The genetic and lifestyle factors that affect Endometriosis , Polycystic Ovarian syndrome (PCOS) and Menopause.
Endometriosis
Endometriosis is categorised by the presence of endometrial tissue (tissue similar to the lining of the uterus) outside the uterus leading to scar tissue formation and inflammation. It is associated with chronic pelvic pain (especially during menstruation), abdominal bloating, heavy menstruation, nausea, fatigue and may be associated with anxiety, depression and infertility. Endometriosis may however be present without any symptoms.
Endometriosis is known to be dependent on estrogen, which increases the inflammation, growth and pain associated with the disease. The absence of estrogen however does not always mean the absence of endometriosis. There is currently no way to prevent endometriosis. Early diagnosis and management may slow the disease progression and hemp to manage symptoms.
Nutritional interventions may be beneficial in managing endometriosis and its associated pain. A diet high in omega-3 fatty acids and low in trans fats may help reduce the symptoms of endometriosis. Plant-based diets and those rich in antioxidants can also help manage inflammation. Reducing the intake of red meat and increasing the consumption of fruits, vegetables, and whole grains are recommended.
Key points include:
Dietary fat and fibre: Reducing dietary fat and increasing fiber can lower circulating estrogen levels, which may benefit individuals with endometriosis, an estrogen-dependent condition
A diet high in Trans fats is associated with increased risk of endometriosis
Omega 3 fatty acids may help to reduce the symptoms of endometriosis due to it’s anti-inflammatory effect
Meat consumption: High red meat consumption (processed and unprocessed) is linked to an increased risk of developing endometriosis
Plant-Based Diets: Plant-based diets with anti-inflammatory properties may help alleviate endometriosis symptoms. It is therefore important to increase the intake of vegetables, fruit and wholegrains
Vitamins: Vitamin D can play a role in reducing inflammation and pain. Vitamin D deficiency have been linked to an increased risk of endometriosis diagnosis and severity of symptoms, Vitamins C and E have been shown to significantly reduce symptoms due to it’s antioxidant activity
Endometriosis is a complex and multifaceted disease, with its exact causes still not fully understood. Both genetic and lifestyle factors play roles in influencing the risk and progression of the disease. Here's an integrated view of how these factors contribute to endometriosis:
Genetic Factors:
1. Familial Clustering and Genetic Inheritance:
Familial Patterns: Endometriosis shows significant familial clustering, with a higher incidence among first-degree relatives of affected individuals. This suggests a strong genetic component.
Polygenic Inheritance: The disease is likely influenced by multiple genetic factors, indicating a polygenic or multifactorial inheritance pattern.
2. Genetic Studies:
Loss of Heterozygosity (LOH): Chromosomal studies have revealed LOH at several loci (e.g., chromosomes 9p, 11q, and 22q), with specific gene mutations (such as in TP53 and PTEN) linked to endometriosis.
Multi-hit Hypothesis: This theory proposes that endometriosis develops through a series of genetic mutations. Initial mutations in genes related to cellular attachment allow endometrial cells to survive and adhere to the peritoneum, followed by further mutations that alter cell biology and metabolism.
3. Gene Mapping:
Candidate Gene Studies: Investigations have focused on genes involved in inflammation, hormone metabolism, and detoxification, with mixed results regarding their associations with endometriosis.
4. Linkage Mapping:
Significant linkage peaks have been identified on chromosomes 10, 20, and 7p, suggesting specific regions of the genome that may harbor susceptibility alleles.
Genome-Wide Association Studies (GWAS): Recent studies have identified SNPs associated with endometriosis near several genes, though further research is needed to confirm these associations and understand their implications.
Lifestyle Factors:
Estrogen and Progesterone: Endometriosis is influenced by hormones, particularly estrogen and progesterone, which are critical in the disease's development and progression. Caffeine intake affects estradiol levels, but recent studies have found no strong, consistent link between caffeine consumption and increased endometriosis risk. This suggests that caffeine's role may be less significant or more complex than previously thought.
Hormone Levels and Inflammation:
Alcohol is known to influence hormone levels and inflammation. However, studies on its impact on endometriosis risk are mixed. Challenges in accurately capturing alcohol consumption before diagnosis may contribute to these inconsistent findings.
