Sexual Dimorphism in Levodopa-Induced Dyskinesia Following Parkinson's Disease: Uncharted Territory

Abstract

Sexual dimorphism is well-documented in Parkinson's disease (PD); however, when it comes to levodopa-induced dyskinesia (LID), epidemiological and clinical findings are scarce. This is an oversight because recent studies show significant correlations between LID risk and female sex. Estrogen strongly impacts neuronal function, affecting cognitive tasks such as movement, object recognition, and reward. In movement pathways, estrogen increases dopamine synthesis, transmission, and regulation, resulting in neuroprotection for PD in women. However, following menopause, PD prevalence, symptom severity, and LID risk increase for women. Consequently, early to mid-life estrogen state is neuroprotective, but later in life becomes a risk factor for PD and LID. This review explores estrogen's action in the brain, specifically within the dopamine system. Sexual dimorphism is described for the prevalence and onset of PD and LID. We examine the cellular basis of estrogen's role in sexual dimorphism and integrate these ideas to hypothesize why the risk for LID is higher for women, than men, with PD. Lastly, this review proposes that women with PD need their symptoms to be considered and managed differently to males. Treatment of women with PD should be based on their menopausal stage, as estrogen may be masking, exacerbating, or complicating symptoms. Importantly, we present these concepts to stimulate discussion among clinical and bench scientists so that key experiments can be conducted to examine the mechanisms underlying LID, so they can be prevented to improve the quality of life for women and men living with PD in the future.

Keywords: Parkinson; basal ganglia; estrogen; levodopa‐induced dyskinesia; menopause; sexual dimorphism; striatum.

FIGURE 1

Female hormone and neurotransmitter levels. Estrogen, progesterone and dopamine levels throughout the female lifespan (A), human menstrual (B) and rodent estrous (C) cycles, and DA transporter and receptor expression throughout the estrous cycle (D). DAT, dopamine transporter; H:L D2, high:low dopamine 2 receptor affinity ratio; VMAT, vesicular monoamine transport. Created with BioRender.com.

FIGURE 2

Estrogen's modulation of DA synapses in dorsal and ventral striatum. Indirect estrogen effects in the dorsal (A, B) and ventral (C, D) striatum during metestrus/diestrus (A, C) and proestrus/estrus (B, D). (A) In the dorsal striatum, estrogen receptors are only expressed postsynaptically on spiny projection neurons (SPNs), and DA release is indirectly modulated by local GABA release. (B) When estrogen concentration is high in proestrus/estrus in the dorsal striatum, GABA release from SPNs decreases, and DA release increases. (C) Estrogen receptors in the ventral striatum are expressed presynaptically and postsynaptically, modulating DA release directly and indirectly. (D) During proestrus/estrus, DA release increases by increasing VMAT activity, decreasing DAT activity, decreasing DA autoreceptor activity, and decreasing local GABA release. Note: DA receptors are not divided into D1/D2 because that would require discussing direct or indirect pathways, respectively. Created with BioRender.com.

FIGURE 3

Proposed mechanism of increased LID in postmenopausal women. (A) In premenopausal women, estrogen controls DA surges generated by levodopa administration via increased DAT activity, decreased D2 autoreceptor activity, and increased postsynaptic binding. (B) Following menopause, when estrogen levels have declined, extracellular DA concentration surges and LID symptoms occur because DA spillover activates receptors on other spiny projection neurons. Note: Synapses are related to Figure 2 but have been simplified for clarity. Created with BioRender.com.