On progesterone and allopregnanolone: effects on the central nervous system (CNS)

Progesterone's and derivative neurosteroids' effect on the central nervous system should shed a light on its involvement in both post-SSRI sexual dysfunction (PSSD) and post-finasteride syndrome (PFS).


Nuclear receptors (Type I):

The progesterone receptor is one of the nuclear receptors, alongside androgen, estrogen and glucocorticoid receptors. This class of receptors is important in post-drug conditions since they can bind to DNA and regulate gene expression, hence being classified as nuclear transcription factors.


Progesterone is synthesized in cerebral glial cells and for this reason it's considered a neurosteroid. Pregnanolone and allopregnanolone (a progesterone derivative), are also synthesized by astrocytes and oligodendrocytes (types of glial cells in the brain). Not only do these neurosteroids act as a positive allosteric modulators of GABA-A receptors, but they also control several other neurotransmitters and neuropeptides, thus, studies have shown a relationship between fluctuation of these neurosteroids and psychological symptoms [1].


Progesterone receptors are classified into nuclear (PR-A, PR-B), transmembrane (7TMPRβ), and membrane-associated 25-Dx PR (PGRMC1). These receptors are broadly expressed throughout the brain [2].


Neurogenesis:

Although progesterone's metabolite allopregnanolone has been shown to possess potent proliferative and neurotrophic action on the hippocampal neural progenitor cells and human cortical neural stem cells [3], this effect was found to be a biphasic dose-dependent process, with concentrations in the low to mid nanomolar range promoting proliferation and concentrations exceeding 1 μM significantly inhibiting neurogenesis [4][5]. Progesterone also blocks estradiol-induced enhancement of neurogenesis [6]. That said, progesterone is a potent modulator of myelination [7] as well as possessing neuroprotective and anti-inflammatory effect [8][9].


Glutamate-GABA balance:

Allopregnanolone, a progesterone-derived neurosteroid, severely impairs learning and memory in rats through GABA-A receptor positive allosteric modulation [13][14][15].


Similar to estradiol, progesterone enhances hippocampal CA1 glutamatergic synaptic transmission and neuroplasticity, but it seems to limit estradiol's effects [10]. Furthermore, after initially augmenting estradiol's enhancement of excitatory synapses [11], sub-chronic exposure to progesterone rapidly decreases dendritic spine density, lowering excitatory synapses drastically both directly and indirectly through its metabolite, allopregnanolone [12]. The down regulation of dendritic spines by progesterone can be partially blocked by the progesterone antagonist, Mifepristone.


The negative mood and physical symptoms associated with premenstrual dysphoric disorder (PMDD) are partially mediated by elevation of progesterone and allopregnanolone, altering GABA-A receptor function [16][17][18]. Postmenopausal women exhibiting intermediate allopregnanolone plasma concentrations subjectively rated themselves as having significantly more negative mood symptoms during progesterone treatment [19].


However, lower allopregnanolone levels after delivery have been found in women who develop postpartum depression [20], and for this reason, postpartum depression has been suggested to be an effect of withdrawal from allopregnanolone, causing a benzodiazepine-like withdrawal symptoms [21]. During progesterone withdrawal, the adaptive upregulation of GABA-A alpha4 subunit was documented in female rats [22].


Low to moderate progesterone/allopregnanolone concentrations in women increases reactivity of the amygdala similar to the changes seen during anxiety reactions. Higher concentrations decreases amygdala activity similar to benzodiazepine treatment with calming, anxiolytic effects [23], and with tolerance setting in similarly [24]. This is a clear evidence that changes in the levels of progesterone/allopregnanolone are involved in premenstrual dysphoric disorder (PMDD) and postpartum depression.


Serotonin:

Progesterone increases serotonin breakdown, downregulates 5HT1A receptors, and blocks estrogen-mediated upregulation of 5HT2A receptors [25][25-2][25-3]. Allopregnanolone potentiates GABA-A mediated inhibition of 5-HT neurons in the dorsal raphe nucleus (DRN) [26]. Lower serum allopregnanolone levels were associated with higher SERT binding in the prefrontal cortex, suggest a link between the typical psychological well-being experienced in the follicular phase when allopregnanolone levels are low in top-down regulation of emotions [27].


Oxytocin:

Allopregnanolone inhibits the release of oxytocin and vasopressin in the supraoptic nucleus of the hypothalamus in the developed brain [28][29].


Beta-endorphin:

Progesterone and progestin has an antagonistic effect on the increase in beta-endorphin level induced by estradiol within the hypothalamus [30]. This antagonistic effect would lead to an increase in gonadotropin secretion [31].


