Woman's Health Flashcards
What is the HPO axis?
Hypothalamic-pituitary-ovarian (HPO) axis = maintains hormonal balance within the female reproductive system. Homeostasis needed.
How are LH (luteinizing hormone) and FSH (Follicle Stimulating Hormone) released (mechanism) and what do they do?
- GnRH (gonadotropin releasing hormone) stimulates the anterior pituitary to produce and release LH (luteinizing hormone) and FSH (Follicle Stimulating Hormone).
- LH and FSH support follicle development, ovulation, corpus luteum maintenance and the production of progesterone, oestrogen and inhibin (inhibit FSH) production. Body uses a negative feedback system to regulate hormones.
- Raised oestrogen and testosterone exert negative feedback over FSH and LH secretion.
What is pregnenolone? How is it synthesised and where?
All our reproductive hormone come from pregnenolone hormone.
Pregnenolone = a hormone synthesised from cholesterol in steroidogenic tissues such as the adrenal gland, gonads, and brain by the mitochondrial enzyme CYP11A1. Role of cholesterol not spoken about. Cholesterol is misunderstood.
Pregnenolone is *Anti-inflammatory and neuroprotective.
Pregnenolone is the precursor of which sex hormones?
- A precursor of DHEA (dehydroepiandrosterone), testosterone, DHT (dihydrotestosterone), oestradiol, progesterone and cortisol.
- DHT = dihydrotestosterone DHEA = dehydroepiandrosterone
What causes low levels of pregnenolone?
Advancing age (>30) and statin use
What are the signs and symptoms of low pregnenolone?
Poor memory; declining concentration and attention; fatigue; dry skin; joint and muscle pain; decreased libido
How to support pregnenolone production?
- Improves sleep, manages stress. Avocado, flax and chia seeds, olive oil, walnuts. B vitamins, vitamin K and D3.
- Improving sleep will impact the whole body. Physiological response to stress.
- For DHEA balance: Maca, rhodiola, magnolia; perilla oil, tribulus
what is the pregnenolone steal theory?
‘Pregnenolone steal theory’ = states that high stress increases the use of pregnenolone for cortisol production, reducing the total amount of pregnenolone available for production of sex hormones.
* However, there is no ‘giant pregnenolone pool’. Most is synthesised within the cell via its own pathway.
* Stress does have a major influence on sex hormones via downregulation of LH and FSH (e.g., ↓ ovulation).
Where is produced progesterone?
- Produced: In the corpus luteum (the yellow body from the follicle that converts after ovulation) after ovulation, in the adrenal cortex (small amounts) and by the placenta during pregnancy (large amounts).
What are the functions of progesterone?
o Maintains the endometrium for implantation and pregnancy. Increases cervical mucus (producing a barrier). Prepare the epithelial lining for the egg to implant during pregnancy.
o Progesterone metabolites potentiate the inhibitory actions of GABA by modulating receptors (increasing the receptor affinity to gaba); help relax smooth muscle. True calming neurotransmitter. If we can increase GABA we can relax muscles and calm anxiety. Does this by modulating the receptors through the metabolite allopregnanolone - Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone.
o Supports bone health and mammary development.
What cause progesterone imbalance?
- Progesterone imbalances: Perimenopause (going into menopause ovulation becomes erratic and start of menopausal symptom because difference in fluctuation in hormone), PCOS, infertility.
If you have low progesterone, you may have the symptoms of low oestrogen even if your oestrogen level is correct, the fact that progesterone is not is a tipping point and oestrogen:progesterone (O:P) ratio is not correct.
Other Causes of low progesterone?
Chronic stress, synthetic progesterones (don’t act like progesterone in the body – think OCP), xenoestrogens (chemicals that mimic oestrogen in the body).
Signs and symptoms of low progesterone?
- Signs and symptoms: Irritability, mood swings and insomnia.
Also = a higher risk of breast cancer in premenopausal women – because of the oestrogen dominance situation.
