By Andrew Rubman, ND
Estradiol and Serotonin
At optimal levels, estradiol (E2) supports serotonin in several ways:
• E2 increases tryptophan hydroxylase, the rate-limiting step in serotonin synthesis
• E2 receptor (E2β) simulation upregulates the expression of serotonin receptors (5-HT2A)
• E2 acts as a serotonin reuptake inhibitor
• E2 inhibits monoamine oxidase activity, thus preventing the breakdown of serotonin
Consequently, if estradiol levels decrease, serotonin activity may decrease as well. Low estradiol levels may result in symptoms associated with low serotonin, e.g. low mood, sleep difficulties, hot flashes, uncontrolled appetite, and headaches. Supporting serotonin may counter the effects of decreased estradiol.
Progesterone and GABA
Progesterone’s metabolite allopregnanolone acts at the GABA receptor to increase GABA activity, thus promoting calming effects. Low progesterone levels may result in symptoms associated with low GABA, e.g. anxiousness and sleep difficulties. Supporting GABA may counter the effects of decreased progesterone
Cortisol and the Monoamines
Cortisol can stimulate monoamine oxidase (MAO) to dampen the production of various neurotransmitters, including serotonin, epinephrine, norepinepherine, and dopamine. In addition, MAO can enhance tyrosine hydroxylase to cause an increase the same neurotransmitters, including GABA, if needed. Furthermore, an upregulated immune system can be dampened by increased cortisol as necessary.
The human body consists of multiple systems that communicate to maintain homeostasis and health. The coordinated interconnectedness of the nervous, endocrine, and immune systems is often overlooked when considering patient care. Nevertheless, our health is hinged on the existence of neurotransmitters, hormones, and cytokines, which are essential chemical signals that mediate the communication between the nervous, endocrine, and immune systems, respectively. Collectively, these
systems constitute the Neuro-Endo-Immune (NEI) “Supersystem.”
Taking a closer look at the role of endocrinology in the NEI “supersystem,” there are several important hormone-neurotransmitter interactions and three axes at which much hormone-neurotransmittercytokine interaction occurs; including the hypothalamic-pituitary-adrenal (HPA) axis, the hypothalamicpituitary-thyroid (HPT) axis, and the hypothalamic-pituitary-gonadal (HPG) axis
The hypothalamic-pituitary-adrenal axis (HPA axis) is a neuroendocrine system that regulates the reactions to stress, energy storage, and the immune system. Cytokines act at several levels of the HPA axis to induce the release of cortisol and epinephrine. Cortisol and epinephrine act to suppress the immune response, thus forming a negative feedback loop.
The hypothalamic-pituitary-gonadal axis (HPG axis) is a neuroendocrine system that regulates the reproductive system. The hypothalamus releases gonadotropin-releasing hormone (GnRH) to stimulate the pituitary to release luteinizing hormone (LH), which then signals the gonads. This communication pathway ultimately leads to the production of testosterone, estrogen, and progesterone from the gonads.
Estrogen tends to have a stimulatory effect on the immune system, while testosterone tends to have suppressive effects. For example, estrogen enhances the secretion of the cytokines IFN-γ, IL-1, and IL10. Testosterone generally decreases the secretion of the cytokines IFN-γ, IL-4, and IL-5. The cytokine IL-1β inhibits hypothalamic release of GnRH, and IL-1α inhibits LH release from the pituitary, both of which could lead to reduced sex hormone release from the gonads
The hypothalamic-pituitary-thyroid axis (HPT axis) is a neuroendocrine system that regulates metabolism. When the hypothalamus senses low circulating levels of the hormones T3 and T4, it signals to the pituitary, which then signals the thyroid gland to release T3 and T4. T4 normally is converted to the more active T3, but T4 can also be converted to reverse T3 (rT3). Reverse T3 antagonizes the T3 receptor, so high levels can be detrimental. The cytokines IL-1β, TNF-α, IFN-γ, and IL-6 can inhibit the conversion of T4 to T3, thereby shunting T4 towards the production of the potentially detrimental rT3. T3 can stimulate dendritic cell (DC) maturation, leading to DC-induced T cell proliferation and IFN-γ release.