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Polycystic Ovary Syndrome and the Neuroendocrine Consequences of Androgen Excess

Mauro S.B. Silva, Rebecca E. Campbell

10.1002/cphy.c210025

Source: Volume 12, Issue 2, April 2022

Published online: March 2022

Full Article on Wiley Online Library



Abstract

Polycystic ovary syndrome (PCOS) is a major endocrine disorder strongly associated with androgen excess and frequently leading to female infertility. Although classically considered an ovarian disease, altered neuroendocrine control of gonadotropin‐releasing hormone (GnRH) neurons in the brain and abnormal gonadotropin secretion may underpin PCOS presentation. Defective regulation of GnRH pulse generation in PCOS promotes high luteinizing hormone (LH) pulsatile secretion, which in turn overstimulates ovarian androgen production. Early and emerging evidence from preclinical models suggests that maternal androgen excess programs abnormalities in developing neuroendocrine circuits that are associated with PCOS pathology, and that these abnormalities are sustained by postpubertal elevation of endogenous androgen levels. This article will discuss experimental evidence, from the clinic and in preclinical animal models, that has significantly contributed to our understanding of how androgen excess influences the assembly and maintenance of neuroendocrine impairments in the female brain. Abnormal central gamma‐aminobutyric acid (GABA) signaling has been identified in both patients and preclinical models as a possible link between androgen excess and elevated GnRH/LH secretion. Enhanced GABAergic innervation and drive to GnRH neurons is suspected to contribute to the pathogenesis and early manifestation of neuroendocrine derangement in PCOS. Accordingly, this article also provides an overview of GABA regulation of GnRH neuron function from prenatal development to adulthood to discuss possible avenues for future discovery research and therapeutic interventions. © 2022 American Physiological Society. Compr Physiol 12:3347‐3369, 2022.

