obesity also plays a significant role in explaining the metabolic characteristics of PCOS: patients display an atherogenic lipid profile, associated with elevated levels of low-density lipoprotein, triglycerides, and cholesterol, along with reduced levels of high-density lipoprotein. However, it is important to remark that these metabolic abnormalities may also be present in non-obese patients.
Diagnostic Criteria for PCOS
The diagnosis of PCOS can be elusive because every woman with PCOS does not necessarily have unwanted hair growth or irregular periods. One of the key findings in women with PCOS is insulin resistance and elevated insulin levels for which there may be a lack of physical symptoms. Because PCOS is a syndrome, there isn’t a single test that can be done to make the diagnosis. There are diagnostic criteria which is named the Rotterdam criteria for the diagnosis of PCOS. This includes evidence of elevated androgens, either clinically or in a blood test, irregular ovulation, and a pelvic ultrasound showing ovarian polycystic morphology.
The Role of Insulin Resistance
The positive correlations between hyperinsulinemia and androgen levels suggested that insulin contributes to hyperandrogenism in women with PCOS. The ovaries of PCOS patients usually maintain a normal response to insulin. A partial elucidation of this mechanism is explained by the action of insulin on the ovary through the IGF-1 receptor. This binding occurs when insulin reaches high concentrations, as in compensatory hyperinsulinemia. Insulin actions on the ovary are also mediated by the glycan molecules that contain D-chiro-inositol (DCI), a different second messenger from the classical one activated by phosphorylation of the receptor at tyrosine level in other tissues. Hyperinsulinemia stimulates thecal cell proliferation, amplifies LH-mediated androgen secretion, and increases expression of LH and IGF-1 receptor. Furthermore, high insulin levels inhibit both the production of sex hormone binding globulin (SHBG) by the liver, causing increased levels of free testosterone, and the synthesis of IGF-BP1, increasing level of free IGF-1.
Dietary Patterns in PCOS
Interestingly, excess carbohydrate intake and low-grade inflammation mutually interact with insulin resistance and hyperandrogenism to reinforce the metabolic phenotype of PCOS. In fact, acute hyperglycaemia is known to increase inflammation and oxidative stress through the generation of reactive oxygen species (ROS). PCOS women present a peculiar dietary pattern, characterized by reduced use of extra-virgin olive oil, legumes, seafood and nuts, a lower amount of complex carbohydrate, fiber, monounsaturated fatty acids, and higher simple carbohydrates, total fat and saturated fatty acid, compared to normal women. These nutritional habits are associated with an adverse body composition, characterized by reduced fat-free mass.
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Current Treatment Approaches
A univocal therapy for PCOS does not exist; the peculiar heterogeneity of this pathology requires that the treatment should be personalized, depending on the clinical presentation and needs of the patient. The current guidelines as first-line treatment for menstrual irregularities, acne, and hirsutism recommend hormonal contraceptives, at any age. Antiandrogens are suggested in the case that estroprogestinics are contraindicated or in the presence of severe hirsutism. Metformin has long been used in therapeutic protocols, although alternatives are investigated, because of gastroenteric side effects; inositol represents an alternative approach. Anyway, metformin does not increase weight loss in patients treated with lifestyle modifications (diet and exercise programs). Therefore, diet and exercise, not metformin, should be the first line of therapy in obese women with PCOS. Metformin should be considered if the patient fails with diet and exercise. Weight loss represents the most important factor to improve PCOS phenotype. A 5-10% weight loss improves ovulatory function and pregnancy rates, with reduction of insulin and free testosterone levels. However, even though lifestyle modification based on the principles of caloric restriction remains a primary therapy for PCOS and caloric restriction seems more important than macronutrient composition, little data are available about diet’s macronutrient modification as therapeutic approach. Indeed, it is controversial whether diet composition per se has an effect on reproductive and metabolic outcomes.
The Ketogenic Diet: An Overview
Considering the aforementioned conditions, it would be reasonable that a ketogenic diet (KD) might have positive effects on PCOS. A KD is a nutritional protocol in which carbohydrates are lower than 30 g per day or 5% of total energy intake relative increase in the proportions of protein and fat. The reduction of the amount of circulating glucose and insulin produces a reduction of the oxidation of glucose and an increase of the fat oxidation as showed by the reduction of the respiratory ratio. Another important effect of KD for PCOS is the activation of AMPK and SIRT-1, even in the absence of caloric deprivation. Once activated, SIRT1 and AMPK produce beneficial effects on glucose homeostasis and improve insulin sensitivity.
How the Keto Diet Works
On the low carb, high fat keto diet, your carb intake is significantly decreased, which forces the body into a state of ketosis - where you burn fat rather than carbs for energy. On a keto diet, most people reduce their carb intake to less than 50 grams of total carbs per day. Studies have shown that the ketogenic diet can lead to weight loss and improves IR, a driver of fat storage. The Keto diet is a very low-carb high-fat diet which does not restrict calories, but rather the quality of foods.