Hormone Metabolism and Inflammation:
Smoking could potentially alter hormone metabolism and inflammation. Despite this, reviews have found no clear association with endometriosis, possibly due to reliance on self-reported data and variability in study methodologies.
Health Benefits and Reproductive Issues:
While physical activity generally benefits health, high-intensity exercise has been linked to reproductive issues in some studies. Epidemiological data on physical activity's impact on endometriosis risk are mixed, with some studies suggesting a protective effect and others showing no significant association.
The interplay between genetic and lifestyle factors in endometriosis is complex. Genetic studies underscore the importance of inherited and multi-hit mutations in the disease's development. In contrast, lifestyle factors like caffeine, alcohol, smoking, and physical activity may influence hormone levels and inflammation, but their specific roles in endometriosis remain unclear and inconsistent. Future research should continue to explore these genetic and lifestyle factors to elucidate their contributions to endometriosis risk and progression. Improved understanding of these factors may lead to better diagnostic, preventive, and therapeutic strategies for managing endometriosis.
Polycystic Ovary Syndrome (PCOS)
Polycystic ovary syndrome (PCOS) is a common endocrine disorder of unknown cause that affects an estimated 3% to 12% of women of reproductive age in Western societies. The condition is characterized by reproductive issues such as amenorrhea or other menstrual irregularities, anovulation, enlarged ovaries with multiple cysts, and infertility. These ovarian cysts alter the testosterone-oestrogen balance, resulting in insulin resistance and infertility. A healthy diet and exercise program helps parents prepare for an optimal pregnancy outcome, with the goal of achieving normal weight before conception.
Inflammatory conditions of endometriosis, PCOS, and unexplained infertility are the most common related diseases worldwide. Oxidative stress and its accompanying inflammation are postulated as the most important pathways in female infertility. Other conditions such as “estrogen dominance” carry inflammatory problems as in uterine fibroids, fibrocystic breasts, hypothyroid or autoimmune thyroiditis, diabetes type 1 and type 2, and adrenal stress.
The aetiology of PCOS is largely unknown, although the latest studies have decreased sensitivity of the gonadotropin-releasing hormone (GnRH) pulse generator to inhibition by ovarian steroids, mostly progesterone. Women with polycystic ovary syndrome (PCOS) need higher levels of progesterone to slow the frequency of GnRH pulse secretion, resulting in insufficient plasma follicle-stimulating hormone (FSH) synthesis and persistent plasma luteinizing hormone (LH) stimulation of ovarian androgens. A healthy diet and exercise program helps parents prepare for an optimal pregnancy outcome, with the goal of achieving normal weight before conception.
PCOS is associated with increased levels of insulin resistance (this needs to be screened for in a bloodtest). Hyperinsulinemia existed in about 80% of obese PCOS women and in 30–40% of normal weight women with PCOS, and affected 50 – 75% of all PCOS cases. Metformin increases insulin sensitivity in the liver by reducing gluconeogenic enzyme activities, inhibiting hepatic uptake of lactate and alanine, increasing the conversion of pyruvate to alanine and inhibiting glucose output. Clinical trials have shown that metformin can effectively reduce androgens, improve insulin sensitivity, and simplify weight loss in patients with PCOS. Recent recommendations suggest that 5% to 10% weight loss is preferred to the use of metformin for ovulation induction in patients with PCOS.
Oestrogen is produced by the ovaries (and in small quantities by the adrenal glands). This hormone is essential for the development of females reproductive organs and the menstrual cycle. Oestrogen helps to thicken the endometrium for ovulation. Oestrogen in commonly high in women with PCOS (oestrogen dominant). Hence, when levels are unbalanced the symptoms can lead to irregular periods, unwanted hair growth, and acne. It is characterized by multiple fluid-filled, cyst-like sacs on the ovaries, although this does not have to be present for a diagnosis of this condition. It is recommended that you should have routine scans with your gynaecologist to check for the presence of cysts. PCOS is the most common cause of ovulatory infertility and it’s believed that oestrogen dominance plays a part, along with other hormonal imbalances, including elevated testosterone.
