Sex hormones

Question 1

Hypothalamic-pituitary-ovarian (HPO) axis

Answer 1

Hypothalamic-pituitary-ovarian (HPO) axis = maintains hormonal balance within the female reproductive system.
* GnRH stimulates the anterior pituitary to produce and release LH and FSH.
* LH and FSH support follicle development, ovulation, corpus luteum maintenance and the production of progesterone, oestrogen and inhibin.
* Raised oestrogen and testosterone exert negative feedback over FSH and LH secretion.
* Progesterone and oestrogen regulate the function of target organs, e.g., uterus, mammary glands

Question 2

Pregnenolone

Answer 2

Pregnenolone = a hormone synthesised from cholesterol in steroidogenic tissues such as the adrenal gland, gonads, and brain by the mitochondrial enzyme CYP11A1.
* A precursor of DHEA, testosterone, DHT, oestradiol, progesterone and cortisol.
* Anti-inflammatory and neuroprotective.
Low levels are caused by:
* Advancing age (>30) and statin use.
Symptoms of low pregnenolone:
* Poor memory; declining concentration and attention; fatigue; dry skin; joint and muscle pain; decreased libido.

Question 3

Supporting healthy pregnenolone levels

Answer 3

• Improves sleep, manages stress. Avocado, flax and chia seeds, olive oil, walnuts. B vitamins, vitamin K and D3.
• For DHEA balance: Maca, rhodiola, magnolia; perilla oil, tribulus

Question 4

‘Pregnenolone steal theory’

Answer 4

‘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)

Question 5

Progesterone: Produced

Answer 5

In the corpus luteum after ovulation, in the adrenal cortex and by the placenta during pregnancy.
So, a lack of ovulation = a lack of progesterone.

Question 6

Progesterone: functions

Answer 6

‒ Maintains the endometrium for implantation and
pregnancy. Increases cervical mucus (producing a barrier).
‒ Progesterone metabolites potentiate the inhibitory actions
of GABA by modulating receptors; help relax smooth muscle.
‒ Supports bone health and mammary development.

Question 7

Progesterone imbalances

Answer 7

Perimenopause, PCOS, infertility

Question 8

Low progesterone

Answer 8

Leads to oestrogen dominance / tipping the ratio of oestrogen:progesterone (O:P).
* Causes: Chronic stress, synthetic progesterones, xenoestrogens.
* Signs and symptoms: Irritability, mood swings and insomnia.
Also = a higher risk of breast cancer in premenopausal women.

Question 9

To balance progesterone

Answer 9

Support oestrogen detoxification, increase fibre, 3 balanced
(not processed) meals / day, no snacking, avoid
alcohol until balanced, magnesium, vitamin C
and B6, zinc. Vitex Agnus castus, Australian bush flower
essence (she oak), exercise and box breathing with anxiety.

Question 10

Oestrogens

Answer 10

Oestrogens = a group of steroid hormones, including oestrone (E1), oestradiol (E2) and oestriol (E3).

Question 11

Oestrogens: produced

Answer 11

By conversion of androgens via aromatase (aromatisation), e.g., in the ovaries, bone, breast, adipose tissue.

Question 12

Oestrogents: activity

Answer 12

Oestrogens exert their actions by binding to specific oestrogen receptors: ERα, ERβ, and GPER. Oestradiol (E2) ― most physiologically active during reproductive years.

Question 13

Oestrogens: functions

Answer 13

Reproductive tract development, menstrual cycle, promotes cell proliferation (esp. breasts), glucose homeostasis, immune robustness; bone and cardiovascular health.

Question 14

Oestrogen dominance

Answer 14

Oestrogen dominance = A state of excess oestrogenic activity encompassing some or all of:
▪ 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.
▪ Excess oestrogen induces an overexpression of ERα and ERβ.
* Associated with: Fibroids, endometriosis, PMS, fibrocystic
breasts, dysmenorrhea, infertility, miscarriages, perimenopause,
breast / ovarian / endometrial cancers, insulin resistance, thyroid
dysfunction (e.g., Hashimoto’s), brain fog, anxiety and depression.