Therapeutic Applications of the Keto Diet
The therapeutic role of KD has been investigated for a long time and several works have supported the thesis that physiological ketosis can be useful in many pathological conditions, such as epilepsy, neurological diseases, cancer (with a ketogenic isocaloric diet) and obesity, type 2 diabetes, acne, and the amelioration of respiratory and cardiovascular disease risk factors (with a generally low calorie ketogenic diet). This is an important aim, since the use of food as a drug has very relevant social and economic implications, both in economic and social terms.
Keto Diet and PCOS: The Connection
Blood glucose levels are affected by carbohydrate intake and regulate insulin secretion from the pancreas, so very-low carbohydrates diets may be superior to standard hypocaloric diets in terms of improving fertility, endocrine/metabolic parameters, weight loss and satiety in women with PCOS. In PCOS, evidence for the effects of KD are scarce: only a small uncontrolled pilot study showed a significant reduction in body weight, free testosterone, LH to FSH ratio, and fasting insulin after a KD regimen, suggesting favorable effects in affected patients. Other data describe several mechanisms consistent with the favorable effects of such diet therapy. A recent position statement of the Italian Society of Endocrinology suggested a weight-loss program with a very low calorie ketogenic diet for overweight/obese patients with PCOS) not responsive to multicomponent standardized diet to improve insulin resistance, ovulatory dysfunctions and hyperandrogenemia, even if further controlled studies are deemed necessary to confirm the beneficial effects of KD in this clinical context.
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Benefits of Keto Diet for PCOS
Researchers have found that keto diets may improve insulin sensitivity, help balance hunger hormones, and promote weight loss in people with obesity and type 2 diabetes. A handful of recent studies have investigated the effects of keto diets on PCOS, too. Recent research confirms that a ketogenic diet may significantly improve PCOS symptoms through effective insulin regulation. The ketogenic diet is a restrictive low-carb diet plan that focuses on low carbs, low fats and a normal amount of proteins. Patients often see weight loss results-which helps reduce PCOS symptoms-but women with PCOS see improvements because the problem in PCOS is carbohydrate/insulin resistance. If we are able to control insulin resistance, then we are able to reduce many of the PCOS symptoms and complications, including weight, diabetes, high blood pressure, heart disease, and infertility.
Improved Insulin Sensitivity
Insulin resistance is thought to contribute to the development of PCOS. The hormone insulin helps regulate blood sugar levels by shuttling glucose from the blood into the cells, where it can be used for energy or stored for later use. However, people with insulin resistance tend to have elevated blood sugar levels and elevated insulin levels because their body compensates for the insulin resistance by producing more insulin. Insulin resistance occurs when your cells stop responding appropriately to insulin, which increases blood sugar levels and results in the pancreas making more insulin. Because insulin is also responsible for fat storage, high insulin levels and insulin resistance are also associated with weight gain and obesity. When left unmanaged, insulin resistance may also lead to type 2 diabetes. Since the keto diet may help to improve insulin sensitivity, it may be useful for PCOS management.
In a 12-week study of 14 women with PCOS, a keto diet high in plant foods (like low carb veggies) resulted in significantly lower blood sugar and insulin levels, as well as better insulin resistance scores - indicating higher insulin sensitivity. In another study of 18 women with PCOS, liver dysfunction, and obesity, participants received either conventional prescription medications or consumed a ketogenic diet for 12 weeks. Researchers found that the keto group experienced significant improvements in blood sugar levels, which suggests an improvement in insulin sensitivity - although this study didn’t measure insulin or insulin resistance scores. Finally, a 45-day study of 17 women with obesity and PCOS found that a keto diet reduced average blood sugar levels by 10 mg/dL and mean insulin levels by nearly 13 micro-IU/mL. Insulin resistance scores, which reflect increased insulin sensitivity, also improved.
Hormonal Balance
Following ≥45 days of intervention with ketogenic diet among women with PCOS, significant improvement was observed in reproductive hormone levels, with reduced LH/FSH ratio (d −0.851; 95% CI −1.015, −0.686; P < .001), reduced serum free testosterone (d −0.223; 95% CI −0.328, −0.119; P< .001), and an increased in serum sex hormone binding globulin (SHBG) (d 9.086; 95% CI 3.379, 14.792; P = .002). The pathophysiology of PCOS closely relates to an abnormality in the hypothalamic-pituitary-ovarian or adrenal axis with disturbance in the secretory pattern of the gonadotropin-releasing hormone (GnRH) that results in the relative increase in LH to FSH ratio. In healthy women, the LH to FSH ratio usually lies between 1 and 2, whereas this ratio becomes reversed in women with PCOS, reaching as high as 2 or 3. An excess in serum LH stimulates ovarian androgen production, whereas a relative deficit in FSH further impairs follicular development. Hence, as a result of raised LH/FSH ratio, ovulation does not occur in women with PCOS. A ketogenic diet significantly reduced the LH/FSH ratio.