How to support progesterone production and oestrogen detox?
increase fibre, 3 balanced (not processed) meals / day, no snacking, avoid alcohol until balanced (in the presence of alcohol the liver is going to stop anything else that is does because alcohol is more of a toxic issue, incl. oestrogen metabolism), magnesium, vitamin C and B6, zinc. Vitex Agnus castus (chast tree – action via pituitary gland, increase progesterone production via an increase in LH boosting ovulation => Corpus Luteum and Progesterone production)
What are oestrogen? name the 3 types
Oestrogens = a group of steroid hormones, including oestrone (E1 – seen in post-menopausal woman), oestradiol (E2 – in menstruating female) and oestriol (E3 - pregnancy).
How is oestrogen produced?
By conversion of androgens via aromatase (aromatisation - a CYP450 enzyme responsible for the biosynthesis of oestrogens), e.g., in the ovaries, bone, breast, adipose tissue.
Describe oestrogen activity and the 3 types of oestrogen receptors ER alpha, ER beta and GPER
- Activity: Oestrogens exert their actions by binding to specific oestrogen receptors (ER): ERα (receptors located in the ovaries and the womb. Associated with female conditions SORM (selective Oestrogen Receptor Modulators medication like tamoxifen given post breast cancer, Erα are the preferable binding sites for those), Erβ (more widely spread in the body, also in brain, bladder and bones and products the modulating effect of the plants oestrogen like genistein found in soy beans, receptors for phytoeastrogen), and GPER (G-protein coupled estrogen receptor). Oestradiol (E2) ― most physiologically active during reproductive years.
What are the functions of oestrogen?
: Reproductive tract development, menstrual cycle, promotes cell proliferation (esp. breasts), glucose homeostasis, immune robustness; bone and cardiovascular health. Oestrogen is not just linked to female reproductive health and that is why we see an array of symptoms in menopause because we start loosing the oestrogen.
What is oestrogen dominance? what could be the 3 causes?
- Elevated oestrogen relative to progesterone. High O:P ratio despite normal oestrogen.
- Elevated specific types of oestrogen or metabolites due to poor detoxification and elimination. Liver function good? Phase 1 and 2 Detox good? Gut microbiome balanced? If not any excess oestrogen will lead to an overexpression of ERs
- Excess oestrogen induces an overexpression of ERα and ERβ.
What is oestrogen dominance associated with?
Associated with: Fibroids, endometriosis (tissue overexpression of oestrogen receptors), PMS, fibrocystic breasts, dysmenorrhea, infertility, miscarriages, perimenopause, breast / ovarian / endometrial cancers, insulin resistance, thyroid dysfunction (e.g., Hashimoto’s), brain fog, anxiety and depression (all hormones are interlinked).
oestrogen dominance aetiology/causes?
- Synthetic HRT and oral contraceptive pills — negative feedback and prevention of ovulation; synthetic progestin acts like testosterone and not progesterone so you push towards an oestrogen dominance.
- Xenoestrogens — e.g., in plastic, non-organic food, water supply.
- Heavy metals can bind to the oestrogens receptors sites triggering its action — e.g., lead, mercury, cadmium, aluminium. No pathways to deal with these heavy metals.
- Obesity lifestyle factor — ↑ aromatisation (in fat tissues) of testosterone to oestrogen. Increasing those levels.
- Poor liver detoxification and methylation.
- Constipation — oestrogen recirculates.
- Genetic mutations e.g., COMT (breaks down oestrogen) SNP – metalation pathway to breakdown and remove oestrogen.
- Intestinal dysbiosis (see later).
- Chronic stress (downregulates LH and FSH) – affecting fertility and foetus.
In Phase 1 oestrogen ‘biotransformation’ via CYP450 enzymes in which 3 metabolites can E1 be converted to? Which are the three pathways?
- 2-OH-E (broken down via the CYP1A1 pathway) — weakest, protective form. COMT de-activates 2-OHE1 to the protective 2-MeOE1 metabolite. We want to try and promote this pathway because it is the weakest form, protective. Deactivated via COMT to be eliminated.