Lack of ovulation results in continuous high levels of oestrogen and insufficient progesterone.
It is important to identify the difference between cysts and fibroids:
“Nutritional interventions that may be beneficial for women with PCOS include dietary modifications designed to enhance insulin sensitivity. This includes restricting refined carbohydrates and total calories; consuming high-fiber foods; and eating small, frequent meals. Some patients with insulin resistance fare better on a diet high in complex carbohydrates (approximately 60% of total calories), whereas others respond better to a low-carbohydrate diet (#40% of total calories). In addition, supplementation with vitamin D3 (up to 10,000 IU/day)”
Whole foods
“Functional foods” are foundational in achieving wellness
Avoid processed foods
Low GI Diet
Low– glycemic index diets historically have been recommended without evidence of their clinical effectiveness. However, the capacity of dietary carbohydrates to increase postprandial blood sugar response may be an important consideration for optimizing metabolic and clinical outcomes in PCOS. Furthermore, independent of weight loss, a low–glycemic index diet appears to result in greater improvements in health, including improved insulin sensitivity, improved menstrual regularity, better emotion state, and decreased markers of inflammation compared with a conventional low-fat diet when matched closely for macronutrient and fiber content.
To see if a starch/ grain is high fibre look at the back of the nutritional label:
>6g of fibre per 100g is a high fibre product (and a good alternative
Vitamin D
Deficiency is very common in PCOS cases. It is important to screen for this:
<12ng/mL = Deficiency | See Doctor for supplementation. Often Calciferol is needed weekly up 6 months
12 – 20ng/mL = Insufficiency | An over-the-counter supplement could be used
35 – 55ng/mL = Ideal | Maintain through diet and current supplementation
Weight loss
AN elevated BMI is proven to increase the risk and severity of PCOS. Weight loss is recommended if BMI >30kg/m².
Weight loss does not guarantee the full reversal of insulin resistance.
Iron deficiency
Due to heavy/ irregular period, excessive blood loss can lead to chronic anaemia- it is important to test iron (iron amount, saturation, transport as well as storage)
Fat type
Due to the increased risk of hypertriglyceridemia, it is important to watch the types of fat that you eat (quality of fat). A high Triglyceride value can be caused/ exacerbated by a high intake of animal fats and highly processed foods. E.g.: Cakes, chocolates, fast foods, baked goods, alcohol, etc
Prioritize plant fats: Avocado, Olive Oil, Canola Oil, Seeds, Nuts, Olives
Limit animal fats: Butter, cream, fat on the red meat, chicken skin, full cream dairy
PCOS patients are also at a higher risk of increased blood pressure, hence it is important to also:
Reduce fat intake (quantity)
Refined carbohydrates/ sugars
Increase vegetable intake
Increase fibre intake (specifically soluble fibre)
Increase exercise
Alcohol
Decreasing alcohol intake in important in reducing systemic inflammation.
"Sustained inflammation is the common denominator of all chronic disease. Nutrition and lifsetyle are modulators or sustained inflammation"
Oxidative stress
Oxidative stress is higher in patients with an elevated BMI
A direct reducer of oxidative stress is ANTIoxidants (namely vitamin A, C and E).
It is important to eat brightly coloured foods - E.g.: Berries, carrots, beetroot, spinach, broccoli, asparagus
Thyroid health
Before treatment of the thyroid can be initiated, you must first check thyroid health (TSH and T4 bloodtests). Hypothyroidism (an underactive thyroid) is seen in some cased. It is recommended to star to using Iodized salt instead of normal table salt in these cases (to provide the body with more Iodine in order to create my T4 hormone).