Figure 1. Figure 1. The cardinal features and heterogeneous manifestation of PCOS. Current diagnostic criteria for PCOS include androgen excess, menstrual irregularities, and polycystic ovarian morphology (PCOM) as the cardinal features of the disease. Other comorbidities, strongly associated with PCOS in the general population, are also illustrated. As androgen excess is a hallmark of PCOS, it is unclear whether menstrual irregularities and PCOM without hyperandrogenemia accurately represent PCOS. Adapted, with permission, from Lizneva D, et al., 2016 138.
Figure 2. Figure 2. An overview of the hypothalamic‐pituitary‐gonadal (HPG) axis in healthy women and women with PCOS. Panel (A) illustrates the normal HPG axis in females throughout the follicular phase. GnRH neurons secrete pulsatile GnRH into the hypophyseal portal system. In the pituitary gland, GnRH signaling coordinates the secretion of luteinizing hormone (LH) and follicle‐stimulating hormone (FSH). Both gonadotropins act downstream to orchestrate folliculogenesis and the synthesis of steroid hormones such as estrogens and progesterone. Gonadal steroid hormones act on steroid‐sensitive afferent neurons in the brain to ultimately control GnRH neuron activity. Panel (B) indicates the relationship between impaired gonadal steroid‐mediated negative feedback and, high frequency LH secretion in PCOS patients. Elevated LH signaling leads to increased ovarian androgen production reduced FSH impairs follicular development. Inappropriately high levels of androgens indirectly maintain the impaired negative feedback in the brain.
Figure 3. Figure 3. GABAergic signaling to GnRH neurons. GABA is produced through the catalysis of glutamate by the glutamic acid decarboxylase (GAD) enzyme. Next, GABA is efficiently packaged into presynaptic vesicles containing vesicular GABA transporter (VGAT) for release into the synaptic cleft. The expression of chloride (Cl−) cotransporters dictates the intracellular Cl− concentration in GnRH neurons. High Na+‐K+‐Cl− cotransporter 1 (NKCC1) expression in GnRH neurons increases Cl− inward flux, bringing the membrane potential to the depolarized reversal potential for Cl− and establishing a depolarized membrane potential for GABA. Thus, GABA binding to its GABAAR, a Cl− channel, promotes neuronal excitation of GnRH neurons. GABA also binds to GABAAB receptors, which are present at either presynaptic or postsynaptic sites. Through this signaling pathway, GABA may silence presynaptic GABAergic neurons through the inhibition of voltage‐gated Ca2+ channels and/or silence postsynaptic GnRH neurons through activation of G protein‐coupled inwardly‐rectifying K+ (GIRK) channels.
Figure 4. Figure 4. Enhanced putative GABAergic input to GnRH neurons is evident prior to puberty in PCOS‐like mice. (A) Representative confocal images of labeled GnRH neurons (green) and vesicular GABA transporter (VGAT) (red puncta) in the rostral preoptic area of the brain (rPOA) of control and prenatally androgenized (PNA) mice at postnatal day 25 (Scale bar = 10 μm). Insets show labeled VGAT close appositions to GnRH neuron soma (i) and dendrite (ii and iii). White arrowheads point to putative GABA inputs to the nonspiny GnRH neuron membrane and blue arrowheads show labeled VGAT puncta associated with spines (Scale bar = 5 μm). Figure 02[p. 004]/with permission from American Society for Clinical Investigation. (B‐D) Histograms (mean ± SEM) illustrate the significant increase in GABA appositions and density to GnRH neurons in PNA mice compared to controls at a prepubertal time point. Adapted, with permission, from Silva MSB, et al., 2018 214.
Figure 5. Figure 5. Long‐term androgen receptor (AR) blockade reverses GnRH neuron circuit abnormalities in adult PCOS‐like mice. (A) Projected 3D reconstruction of a GnRH neuron from an adult prenatally androgenized (PNA) mouse illustrating labeled vesicular GABA transporter (VGAT) puncta in close association with GnRH neurons. Adapted from Silva MSB, et al., 2018 214, Figure 03[p. 005]/with permission from American Society for Clinical Investigation. (B) Histogram (mean ± SEM) showing the elevated putative GABAergic contact to GnRH neurons in adult PNA mice compared with controls conditions; however, chronic treatment with flutamide (Flut), an AR antagonist, reverses neuroanatomical abnormalities. Adapted, with permission, from Silva MSB, et al., 2018 214.
Figure 6. Figure 6. Development of altered GABAergic innervation to GnRH neurons induced by prenatal androgenization. In utero androgen elevation may be achieved through either direct prenatal androgenized (PNA) or prenatal anti‐Müllerian hormone (PAMH) exposure during late pregnancy in mice 232,236. During prenatal development, overactivation of androgen signaling in steroid‐sensitive GABAergic afferents may program altered brain wiring. Over prepubertal life, altered GABAergic innervation on GnRH neurons can be detected in the hypothalamus, which may promote the increase of GABAergic transmission to GnRH neurons and disturb GnRH neuron activity. During pubertal development and maturation of the reproductive system, homeostatic control is lost, allowing the manifestation of neuroendocrine impairments of PCOS such as elevated GnRH/LH pulse secretion.


Figure 1. The cardinal features and heterogeneous manifestation of PCOS. Current diagnostic criteria for PCOS include androgen excess, menstrual irregularities, and polycystic ovarian morphology (PCOM) as the cardinal features of the disease. Other comorbidities, strongly associated with PCOS in the general population, are also illustrated. As androgen excess is a hallmark of PCOS, it is unclear whether menstrual irregularities and PCOM without hyperandrogenemia accurately represent PCOS. Adapted, with permission, from Lizneva D, et al., 2016 138.


Figure 2. An overview of the hypothalamic‐pituitary‐gonadal (HPG) axis in healthy women and women with PCOS. Panel (A) illustrates the normal HPG axis in females throughout the follicular phase. GnRH neurons secrete pulsatile GnRH into the hypophyseal portal system. In the pituitary gland, GnRH signaling coordinates the secretion of luteinizing hormone (LH) and follicle‐stimulating hormone (FSH). Both gonadotropins act downstream to orchestrate folliculogenesis and the synthesis of steroid hormones such as estrogens and progesterone. Gonadal steroid hormones act on steroid‐sensitive afferent neurons in the brain to ultimately control GnRH neuron activity. Panel (B) indicates the relationship between impaired gonadal steroid‐mediated negative feedback and, high frequency LH secretion in PCOS patients. Elevated LH signaling leads to increased ovarian androgen production reduced FSH impairs follicular development. Inappropriately high levels of androgens indirectly maintain the impaired negative feedback in the brain.


