Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome

D. M. Liu, L. C. Torchen, Y. Sung, R. Paparodis, R. S. Legro, S. K. Grebe, Ravinder Jit Singh, R. L. Taylor, A. Dunaif

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

STUDY QUESTION Are there abnormalities in gonadotrophin secretion, adrenal steroidogenesis and/or testicular steroidogenesis in brothers of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Brothers of women with PCOS have increased gonadotrophin responses to gonadotrophin releasing hormone (GnRH) agonist stimulation and alterations in adrenal and gonadal steroidogenesis. WHAT IS KNOWN ALREADY PCOS is a complex genetic disease. Male as well as female first-degree relatives have reproductive features of the syndrome. We previously reported that brothers of affected women have elevated circulating dehydroepiandrosterone sulfate levels. STUDY DESIGN, SIZE, DURATION This was a case-control study performed in 29 non-Hispanic white brothers of 22 women with PCOS and 18 control men. PARTICIPANTS/MATERIALS, SETTING, METHODS PCOS brothers and control men were of comparable age, weight and ethnicity. Adrenocorticotrophic hormone (ACTH) and GnRH agonist stimulation tests were performed. Gonadotrophin responses to GnRH agonist as well as changes in precursor-product steroid pairs (delta, Δ) across steroidogenic pathways in response to ACTH and GnRH agonist were examined. MAIN RESULTS AND THE ROLE OF CHANCE Basal total (T) levels did not differ, but dehydroepiandrosterone (DHEA) levels (0.13 ± 0.08 brothers versus 0.22 ± 0.09 controls, nmol/l, P = 0.03) were lower in brothers compared with control men. ACTH-stimulated Δ17-hydroxypregnenolone (17Preg)/Δ17-hydroxyprogesterone (17Prog) (7.8 ± 24.2 brothers versus 18.9 ± 21.3 controls, P = 0.04) and ΔDHEA/Δandrostenedione (AD) (0.10 ± 0.05 brothers versus 0.14 ± 0.08 controls, P = 0.04) were lower in brothers than in the controls. GnRH agonist-stimulated Δ17Prog/ΔAD (0.28 ± 8.47 brothers versus 4.79 ± 10.28 controls, P = 0.003) was decreased and luteinizing hormone (38.6 ± 20.6 brothers versus 26.0 ± 9.8 controls, IU/l, P = 0.02), follicle-stimulating hormone (10.2 ± 7.5 brothers versus 4.8 ± 4.1 controls, IU/l P = 0.002), AD (1.7 ± 1.4 brothers versus 0.9 ± 1.5 controls, nmol/l, P = 0.02) and ΔAD/ΔT (0.16 ± 0.14 brothers versus 0.08 ± 0.12 controls, P = 0.005) responses were increased in brothers compared with controls. LIMITATIONS, REASONS FOR CAUTION The modest sample size may have limited our ability to observe other possible differences in steroidogenesis between PCOS brothers and control men. WIDER IMPLICATIONS OF THE FINDINGS Decreased ACTH-stimulated Δ17Preg/Δ17Prog and ΔDHEA/ΔAD responses suggested increased adrenal 3β-hydroxysteroid dehydrogenase activity in the brothers. Decreased Δ17Prog/ΔAD and increased ΔAD/ΔT responses to GnRH agonist stimulation suggested increased gonadal 17,20-lyase and decreased gonadal 17β-hydroxysteroid dehydrogenase activity in the brothers. Increased LH and FSH responses to GnRH agonist stimulation suggested neuroendocrine alterations in the regulation of gonadotrophin secretion similar to those in their proband sisters. These changes in PCOS brothers may reflect the impact of PCOS susceptibility genes and/or programming effects of the intrauterine environment.

