Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries.

Gilling-Smith, Carole; Willis, Debbie; Beard, R. W.; Franks, Stephen

doi:10.1210/jcem.79.4.7962289

Cited by 189 publications

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“…It is not too difficult to identify biochemical pathways that may be disrupted in PCOS. There is evidence for an intrinsic disorder of ovarian folliculogenesis, [45][46][47] constitutive hypersecretion of androgens by theca cells 48,49 and disordered secretion and action of insulin 50 (Figure 1). There are, however, obvious problems in searching for candidate genes in PCOS: the heterogeneous nature of the syndrome has given rise disagreement about definition and diagnostic criteria; in addition expression of features of PCOS occurs predominantly in women of reproductive age and there is no clear male phenotypeFboth of which make family-based studies difficult.…”

Section: Introductionmentioning

confidence: 99%

“…The studies from our own laboratory provide a cautionary tale in the saga of the quest for candidate genes. On the basis of the evidence for a primary abnormality in theca cells steroidogenesis, 48,49 we investigated a polymorphism (a pentanucleotide repeat sequence) in the promoter of CYP11A (coding for P450 cholesterol sidechain cleavage, the rate-limiting enzyme at the origin of the steroidogenic pathway) in a relatively small case-control series and a family-based study. We found evidence for linkage and association with PCOS and testosterone levels at the CYP11A locus.…”

Section: Introductionmentioning

confidence: 99%

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Polycystic ovary syndrome in adolescents

2008

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Background: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women and typically presents during adolescence. The clinical and biochemical presentation is heterogeneous, but elevated serum concentrations of androgens are the most consistent biochemical abnormality and may be considered to be the hallmark of the syndrome. Many women with PCOS also have insulin resistance and hyperinsulinaemia, which may contribute to the clinical and endocrine abnormalities. The aetiology of PCOS is not clear but studies in the Rhesus monkey suggest that exposure to excess androgen during intrauterine life results in many of the features of human PCOS, including ovarian dysfunction, abnormal LH secretion and insulin resistance. Objective: To review the studies from the literature, including those of the author, regarding aetiology, presentation and management of PCOS in adolescents. Results and conclusions: We have proposed that PCOS in adolescents arises as a result of a genetically determined disorder of ovarian function that results in hyper-secretion of androgens, possibly during fetal life and also during physiological activation of the hypothalamic-pituitary-ovarian in infancy and at the onset of puberty. There is plentiful evidence for a genetic basis for PCOS (it appears to be a complex endocrine disorder resulting from the effects of a several genes), but environmental factors, notably nutrition, influence the clinical and biochemical phenotype. Obesity unmasks or amplifies symptoms, endocrine and metabolic abnormalities. The increasing incidence of childhood obesity has resulted in an alarming Increase not only in distressing symptoms but also impaired glucose tolerance and even diabetes among adolescent girls with PCOS. The search for PCOS genes in this condition, that is not only heterogeneous but also presents only in women of reproductive age, is not straightforward and has produced few convincing candidates so far. In due course, however, identification of the major susceptibility loci is likely to provide key insight into the aetiology of the syndrome and improve diagnosis and management.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polycystic ovary syndrome in adolescents

2008

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“…Studies on freshly isolated thecal tissue or cultures of theca cells derived from normal and PCOS women have demonstrated that PCOS theca secretes greater amounts of androgen than theca tissue or cells from regularly ovulating women (12,(14)(15)(16)(17)(18)(19). Increased androgen biosynthesis in PCOS theca cells results from increased expression of the key enzymes involved in androgen biosynthesis, steroid-17-α-hydroxylase/17,20 lyase (encoded by the CYP17A1 gene) and cholesterol side-chain cleavage enzyme, mitochondrial (encoded by the CYP11A1 gene) (15)(16)(17)20).…”

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Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