Not clinically proven, but might help:
Other beneficial micro and phyto-nutrients that impact oestrogen metabolism include calcium D-glucarate, curcumin, green tea polyphenols and D-limonene
Calcium D-glucarate may lower oestrogen: Oranges, apples, grapefruit and cruciferous vegetables
Green tea polyphenols
D-limonene: Citrus peel (this can tastefully be added to smoothies and savoury dishes)
The benefits of Folic acid supplementation (>400mcg/day) has not been studied in the prevention of PCOS yet
Chromium picolinate: (200 to 1000 mcg/day) has been reported to improve glucose tolerance, insulin secretion, and insulin sensitivity in human subjects and laboratory animals. However, Research shows that deficiencies are rare, and that treatment should rathe the short-term
Recommended Bloodtest:
Testosterone (Can be elevated)
FSH and LH within the first 5 days post period (Ratio: 1:2)
Insulin (Can be elevated)
Vitamin D (Can be deficiency)
Folic acid (Can be deficient)
Iron Studies (Can be deficient)
TGL (Triglycerides) (Can be elevated)
TSH and T4 (Can be abnormal)
These blood tests will not diagnose PCOS, but rather address the additional symptoms that can be directly impacted by food intake and lifestyle.
PCOS is a multifaceted syndrome influenced by genetic, hormonal, environmental, lifestyle, and oxidative stress factors.
1. Genetic Factors:
Heritability: PCOS has a notable genetic component, with a higher prevalence among women with a family history of PCOS or diabetes. Genetic predisposition involves multiple gene variants related to insulin resistance and ovarian function.
Gene Variants:
Specific genetic polymorphisms, such as those affecting insulin signaling and steroidogenesis, contribute to PCOS. Genome-Wide Association Studies (GWAS) have identified several loci associated with the condition, including chromosomes 2p16.3, 2p21, and 8q24.2. These genetic variations impact hormonal imbalances and metabolic dysfunctions seen in PCOS. Genes involved in insulin resistance and androgen production, such as FSHR and INSR, have been linked to PCOS.
Several key genes thought to play a role in its development:
Androgen Receptor Gene (AR): Located on chromosome Xq12, AR is important for androgen signaling. Mutations or disruptions in AR can affect this pathway, potentially leading to PCOS. Genome-wide studies aim to find new mutations related to PCOS
Follicle Stimulating Hormone Receptor (FSHR): Found on chromosome 2p16.3, FSHR is crucial for gonad development and hormone regulation. Abnormalities in FSHR can affect ovarian function and the severity of PCOS
Fat Mass and Obesity-associated Gene (FTO): Positioned on chromosome 16q12.2, FTO is linked to obesity and type 2 diabetes. Variations in the FTO gene, such as the rs9939609 SNP, are associated with increased BMI in PCOS patients
Calpain 10 (CAPN10): On chromosome 2q37.3, CAPN10 is involved in insulin action. Polymorphisms in CAPN10 are linked to insulin resistance, a common issue in PCOS
Aromatase and Cytochrome P450 Genes: Aromatase, part of the Cytochrome P450 family, helps convert androgens to estrogen. Genetic defects in these enzymes, including CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP1A1, CYP21A2, and CYP3A7, can disrupt this process and contribute to PCOS. For example, variations in CYP19A1 are linked to increased androgen levels and PCOS symptoms
CYP1A1: Located on chromosome 15q24.1, this gene’s polymorphisms are associated with PCOS and elevated androgen levels
CYP11A1: This gene, found on chromosome 15q24.1, is involved in steroid synthesis. Polymorphisms here are linked to an increased risk of PCOS, especially when influenced by environmental factors
CYP21A2: On chromosome 6p21.33, mutations in this gene may contribute to PCOS, though its role is less well-defined
CYP3A7: Located on chromosome 7q22.1, CYP3A7 affects androgen metabolism. Variants here are associated with lower DHEAS levels and may reduce PCOS severity
2. Hormonal and Metabolic Factors:
Hormonal Imbalance: Women with PCOS generally exhibit elevated androgen levels and lower estrogen levels. High Anti-Müllerian Hormone (AMH) levels are linked with the severity of PCOS.
Insulin Resistance: A significant factor in PCOS, insulin resistance is influenced by genetic and lifestyle factors. It contributes to metabolic complications such as type 2 diabetes.
3. Environmental and Occupational Factors:
Endocrine Disruptors (EDs): Exposure to chemicals like BPA and phthalates, which can act as endocrine disruptors, may worsen or contribute to PCOS. These chemicals interfere with hormonal regulation and reproductive function, possibly exacerbating PCOS symptoms.
