Androgens and ovarian function: translation from basic discovery research to clinical impact

Walters, Kirsty A; Paris, Valentina Rodriguez; Aflatounian, Ali; Handelsman, David J.

doi:10.1530/joe-19-0096

Cited by 79 publications

(54 citation statements)

References 200 publications

(258 reference statements)

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“…Previous studies have demonstrated that androgens serve crucial roles in the regulatory process of follicle development. They mediate their regulatory actions mainly via their specific AR receptors, affecting the transcription and translation of multiple female follicle development-associated downstream target genes (32,33). Furthermore, previous studies have revealed that nucleotide change (19,34) or aberrant expression (32,35) of AR may promote the progression of PCOS.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor gene mutations in 258 Han Chinese patients with polycystic ovary syndrome

et al. 2020

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Polycystic ovary syndrome (PCOS) affects 8-13% of reproductive-age females worldwide and mutations or aberrant expression of androgen receptor (AR) may cause the onset of this disease. In the present study, 258 samples from Han Chinese patients with PCOS were analyzed for the presence of AR mutations via sequencing of all coding exons of the AR gene. A total of five heterozygous missense mutations, namely p.V3M, p.Q72R, p.S158L, p.S176R and p.G396R, were identified in five of the patients. Among these, p.S158L was a novel mutation that, to the best of our knowledge, has not been reported previously. Although the remaining four mutations have been reported previously, they existed at low frequencies or were absent in the control subjects and in the Exome Aggregation Consortium database. The results of evolutionary conservation and in silico analysis revealed that the p.V3M, p.S158L and p.S176R mutations were pathogenic, whereas the p.Q72R and p.G396R mutations were benign. Compared with the patients with PCOS without AR mutations or with benign AR mutations, markedly lower estrogen levels on the day of human chorionic gonadotropin injection were observed in the three patients with PCOS with potentially pathogenic mutations. In addition, patients with PCOS with pathogenic mutations had lower numbers of oocytes; however, the difference was not statistically significant. Of note, these observations should be interpreted with caution due to the relatively small sample size in the present study. Therefore, a larger number of samples should be collected to validate the results of the present study in future studies. In summary, the present study identified three potential pathogenic mutations in 258 Han Chinese patients with PCOS and these mutations may have an implication in the pathogenesis of PCOS.

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Section: Discussionmentioning

confidence: 99%

Androgen receptor gene mutations in 258 Han Chinese patients with polycystic ovary syndrome

et al. 2020

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“…The pathophysiology of PCOS is complex and has long been controversial. PCOS may have multifactorial causes related to genetic, metabolic, fetal, and environmental factors [67][68][69][70][71][72][73]. There are several genes and pathways reported to be related to the PCOS phenomenon.…”

Section: The Pathophysiology Of Polycystic Ovary Syndrome (Pcos)mentioning

confidence: 99%

“…Hyperinsulinemia apparently increases ovarian androgen production in PCOS via the inhibition of hepatic SHBG production [69]. Furthermore, insulin counters normal homologous desensitization, upregulating the granulosa or theca cell LH receptors and ovarian cytochrome P450c17a activity, and acting synergistically with LH to enhance theca cell androgen production [69,72,79]. In PCOS patients, ovarian androgen is the main source of hyperandrogenism, accounting for 70% of the total androgen level in PCOS [79].…”

Section: The Molecular Mechanisms Of Ir In Polycystic Ovary Syndromementioning

confidence: 99%

Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome

Seow¹,

Chang

Chen

et al. 2020

IJMS

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Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ultrasonography, and affects 5–10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5–15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30–90% and final pregnancy rates of 13–88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of “toxic” follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the “hypothalamus–pituitary–ovary” axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article.

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“…Androgen receptors (AR) are expressed in the theca cells, granulosa cells, and ova (25,(32)(33)(34). Expression of AR in follicular cells is critical for normal folliculogenesis and ovulation (25,(32)(33)(34). Therefore, various androgens, mainly testosterone and DHEA, have been clinically tried as cotreatment before and during COS in patients with POR but the success was very limited and equivocal.…”

Section: Androgensmentioning

confidence: 99%

“…Therefore, various androgens, mainly testosterone and DHEA, have been clinically tried as cotreatment before and during COS in patients with POR but the success was very limited and equivocal. (25,(32)(33)(34). Whereas androgens may augment the early stages of folliculogenesis, they may be detrimental, in supraphysiologic concentrations, on the later stages of folliculogenesis, leading to follicular arrest in the sizes of 2-9 mm, inhibiting the formation of a mature Graaffian follicle, as it is in PCOS patients (33)(34)(35).…”

Section: Androgensmentioning

confidence: 99%

What Is the Best Regimen for Ovarian Stimulation of Poor Responders in ART/IVF?

Blumenfeld

2020

Front. Endocrinol.

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The infertile patients with aging ovaries-also sometimes referred to as impending premature ovarian insufficiency (POI), impending premature ovarian failure (POF), or poor ovarian responders (POR), constitute a significant and increasing bulk of the patients appealing to IVF/ART. Different causes have been cited in the literature, among the identified etiologies, including chromosomal and genetic etiology, metabolic, enzymatic, iatrogenic, toxic, autoimmune, and infectious causes. Although the most successful and ultimate treatment of POI/POF/POR patients is egg donation (ED), many, if not most, of these infertile women are reluctant to consent to ED upon the initial diagnostic interview, requesting alternative solutions despite the low odds for success. Despite anecdotal case reports, no unequivocal treatment proved to be successful for these patients in prospective randomized controlled trials. Nevertheless, the addition of growth hormone (GH) to ovarian stimulation in POR with GH deficiency may improve the results of controlled ovarian hyperstimulation (COH) and the IVF success. In patients with autoimmune etiology for POR/POI, the combination of glucocorticosteroids, pituitary-ovarian suppression, and COH may be successful in achieving the desired conception.

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Androgens and ovarian function: translation from basic discovery research to clinical impact

Cited by 79 publications

References 200 publications

Androgen receptor gene mutations in 258 Han Chinese patients with polycystic ovary syndrome

Androgen receptor gene mutations in 258 Han Chinese patients with polycystic ovary syndrome

Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome

What Is the Best Regimen for Ovarian Stimulation of Poor Responders in ART/IVF?

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