Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys

Abbott, DH; Bh, Rayome; Dumesic, Daniel A.; Kc, Lewis; Edwards, A. K.; Wallen, Kim; Me, Wilson; Appt, SE; Je, Levine

doi:10.1093/humrep/dex036

Cited by 59 publications

(49 citation statements)

References 125 publications

(134 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Modified from [11], with late gestation T-exposed data modified from [12]. a Phenotypes: type A, hyperandrogenism or hirsutism (Women only) (HA) + intermittent/absent cycles (OD) + polycystic ovary morphology or circulating AMH level ≥ 10 ng/mL (PCOM); type B, HA + OD; type C, HA + PCOM; type D, OD + PCOM, as described [13].…”

Section: -----------67%-----------mentioning

confidence: 99%

“…Such etiopathogenic mechanism(s) also include the non-hyperandrogenic adult PCOS phenotype (type D), which shares gene variant associations with hyperandrogenic phenotypes [28]. Moreover, gestational T excess produces female macaque offspring that exhibit both hyperandrogenic and non-hyperandrogenic adult phenotypes [12], while hyperandrogneic and non-hyperandrogenic PCOS-related phenotypes also occur naturally in female macaques [13].…”

Section: Pcos and Its Potential Originsmentioning

confidence: 99%

See 1 more Smart Citation

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

et al. 2019

View full text Add to dashboard Cite

Indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (PCOS) implicate both female hyperandrogenism and developmental molecular origins as core components of PCOS etiopathogenesis. Establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. Paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of PCOS, including hyperandrogenic fetal and peripubertal origins, epigenetic programming, altered neural function, defective oocytes and embryos, adipogenic constraint enhancing progression to insulin resistance, pancreatic decompensation and type 2 diabetes, together with placental compromise, all contributing to transgenerational transmission of traits likely to manifest in adult PCOS phenotypes. Our recent demonstration of PCOS-related traits in naturally hyperandrogenic (High T) female macaques additionally creates opportunities to employ whole genome sequencing to enable exploration of gene variants within human PCOS candidate genes contributing to PCOS-related traits in macaque models. This review will therefore consider Indian macaque model contributions to various aspects of PCOS-related pathophysiology, as well as the benefits of using macaque models with compellingly close homologies to the human genome, phenotype, development and aging.

show abstract

Section: -----------67%-----------mentioning

confidence: 99%

Section: Pcos and Its Potential Originsmentioning

confidence: 99%

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In female rodents and sheep, for example, fetal T commonly abolishes maturation of ovarian E 2 -induced GnRH/LH surges in adulthood, preventing ovulation [51,85]. In contrast, adult female monkeys exposed to naturally occurring [36] or experimentally induced [33,61] fetal T excess retain the ability to demonstrate ovarian E 2 -induced LH (and likely GnRH) surges and ovulatory menstrual cycles. Women with PCOS [86], and with known exposure to fetal T excess [87], also demonstrate E 2 -induced LH surges or ovulatory menstrual cycles.…”

Section: Discussionmentioning

confidence: 99%

“…Emulating LH traits in women with PCOS, elevated LH levels in PA monkeys show resistance to negative feedback suppression from either exogenous estradiol [33] or gonadotropin hyperstimulated, endogenous ovarian hormone release [34]. In a separate study, adult female rhesus monkeys with naturally occurring hyperandrogenism also exhibit elevated LH levels and accompanying PCOS-like reproductive dysfunction [35,36], together with genital biomarkers indicative of fetal T excess [36]. Numerous studies have since demonstrated fetal T or dihydrotestosterone (DHT) programming of LH hypersecretion as a consequence of elevated episodic release of GnRH/LH in PA adult female sheep [37][38][39], rats [40,41], and mice [42,43].…”

