Do you suffer with PMS or PMDD? Did you have post-partum depression? Are you struggling with HRT because of Progesterone side effects, such as poor mood, anxiety, or the opposite sleepiness, bloating, constipation, etc.? Then you need to read this article.
What is Progesterone?
- Progesterone is a steroid hormone, made from cholesterol, that has numerous functions in the male and female body, especially within the reproductive systems
- Progesterone is commonly produced in males and females in
– The Adrenal glands
– The Gonads, ie the Ovaries and the Testes
– The Brain, CNS and Glial cells (specialised nerve cells that produce myelin)
– In females it is also secreted by the Corpus Luteum in the luteal phase of the menstrual cycle, during the first 10 weeks of pregnancy, and then by the placenta for the remaining pregnancy.
- Progesterone is NOT a female sex hormone; it plays NO part in the secondary sexual characteristics that develop in puberty. BUT Progesterone is a precursor to the 2 sex hormones Estrogen and Testosterone
- Progesterone metabolizes in the liver to 2 new Progesterone’s
– 5a-pregnenediol
– 5b-pregnanediol
- This metabolism is genetically controlled, ie you might prefer to make 5a or 5b
- 5b-pregnanediol represent a larger percent of total progesterone metabolism overall, but has less activity in the body
- 5a-pregnanediol crosses the blood brain barrier and in the brain, it converts to the neuro-steroid (brain-hormone) Allopregnanolone
The Good and the Bad of Allopregnanolone
- Alloprgenanolone also called ALLO works by stimulating GABA-A receptor
- GABA is a neurotransmitter, known as the peacekeeper of the nervous system as it brings calm
- So when ALLO locks on to GABA-A receptors it increases calm
- Variations in ALLO levels will influence the activity of the GABA-A receptor and thereby the ‘GABA effect’ causing a vulnerability to mental and emotional disease.
- ALLO activates GABA-A receptors similar to benzodiazepines
- There are physiological conditions in which ALLO production increases
– Luteal phase of menstrual cycle
– Pregnancy
– Acute stress situations
- All of these situations expose GABA-A receptor to high and continuous ALLO concentrations.
- High ALLO = high calm
- Apparently, the brain doesn’t like high levels of calm and develops a ‘tolerance’ to ALLO by reducing GABA-A receptors, which may create various conditions and syndromes.
NB! – too much ‘calm’ can be bad thing.
Study – Tolerance to allopregnanolone with focus on the GABA-A receptor – 2011
Various ALLO ‘Tolerance’ Conditions
PMDD/PMS
- The aetiology of which is not yet clearly known, but evidence from studies indicates that it involves both ovarian steroid hormones and an altered GABA-A function
- Study – Role of allopregnanolone-mediated γ-aminobutyric acid A receptor sensitivity in the pathogenesis of premenstrual dysphoric disorder: Toward precise targets for translational medicine and drug development – March 2023
Catamenial Epilepsy
- Some women with epilepsy show an exacerbation in seizure frequency during menstruation
- This has been interpreted as a withdrawal symptom suggesting that there is an antiepileptic factor present during the luteal phase that is rapidly removed at the time of menstruation
- ALLO and pregnanolone have antiepileptic effects
- The abrupt decrease in progesterone and thereby allopregnanolone secretion during the premenstrual period play a central role in the pathogenesis of the catamenial seizure pattern
Sedation During Pregnancy
- Pregnant women experience marked alterations in both psychology and physiology.
- Memory impairment, cognitive changes and mood changes during pregnancy and in the postpartum period are all well documented
- ALLO increases substantially during pregnancy, due to the significant increases in Progesterone
– initially during the first part of a pregnancy marked sleepiness is observed
– sleepiness ‘goes over’ in the later part of pregnancy, even though Progesterone and ALLO levels are still increased, indicating tolerance to ALLO develops during pregnancy
Postpartum Blues and Depression
- GABA-A receptors are downregulated during pregnancy – due to the excess Progesterone/ALLO.
- Due to the down-regulated GABA-A receptors, the rapid postpartum fall of Progesterone and its metabolites increases excitability, anxiety ie. lack of calm
- This could be an explanation for postpartum neurological and mood disorders.
- Increased seizure frequency is also noticed during labour and delivery among women with epilepsy
- ‘Third day blues’, postpartum depression and postpartum psychosis also indicate that hormone-related phenomena such as PMDD are related to the occurrence of postpartum mood disorders.
- These results support the hypothesis that the aetiology for postpartum mood disorders may be related to neuro-steroid hormone sensitivity.
Negative Mood Symptoms in Postmenopausal Women on HRT
- Negative mood changes are also clinically well-known side effects of combined hormone replacement therapy (HRT – Estrogen + Progesterone) and constitute a major problem concerning compliance.
- In postmenopausal women taking continuous combined Estrogen/Progestogen HRT, negative side effects (negative mood changes, sleepiness, bloating, etc) arise shortly after the introduction of the treatment, but the severity of the symptoms decreases after 3–6 months, suggesting that an adaptation to the treatment has occurred
- Women on Estrogen-only HRT do not develop negative mood changes
- All Progestagens (hormones with similar effects to progesterone) seem to be able to induce negative mood changes
- In sequential treatment, negative mood symptoms begin shortly after adding Progesterone to the treatment and continue to rise in severity until the Progesterone treatment has ended
Changes During Acute and Chronic stress
· The brain (like the gonads and adrenals), produces neuroactive steroid hormones
- Measuring serum levels of neuroactive steroid hormones may inaccurately reflect their levels in the brain.
- ALLO is released during stress and has been shown to interfere the regulation of CRH / corticotrophin-releasing hormone release (the hormone that stimulates the production of Cortisol and DHEA) and gene transcription
- This indicates that ALLO might affect the response to acute stress by influencing the hypothalamus-pituitary-adrenal axis ie. the production of Cortisol and DHEA
- Repetitive stress has been shown to result in alterations in function and sensitivity of the GABA-A receptor. BUT the mechanisms remain unclear
What to do
- Most focus is on the treatment of post-partum depression has been on
– Fast-acting agents, such as Brexanolone an injectable form of allopregnanolone,
- Neuro-steroidogenic targets have been recently suggested that may result in new drug development
- Improving deficits with functional foods is an emerging novel approach to treat mood disorders in a more natural way without exposing pregnant women to drugs.
- Such as
– Anti-inflammatory foods
– Antioxidants, such resveratrol
– Oils – olive and avocado and Omega 3’s EPA and DHA
– Oily fish
– Supplements – Vitamin D, Magnesium, B vitamins specifically B6, B9, B12, Taurine
- Study – Allopregnanolone: A neurosteroid for managing acute and chronic pain conditions – 2019
- ALLO appears to be a multifaceted neurosteroid found useful in alleviating acute pain, chronic neuropathic pain due to systemic diseases like diabetes mellitus and ongoing chemotherapy.
- It also has antidepressant, neuroprotective, and anxiolytic effects.
- Further studies could throw light on the dose, optimal route of administration, duration, and adverse effect of ALLO when used in above mentioned conditions.
