Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries

Stine Gry Kristensen; Ajay Kumar; Linn Salto Mamsen; Bhanu Kalra; Susanne Elisabeth Pors; Jane Alrø Bøtkjær; Kirsten Tryde Macklon; Jens Fedder; Erik Ernst; Kate Hardy; Stephen Franks; Claus Yding Andersen

doi:10.1210/clinem/dgac272

Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries

Stine Gry Kristensen^*, Ajay Kumar, Linn Salto Mamsen, Bhanu Kalra, Susanne Elisabeth Pors, Jane Alrø Bøtkjær, Kirsten Tryde Macklon, Jens Fedder, Erik Ernst, Kate Hardy, Stephen Franks, Claus Yding Andersen

^*Corresponding author for this work

Department of Clinical Medicine - Kvindesygdomme og Fødsler, Horsens

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Abstract

CONTEXT: The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant regulation might contribute to the pathogenesis of polycystic ovary syndrome.

OBJECTIVE: Are there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)?

DESIGN AND SETTING: Follicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation.

PATIENTS: Twenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size.

MAIN OUTCOME MEASURES: Intrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays.

RESULTS: The detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P < 0.0001). GDF9 was significantly higher in women with PCO (PCO: 4230 ± 189 pg/mL [mean ± SEM], n = 188; non-PCO: 3498 ± 199 pg/mL, n = 168; P < 0.03), whereas BMP15 was lower in women with PCO (PCO: 431 ± 40 pg/mL, n = 125; non-PCO: 573 ± 55 pg/mL, n = 109; P = 0.10), leading to a significantly higher GDF9:BMP15 ratio in women with PCO (P < 0.01). Significant positive associations between BMP15 and AMH, activins, and inhibins in non-PCO women switched to negative associations in women with PCO.

CONCLUSIONS: Intrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new biomarker for PCO.

Original language	English
Journal	The Journal of Clinical Endocrinology & Metabolism
Volume	107
Issue	8
Pages (from-to)	e3374-e3383
Number of pages	10
ISSN	0021-972X
DOIs	https://doi.org/10.1210/clinem/dgac272
Publication status	Published - Aug 2022

Keywords

Anti-Mullerian Hormone/analysis
Biomarkers/analysis
Bone Morphogenetic Protein 15/analysis
Female
Follicular Fluid/chemistry
Growth Differentiation Factor 9/analysis
Humans
Inhibins/metabolism
Oocytes/metabolism
Polycystic Ovary Syndrome/diagnosis
Transforming Growth Factor beta/metabolism

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Kristensen, S. G., Kumar, A., Mamsen, L. S., Kalra, B., Pors, S. E., Bøtkjær, J. A., Macklon, K. T., Fedder, J., Ernst, E., Hardy, K., Franks, S., & Andersen, C. Y. (2022). Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries. The Journal of Clinical Endocrinology & Metabolism, 107(8), e3374-e3383. https://doi.org/10.1210/clinem/dgac272

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title = "Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries",

abstract = "CONTEXT: The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant regulation might contribute to the pathogenesis of polycystic ovary syndrome.OBJECTIVE: Are there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)?DESIGN AND SETTING: Follicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation.PATIENTS: Twenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size.MAIN OUTCOME MEASURES: Intrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays.RESULTS: The detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P < 0.0001). GDF9 was significantly higher in women with PCO (PCO: 4230 ± 189 pg/mL [mean ± SEM], n = 188; non-PCO: 3498 ± 199 pg/mL, n = 168; P < 0.03), whereas BMP15 was lower in women with PCO (PCO: 431 ± 40 pg/mL, n = 125; non-PCO: 573 ± 55 pg/mL, n = 109; P = 0.10), leading to a significantly higher GDF9:BMP15 ratio in women with PCO (P < 0.01). Significant positive associations between BMP15 and AMH, activins, and inhibins in non-PCO women switched to negative associations in women with PCO.CONCLUSIONS: Intrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new biomarker for PCO.",

keywords = "Anti-Mullerian Hormone/analysis, Biomarkers/analysis, Bone Morphogenetic Protein 15/analysis, Female, Follicular Fluid/chemistry, Growth Differentiation Factor 9/analysis, Humans, Inhibins/metabolism, Oocytes/metabolism, Polycystic Ovary Syndrome/diagnosis, Transforming Growth Factor beta/metabolism",