Section: Introductionmentioning

confidence: 93%

Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation

et al. 2018

View full text Add to dashboard Cite

Background/Aims: Ovarian theca cell hyperandrogenism in women with polycystic ovary syndrome (PCOS) is compounded by androgen receptor-mediated impairment of estradiol and progesterone negative feedback regulation of episodic luteinizing hormone (LH) release. The resultant LH hypersecretion, likely the product of accelerated episodic release of gonadotropin-releasing hormone (GnRH) from the median eminence of the hypothalamus, hyperstimulates ovarian theca cell steroidogenesis, enabling testosterone (T) and androstenedione excess. Prenatally androgenized (PA) female monkeys exposed to fetal male levels of T during early-to-mid gestation, when adult, demonstrate PCOS-like traits, including high T and LH levels. This study tests the hypothesis that progesterone resistance-associated acceleration in episodic LH release contributes to PA monkey LH excess. Methods: A total of 4 PA and 3 regularly cycling, healthy control adult female rhesus monkeys of comparable age and body mass index underwent (1) a 10 h, frequent intravenous sampling assessment for LH episodic release, immediately followed by (2) IV infusion of exogenous GnRH to quantify continuing pituitary LH responsiveness, and subsequently (3) an SC injection of a progesterone receptor antagonist, mifepristone, to examine LH responses to blockade of progesterone-mediated action. Results: Compared to controls, the relatively hyperandrogenic PA females exhibited ~100% increase (p = 0.037) in LH pulse frequency, positive correlation of LH pulse amplitude (p = 0.017) with androstenedione, ~100% greater increase (p = 0.034) in acute (0–10 min) LH responses to exogenous GnRH, and an absence (p = 0.008) of modest LH elevation following acute progesterone receptor blockade suggestive of diminished progesterone negative feedback. Conclusion: Such dysregulation of LH release in PCOS-like monkeys implicates impaired feedback control of episodic release of hypothalamic GnRH reminiscent of PCOS neuroendocrinopathy.

show abstract

“…Table 1 Example of diseases and traits reported in rhesus macaques. Diseases are grouped based on whether a genetic association has been reported in macaques for that disease Genetic Association Reported SIV progression [1][2][3] Age-related macular degeneration [4,5] Colorectal cancer [6] Krabbe disease [7] Ammenorhea [8] Naltrexone response [9] HPA axis dysregulation [10] Alcohol intake levels [11][12][13] Anxiety [14,15] No Genetic Association Reported Autism [16] Age-associated coginitive decline [17] Polycystic ovary syndrome (PCOS) [18] Endometriosis [19][20][21] Left ventricular hypertrophy [22] Type III Von-Willebrand [23] Type II Diabetes [24][25][26] Squamous cell carcinoma [27] Coat-like retinopathy [28] TB progression [29] Osteoporosis [30]…”

Section: Introductionmentioning

confidence: 99%

mGAP: the macaque genotype and phenotype resource, a framework for accessing and interpreting macaque variant data, and identifying new models of human disease

et al. 2019

View full text Add to dashboard Cite

Background Non-human primates (NHPs), particularly macaques, serve as critical and highly relevant pre-clinical models of human disease. The similarity in human and macaque natural disease susceptibility, along with parallel genetic risk alleles, underscores the value of macaques in the development of effective treatment strategies. Nonetheless, there are limited genomic resources available to support the exploration and discovery of macaque models of inherited disease. Notably, there are few public databases tailored to searching NHP sequence variants, and no other database making use of centralized variant calling, or providing genotype-level data and predicted pathogenic effects for each variant. Results The macaque Genotype And Phenotype (mGAP) resource is the first public website providing searchable, annotated macaque variant data. The mGAP resource includes a catalog of high confidence variants, derived from whole genome sequence (WGS). The current mGAP release at time of publication (1.7) contains 17,087,212 variants based on the sequence analysis of 293 rhesus macaques. A custom pipeline was developed to enable annotation of the macaque variants, leveraging human data sources that include regulatory elements (ENCODE, RegulomeDB), known disease- or phenotype-associated variants (GRASP), predicted impact (SIFT, PolyPhen2), and sequence conservation (Phylop, PhastCons). Currently mGAP includes 2767 variants that are identical to alleles listed in the human ClinVar database, of which 276 variants, spanning 258 genes, are identified as pathogenic. An additional 12,472 variants are predicted as high impact (SnpEff) and 13,129 are predicted as damaging (PolyPhen2). In total, these variants are predicted to be associated with more than 2000 human disease or phenotype entries reported in OMIM (Online Mendelian Inheritance in Man). Importantly, mGAP also provides genotype-level data for all subjects, allowing identification of specific individuals harboring alleles of interest. Conclusions The mGAP resource provides variant and genotype data from hundreds of rhesus macaques, processed in a consistent manner across all subjects ( https://mgap.ohsu.edu ). Together with the extensive variant annotations, mGAP presents unprecedented opportunity to investigate potential genetic associations with currently characterized disease models, and to uncover new macaque models based on parallels with human risk alleles. Electronic supplementary material The online version of this article (10.1186/s12864-019-5559-7) contains supplementary material, which is available to authorized users.

show abstract

Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys

Abstract: Funded by competitive supplement to P51 OD011106 (PI: Mallick), by P50 HD028934 (PI: Marshall) and by P50 HD044405 (PI: Dunaif). The authors have no potential conflicts of interest.

Cited by 59 publications

References 125 publications

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation

mGAP: the macaque genotype and phenotype resource, a framework for accessing and interpreting macaque variant data, and identifying new models of human disease

Contact Info

Product

Resources

About