Figure 3. GABAergic signaling to GnRH neurons. GABA is produced through the catalysis of glutamate by the glutamic acid decarboxylase (GAD) enzyme. Next, GABA is efficiently packaged into presynaptic vesicles containing vesicular GABA transporter (VGAT) for release into the synaptic cleft. The expression of chloride (Cl−) cotransporters dictates the intracellular Cl− concentration in GnRH neurons. High Na+‐K+‐Cl− cotransporter 1 (NKCC1) expression in GnRH neurons increases Cl− inward flux, bringing the membrane potential to the depolarized reversal potential for Cl− and establishing a depolarized membrane potential for GABA. Thus, GABA binding to its GABAAR, a Cl− channel, promotes neuronal excitation of GnRH neurons. GABA also binds to GABAAB receptors, which are present at either presynaptic or postsynaptic sites. Through this signaling pathway, GABA may silence presynaptic GABAergic neurons through the inhibition of voltage‐gated Ca2+ channels and/or silence postsynaptic GnRH neurons through activation of G protein‐coupled inwardly‐rectifying K+ (GIRK) channels.


Figure 4. Enhanced putative GABAergic input to GnRH neurons is evident prior to puberty in PCOS‐like mice. (A) Representative confocal images of labeled GnRH neurons (green) and vesicular GABA transporter (VGAT) (red puncta) in the rostral preoptic area of the brain (rPOA) of control and prenatally androgenized (PNA) mice at postnatal day 25 (Scale bar = 10 μm). Insets show labeled VGAT close appositions to GnRH neuron soma (i) and dendrite (ii and iii). White arrowheads point to putative GABA inputs to the nonspiny GnRH neuron membrane and blue arrowheads show labeled VGAT puncta associated with spines (Scale bar = 5 μm). Figure 02[p. 004]/with permission from American Society for Clinical Investigation. (B‐D) Histograms (mean ± SEM) illustrate the significant increase in GABA appositions and density to GnRH neurons in PNA mice compared to controls at a prepubertal time point. Adapted, with permission, from Silva MSB, et al., 2018 214.


Figure 5. Long‐term androgen receptor (AR) blockade reverses GnRH neuron circuit abnormalities in adult PCOS‐like mice. (A) Projected 3D reconstruction of a GnRH neuron from an adult prenatally androgenized (PNA) mouse illustrating labeled vesicular GABA transporter (VGAT) puncta in close association with GnRH neurons. Adapted from Silva MSB, et al., 2018 214, Figure 03[p. 005]/with permission from American Society for Clinical Investigation. (B) Histogram (mean ± SEM) showing the elevated putative GABAergic contact to GnRH neurons in adult PNA mice compared with controls conditions; however, chronic treatment with flutamide (Flut), an AR antagonist, reverses neuroanatomical abnormalities. Adapted, with permission, from Silva MSB, et al., 2018 214.


Figure 6. Development of altered GABAergic innervation to GnRH neurons induced by prenatal androgenization. In utero androgen elevation may be achieved through either direct prenatal androgenized (PNA) or prenatal anti‐Müllerian hormone (PAMH) exposure during late pregnancy in mice 232,236. During prenatal development, overactivation of androgen signaling in steroid‐sensitive GABAergic afferents may program altered brain wiring. Over prepubertal life, altered GABAergic innervation on GnRH neurons can be detected in the hypothalamus, which may promote the increase of GABAergic transmission to GnRH neurons and disturb GnRH neuron activity. During pubertal development and maturation of the reproductive system, homeostatic control is lost, allowing the manifestation of neuroendocrine impairments of PCOS such as elevated GnRH/LH pulse secretion.
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Article Title: Polycystic Ovary Syndrome and the Neuroendocrine Consequences of Androgen Excess
 

How to Cite

Mauro S.B. Silva, Rebecca E. Campbell. Polycystic Ovary Syndrome and the Neuroendocrine Consequences of Androgen Excess. Compr Physiol 2022, 12: 3347-3369. doi: 10.1002/cphy.c210025