ALLOPREGNANOLONE

A butte above the clouds, close to Quito, looks like an elephant: symbolic of Allopregnanolone, the hidden protector of the brain.

The elephant in the room: ALLOPREGNANOLONE does brain maintenance and repair.

The brain makes Progesterone from Pregnenolone, then uses the Progesterone to make Allopregnanolone.**
Allopregnanolone does brain maintenance and repair, along with DHEA, Melatonin, Vitamin D and T3.
Taking Progesterone reliably increases allopregnanolone levels in the brain: taking PEA (PalmitoylEthanolAmide, available in capsules) can also boost Allopregnanolone. See the INSIGHT newsletter, at https://www.doctorsdata.com/resources/uploads/newsletters/allopregnanolone-for-mood-brain-and-hpa-axis-support.html

* Functional medicine practitioners prescribe Progesterone, 100-300mg for women and 50-100mg (minimum) for men.
** FOR THE NERDS AMONG YOU (this is from the “Science Direct”webpage): see POST-FINASTERIDE SYNDROME :


Allopregnanolone is synthesized from progesterone by the sequential actions of two enzymes, 5α-reductase type I (5α-RI), which transforms progesterone into 5α-dihydroprogesterone, and 3α-hydroxysteroid dehydrogenase (3α-HSD), which converts 5α-dihydroprogesterone into allopregnanolone.

Wikipedia describes Allopregnanolone as “stress reducing, rewarding, prosocial, anti-aggressive, pro-sexual, sedative, sleep facilitating, pro cognitive, memory enhancing, analgesic, anticonvulsant, neuroprotective and neurogenic”. (4)
I refer to Allopregnanolone as the brain’s “housekeeper” (see the page on Alzheimer’s disease).

Allopregnanolone was synthesised and marketed as “BREXANOLONE” in 2019, but it was extremely expensive and needed to be given by intravenous infusion.
A new product, Zuranolone, was approved for medical use in the United States for postpartum depression, in August, 2023.
However Palmitoylethanolamide (PEA), found in eggs, peanuts and many other foods, is processed into Allopregnanolone by the brain. PEA is available OTC in health food stores.

Allopregnanolone’s actions

Allopregnanolone does brain maintenance and repair, facilitating removal of beta Amyloid from the brain, during sleep.
– It stimulates “BDNF” (brain–derived neurotrophic factor), which encourages new brain cells to connect with old ones.
– It works with progesterone, DHEA, melatonin and thyroid hormone (“T3”) to wrap nerve fibres with myelin, to insulate them and allow passage of electrical signals.
By the same mechanism it promotes remyelination in Multiple Sclerosis.
– It is anti-apoptotic: along with Melatonin and Progesterone, Allopregnanolone prevents brain cell death and promotes cell repair after concussions and other types of injury.
Allopregnanolone relieves depression: “SSRI”antidepressants work by increasing Allopregnanolone production. (6)
It reduces anxiety and in so doing, relieves “perceived stress”, (see “stress”, under “notes and definitions” in page entitled “intracellular hypothyroidism and thyroid hormone“), thereby preventing intracellular hypothyroidism.
– By preventing stress it lowers the blood pressure, therefore reducing the risk of kidney and heart disease.
– It reduces aggression and increases oxytocin, the hormone which increases our “friendliness” and the “warm and fuzzy” attitude we need for social and sexual interaction.
Allopregnanolone puts us to sleep (for sleep, it is more important than Melatonin).
– It enhances our thinking ability and facilitates formation of memories.
– It reduces perception of pain by generation of “endorphins”, our internal painkiller.
In conditions like multiple sclerosis (MS), in which the nerves have lost Myelin,
allopregnanolone, progesterone, DHEA and T3 work together to re-myelinate the nerve fibres.

During pregnancy, Allopregnanolone is active in the normal development of the baby’s brain and nerves. It also acts along with Progesterone, DHEA, Testosterone and Triiodothyronine (T3), to reduce the mother’s perceived stress and to relax and calm the baby. (4)

Allopregnanolone works with DHEA and T3 to promote neurogenesis, neuronal survival, myelination, increased memory, and to reduce neurotoxicity (2).
Treatment with intravenous Allopregnanolone (too expensive to be practical), Brexanolone (very expensive) or Progesterone, given transdermally, vaginally or orally, has been used to relieve postpartum depression, major depression, TBI (traumatic brain injury) and stroke (CVA): PEA has also been used for depression, but the literature on the subject is sparse, since it is a natural product and not patentable.

Deficiency of Allopregnanolone, DHEA, Testosterone and Triiodothyronine (T3) leads to mood swings and anxiety.
Allopregnanolone deficiency by itself can cause premenstrual dysphoric disorder (PMDD, PMS), postpartum depression, major depression, anxiety disorders, catamenial epilepsy and other neuropsychiatric conditions.
However all of these distressing conditions are worse when DHEA, Testosterone and T3 are also low.

2023 study of Allopregnanolone as treatment for early Alzheimer’s disease.