Inhibition of the reinforcing effects of drug of abuse:

While estradiol augments drug rewarding effects, progesterone attenuates them [32][33][34]. Among the range of substances, this includes opioids [35], amphetamines [36], cocaine [37][38][39][40] and tobacco/nicotine [41][42][43][44][45].


Role of progesterone in male sexual behavior

Elevated progesterone levels generally reduce sexual desire in males. This fact lead to progestins being used in chemical castration of male sex offenders [46]. The mechanism by which progesterone and progestins reduce male libido is not fully explained by their ability to reduce plasma testosterone, as normal testosterone level can be found in both impotent and hypersexual males [47]. In fact, as long as a physiological testosterone minimum is available, it serves its purpose as one of interdependent factors in male libido [48].


It's interesting to note that in castrated male rats, progesterone was able to fully initiate the sexual behavior, whereas testosterone alone was not enough to completely restore male sexual behavior without the combination with progesterone [49][50]. Even though animal models provide convincing evidence for progesterone's pro-sexual effects, caution must be exercised when extrapolating this data to the human sexual behavior.


Progesterone and derived neurosteroids' involvement in post-SSRI sexual dysfunction (PSSD) and post-finasteride syndrome (PFS)


Initially, I refused to believe that PSSD and PFS are connected. My reasoning was: just because the symptoms are similar doesn't mean they share the same etiology. Upon further researching, it has become clear to me that there exist shared pathways.


Consider the following reactions:

a. Progesterone → 5α-DHP (by 5α-reductase enzyme)

b. 5α-DHP → allopregnanolone (by 3α-HSD enzyme - this reaction is reversible and uses NADP/NADPH).


SSRIs such as Fluoxetine and Paroxetine increase the affinity of 3α-HSD enzyme for the substrate 5α-DHP, favoring conversion to allopregnanolone by several fold [51]. This effect is demonstrated in Fluoxetine, Paroxetine, Sertraline, Venlafaxine, and Mirtazapine but not in Imipramine [52][53][54].


Problems caused by increased allopregnanolone level (in PSSD):

1. Although elevation of allopregnanolone is shown to have anxiolytic and antidepressant effects in an acute manner, chronic elevation of allopregnanolone is associated with negative mood in lieu of a compensatory mechanism [24]. In particular, postpartum depression has been shown to be a manifestation of allopreganolone withdrawal, as allopregnanolone is significantly increased during pregnancy and is sharply decreased thereafter [22]. Rats administered Fluoxetine chronically had significantly decreased lordosis responses to midbrain allopregnanolone, which means chronic SSRI intake desensitizes the brain to allopregnanolone's effect through as-of-yet unclear compensatory mechanism [55].


2. As mentioned earlier in the article, high concentration of allopregnanolone significantly inhibits neurogenesis, as it follows a biphasic dose-dependent effect on it. Allopregnanolone also significantly alters resting-state amygdala connectivity, causing decreased amygdala reactivity [56].


3. Preferential conversion in the direction of allopregnanolone also translates to reduced conversion to 5α-DHP which possesses significant progestogenic potency [57]. This might have an effect on sex hormone balance and sexual behavior.


4. Allopregnanolone increases mesolimbic dopamine release [58][59]. Central insensitivity to allopregnanolone would therefore reduce this effect.


Problems caused by decreased allopregnanolone level (in PFS):

Finasteride, and other 5α-reductase inhibitors, prevent neurosteroids synthesis [60][61], an effect that seems to linger even after withdrawal of the offending drug [62][63]. In a sense, at least when it comes to neurosteroids, PFS is the opposite side of the coin to PSSD.


1. Since GABA-A receptor loses important positive allosteric modulators, this translates into disinhibited glutamate firing and increased excitatory tone of the brain [64][65][66][67]. Compensatory re-regulation of several GABA-A receptor subunits and glutamate receptors is expected to follow thereafter.


2. Neurosteroid-mediated neurogenesis and neuroprotective effects are out the window as well. Profound pro-depressive effects due to altered amydalar and hippocampal connectivity and transmitter level should also be expected [68][69].


3. Antipsychotic-like effect and anhedonia induced by inhibition of allopregnanolone-mediated dopamine release [70][71].

Conclusion

Progesterone plays an important role in human sexual behavior as well as various neurological functions through both direct and indirect means.


To get the whole picture on PSSD and PFS, one must learn of the small pieces and then connect them together. If there is a neurosteroid deficiency in PFS, there's a partial neurosteroid insensitivity in PSSD. My personal hypotheses on these complex conditions are beyond the scope of this article, however.

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