Menopause
Menopause is a point in time 12 months after a woman's last period. The years leading up to that point, when there are changes in monthly cycles, hot flashes, mood changes, weight gain and other symptoms, are called the perimenopause. This transition often takes place between ages 45 and 55, although it may be earlier or later. The timing and duration can depend on lifestyle factors such as smoking, race/ethnicity and genetics.
During perimenopause, the body's production of oestrogen and progesterone, two hormones made by the ovaries, varies greatly. Progesterone is the first hormone to decline, and can contribute to weight gain, low libido, brain fog, mood swings and/or sleep disruption. Oestrogen fluctuates and can be volatile before flattening off in menopause.
While a functional test can measure hormones and metabolites levels at a point in time, a nutrigenomics test can identify personal sensitivity and responses to hormones and to changes in hormones levels. It can help you to understand your symptoms, risks and vulnerabilities and - most importantly - support your personal decisions (for example about HRT, nutrition and other lifestyle choices), to manage symptoms and optimise your health. As your genetic code is fixed, a nutrigenomics test is useful for life and can be referred to at any point.
Genetics
Progesterone
AlloP (Allopregnanolone) is made from progesterone and plays an important role in neurological functions. It exerts neuroprotective, antidepressant and anxiolytic effects via GABA receptors. Indeed, progesterone is typically regarded as the calming, anxiety-relieving hormone.
Progesterone is converted to 5a-DHP by 5aR (5alpha-Reductase) using NADH as a cofactor. 5aR is coded by the SDR5A2 gene. A variant (called SNP) on this gene slows its activity which may contribute to lower AlloP levels. It can also lead to higher cortisol levels, and adverse metabolic effects such as weight gain or insulin resistance. Lower 5aR activity is detrimental in the context of low levels of AlloP which have been associated with increased risk of anxiety and depression.
AKR1C4 is the gene that codes for 3alpha-hydroxysteroid dehydrogenase (3a-HSD), which converts 5a-DHP to AlloP. A SNP on AKR1C4 has been associated with a 66 to 80% decrease in the catalytic activity of the enzyme which may confer lower AlloP production.
Because of these variances, you might not feel as much of the benefit of AlloP as you should, especially when progesterone starts to decline in perimenopause. To compensate for these SNPs, some 3a-HSD inducers can help such as calcium, omega 3-fatty acids in particular palmitoylethanolamide (PEA), evening primrose oil, gingko biloba and crocus sativus. SSRIs can also directly enhance the conversion from 5a-DHP to AlloP, and have been shown to have a short onset of action (and at relatively low doses) which may help resolve irritability, affectivity lability and mood swings.
Cortisol and Adrenaline
Additionally, during menopause, there is a shift towards cortisol and testosterone, and the genes involved in these pathways can reinforce this transition. Cortisol is a glucocorticoid hormone which is mainly produced in the adrenal glands and is released with a diurnal cycle and in response to stress and low blood sugar. It raises blood sugar by gluconeogenesis (synthesis of new sugar) and by reducing insulin sensitivity. Cortisol also regulates and modulates inflammation (and inhibits the immune system), regulates hunger cravings, digestion, blood pressure, sleep/wake patterns and capacity to cope with stress.
An upregulated CYP17A1 gene (due to SNPs or stress) also sets the scene for upregulated cortisol synthesis. This can potentially lead to a “pregnenolone steal”, which (although controversial) is when, in a high stress situation, pregnenolone is diverted to cortisol production, reducing the amount (of pregnenolone) available for the production of other steroid hormones, such as progesterone. CYP17A1 activity can be reduced by polyphenols found in berries, cocoa, nuts, flaxseeds and many herbs & spices such as cloves, peppermint, sage, oregano and thyme.
The hypothalamic–pituitary–adrenal axis (HPA axis) is a major neuroendocrine system that controls responses to stress. FKBP5 is an important stress regulating gene responsible for controlling the body's response to cortisol by signalling to the brain to lower the levels after they have been raised in response to stress (negative feedback loop). FKBP5 forms a complex with the glucocorticoid receptor (GR) and regulates its activity. When it is attached to inactive GR, it reduces GR affinity for glucocorticoids and also decreases overall GR signaling.
SNPs on the FKBP5 gene are associated with prolonged stress response and increased reactivity due to impaired lowering of cortisol levels after a stressful event. This FKBP5 genotype is also linked to stress-related disorders such as depression, anxiety and post traumatic stress disorder (PTSD) in adulthood particularly as a result of childhood trauma.
Adrenaline is the hormone and neurotransmitter that plays an important role in the fight or flight (short term) stress response - by increasing heart rate, blood pressure, expanding air passages of the lungs, enlarging the pupil in the eye, redistributing blood to the muscles and altering the body’s metabolism to maximise blood glucose levels. ADRB1 and ADRB2 are the adrenergic receptors that are activated by adrenaline. Variances present on these genes can lead to increased sensitivity to adrenaline. You may be more vulnerable to physiological effects, such as hypertension, metabolic dysfunction, panic attacks/anxiety, hot flushes, in response to chronic stress. It can be helpful to know your genotype to be proactive and mitigate side effects as much as possible. For example, caffeine and sugar can be detrimental as they trigger adrenaline release.
