Updated: Mar 31
There is a clear link between male sex hormones and libido but the role that the so-called female sex hormones play in male libido is often overlooked despite being essential. What role could it potentially play in post-SSRI sexual dysfunction (PSSD) is the topic I will discuss here.
In the human male, estradiol, the prominent form of estrogen, is acquired by aromatization of testosterone by the aromatase enzyme. Estradiol is essential for modulating libido and erectile function. In fact, estrogen receptors, as well as aromatase enzyme are abundant in the brain, penis, and testis.
To better understand estradiol's modulatory effect, we can to take into consideration testosterone level. When testosterone level is low or absent, estradiol can sustain libido . When testosterone level is normal, estradiol has no effect on libido . In males receiving testosterone replacement therapy with an aromatase inhibitor, lowering estradiol too much resulted in decreased libido , suggesting that complete elimination of estradiol and decreasing the T/E ratio too severely adversely affects male libido. Erectile function: Estradiol has a detrimental effect on erectile function in lieu of its ability to inhibit the hypothalamic-pituitary-gonadal axis and subsequently inhibiting follicle-stimulating hormone (FSH) and luteinizing hormone (LH), leading to reduction in testosterone synthesis . Furthermore, high estradiol level can directly induce erectile dysfunction even in the presence of testosterone, suggesting a more direct action on the physiology of penile tissues . Therefore, a fine ratio of E:T is essential for a healthy sexual response in males.
Let's explore estrogen's action on the brain a bit more in-depth
There are two classical type of estrogen receptors: ER-α and ER-β. Both receptor subtypes mediate potent neuroprotection through activation of ERK and PI-3K-Akt pathways, antioxidant effect, and attenuation of NMDA receptor activation . Estrogen and progesterone control various elements of limbic neuroplasticity, modulating dendritic spine and synapse density in areas such as the hippocampus, hypothalamus, nucleus accumbens, and amygdala as well as enhancement of myelination . Some of these effects are mediated downstream via mGluRs . Acetylcholine: Estrogen receptors activation potentiates cholinergic neurotransmission by increasing high affinity choline uptake, choline acetyltransferase activity and mRNA expression, resulting in increased NGF and BDNF expression . It also upregulates hippocampal muscarinic receptors (M1 to M5) . Whereas, ER-β activation upregulates nicotinic receptor on the hypothalamus . While we are on the topic of acetylcholine, let me mention that there is a third type of estrogen receptor, which is a G protein-coupled receptor unlike the classical ones that are nuclear receptors. This receptor is called GPER aka GPR30. Activation of that receptor rapidly increases forebrain -> hippocampal cholinergic signalling .
Serotonin & oxytocin:
Estradiol upregulates tryptophan hydroxylase enzyme  as well as SERT expression . ER-α activation upregulates 5HT1A receptors  whereas ER-β activation upregulates 5HT2A receptors . Activation of 5HT2A receptors increases protein kinase C (PKC), which in turn desensitizes presynaptic 5HT1A autoreceptors , resulting in increased postsynaptic 5HT1A heteroreceptor activation. Furthermore, estradiol directly desensitizes hypothalamic 5HT1A receptors , possibly through GPR30 . ER-α activation induces oxytocin receptor expression both in the brain and periphery , whereas ER-β activation induces hypothalamic oxytocin release . Oxytocin neurons of the paraventricular and supraoptic nuclei express GPR30, so activation of GPR30 causes oxytocin release , which might mediate estradiol's rapid antidepressant effect. Dopamine: Estradiol is known to potentiate the mesolimbic pathway by increasing dopamine release and upregulating dopamine receptors as well as modulating DAT expression and functional reversal . Glutamate: Aside from attenuation of NMDA activation, ER-α and ER-β can stimulate mGluRs to initiate intracellular signaling cascades independently of glutamate, this is done through caveolin proteins. Through this mechanism, estradiol has a rapid influence over all of the functions typically ascribed to G-protein coupled receptor function of mGluRs, being area specific to the hypothalamus, hippocampus, striatum, and the dorsal root ganglion . ER-α activates striatal mGluR5 signaling. Furthermore, ER-α and ER-β activate mGluR3 to attenuate L-type calcium channel activity .
Norepinephrine: ER-α activation stimulates dopamine beta-hydroxylase (DBH) and tyrosine hydroxylase (TH) mRNA expression . Estradiol also reduces alpha-2 receptor binding potential and mRNA expression, essentially acting like a blocker .
Estrogen's possible association with PSSD:
Recently, it has been found that Citalopram causes genome-wide DNA methylation (silencing) of human cells, independently of its serotonergic action . It's also interesting to note that progesterone's level is often found to be abnormal in PSSD sufferers, even though testing in males isn't reliable. Another thing to note is that some patients report losing their response to Clomiphene, no longer experiencing the same effects they used to before PSSD. What if certain area-specific estrogen receptor expression have been epigenetically silenced (methylated) in complex types of PSSD? couldn't that explain some symptoms with reduction of several neuronal functions? Just something to think about.