Question 15

Oestrogen dominance ― aetiology

Answer 15

• Synthetic HRT and oral contraceptive pills — negative feedback and prevention of ovulation; synthetic progestin acts like testosterone.
• Xenoestrogens — e.g., in plastic, non-organic food, water supply.
• Heavy metals — e.g., lead, mercury, cadmium, aluminium.
• Obesity — ↑ aromatisation of testosterone to oestrogen.
• Poor liver detoxification and methylation.
• Constipation — oestrogen recirculates.
• Genetic mutations e.g., COMT SNP.
• Intestinal dysbiosis (see later).
• Chronic stress (downregulates LH and FSH).

Question 16

Phase 1 oestrogen ‘biotransformation’ — CYP450 enzymes

Answer 16

Enzymes convert E1 into one of three metabolites:
* 2-OH-E (CYP1A1) — weakest, protective form. COMT de-activates 2-OHE1 to the protective 2-MeOE1 metabolite.
* 4-OH-E (CYP1B1) — a pro-carcinogenic oestrogen metabolite neutralised by COMT into protective 4-MeOE1 metabolites. Overuse of this pathway is, therefore, problematic.
* 16α-OH-E (CYP3A4) — highest binding affinity for oestrogen receptors with high proliferative effects.
High 16α-OH-E is associated with a higher risk of oestrogen
dependent conditions, e.g., breast cancer, fibroids, endometriosis.

Question 17

Phase 2 oestrogen metabolism — via sulphation, methylation or glucuronidation

Answer 17

• 2-OH-E and 4-OH-E undergo methylation via COMT to become less reactive metabolites which can be excreted in urine or bile.
  COMT
  ‒ 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).
  ‒ 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.

Question 18

Supporting phase I oestrogen metabolism

Answer 18

Include: Support CYP3A4, CYP1A1 and 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: Paracetamol, PCBs, smoking, grapefruit.

Question 19

Supporting phase II oestrogen metabolism

Answer 19

• 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.

Question 20

oestrobolome

Answer 20

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.
* 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 — 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.

Question 21

Maintaining healthy beta-glucuronidase levels

Answer 21

• 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).

Question 22

Testosterone

Answer 22

Testosterone — an essential hormone for women.
* Produced: In the ovaries and adrenal cortex.
* Converted to: E2 via aromatase (most testosterone), and DHT.
* Functions: Ovarian density, libido, bone strength, mood, cognition.
* Testosterone imbalances:
‒ Androgen dominance is seen in PCOS. Associated with
anovulation, hirsutism and acne vulgaris. This is driven by insulin resistance so create your client’s plan accordingly.
‒ Low testosterone may be associated with low mood, low libido
and cognitive dysfunction. This is noted during perimenopause.
L-tyrosine may help but also address the cause.

Question 23

Testosterone — DHT

Answer 23

• 5α-reductase converts
  testosterone into a more potent form (DHT). This pathway is:
• Upregulated by:
  Insulin, inflammation, obesity.
• Downregulated by: Nettle (esp. nettle root), saw palmetto, lycopene, turmeric, green tea, zinc, GLA and EPA.

Question 24

Sex hormone binding globulin (SHBG)

Answer 24

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.
* SHBG imbalances:
‒ Lower levels = higher circulating free / active
levels of these hormones. Associated with hyperinsulinemia, obesity, metabolic syndrome, T2DM, hypothyroidism, PCOS.
‒ High levels: Seen in anorexia, pregnancy, androgen deficiency, hyperthyroidism, liver disease.

Question 25

Prolactin

Answer 25

Prolactin = a key hormone controlled by oestrogen and dopamine.
* Functions: Lactation, breast maturation, inhibits menstruation.
* Hyperprolactinaemia: Occurs naturally in pregnancy and lactation but can also occur in non-pregnant women.
- Associated with: Infertility, menstrual irregularities, low libido, osteopenia, breast pain and vaginal dryness.
* Increased by: High cortisol (stress),
pituitary tumours, circadian disruption,
renal failure, vitamin D deficiency, drugs
e.g., domperidone (dopamine antagonists).