Potentially, Allopregnanolone should be helpful in stabilising neurological diseases, including MS, Parkinson’s and Alzheimer’s disease.
This has been experimentally demonstrated in mice. It has not as yet been proven in humans, but a study, using Allopregnanolone to treat mild Alzheimer’s disease, will be starting next year.

NORMAL CIRCULATING LEVELS OF ALLOPREGNANOLONE

As noted by Genazzani et al. in 1998 (1) (see Fig.1), Allopregnanolone levels vary with age and gender.

In women, when progesterone production increases, the Allopregnanone level goes up.
Particularly in pregnancy, Allopregnanolone levels increase along with progesterone and DHEA (1).

In young males, the level is the same as in females during the first two weeks of the menstrual cycle, but it falls gradually from age 26 and can approach zero, in old age.

In postmenopausal females, Allopregnanolone is at young-male levels, but further age-related reduction is very slow.

Production of Allopregnanolone is increased by stress relief: fun, laughter, rest, sleep, alcohol, tranquilizers, antidepressants, meditaton.

Taking Progesterone Orally helps to maintain Allopregnanolone levels in the brain.

I say this because of the demonstrated effectivenes of Progesterone in promoting normal sleep and improving memory, especially in menopause, but also in males of all ages.

See figure 1, for gender and age comparison and figure 2, for Allopregnanolone levels in the menstrual cycle (1).
In each age group, black shows the men’s values.
White shows the women’s values (fertile women in the follicular phase, before the ovary releases an egg) ***.                                                                                                                          

graphical representation of Allopregnanolone levels in men and women

Figure 1, from Genazzani AR, et al. The Journal of Clinical Endocrinology & Metabolism, Vol 83, # 6, 1 June 1998:  https://academic.oup.com/jcem/article/83/6/2099/2865559

In females, the level of Allopregnanolone parallels that of progesterone
(Fig.2, from Genazzani et al), being lowest (approximating adult male levels) during the menstrual “period”, remaining low in the follicular phase (2nd week) of the cycle and increasing to a maximum in the luteal phase (15th – 24th day).

Figure 2. Allopregnanolone (•), P (▪), and DHEA (▴) levels during the menstrual cycle, providing that Progesterone is normal).

DHEA, progesterone and Allopregnanolone levels in the menstrual cycle.

Figure 2, from Genazzani AR, et al. The Journal of Clinical Endocrinology & Metabolism, Vol 83, # 6, 1 June 1998: https://academic.oup.com/jcem/article/83/6/2099/2865559

DEFICIENCY of ALLOPREGNANOLONE:

Since Allopregnanolone is made from progesterone, a deficiency of Allopregnanolone will exist whenever progesterone levels are subnormal.

Many young women are progesterone under-producers, so deficiency can begin at any age, but there are two groups: those deficient ab initio and those in whom progesterone underproduction results from steroidopenia due to low DHEA **.

There is a tendency to suppression of Allopregnanolone production by stress, leading to depression and reduced neurogenesis.
This may result in failure of children to achieve optimal brain development in situations of chronic stress. (5)
This hypothesis, as yet unproven, would explain the reduction in cognitive function among the socially disadvantaged.

Reduced progesterone and Allopregnanolone production is seen in postpartum depression, major depression, anxiety disorders, premenstrual dysphoric disorder, impulsive aggression, schizophrenia and autism.
In PMS, progesterone is lower and DHEA higher in both follicular and luteal phases of the menstrual cycle and free testosterone  is higher in the luteal phase. (Since DHEA and free testosterone fall rapidly beginning at age 26, this statement is valid only for females in the 2nd and 3rd decades).

This explains the anxiety, aggression and irritability reported by young PMS patients.

In the autism spectrum, reduced Allopregnanolone production parallels the severity of the condition.

SUPPRESSION OF ALLOPREGNANOLONE:
An enzyme called 5-alpha reductase changes progesterone into Allopregnanolone, so any drug which blocks 5-alpha reductase suppresses Allopregnanolone production. One drug which does this is FINASTERIDE, used to shrink enlarged prostates and to treat hair loss in men.
Unsurprisingly, the major side effect of finasteride (the post-finasteride syndrome) is anxiety, depression and suicidal attempts.

ENHANCEMENT of ALLOPREGNANOLONE PRODUCTION:
Any relaxant or antidepressant drug or activity will raise Allopregnanolone levels, including tranquilizers, antidepressants, music, yoga, meditation, alcohol and laughter.
This may be the mechanism for “miracle cures” and “healing by prayer and belief”, as well as the improvement in chronic disease sometimes credited to the “snake oil salesman”.

HORMONE RESTORATION THERAPY
Currently, there is no easily available Allopregnanolone preparation. “Zulresso” or “Zuranolone” would work, but are too expensive for ongoing hormone therapy.

SUMMARY

Allopregnanolone, a neurosteroid derived from progesterone, does brain maintenance and repair.

Its assistants are pregnenolone, progesterone, DHEA and triiodothyronine.

Adequate production of this hormone guarantees good “mood”, tranquillity and optimised cognition, but Allopregnanolone production falls when DHEA, Testosterone, Progesterone or T3 levels are too low.

Women produce much more Allopregnanolone than men do, in the 2nd fortnight of the menstrual cycle and during pregnancy. They tend to anxiety/depression when their Allopregnanolone production falls.

