Pregnenolone and Allopregnenolone

-Resume:

Pregnenolone is included within the group of progestogens. As such, it is a prohormone.
Pregnenolone sulfate antagonizes the GABAB1 receptor and increases neurogenesis in the hippocampus and is a negative modulator of the endocannabinoid CB1 receptor.
Allopregnanolone, also known as Brexanolone, is a steroid produced naturally in the superrenal, which acts on the brain. It is a neurosteroid and acts as a GABA A receptor modulator

-Discussion:

Pregnenolone can be administered orally, subcutaneously, intravenously, intranasally, and topical / transdermal. Oral pregnenolone has a high metabolism and low bioavailability.
It is lipophilic and readily crosses the blood-brain barrier. There is very little data on the pharmacokinetics of exogenous pregnenolone.
Oral pregnenolone is preferentially metabolized to allopregnanolone, rather than other hormones biosynthesized from the pregnenolone substrate, such as cortisol or DHEA.
Allopregnenalone as a medicine, sold under the brand name Zulresso, is used to treat postpartum depression by injection into a vein over a 60-hour period under medical supervision.
Side effects of brexanolone can include sedation, drowsiness, dry mouth, hot flashes, and loss of consciousness.
The main biological target of this neurotransmitter is as a γ-aminobutyric acid (GABA) inhibitor.
Brexanolone was approved for medical use in the United States in 2019.
The United States Food and Drug Administration (FDA) considers it a first-class drug.
The long administration time, as well as the cost of a one-time treatment, have raised concerns about accessibility for many women.
Premenstrual dysphoric disorder (PMDD) is a much more serious form of premenstrual syndrome (PMS). It can affect women of childbearing age.
It is a serious and chronic medical condition that needs attention and treatment. Lifestyle changes and sometimes medications can help control symptoms.
Some women experience negative mood symptoms during the menstrual cycle and the addition of progesterone in estrogen treatments.
Negative mood symptoms associated with increased allopregnanolone during the luteal phase of ovulatory menstrual cycles increase in women with PMDD.
In anovulatory cycles there are no symptoms or increase in sex steroids. This is unexpected, as positive GABA-A receptor modulators often increase mood.
This paradoxical effect has led to the hypothesis that the symptoms are caused by allopregnanolone and the GABA-A receptor system. GABA-A is the main inhibitory system in the brain.
Positive GABA-A receptor modulators include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol.
GABA-A receptor modulators, in low concentrations, are known to induce adverse effects and anxiogens, while in higher concentrations they show beneficial and calming properties.
The mechanism behind a paradoxical reaction could be similar between those that react with positive GABA-A receptor modulators and in women with PMDD.
In women, the severity of these mood symptoms is related to serum allopregnanolone concentrations in an inverted U-shaped curve.
Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to the endogenous levels of the luteal phase, while low and high concentrations have less effect on mood.
Low to moderate levels of progesterone / allopregnanolone in women increase activity in the amygdala (measured with fMRI) similar to changes seen during anxiety reactions.
Higher concentrations cause a decrease in amygdala activity similar to that observed during benzodiazepine treatment with calming anxiolytic effects.
Patients with PMDD show a lower sensitivity of GABA-A receptors to diazepam and pregnanolone, while the sensitivity to allopregnanolone increases.
This is consistent with findings in animals showing a relationship between changes in the alpha4 and delta subunits of the GABA-A receptor and the anxigenic effects of allopregnanolone.
These results suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated through the GABA-A receptor.

-Conclusions:

The adrenal glands use cholesterol to make pregnenolone, an essential precursor hormone that is then converted to steroid hormones such as estrogen, progesterone, testosterone, and cortisol.
Highly concentrated in the brain, it works as an important neurotransmitter. Pregnenolone deficiency leads to a deficiency of the male and female sex hormones and cortisol.
Normal circulating levels of pregnenolone are as follows
Men: 10 to 200 ng / dL
Women: 10 to 230 ng / dL
Children: 10 to 48 ng / dL
Pregnenolone deficiency is established by a blood test. Pregnenolone supplements should be taken only under medical supervision, daily doses of pregnenolone greater than 200 or 300 are not advisable
Decreased libido and secondary sexual characteristics
Pregnenolone deficiency can manifest as symptoms related to decreased male and female sex hormones.
Pregnenolone production declines with age, as do sex hormones. Estrogen deficiency can present as premature ovarian failure, vaginal atrophy, and dryness, which are essentially symptoms of the postmenopausal state.
Testosterone levels decline with age, dropping 1 percent a year after age 30. Male hypogonadism or low testosterone can manifest as a decrease in libido.
Lower sperm production, decreased bone density, changes in fat distribution, and decreased strength and muscle mass.
Men with low testosterone levels can also experience emotional changes such as low self-confidence, sadness, and trouble concentrating.
Other symptoms of low pregnenolone that present as decreased secondary sexual characteristics are: decreased or absent axillary and pubic hair, dry eyes, hot flashes, and fatigue.
Pregnenolone deficiency can manifest as symptoms related to decreased male and female sex hormones Decreased memory and mental awareness
Pregnenolone is 10 times more concentrated in the brain than it is in the blood. An important neurotransmitter that helps memory, pregnenolone deficiency can manifest itself as a memory impairment.
People with pregnenolone deficiency may also experience generalized fatigue, muscle weakness, and joint pain.
The combination of these symptoms can lead to decreased mobility. Inactivity in general is known to contribute to poor health. A sedentary lifestyle contributes to obesity, type 2 diabetes, and high blood pressure.
References:
-Pullen MA, Laping N, Edwards R, Bray J (September 2006). Determination of conformational changes in the progesterone receptor using ELISA-like assays ». Steroids 71 ​​(9): 792-8. PMID 16784762.
-Brexanolone as adjunctive therapy in super-refractory status epilepticus.
-Rosenthal ES, Claassen J, Wainwright MS, Husain AM, Vaitkevicius H, Raines S, Hoffmann E, Colquhoun H, Doherty JJ, Kanes SJ. Ann Neurol. 2017 Sep; 82 (3): 342-352. doi: 10.1002 / ana.25008. Epub 2017 Sep 11.PMID: 28779545

Keywords:
Allopregnanolone, pregnenolone, GABA-A, GABA-A receptor modulating steroids, Premenstrual dysphoric disorder, PMS, gamma-butyric acid-A, hormone replacement therapy, GABA 1B receptor antagonist, sexual dysfunction, loss of libido, hot flashes and pregnenolone, fatigue and pregnenolone, CB1 receptor antagonist and pregnenolone

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