Original languageEnglish (US)
Pages (from-to)2764-2772
Number of pages9
JournalHuman Reproduction
Volume29
Issue number12
DOIs
StatePublished - Jun 26 2014

Fingerprint

Polycystic Ovary Syndrome
Gonadotropins
Siblings
Androstenedione
Gonadotropin-Releasing Hormone
17-alpha-Hydroxyprogesterone
Adrenocorticotropic Hormone
Dehydroepiandrosterone
17-alpha-Hydroxypregnenolone
3-Hydroxysteroid Dehydrogenases
Steroid 17-alpha-Hydroxylase
Dehydroepiandrosterone Sulfate
Inborn Genetic Diseases
Aptitude

Keywords

  • male phenotype
  • polycystic ovary syndrome
  • steroidogenesis
  • steroidogenic enzymes

ASJC Scopus subject areas

  • Rehabilitation
  • Obstetrics and Gynecology
  • Reproductive Medicine

Cite this

Liu, D. M., Torchen, L. C., Sung, Y., Paparodis, R., Legro, R. S., Grebe, S. K., ... Dunaif, A. (2014). Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome. Human Reproduction, 29(12), 2764-2772. https://doi.org/10.1093/humrep/deu282

Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome. / Liu, D. M.; Torchen, L. C.; Sung, Y.; Paparodis, R.; Legro, R. S.; Grebe, S. K.; Singh, Ravinder Jit; Taylor, R. L.; Dunaif, A.

In: Human Reproduction, Vol. 29, No. 12, 26.06.2014, p. 2764-2772.

Research output: Contribution to journalArticle

Liu, DM, Torchen, LC, Sung, Y, Paparodis, R, Legro, RS, Grebe, SK, Singh, RJ, Taylor, RL & Dunaif, A 2014, 'Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome', Human Reproduction, vol. 29, no. 12, pp. 2764-2772. https://doi.org/10.1093/humrep/deu282
Liu, D. M. ; Torchen, L. C. ; Sung, Y. ; Paparodis, R. ; Legro, R. S. ; Grebe, S. K. ; Singh, Ravinder Jit ; Taylor, R. L. ; Dunaif, A. / Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome. In: Human Reproduction. 2014 ; Vol. 29, No. 12. pp. 2764-2772.
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abstract = "STUDY QUESTION Are there abnormalities in gonadotrophin secretion, adrenal steroidogenesis and/or testicular steroidogenesis in brothers of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Brothers of women with PCOS have increased gonadotrophin responses to gonadotrophin releasing hormone (GnRH) agonist stimulation and alterations in adrenal and gonadal steroidogenesis. WHAT IS KNOWN ALREADY PCOS is a complex genetic disease. Male as well as female first-degree relatives have reproductive features of the syndrome. We previously reported that brothers of affected women have elevated circulating dehydroepiandrosterone sulfate levels. STUDY DESIGN, SIZE, DURATION This was a case-control study performed in 29 non-Hispanic white brothers of 22 women with PCOS and 18 control men. PARTICIPANTS/MATERIALS, SETTING, METHODS PCOS brothers and control men were of comparable age, weight and ethnicity. Adrenocorticotrophic hormone (ACTH) and GnRH agonist stimulation tests were performed. Gonadotrophin responses to GnRH agonist as well as changes in precursor-product steroid pairs (delta, Δ) across steroidogenic pathways in response to ACTH and GnRH agonist were examined. MAIN RESULTS AND THE ROLE OF CHANCE Basal total (T) levels did not differ, but dehydroepiandrosterone (DHEA) levels (0.13 ± 0.08 brothers versus 0.22 ± 0.09 controls, nmol/l, P = 0.03) were lower in brothers compared with control men. ACTH-stimulated Δ17-hydroxypregnenolone (17Preg)/Δ17-hydroxyprogesterone (17Prog) (7.8 ± 24.2 brothers versus 18.9 ± 21.3 controls, P = 0.04) and ΔDHEA/Δandrostenedione (AD) (0.10 ± 0.05 brothers versus 0.14 ± 0.08 controls, P = 0.04) were lower in brothers than in the controls. GnRH agonist-stimulated Δ17Prog/ΔAD (0.28 ± 8.47 brothers versus 4.79 ± 10.28 controls, P = 0.003) was decreased and luteinizing hormone (38.6 ± 20.6 brothers versus 26.0 ± 9.8 controls, IU/l, P = 0.02), follicle-stimulating hormone (10.2 ± 7.5 brothers versus 4.8 ± 4.1 controls, IU/l P = 0.002), AD (1.7 ± 1.4 brothers versus 0.9 ± 1.5 controls, nmol/l, P = 0.02) and ΔAD/ΔT (0.16 ± 0.14 brothers versus 0.08 ± 0.12 controls, P = 0.005) responses were increased in brothers compared with controls. LIMITATIONS, REASONS FOR CAUTION The modest sample size may have limited our ability to observe other possible differences in steroidogenesis between PCOS brothers and control men. WIDER IMPLICATIONS OF THE FINDINGS Decreased ACTH-stimulated Δ17Preg/Δ17Prog and ΔDHEA/ΔAD responses suggested increased adrenal 3β-hydroxysteroid dehydrogenase activity in the brothers. Decreased Δ17Prog/ΔAD and increased ΔAD/ΔT responses to GnRH agonist stimulation suggested increased gonadal 17,20-lyase and decreased gonadal 17β-hydroxysteroid dehydrogenase activity in the brothers. Increased LH and FSH responses to GnRH agonist stimulation suggested neuroendocrine alterations in the regulation of gonadotrophin secretion similar to those in their proband sisters. These changes in PCOS brothers may reflect the impact of PCOS susceptibility genes and/or programming effects of the intrauterine environment.",
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author = "Liu, {D. M.} and Torchen, {L. C.} and Y. Sung and R. Paparodis and Legro, {R. S.} and Grebe, {S. K.} and Singh, {Ravinder Jit} and Taylor, {R. L.} and A. Dunaif",
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T1 - Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome

AU - Liu, D. M.

AU - Torchen, L. C.

AU - Sung, Y.

AU - Paparodis, R.

AU - Legro, R. S.

AU - Grebe, S. K.

AU - Singh, Ravinder Jit

AU - Taylor, R. L.

AU - Dunaif, A.

PY - 2014/6/26

Y1 - 2014/6/26

N2 - STUDY QUESTION Are there abnormalities in gonadotrophin secretion, adrenal steroidogenesis and/or testicular steroidogenesis in brothers of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Brothers of women with PCOS have increased gonadotrophin responses to gonadotrophin releasing hormone (GnRH) agonist stimulation and alterations in adrenal and gonadal steroidogenesis. WHAT IS KNOWN ALREADY PCOS is a complex genetic disease. Male as well as female first-degree relatives have reproductive features of the syndrome. We previously reported that brothers of affected women have elevated circulating dehydroepiandrosterone sulfate levels. STUDY DESIGN, SIZE, DURATION This was a case-control study performed in 29 non-Hispanic white brothers of 22 women with PCOS and 18 control men. PARTICIPANTS/MATERIALS, SETTING, METHODS PCOS brothers and control men were of comparable age, weight and ethnicity. Adrenocorticotrophic hormone (ACTH) and GnRH agonist stimulation tests were performed. Gonadotrophin responses to GnRH agonist as well as changes in precursor-product steroid pairs (delta, Δ) across steroidogenic pathways in response to ACTH and GnRH agonist were examined. MAIN RESULTS AND THE ROLE OF CHANCE Basal total (T) levels did not differ, but dehydroepiandrosterone (DHEA) levels (0.13 ± 0.08 brothers versus 0.22 ± 0.09 controls, nmol/l, P = 0.03) were lower in brothers compared with control men. ACTH-stimulated Δ17-hydroxypregnenolone (17Preg)/Δ17-hydroxyprogesterone (17Prog) (7.8 ± 24.2 brothers versus 18.9 ± 21.3 controls, P = 0.04) and ΔDHEA/Δandrostenedione (AD) (0.10 ± 0.05 brothers versus 0.14 ± 0.08 controls, P = 0.04) were lower in brothers than in the controls. GnRH agonist-stimulated Δ17Prog/ΔAD (0.28 ± 8.47 brothers versus 4.79 ± 10.28 controls, P = 0.003) was decreased and luteinizing hormone (38.6 ± 20.6 brothers versus 26.0 ± 9.8 controls, IU/l, P = 0.02), follicle-stimulating hormone (10.2 ± 7.5 brothers versus 4.8 ± 4.1 controls, IU/l P = 0.002), AD (1.7 ± 1.4 brothers versus 0.9 ± 1.5 controls, nmol/l, P = 0.02) and ΔAD/ΔT (0.16 ± 0.14 brothers versus 0.08 ± 0.12 controls, P = 0.005) responses were increased in brothers compared with controls. LIMITATIONS, REASONS FOR CAUTION The modest sample size may have limited our ability to observe other possible differences in steroidogenesis between PCOS brothers and control men. WIDER IMPLICATIONS OF THE FINDINGS Decreased ACTH-stimulated Δ17Preg/Δ17Prog and ΔDHEA/ΔAD responses suggested increased adrenal 3β-hydroxysteroid dehydrogenase activity in the brothers. Decreased Δ17Prog/ΔAD and increased ΔAD/ΔT responses to GnRH agonist stimulation suggested increased gonadal 17,20-lyase and decreased gonadal 17β-hydroxysteroid dehydrogenase activity in the brothers. Increased LH and FSH responses to GnRH agonist stimulation suggested neuroendocrine alterations in the regulation of gonadotrophin secretion similar to those in their proband sisters. These changes in PCOS brothers may reflect the impact of PCOS susceptibility genes and/or programming effects of the intrauterine environment.