Industrial Chemicals: Prenatal exposure to endocrine-disrupting chemicals, such as BPA, is linked to hormonal disturbances and PCOS. Elevated BPA levels correlate with higher androgen levels and PCOS symptoms in women and teenagers.
Lifestyle and Occupational Exposure: Environmental contaminants and lifestyle factors, including plastic-packaged food consumption, pesticide exposure, and occupational hazards, may be associated with increased PCOS risk. However, more research is needed to clarify these relationships.
4. Lifestyle and Dietary Factors:
Impact of Weight: Weight gain and obesity exacerbate PCOS symptoms, while weight loss can alleviate them. Managing weight through diet and exercise is crucial for improving PCOS symptoms and overall health
Dietary Interventions: A balanced diet rich in fiber, lean proteins, and healthy fats is beneficial. Regular physical activity improves menstrual irregularities, insulin sensitivity, and overall metabolic health
Lifestyle Changes: Programs focusing on diet, exercise, and behavioral management have shown success in reducing diabetes risk and improving fertility outcomes in women with PCOS
Genetic variations in these genes play a significant role in the development and progression of PCOS. Understanding these genetic factors helps in identifying individuals at risk and may guide future treatment strategies. Adopting a healthy lifestyle, including weight management and a balanced diet, is crucial for managing PCOS. For severe cases, treatments like medications and assisted reproductive technologies may be recommended.
(Ajmal, N., Khan, S.Z., and Shaikh, R., 2019. Polycystic ovary syndrome (PCOS) and genetic predisposition: A review article. European Journal of Obstetrics & Gynecology and Reproductive Biology: X.
Kshetrimayum, C., Sharma, A., Mishra, V.V. and Kumar, S., 2019. Polycystic ovarian syndrome: Environmental/occupational, lifestyle factors; an overview)
“Eating for your cycle”
A regular menstrual cycle is a strong sign of a healthy reproductive system and an important indicator for possible pregnancy. A healthy menstrual cycle lasts between 21 and 35 days and consists of three phases including the follicular phase, ovulation and the luteal phase.
Follicular phase starts on day 1 of heavy flow in menstruation and may last about 14 days until ovulation occurs. During this time follicle stimulating hormone (FSH) stimulates the growth of follicles and the production of estrogen, progesterone and testosterone. Estradiol is also produced which supports the uterine lining to prepare for a potential pregnancy. During this phase, feelings of happiness and improved blood glucose control commonly occur.
Ovulation occurs when Luteinizing hormone (LH) cause the egg (ovum) to break free from the follicle and move to the fallopian tube for possible fertilization by sperm.
Luteal phase occurs after ovulation and lasts 10-16 days until the first day of heavy flow. The follicle (corpus luteum) starts secreting progesterone which prepares the uterine lining for possible pregnancy. If fertilization occurs, the corpus luteum will continue to make progesterone through the 1st trimester. If not, it will shrink in size, causing progesterone levels to drop and the uterus will “shed” its lining.
Interesting facts:
High cortisol levels can cause a decreased production in FSH and LH – inhibiting ovulation
Insulin resistance can also have a negative effect on ovulation due to an increased production of testosterone by the ovaries
Hypothyroidism may also lead to ovulation suppression due to imbalanced hormones
Research has shown that factors like obesity, stress, and smoking can disrupt menstrual cycles and lead to early menopause. One study demonstrated that smoking can cause hypoestrogenism. A high BMI has been demonstrated to influence the sex hormone-binding globulin (SHBG), free androgen index (FAI), testosterone, and insulin levels. Interestingly, women who had more than three of these risk factors had a 1.7 times greater chance of having irregular periods compared to those without any of these factors. Smoking, especially when started at a young age (under 19) or in large amounts, was also associated with early menopause. It has been found that these modifiable factors—smoking, obesity, and stress—are closely linked to irregular periods.
Certain dietary habits might help with menstrual symptoms, but there’s no clear scientifical evidence on which foods or supplements are proven enough to be recommended for easing these symptoms in people who have regular periods.
There is some evidence suggesting that vitamin D, calcium, zinc, and curcumin may help reduce menstrual symptoms in people who use non-hormonal contraceptives. However, more research is needed to confirm these findings.