McAllister

Modi

Miller³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

191

157

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Polycystic ovary syndrome (PCOS), characterized by increased ovarian androgen biosynthesis, anovulation, and infertility, affects 5-7% of reproductive-age women. Genome-wide association studies identified PCOS candidate loci that were replicated in subsequent reports, including DENND1A, which encodes a protein associated with clathrin-coated pits where cell-surface receptors reside. However, these studies provided no information about functional roles for DENND1A in the pathogenesis of PCOS. DENND1A protein was located in the cytoplasm as well as nuclei of theca cells, suggesting a possible role in gene regulation. DENND1A immunostaining was more intense in the theca of PCOS ovaries. Using theca cells isolated and propagated from normal cycling and PCOS women, we found that DENND1A variant 2 (DENND1A.V2) protein and mRNA levels are increased in PCOS theca cells. Exosomal DENND1A.V2 RNA was significantly elevated in urine from PCOS women compared with normal cycling women. Forced overexpression of DENND1A.V2 in normal theca cells resulted in a PCOS phenotype of augmented CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis. Knock-down of DENND1A.V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene transcription. An IgG specific to DENND1A.V2 also reduced androgen biosynthesis and CYP17 and CYP11A1 mRNA when added to the medium of cultured PCOS theca cells. We conclude that the PCOS candidate gene, DENND1A, plays a key role in the hyperandrogenemia associated with PCOS. These observations have both diagnostic and therapeutic implications for this common disorder. P olycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 5-7% of reproductive age women world-wide (1). PCOS is associated with hyperandrogenemia/ hyperandrogenism, anovulation, infertility, and a characteristic ovarian morphology consisting of multiple small subcortical follicular "cysts" embedded in bilaterally enlarged ovaries (2-5). The presence of elevated circulating concentrations of testosterone results primarily from increased production of androgens by the ovaries, and is a classic endocrine phenotype of women with PCOS. Although there has been debate about the diagnostic criteria for PCOS, hyperandrogenemia/hyperandrogenism and anovulation, not explained by other causes, is a hallmark of the disorder, and is included as a key element in all "consensus" diagnosis schemes (6-10).There is consensus that the ovarian theca cells are the primary source of excess androgen biosynthesis in women with PCOS (11-13). Studies on freshly isolated thecal tissue or cultures of theca cells derived from normal and PCOS women have demonstrated that PCOS theca secretes greater amounts of androgen than theca tissue or cells from regularly ovulating women (12,(14)(15)(16)(17)(18)(19). Increased androgen biosynthesis in PCOS theca cells results from increased expression of the key enzymes involved in androgen biosynthesis, steroid-17-α-hydroxylase/17,20 lyase (encoded by the CYP17...

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“…Polycystic ovaries appear to occur as a dominant trait, with a suggestion of a counterpart male phenotype of premature male-pattern baldness [44,45]. Polycystic ovaries from asymptomatic women have an abnormal steroidogenic pattern similar to that of women with PCOS in vitro [46], and ovarian function testing shows them to have a subclinical increase in androgens [47][48][49].…”

Section: Etiology Of Polycystic Ovary Syndromementioning

confidence: 99%

Polycystic Ovary Syndrome in Adolescence

Driscoll

2003

Semin Reprod Med

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Polycystic ovary syndrome (PCOS) is a syndrome of variable combinations of menstrual irregularity, hirsutism or acne, and obesity. It can be diagnosed in adolescence and has early childhood antecedents. PCOS is the single most common endocrine cause of anovulatory infertility and a major risk factor for the metabolic syndrome and, in turn, development of type 2 diabetes mellitus (T2DM) in women. Thus, it appears that PCOS increases a woman's risk of developing cardiovascular disease. Therefore, identifying girls at risk for PCOS and implementing treatment early in the development of PCOS may be an effective means of preventing some of the long-term complications associated with this syndrome. This article reviews the definition, clinical features, diagnosis, and treatment of PCOS. Definition Classic polycystic ovary syndromeThe classic syndrome originally was described in 1935 by Stein and Leventhal as the association of amenorrhea with polycystic ovaries in women, of whom about two thirds were hirsute, and one half were obese [1]. The term PCOS was introduced upon recognition of a broader spectrum of clinical symptoms and ovarian histology, including stromal hyperplasia with multiple subcapsular follicles. Approximately two-thirds of patients with classic PCOS have hirsutism (or hirsutism equivalents, acne vulgaris or pattern alopecia), two-thirds have anovulatory symptoms (manifested as amenorrhea, oligomenorrhea, dysfunctional uterine bleeding, or unexplained infertility), and one-half are obese. Thus, only about one-third of classic cases have the full-blown clinical picture (Fig. 1). The laboratory diagnostic criteria for classic PCOS require biochemical evidence of hyperandrogenism with either a polycystic ovary by ultrasound or an increased serum level of luteinizing hormone (LH) or LH to follicle-stimulating hormone (FSH) ratio. These criteria have proven to not necessarily coincide (Fig. 2). Nonclassic and atypical polycystic ovary syndromeIn 1990, the National Institutes of Health (NIH) Conference on PCOS considered the implications of recent research findings for the diagnosis [2]. Fifty percent to 60% of those present concurred that the criteria for PCOS should consist of chronic anovulation with clinical or biochemical signs of hyperandrogenism that was not explained by other etiologies. This recognized the spectrum of the syndrome to include androgen excess in the absence of ultrasonographic and gonadotropic abnormalities (here termed nonclassic PCOS). NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe androgen excess of PCOS usually results from characteristic types of functional ovarian hyperandrogenism (FOH) or functional adrenal hyper-androgenism (FAH) [3,4]. FOH is gonadotropin-dependent excessive ovarian androgen production, and it occurs in most women with classic PCOS. It is also found in an equal number of hyperandrogenic women who do not meet the criteria for classic PCOS. It is characterized by 17-hydroxyprogesterone hyper-responsiveness to gonadotropin...

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Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries.

Cited by 189 publications

References 1 publication

Polycystic ovary syndrome in adolescents

Polycystic ovary syndrome in adolescents

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype

Polycystic Ovary Syndrome in Adolescence

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