- 4-OH-E (metabolised via the CYP1B1 pathway) — a pro-carcinogenic oestrogen metabolite neutralised by COMT into protective 4-MeOE1 metabolites. Overuse of this pathway is, therefore, problematic. If not broken down and deactivated can cause the DNA damaging quinones.
- 16α-OH-E (CYP3A4) — highest binding affinity for oestrogen receptors with high proliferative effects. It is protective (especially post menopause for bone health) but at the same time it has a high affinity for oestrogen receptors and is highly proliferative. We want to modulate this pathway.
High 16α-OH-E is associated with a higher risk of oestrogen dependent conditions, e.g., breast cancer, fibroids, endometriosis.
describe the phase 2 oestrogen metabolism — via sulphation, methylation or glucuronidation for 2-OH-E, 4-OH-E and 16alpha-OH-E:
- 2-OH-E and 4-OH-E undergo methylation via COMT to become less reactive metabolites which can be excreted in urine or bile.
o 4-OH-E and 16α-OH-E levels may elevate if methylation is compromised (e.g., due to lack of key nutrients or a COMT SNP).
o Poor methylation ↑ conversion of 4-OH-E to quinones which can cause oxidative damage to DNA, increasing cancer risk. - 16α-OH-E metabolises to E3 which then undergoes sulphation. 2-OH-E and 4-OH-E also undergo sulphation and glucuronidation
How to Supporting phase I oestrogen metabolism:
- Include: modulate CYP3A4, Support CYP1A1 and block CYP1B1:
I3C, cruciferous vegetables, antioxidants, glutathione (also neutralises reactive quinone species), turmeric, resveratrol, berries, rooibos tea and celery. Support a healthy microbiome. - Avoid: CYP450 inducers a it accelerate the pathway especially the CYP1B1 pathway: Paracetamol, PCBs, smoking, grapefruit.
How to Supporting phase II oestrogen metabolism:
- Include: Conjugation pathway support (e.g. cruciferous vegetables, allium vegetables, magnesium, antioxidants incl. glutathione). Methylation support (e.g., folate, B12, B6, SAMe, choline).
- Avoid — OCP, high alcohol, high cortisol, mould exposure etc.
what are The ‘oestrobolome’ ? Which bacteria they produce?
The ‘oestrobolome’ = a collection of microbes capable of metabolising oestrogens.
* These bacteria produce beta-glucuronidase: — Bacteroides fragilis, Bacteroides vulgatus, Escherichia coli, Clostridium perfringens.
* Beta-glucuronidase is an enzyme which deconjugates (reactivates) oestrogens that were already conjugated for elimination.
* These deconjugated oestrogens can be reabsorbed via the enterohepatic circulation — increasing oestrogen load in the body.
* A healthy gut produces the right amount of beta-glucuronidase to maintain oestrogen homeostasis.
What is the issue with dysbiosis one relation to the oestrobolome?
- A dysbiotic microbiome, especially when coupled with low fibre intake and poor bile flow, increases the chances of the entero-toxigenic circulation. Hence why improving GIT function and microbial patterns can help with overall oestrogenic load.
- Imbalances in beta-glucuronidase can promote conditions such as:
endometriosis, breast cancer. ovarian cancer, PCOS, endometrial cancer
Explain the role of beta glucuronidase in endometriosis and PCOS
- Endometriosis — may have larger numbers of beta-glucuronidase producing bacteria (↑ circ. oestrogen→oestrogen dominance).
- PCOS — lower beta-glucuronidase activity may promote increased androgen biosynthesis and reduced oestrogen levels. Specific group where there is a High fat high sugar diet and a gut issue – maybe a leaky gut => leading to lipopolysaccharides leaking and low grade inflammation adding to any insulin resistance => increase testosterone => add to the symptoms of PCOS. Having a good gut microbiome is really important.
How to maintain healthy beta-glucuronidase levels:
- Optimise the microbiome (probiotics, prebiotics).