The slowly progressive reduction of neurosteroid biosynthesis, including DHEA, progesterone and testosterone, which begins at age 26 in both men and women, leads to a reduction of Allopregnanolone synthesis, which contributes to the development of “psycho-cognitive loss”: anxiety/depression, fuzzy thinking, memory loss and confusion (6).

This condition mimics early Alzheimer’s disease, but is easily reversed by hormone balancing, includingi supplementation of DHEA (which reliably increases Testosterone), Progesterone (which is converted to Allopregnanolone), Thyroid 3 hormone (which increases the efficiency of all cells, including brain cells) and in the menopause, Estradiol.

Allopregnanolone levels are decreased in stress‐induced psychiatric disorders, including depression and post‐traumatic stress disorder (PTSD), cognitive decline, neurological diseases including Alzheimer’s and MS, traumatic brain injury, stroke and chronic diseases generally.

Elevating Allopregnanolone levels by prescribing progesterone and/or pregnenolone, with DHEA and T3 as necessary is a valid therapeutic approach to counteract behavioural/cognitive/psychological dysfunction in many cases.

Most people suffering from Allopregnanolone deficiency are also deficient in many, or all, of the other neurosteroid hormones, so the entire range of hormones should be assessed and restored to normal.
Progesterone, by mouth, transdermally or per vaginam, provides the raw material for making Allopregnanolone. DHEA produces effects similar to those of Allopregnanolone in two ways: via production of Testosterone and by acting as raw material for micro-hormone production throughout the body, including the brain.
Triiodothyronine (“T3”, the active form of thyroid hormone) is also essential to cognition, mood elevation and general well-being, because it optimises cell efficiency and without it, all functions slow down. People suffering from Allopregnanolone deficiency tend to low T3 and high reverse T3 levels.
Melatonin and Vitamin D3 (actually a hormone, not a vitamin) assist Allopregnanolone in its work.
Music, meditation, alcohol and CBD aid Allopregnanolone production, which is why they improve mood.

* Some stress may not be recognised as such by the individual, but subconsciously registered and reacted to by the brain. “Perceived stress” is stress which is high enough for the subconscious brain to recognise it.

** “penia” means “shortage of”, so “STEROIDOPENIA” is “low neurosteroid level”.

*** see also the page entitled “PROGESTERONE”

TREATING ALLOPREGNANOLONE DEFICIENCY
A synthetically produced, but bioidentical Allopregnanolone called Brexanolone (trade name Zulresso) was approved for intravenous administration by the USDA in 2019, for treatment of postpartum depression and in 2023, oral Zuranolone has been approved.

However it is unlikely that Brexanolone or Zuranolone will produce a permanent “cure” of depression (particularly, PFS) and anyway, the effect of these medications will be short-lived unless the stress reduction produced translates into relief of underlying stress-related functional hypothyroidism, with resumption of Allopregnanolone production.

A better suggestion would be to consult with a Functional or Metabolic Medicine MD, with a view to:
[1] Testing DHEA, Free Testosterone, Progesterone, Oestradiol, HSCRP, Homocysteine and IGF ( Growth Hormone indicator), then
[2] Taking DHEA, 50mg at 8AM.
[3] Taking NAC, 900mg, MTHF (Vit B9) 2 mg and Magnesium Threonate 2G twice daily to reduce brain inflammation.
[4] Taking Progesterone 100 mg and Melatonin, 5-10 mg at night.
[5] Restoring T3 level with oral T3 (at 04:00AM), if the Free T3/Reverse T3 ratio (see “Thyroid Hormone”) is lower than 24,
[6] Trial of PEA as a supplement, or Zuranolone, to provide Allopregnanolone support.
[7] Continuing MD supervision and T3 correction until the FreeT3/Reverse T3 ratio has been greater than 20 for six months.
CAVEAT: Since hormone production will not increase, selected supplements should continue permanently, excepting for T3 in the case of reversible, stress-related intracellular hypothyroidism.

REFERENCES
These references have been selected from several dozen excellent “papers”: readers who need more in-depth information will find it easily by locating these references on-line and looking for “similar articles”.
THE BEST ARE:
(1) Allopregnanolone: An overview on its synthesis and effects, by Silvia Diviccaro, Lucia Cioffi, Eva Falvo, et al, In J Neuroendocrinol. 2022 Feb; 34(2): e12996.
Published online 2021 Jun 29. (J. Wiley and Sons) doi: 10.1111/jne.12996
(2) Allopregnanolone Promotes Regeneration and Reduces β-Amyloid Burden in a Preclinical Model of Alzheimer’s Disease, by Shuhua Chen, Jun Ming Wang, Ronald W. Irwin, Jia Yao, Lifei Liu, and Roberta Diaz Brinton, in PLoS One. 2011; 6(8): e24293.
Published online 2011 Aug 30. doi: 10.1371/journal.pone.0024293 PMCID: MC3168882
PMID: 21918687
(3) PEA – a natural antidepressant, by “clinical education.org”, https://www.clinicaleducation.org/resources/reviews/pea-a-natural-antidepressant/