Dataset Information

Mild hyperandrogenemia in presence/absence of a high-fat, Western-style diet alters secretory phase endometrial transcriptome in nonhuman primates.

ABSTRACT:

Objective

To identify novel transcriptomic changes to eutopic endometrium by exposure to chronic mild hypernadrogenemia (testosterone [T]) with/without exposure to an obesogenic Western-style diet (WSD).

Design

Two-by-two factorial arrangement of treatments.

Setting

National primate research center.

Animals

Rhesus macaque females were chronically exposed to T and/or consumed a WSD from menarche through adulthood. After 4.5 years of treatment, Tru-Cut endometrial biopsies were obtained at the midsecretory phase (n = 6-4/group), and paired-end sequencing of RNA was performed. Several females in the T, WSD, and T+WSD cohorts developed endometriosis within 6 months of biopsy; a separate analysis was performed contrasting diagnosis of endometriosis stage 0-2 versus stages 3 and 4 (American Society for Reproductive Medicine revised criteria).

Interventions

Chronic exposure to mild elevation of T (~five-fold elevation) and/or WSD from menarche until adulthood.

Main outcome measures

Limma voom empirical Bayes pipeline was performed to detect differentially expressed RNAs (DEs) significantly impacted by treatments and endometriosis severity. Differentially expressed RNAs were then interrogated by Ingenuity Pathway Analyses and Protein Analysis through Evolutionary Relationships.

Results

Total DEs included C versus T, 469; C versus WSD, 525; C versus T+WSD, 549; and T versus T+WSD, 1,505. The majority of DEs mapped to the ontology pathways: heterotrimeric G-protein signaling pathways Gi alpha and Gs alpha (C vs. T), WNT signaling (C vs. WSD and T vs. T+WSD), and Huntington disease (C vs. T+WSD). A total of 2,171 DEs from eutopic endometrium were altered by the presence of stage 3 and 4 endometriosis lesions.

Conclusions

The present global transcriptomic analyses demonstrate that the greatest magnitude of changes occurred in contrasts of C and T versus T+WSD, adding to the evidence that these two insults have a synergistic effect on female physiology. These data also support the concept that prior alterations to the function of eutopic endometrium increase the risk for endometriosis.

SUBMITTER: Bishop CV

PROVIDER: S-EPMC7861567 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Study questionDoes developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone?Summary answerYoung female rhesus macaques treated for 3 years, beginning at menarche, with combined testosterone (T) and WSD have increased weight gain and insulin resistance compared to controls and animals treated with either T or WSD alone.What is known alreadyHyperandrogenemia is a well-established component of polycystic ovary syndrome (PCOS) and can be observed in peripubertal girls, indicating a potential pubertal onset of the disease. Obesity is often associated with hyperandrogenemia in peripubertal girls, and overweight girls appear to be at higher risk for the development of PCOS later in life.Study design, size, durationJuvenile (2.5- year old) female rhesus macaques were divided into four groups (n = 10/group): control animals receiving cholesterol implants and a control diet with 15% of calories derived from fat (C), animals receiving T implants (mean serum levels: 1.35 ± 0.01 ng/ml) and a control diet (T), animals receiving a cholesterol implant and a WSD with 36% of calories derived from fat (WSD) and animals receiving a T implant and a WSD (T + WSD). Animals were maintained on the treatments for 36 months and were 5.5 years old at study completion.Participants/materials, setting, methodsMetabolic testing consisted of body measurements including weight, dual-energy X-ray absorptiometry scans, activity monitoring, and glucose tolerance testing at zero months and at least once every 12 months for the remainder of the study. Indirect calorimetry and serum hormone assays were performed following 36 months of treatment.Main results and the role of chanceBody weight and fat mass gain were significantly increased in T + WSD at 24 and 36 months of treatment compared to the other three groups. Log transformed fasting insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were significantly increased in T + WSD animals at 3 years of treatment compared to all other groups. T-treatment caused a greater rate of decline in activity after 18 months, while food intake and metabolic rate were largely unaffected by treatments.Limitations reasons for cautionVariability was present in the metabolic parameters measured; however, this is similar to the heterogeneity observed in human populations.Wider implications of the findingsChronic hyperandrogenemia beginning at puberty may exacerbate metabolic dysfunction in women consuming a WSD and account for the increased rates of obesity and insulin resistance observed in PCOS patients. Counseling of female patient populations with elevated androgens about the potential benefit of consuming a lower fat diet could improve long-term metabolic health outcomes.Study funding/competing interest(s)Eunice Kennedy Shriver National Institute of Child Health & Human Development P50HD071836 and Oregon National Primate Center Grant P51 OD011092. The authors have no competing conflict of interests to disclose.