- If high: ↑ dietary fibre; calcium D-glucarate (a beta-glucuronidase inhibitor) and glucaric acid-rich foods such as mung bean sprouts, apples, cruciferous vegs. Milk thistle, Lactobacilli and Bifidum bacteria. Consider the 5R protocol.
- If low: Focus on commensal support (e.g., probiotics).
- Consider a stool analysis: look on the beta-glucuronidase levels to help correct any imbalances
Where is testosterone produce?
Testosterone — an essential hormone for women. We only need a tiny amount.
* Produced: In the ovaries and adrenal cortex. That is a reason why to look after you adrenals because they produce testosterone which post-menopausal is very important to maintain things such as sex drive.
What is testosterone converted to?
- Converted to: E2 via aromatase (most testosterone), and DHT.
Testosterone functions?
Ovarian density, libido, bone strength, stamina, mood, cognition
What causes testosterone imbalance?
- Androgen dominance is seen in PCOS. Associated with anovulation, hirsutism and acne vulgaris (on shoulders, back, hairline and face), male pattern baldness. This is driven by insulin resistance (insulin resistance inhibit the production of SHBG by the liver that then allows for the testosterone to be unregulated) so create your client’s plan accordingly.
- Low testosterone may be associated with low mood, low libido and cognitive dysfunction, brain fog. This is noted during perimenopause. L-tyrosine may help but also address the cause.
How is testosterone converted to DHT? What is it unregulated and downregulated by?
- 5α-reductase enzyme converts testosterone into a more potent form (DHT). This pathway is:
- Upregulated by: Insulin, inflammation, obesity. (Seen in PCOS, up regulated by insulin resistance inflammation and obesity)
- Downregulated by: Nettle (esp. nettle root), saw palmetto, lycopene (found in cooked tomatoes), turmeric, green tea, zinc, GLA and EPA.
What is SHBG? where is it produced? What are its functions?
Sex hormone binding globulin (SHBG) — Sex hormones are not water-soluble so need to be transported in blood bound to SHBG.
* Produced: A glycoprotein synthesised by the liver.
* Functions: Binds to oestradiol, testosterone, DHT.
Only unbound hormones are biologically active.
What is associated with low levels and high levels of SHBG?
- Lower levels = higher circulating free / active levels of these hormones. Associated with hyperinsulinemia, obesity, metabolic syndrome, T2DM, hypothyroidism, PCOS. High levels of insulin prevents the liver from producing SHBG.
- High levels: Seen in anorexia, pregnancy (because the placenta produces SHBG in the 3rd trimester), androgen deficiency, hyperthyroidism, liver disease.
What is prolactin? Functions?
Prolactin = a key hormone controlled by oestrogen and dopamine.
* Functions: Lactation, breast maturation, inhibits menstruation.
What is Hyperprolactinaemia?
- Hyperprolactinaemia: Occurs naturally in pregnancy and lactation but can also occur in non-pregnant women (high cortisol levels while elevate prolactin levels to act as a natural contraceptive, could be a pituitary tumour or a deficiency in vitamin D (increases prolactin receptors in pituitary gland), or dopamine antagonist medication).
What are high levels of protection associated with?
High levels Associated with: Infertility, menstrual irregularities, low libido, osteopenia, breast pain and vaginal dryness.
What is prolactin increased by?
Increased by: High cortisol (stress), pituitary tumours, circadian disruption, renal failure, vitamin D deficiency, drugs e.g., domperidone (dopamine antagonists).
What are endocrine disruptors?
Endocrine disrupting chemicals (EDCs) = exogenous agents that interfere with the production, release, transport, metabolism, binding, action, or elimination of bodily hormones. We have no pathway to deal with them in the body so the body retains them. Can interfere with hormonal actions.
Give 3 examples of endocrine disruptors?
Includes: BPA (e.g., plastic bottles / packaging), PCBs, phthalates (e.g., beauty products), heavy metals (e.g., lead, arsenic, mercury), pesticides and herbicides, fire retardants, dioxins, drugs (e.g., NSAIDs). Tap water (contains many of the above).