author = "Kristensen, {Stine Gry} and Ajay Kumar and Mamsen, {Linn Salto} and Bhanu Kalra and Pors, {Susanne Elisabeth} and B{\o}tkj{\ae}r, {Jane Alr{\o}} and Macklon, {Kirsten Tryde} and Jens Fedder and Erik Ernst and Kate Hardy and Stephen Franks and Andersen, {Claus Yding}",

year = "2022",

month = aug,

doi = "10.1210/clinem/dgac272",

language = "English",

volume = "107",

pages = "e3374--e3383",

journal = "The Journal of Clinical Endocrinology & Metabolism",

issn = "0021-972X",

publisher = "Oxford University Press",

number = "8",

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Kristensen, SG, Kumar, A, Mamsen, LS, Kalra, B, Pors, SE, Bøtkjær, JA, Macklon, KT, Fedder, J, Ernst, E, Hardy, K, Franks, S & Andersen, CY 2022, 'Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries', The Journal of Clinical Endocrinology & Metabolism, vol. 107, no. 8, pp. e3374-e3383. https://doi.org/10.1210/clinem/dgac272

Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries. / Kristensen, Stine Gry; Kumar, Ajay; Mamsen, Linn Salto et al.
In: The Journal of Clinical Endocrinology & Metabolism, Vol. 107, No. 8, 08.2022, p. e3374-e3383.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries

AU - Kristensen, Stine Gry

AU - Kumar, Ajay

AU - Mamsen, Linn Salto

AU - Kalra, Bhanu

AU - Pors, Susanne Elisabeth

AU - Bøtkjær, Jane Alrø

AU - Macklon, Kirsten Tryde

AU - Fedder, Jens

AU - Ernst, Erik

AU - Hardy, Kate

AU - Franks, Stephen

AU - Andersen, Claus Yding

PY - 2022/8

Y1 - 2022/8

N2 - CONTEXT: The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant regulation might contribute to the pathogenesis of polycystic ovary syndrome.OBJECTIVE: Are there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)?DESIGN AND SETTING: Follicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation.PATIENTS: Twenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size.MAIN OUTCOME MEASURES: Intrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays.RESULTS: The detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P < 0.0001). GDF9 was significantly higher in women with PCO (PCO: 4230 ± 189 pg/mL [mean ± SEM], n = 188; non-PCO: 3498 ± 199 pg/mL, n = 168; P < 0.03), whereas BMP15 was lower in women with PCO (PCO: 431 ± 40 pg/mL, n = 125; non-PCO: 573 ± 55 pg/mL, n = 109; P = 0.10), leading to a significantly higher GDF9:BMP15 ratio in women with PCO (P < 0.01). Significant positive associations between BMP15 and AMH, activins, and inhibins in non-PCO women switched to negative associations in women with PCO.CONCLUSIONS: Intrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new biomarker for PCO.

AB - CONTEXT: The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant regulation might contribute to the pathogenesis of polycystic ovary syndrome.OBJECTIVE: Are there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)?DESIGN AND SETTING: Follicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation.PATIENTS: Twenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size.MAIN OUTCOME MEASURES: Intrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays.RESULTS: The detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P < 0.0001). GDF9 was significantly higher in women with PCO (PCO: 4230 ± 189 pg/mL [mean ± SEM], n = 188; non-PCO: 3498 ± 199 pg/mL, n = 168; P < 0.03), whereas BMP15 was lower in women with PCO (PCO: 431 ± 40 pg/mL, n = 125; non-PCO: 573 ± 55 pg/mL, n = 109; P = 0.10), leading to a significantly higher GDF9:BMP15 ratio in women with PCO (P < 0.01). Significant positive associations between BMP15 and AMH, activins, and inhibins in non-PCO women switched to negative associations in women with PCO.CONCLUSIONS: Intrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new biomarker for PCO.

KW - Anti-Mullerian Hormone/analysis

KW - Biomarkers/analysis

KW - Bone Morphogenetic Protein 15/analysis

KW - Female

KW - Follicular Fluid/chemistry

KW - Growth Differentiation Factor 9/analysis

KW - Humans

KW - Inhibins/metabolism

KW - Oocytes/metabolism

KW - Polycystic Ovary Syndrome/diagnosis

KW - Transforming Growth Factor beta/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85134428619&partnerID=8YFLogxK

U2 - 10.1210/clinem/dgac272

DO - 10.1210/clinem/dgac272

M3 - Journal article

C2 - 35511085

SN - 0021-972X

VL - 107

SP - e3374-e3383

JO - The Journal of Clinical Endocrinology & Metabolism

JF - The Journal of Clinical Endocrinology & Metabolism

IS - 8

ER -

Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries

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