In PCOS, hyperandrogenism is attributable to increasing levels of circulating free testosterone due to increased steroidogenesis from proliferation of ovarian theca cells resulting from an imbalance in LH/FSH ratio. Dietary modification with ketogenic diet was found to increase the level of circulating SHBG and hence improved metabolic and ovulatory dysfunction in women with PCOS. The low-carbohydrate ketogenic diet was speculated to result in reduction in hyperinsulinemia and therefore decreased stimulation of ovarian androgen production as well as increased SHBG levels, synergistically limiting the circulating free androgens.
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Weight Loss
One of the hardest components to treat in women with PCOS is the propensity for weight gain. In fact, 80% of women with PCOS are obese. There are many diets and exercise programs that are prescribed to women with PCOS, but often, patients complain they have been on a diet and exercised regularly without losing much weight. In one of the 12-week studies on a plant-food-rich keto diet, participants lost an average of nearly 21 pounds (9 kg). In the 12-week study on PCOS and liver function in women with obesity, participants experienced significant weight loss. In a 45-day study, participants lost an average of 21 pounds (9 kg) and significantly reduced their fat mass and waist-hip ratio. Nutritional ketosis formulation induces weight loss through the following hypothesized mechanisms: reduced appetite due to higher satiety effect of proteins in ketogenic diet formulation, a possible direct appetite-suppressant property of the ketone bodies, reduced lipogenesis and increased lipolysis, reduced resting respiratory quotient and, therefore, better metabolic efficiency when consuming fats, and increased in the metabolic costs of gluconeogenesis, together with the thermic effect of high dietary proteins.
Improved Menstrual Regularity and Fertility
Over the course of a 45-day study, 5 of the 17 participants had their period return after not having had one for several years, 12 women reported improved regularity in their period, and 5 women became pregnant after many unsuccessful prior attempts. Many patients are also reporting regular periods again. Many patients who are interested in pregnancy are now able to achieve pregnancy, some are even able to achieve pregnancy without medications. These are patients who have struggled with pregnancy, and now we are seeing them able to achieve pregnancy and eventually a live birth.
Potential Downsides and Challenges
There may be some downsides or challenges to the keto diet for PCOS. In some studies, researchers have found that following a keto diet increases cholesterol levels. This may be a concern for some people, especially those who already have high cholesterol levels. Additionally, keto diets prove restrictive, so they may be difficult for many people to stick to. On keto, you’ll need to avoid bread, pasta, rice, cereals, potatoes, most fruits, and other foods high in sugar or carbs. Instead, you primarily eat animal products, vegetables, berries, and unsweetened beverages.
ConsiderationsBefore Starting Keto
It is important to look at the baseline characteristics of the study participants when evaluating the effects of ketogenic diet, as they can have a significant impact on the transferability and applicability of the results. Demographic and baseline clinical parameters, such as the gender, weight, BMI, age, and health status (such as comorbid liver or kidney derangements) will impact the risks and benefits of a ketogenic diet. It is also worth highlighting that not all keto studies can be generalized for PCOS due to these potential confounding factors. Furthermore, there is no specific formulation that is tailored for PCOS; in addition, induction of nutritional ketosis may be hard on gut health and some might consider the diet as too demanding, eventually affecting long-term compliance.
Modified Keto Diet: A Potential Solution
A modified KD protocol can be used. The KEMEPHY diet is a Mediterranean eucaloric ketogenic protocol (about 1600/1700 kcal/day) with the use of some phytoextracts. During this protocol subjects are allowed to eat with no limits green leafy vegetables, cruciferous, zucchini, cucumbers and eggplants. The quantity of meat, eggs and fish was limited (120 g of meat or 20 g of fish or 2 eggs).
Study on Modified Keto Diet (KEMEPHY)
Fourteen overweight women with a diagnosis of PCOS underwent a ketogenic Mediterranean diet with phyoextracts (KEMEPHY) for 12 weeks. After 12 weeks, anthropometric and body composition measurements revealed a significant reduction of body weight (− 9.43 kg), BMI (− 3.35), FBM (8.29 kg), and VAT. There was a significant, slightly decrease of LBM. A significant decrease in glucose and insulin blood levels were observed, together with a significant improvement of HOMA-IR. A significant decrease of triglycerides, total cholesterol, and LDL were observed along with a rise in HDL levels. The LH/FSH ratio, LH total and free testosterone, and DHEAS blood levels were also significantly reduced. Estradiol, progesterone, and SHBG increased. The Ferriman Gallwey Score was slightly, although not significantly, reduced.