Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone

C. A. True, D. L. Takahashi, S. E. Burns, E. C. Mishler, K. R. Bond, M. C. Wilcox, A. R. Calhoun, L. A. Bader, T. A. Dean, N. D. Ryan, Ov Slayden, J. L. Cameron, Richard Stouffer

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    Study Question: Does developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone? Summary Answer: Young 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 Already: Hyperandrogenemia 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, Duration: Juvenile (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, Methods: Metabolic testing consisted of body measurements including weight, dualenergy 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 Chance: Body 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 Caution: Variability was present in the metabolic parameters measured; however, this is similar to the heterogeneity observed in human populations. Wider Implications of the Findings: Chronic 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.

    Original languageEnglish (US)
    Pages (from-to)1880-1891
    Number of pages12
    JournalHuman Reproduction
    Volume32
    Issue number9
    DOIs
    StatePublished - Sep 1 2017

    Fingerprint

    Macaca mulatta
    Diet
    Polycystic Ovary Syndrome
    Therapeutics
    Insulin Resistance
    Fats
    Obesity
    Cholesterol
    Conflict of Interest
    Indirect Calorimetry
    Menarche
    Photon Absorptiometry
    National Institutes of Health (U.S.)
    Human Development
    Puberty
    Serum
    Primates
    Population
    Androgens
    Weight Gain

    Keywords

    • Hyperandrogenemia
    • Hyperinsulinemia
    • Macaque
    • Obesity
    • PCOS
    • Western-style diet

    ASJC Scopus subject areas

    • Reproductive Medicine
    • Rehabilitation
    • Obstetrics and Gynecology

    Cite this

    Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone. / True, C. A.; Takahashi, D. L.; Burns, S. E.; Mishler, E. C.; Bond, K. R.; Wilcox, M. C.; Calhoun, A. R.; Bader, L. A.; Dean, T. A.; Ryan, N. D.; Slayden, Ov; Cameron, J. L.; Stouffer, Richard.

    In: Human Reproduction, Vol. 32, No. 9, 01.09.2017, p. 1880-1891.

    Research output: Contribution to journalArticle

    True, CA, Takahashi, DL, Burns, SE, Mishler, EC, Bond, KR, Wilcox, MC, Calhoun, AR, Bader, LA, Dean, TA, Ryan, ND, Slayden, O, Cameron, JL & Stouffer, R 2017, 'Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone', Human Reproduction, vol. 32, no. 9, pp. 1880-1891. https://doi.org/10.1093/humrep/dex246
    True, C. A. ; Takahashi, D. L. ; Burns, S. E. ; Mishler, E. C. ; Bond, K. R. ; Wilcox, M. C. ; Calhoun, A. R. ; Bader, L. A. ; Dean, T. A. ; Ryan, N. D. ; Slayden, Ov ; Cameron, J. L. ; Stouffer, Richard. / Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone. In: Human Reproduction. 2017 ; Vol. 32, No. 9. pp. 1880-1891.
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    abstract = "Study Question: Does developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone? Summary Answer: Young 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 Already: Hyperandrogenemia 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, Duration: Juvenile (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, Methods: Metabolic testing consisted of body measurements including weight, dualenergy 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 Chance: Body 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 Caution: Variability was present in the metabolic parameters measured; however, this is similar to the heterogeneity observed in human populations. Wider Implications of the Findings: Chronic 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.",
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    author = "True, {C. A.} and Takahashi, {D. L.} and Burns, {S. E.} and Mishler, {E. C.} and Bond, {K. R.} and Wilcox, {M. C.} and Calhoun, {A. R.} and Bader, {L. A.} and Dean, {T. A.} and Ryan, {N. D.} and Ov Slayden and Cameron, {J. L.} and Richard Stouffer",
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    T1 - Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone

    AU - True, C. A.

    AU - Takahashi, D. L.

    AU - Burns, S. E.

    AU - Mishler, E. C.

    AU - Bond, K. R.

    AU - Wilcox, M. C.

    AU - Calhoun, A. R.

    AU - Bader, L. A.

    AU - Dean, T. A.

    AU - Ryan, N. D.

    AU - Slayden, Ov

    AU - Cameron, J. L.

    AU - Stouffer, Richard

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    N2 - Study Question: Does developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone? Summary Answer: Young 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 Already: Hyperandrogenemia 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, Duration: Juvenile (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, Methods: Metabolic testing consisted of body measurements including weight, dualenergy 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 Chance: Body 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 Caution: Variability was present in the metabolic parameters measured; however, this is similar to the heterogeneity observed in human populations. Wider Implications of the Findings: Chronic 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.

    AB - Study Question: Does developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone? Summary Answer: Young 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 Already: Hyperandrogenemia 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, Duration: Juvenile (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, Methods: Metabolic testing consisted of body measurements including weight, dualenergy 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 Chance: Body 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 Caution: Variability was present in the metabolic parameters measured; however, this is similar to the heterogeneity observed in human populations. Wider Implications of the Findings: Chronic 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.

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    KW - Hyperinsulinemia

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    KW - Obesity

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