In Search of New Therapeutics—Molecular Aspects of the PCOS Pathophysiology: Genetics, Hormones, Metabolism and Beyond
Abstract
:1. Introduction
- Difficulties in inducing ovulation in some patients, despite stimulation by pharmacological agents (letrozole, clomiphene citrate, or gonadotropins).
- Unsatisfactory reduction of insulin resistance and hyperinsulinemia, in spite of implementing lifestyle changes and undergoing metformin therapy.
- Frequent unsatisfactory results of attempts to counteract hirsutism, acne and androgenic alopecia by application of, e.g., oral Contraceptives—thus, the sensitivity of androgen receptors within the skin to testosterone and dihydrotestosterone (DHT) should be lowered.
2. Leading Factors in PCOS Pathogenesis
2.1. Developmental Programming of PCOS
2.2. Genetics in PCOS
2.3. Hyperandrogenemia
2.4. Insulin Resistance and Hyperinsulinemia
2.5. Environmental Factors
3. Potential Drug Targets and Active Substances in Novel Therapies
3.1. Attenuation of Developmental Programming of PCOS
3.2. Approaches to Alleviate Hyperandrogenism
3.3. Sensitization to Insulin/Reduction of Hyperinsulinemia
3.4. Handling Other PCOS-Related Health Complications
4. Discussion
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AKR | aldo-keto reductase |
AMH | anti-müllerian hormone |
AMP | adenosine monophosphate |
AMPK | adenosine monophosphate-activated protein kinase |
AQP | aquaporin |
BAT | brown adipose tissue |
CYP | cytochrome P450 |
DCI | D-chiro-inositol |
DHT | dihydrotestosterone |
FSH | follicle stimulating hormone |
GABA | -aminobutyric acid |
GLUT | glucose transporter (protein) |
GnRH | gonadotropin-releasing hormone |
hCG | human chorionic gonadotropin |
HNF-4 | hepatocyte nuclear factor 4 alpha |
HSD | hydroxysteroid dehydrogenase |
IGF-1 | insulin-like growth factor-1 |
IPG | inositol phosphoglycan |
LH | luteinizing hormone |
MI | myo-inositol |
PCOS | polycystic ovary syndrome |
SHBG | sex hormone-binding globulin |
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Gene Type | Function | Group |
---|---|---|
CYP11a | Present in all steroid-producing tissues, encodes a cytochrome P450 enzyme that mediates the cleavage of the cholesterol side chain, which is a dominating process in the rate of formation steroid hormones; its role was also confirmed in etiology of hyperandrogenism and PCOS [21,22]. | Ovarian and adrenal steroidogenesis |
CYP17 | Encodes an enzyme cytochrome P450-C17; component of the androgen synthesis pathway, which is dysfunctional in PCOS [23]. Its role in PCOS was also characterized in [24,25]. | |
CYP19 | Encodes important enzymes in androgen synthesis pathways, including cytochrome P450 aromatase. Its role in PCOS was described in [26]. The changes in concentration of P450 was combined with PCOS; for details please see [27] | |
CYP21 | Encodes an important 21-hydroxylase enzyme involved in synthesis pathways of steroid hormones; reported increased frequency of heterozygosity for mutations in the 21-hydroxylase gene in women with PCOS [28,29]. | |
LH | Encodes beta subunit of luteinizing hormone. High level of circulating LH is a common biochemical indicator of PCOS [30]; point mutation-Trp8Arg and Ilg15Thr in the gene encoding beta subunit was identified in patients with PCOS [31]. | Gonadotropin release regulation |
FSHR | Protein encoded by this gene – G-protein coupled receptor is involved in hormonal regulation of gonadal development. Mutation of this gene disrupts the structural conformation of protein and in result causes ovarian hyperstimulation syndrome; the association of follicle-stimulating hormone receptor (FSHR) and PCOS is characterized in [32,33] | |
AMH | Encodes the anti-müllerian hormone, it is involved in gonadotropin secretion. The important role of AMH in the pathophysiology of PCOS was characterized in [34,35]. | |
INSR | Insulin receptor gene on chromosome 19p13.2; Identified region D19S884 was characterized as a fragment of chromosome involved in PCOS [36]. | Insulin secretion and action |
CAPN10 | Encodes Calpain 10 protein, belonging to calcium-dependent cysteine proteases family, which impacts on insulin metabolism and secretion what is the reason for association CAPN10 with PCOS etiology [5,37]. | |
IRS1, IRS2 | Involved in insulin secretion and action; encodes insulin receptor substrates IRS1 and IRS2. Gly972Arg variant of IRS1 was identified more often in women with PCOS [38]. | |
AR | Mutations in androgen receptors cause the disruption of the respective cellular pathways and in result- hyperandrogenism associated with PCOS. | Steroid hormone action |
SHBG | SHBG gene is in 17p13-p12 chromosome and encodes Sex Hormone Binding Globulin, an important biomarker in PCOS risk assessment which binds androgens and other hormones, thus regulates the androgen level in the body [39]. | |
TNF-alpha | Encodes a cytokine Tumor Necrosis Factor which modulates several biological processes, including immunity and inflammation, obesity and insulin resistance; its role in PCOS has been examined [40]. | Chronic inflammation |
FTO | Gene encodes fat mass and obesity-associated protein. FTO rs9939609 polymorphism is significantly associated with risk of PCOS [30]. | Adipose tissue metabolism |
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Wawrzkiewicz-Jałowiecka, A.; Kowalczyk, K.; Trybek, P.; Jarosz, T.; Radosz, P.; Setlak, M.; Madej, P. In Search of New Therapeutics—Molecular Aspects of the PCOS Pathophysiology: Genetics, Hormones, Metabolism and Beyond. Int. J. Mol. Sci. 2020, 21, 7054. https://doi.org/10.3390/ijms21197054
Wawrzkiewicz-Jałowiecka A, Kowalczyk K, Trybek P, Jarosz T, Radosz P, Setlak M, Madej P. In Search of New Therapeutics—Molecular Aspects of the PCOS Pathophysiology: Genetics, Hormones, Metabolism and Beyond. International Journal of Molecular Sciences. 2020; 21(19):7054. https://doi.org/10.3390/ijms21197054
Chicago/Turabian StyleWawrzkiewicz-Jałowiecka, Agata, Karolina Kowalczyk, Paulina Trybek, Tomasz Jarosz, Patrycja Radosz, Marcin Setlak, and Paweł Madej. 2020. "In Search of New Therapeutics—Molecular Aspects of the PCOS Pathophysiology: Genetics, Hormones, Metabolism and Beyond" International Journal of Molecular Sciences 21, no. 19: 7054. https://doi.org/10.3390/ijms21197054