A research study (An Assessment of Women's Knowledge of the Menstrual Cycle and the Influence of Diet) found that women consuming an anti-inflammatory diet containing low-processed products (vegetables, fruit, whole-grain cereals, dairy and legumes) experienced significantly less menstrual pain. In contrast, consumption of highly processed foods, including sweets, processed meat, foods high in saturated fat and low in fiber, was more frequently associated with increased menstrual pain and discomfort.
Menopause
Menopause is the point that marks the end of your menstrual cycles and is diagnosed 12 months after the last menstruation. It is caused by the loss of ovarian follicular function and a decrease in estrogen. Menopause can also be triggered by a hysterectomy or surgical removal of the ovaries.
Perimenopause, also known as the menopausal transition, usually begins in the late forties and includes the years leading up to menopause when menstrual irregularities occur.
During menopause, a significant decrease in estrogen levels leads to various physiological changes and symptoms. Estradiol, a key estrogen, influences metabolism, insulin sensitivity, and fat distribution. Its decline reduces basal metabolism, increases appetite, and leads to weight gain and altered fat distribution, particularly increasing visceral fat. This change can cause low-grade systemic inflammation, raising the risk of chronic conditions such as cardiovascular diseases, type 2 diabetes, and osteoporosis. Menopause is associated with an increased prevalence of obesity, metabolic syndrome, cardiovascular disease and osteoporosis.
Leading a healthier lifestyle—quitting smoking, managing your weight, following a healthy balanced diet with a wide range of nutrients, and reducing stress may significantly improve reproductive health. Making these changes can help maintain regular menstrual cycles and reduce the risk of early menopause, contributing to better overall well-being throughout a woman’s life.
Dietary changes are crucial during menopause to manage these metabolic shifts and associated symptoms. A balanced diet can help prevent weight gain, support metabolic health, and reduce inflammation. Proper nutrition can improve overall health and alleviate menopause-related symptoms, contributing to better management of menopause and its complications. Regular exercise combined with a proper diet can help to prevent weight gain. A balanced diet, staying hydrated and getting enough sleep are some important lifestyle changes. Key nutrients include: Vitamin D, calcium, B vitamins and adequate protein intake.
Summary:
During perimenopause, maintaining a healthy nutritional status (BMI 18.5–24.9 kg/m²) is crucial. For overweight or obese women, a calorie reduction of 500–700 kcal/day and a protein intake of 1–1.2 g/kg/day are advised, though long-term energy intake should not fall below basal metabolic rate (BMR).
Dietary recommendations include:
Balanced Diet: Follow the Nutrition Care Process Model (NCPM) and use body composition tools for assessment
Eating Schedule: Establish a regular eating pattern
Sugar and Alcohol: Avoid simple sugars and limit alcoholic beverages
Protein: Consume 0.8–1.2 g/kg/day, with half from plant sources
Key Nutrients: Ensure adequate intake of calcium, vitamin D, vitamin C, B vitamins, omega-3 fatty acids, and n-3 LCPUFAs
Fruits and Vegetables: Aim for 5 portions daily (300–400 g of vegetables and 200–100 g of fruit)
Legumes: Eat legumes at least once a week
Protein Sources: Opt for low-fat sources like poultry and dairy, and moderate red and processed meats
Fats: Limit saturated fats to less than 10% of total energy intake and use healthier oils like olive or rapeseed
Salt and Sugar: Reduce salt and sugar use; flavor with herbs instead
Fish: Consume deep-sea or freshwater fish twice a week
Nuts and Seeds: Include 30 g of unsalted nuts or seeds daily
Fiber: Incorporate high-fiber foods like whole grains and legumes, aiming for 30–45 g of dietary fiber daily
Processed Foods: Minimize consumption of processed foods high in salt and sugar
Calcium: Intake should be equivalent to about half a liter of milk per day, with consideration for supplementation based on individual needs
Lifestyle changes, including quitting smoking, regular physical activity, and reducing alcohol intake, are also recommended to support overall health and manage menopausal symptoms
Click here to check out Part Two on Nutrition for urological health, Prostate cancer and Andropause in Men