Progesterone and neurotransmitters: the under-recognized relationship

Hormones and the nervous system are linked in ways that may not be obvious. In recent weeks, we’ve explored the connections between estrogen and serotonin and testosterone and dopamine. Progesterone is another hormone that has many implications in the nervous system.

Figure 1. During the follicular phase, estradiol peaks around day 12, this estradiol peak and subsequent dropoff signal LH secretion. This sequence of events allows ovulation to occur around day 14. After day 14, during the luteal phase, the corpus luteum secretes progesterone.

Normally, progesterone is recognized for its role in the luteal phase of the menstrual cycle (Figure 1). During the luteal phase, progesterone levels increase, signaling an egg has been released from the ovary. However, the increase in progesterone has effects beyond reproduction. The luteal rise of progesterone is thought to be the cause of many pre-menstrual syndrome (PMS) symptoms including bloating and irritability and when progesterone levels decline, anxiety and insomnia become more common. This occurs because progesterone has a calming effect.

Figure 2. Allopregnanolone, a metabolite of progesterone, enhances GABAA receptor activity.

Progesterone’s calming effect is due to its metabolite allopregnanolone, which enhances GABA_A receptor activity¹. gamma-Aminobutyric acid (GABA) is a calming neurotransmitter. Poor GABA activity has been linked to premenstrual dysphoric disorder (PMDD)² as well as low mood, anxiety, and sleep disorders. When progesterone levels decrease, GABA_A receptor activity also declines (Figure 2). This decrease in GABA receptor activation results in increased nervous system excitability, which frequently results in sleep disturbances and anxiousness.

Figure 3. Progesterone increases MAO activity which increases the degradation of monoamine neurotransmitters, leading to a decrease in these neurotransmitters.

Another contributing factor is progesterone’s effect on monoamine oxidase (MAO).³  Progesterone has been shown to increase MAO activity. The result is lower levels of the stimulating monoamine neurotransmitters norepinephrine and dopamine. Serotonin, however, is also a monoamine neurotransmitter, and healthy levels are important for sleep. (Figure 3). Too much progesterone could actually add to sleep difficulties by decreasing the serotonin levels.

Progesterone also plays a role in neurotransmission. In the central nervous system, progesterone is made by glial cells and supports neuronal signaling. Researchers are also exploring progesterone’s role in myelin formation during nerve regeneration.⁴

While progesterone is known for its role in embryo implantation and the maintenance of pregnancy, it also has essential nervous system functions. For more information on the assessment of neuroendocrine connections, check out the Reproductive Endocrinology Curriculum (health care provider login required).

Guest author: Megan Geitz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in endocrinology and women’s issues.

References:

1. Follesa, P., et al. (2000). Allopregnanolone synthesis in cerebellar granule cells: roles in regulation of GABA_A  receptor expression and function during progesterone treatment and withdrawal. Molecular Pharmacology, vol 57; no. 6:1262-1270.
2. Cunningham, J.,et al. (2009). Update on research and treatment of premenstrual dysphoric disorder. Harv Rev Psychiatry, 12(2):120-137.
3. Luine,V.N., et al. (1983). Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas. Neuroendocrinology.36(3):235-241.
4. Schumacher, M., et al. (2012). Progesterone synthesis in the nervous system: implications for myelination and myelin repair. Frontiers in Neuroscience, 6:10.