Insulin
As oestrogen levels fall in menopause, your body can become less responsive to insulin, known as insulin resistance. Insulin is a hormone that helps to keep blood sugar in balance. Insulin release triggers cells to take in glucose when levels of blood sugar rise due to carbohydrate consumption or stress. It also inhibits the liver from breaking down glycogen for energy, and unused glucose is stored as fat. The TCF7L2 gene is involved in regulating blood sugar by stimulating insulin release. A SNP on TCF7L2 is associated with up to 5x lower insulin response to ingested glucose, and is strongly associated with Type 2 Diabetes. This risk can be reduced by limiting simple carbohydrates (sugar) consumption. Regular exercise can also help increase insulin sensitivity.
Oestrogen
Finally, we know that oestrogen levels fluctuate throughout life, naturally increasing during puberty and pregnancy, and falling after menopause. The main role of oestrogen in the body is to increase the growth and production of cells. It is responsible for the development and regulation of the female reproductive system and secondary sex characteristics (breasts and pubic hair). It is also involved in maintaining bone density, blood clotting and it affects skin, hair, mucous membranes and pelvic muscles. Oestrogen moves through the blood and is active in the cells where oestrogen receptors (ERs) are present. ERs mediate the action of oestrogens.
There are two types of oestrogen receptors:
- ER alpha - coded by the ESR1 gene, which increases the action of the attached oestrogen
- ER beta - coded by the ESR2 gene, which decreases the action of the attached oestrogen
Having SNPs on these receptors can mean increased severity of symptoms during menopause. Additionally, variants in ESR2 are linked to cardiovascular risk in menopausal women due to increased blood coagulation. Considering the whole lifecycle of oestrogen, and stress load can be helpful to relieve symptoms.
Lifecode Gx® Reports
The Lifecode Gx® Hormones Report analyses genes involved in the regulation, synthesis, signalling, transport and metabolism of corticosteroids and sex steroids hormones. It looks at how gene variants affects hormones imbalance and details the nutrients and environmental factors that can influence and improve their balance.
We also recommend the following report in the context of Menopause:
Nutrient Core Report - Vitamins D and K (calcium regulation - bone and cardiovascular health), B vitamins (cardiovascular health - including cognitive health), Vitamin C (collagen synthesis), Glutathione - antioxidant support, Gut health (FUT2, Vitamin A, Food intolerances) Metabolic section - Leptin (appetite - also linked to HPA), TCF7L2 (Insulin release), PGC1A (metabolic rate, fasting, fat metabolism), and FTO (overall hunger-satiety balance and preference or not for high calorie foods.) - or if Metabolism is a particular area of interest - the Metabolics report (see below) - also includes Cholesterol, Bile, Mitochondria.
Metals and Minerals - A very good 'partner' report to Core. Calcium, Magnesium and Phosphorus (bone health, cardiovascular health, energy...). Magnesium is depleted post Menopause (genotypes indicating higher need would add to this). Lots of antioxidant related genes - impacting need for Selenium, Glutathione and Zinc. Iron (overload/ haemochromatosis) may not have been an issue pre Menopause but could have been masked all along.
Methylation - As Oestrogen is a cofactor for PEMT - Choline synthesis (in the Methionine Cycle) is particularly impacted by Menopause - with potential knock on effects on Homocysteine cycling and SAMe synthesis. There may also be more demand/ drain on methyl donors (such as SAMe) increased adrenaline (hot flushes), histamine, and oestrogen - during perimenopause (when it may be high) or if HRT is being considered/ taken, as these are detoxified/ deactivated via methylation. Methylation is also important for cardiovascular health (which is commonly an issue post menopause), cognitive health (protection from late onset Alzheimer's disease), energy (metabolism), and detoxification.
Histamine - Symptoms of histamine intolerance often worsen or are experienced for the first time in perimenopause or menopause. This can be related to gut health (the DAO enzyme needed to degrade ingested histamine is released by gut epithelial cells), oxidative stress (higher toxic load), or reduced methylation capacity. It is often inversely correlated with Methylation. Some women experience histamine intolerance symptoms in response to HRT - which may be due to the overall toxic load (overflowing histamine 'bucket') as opposed to the HRT specifically.
Detoxification may also be less efficient (more sluggish) as we age, as is evidential by a decreased tolerance to alcohol (for many women). It is useful to identify any particular weak points/need for sulphur foods (also useful to cross reference with Methylation to indicate if sulphur isn't such a good idea), glutathione, glucuronidation (glucuronic acid).
Metabolics - includes Appetite and Nutrient sensing - this is a big one with regard to ageing as it's more important to balance AMPK and mTOR. We need less mTOR - growth as we get older - and most people have too much mTOR activity - due to excess inflammation, glucose - and insulin, hormones - including potential excess during perimenopause, relative to AMPK - which can be supported by exercise, fasting, moderate metabolic stressors (hormesis). The report includes Mitochondria, Cholesterol - and Bile, Sugar and Fat metabolism.
Other Resources
The following Lifecode Gx® Nutrigenomics Snapshot videos are free to register and view