AB - STUDY QUESTION Are there abnormalities in gonadotrophin secretion, adrenal steroidogenesis and/or testicular steroidogenesis in brothers of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Brothers of women with PCOS have increased gonadotrophin responses to gonadotrophin releasing hormone (GnRH) agonist stimulation and alterations in adrenal and gonadal steroidogenesis. WHAT IS KNOWN ALREADY PCOS is a complex genetic disease. Male as well as female first-degree relatives have reproductive features of the syndrome. We previously reported that brothers of affected women have elevated circulating dehydroepiandrosterone sulfate levels. STUDY DESIGN, SIZE, DURATION This was a case-control study performed in 29 non-Hispanic white brothers of 22 women with PCOS and 18 control men. PARTICIPANTS/MATERIALS, SETTING, METHODS PCOS brothers and control men were of comparable age, weight and ethnicity. Adrenocorticotrophic hormone (ACTH) and GnRH agonist stimulation tests were performed. Gonadotrophin responses to GnRH agonist as well as changes in precursor-product steroid pairs (delta, Δ) across steroidogenic pathways in response to ACTH and GnRH agonist were examined. MAIN RESULTS AND THE ROLE OF CHANCE Basal total (T) levels did not differ, but dehydroepiandrosterone (DHEA) levels (0.13 ± 0.08 brothers versus 0.22 ± 0.09 controls, nmol/l, P = 0.03) were lower in brothers compared with control men. ACTH-stimulated Δ17-hydroxypregnenolone (17Preg)/Δ17-hydroxyprogesterone (17Prog) (7.8 ± 24.2 brothers versus 18.9 ± 21.3 controls, P = 0.04) and ΔDHEA/Δandrostenedione (AD) (0.10 ± 0.05 brothers versus 0.14 ± 0.08 controls, P = 0.04) were lower in brothers than in the controls. GnRH agonist-stimulated Δ17Prog/ΔAD (0.28 ± 8.47 brothers versus 4.79 ± 10.28 controls, P = 0.003) was decreased and luteinizing hormone (38.6 ± 20.6 brothers versus 26.0 ± 9.8 controls, IU/l, P = 0.02), follicle-stimulating hormone (10.2 ± 7.5 brothers versus 4.8 ± 4.1 controls, IU/l P = 0.002), AD (1.7 ± 1.4 brothers versus 0.9 ± 1.5 controls, nmol/l, P = 0.02) and ΔAD/ΔT (0.16 ± 0.14 brothers versus 0.08 ± 0.12 controls, P = 0.005) responses were increased in brothers compared with controls. LIMITATIONS, REASONS FOR CAUTION The modest sample size may have limited our ability to observe other possible differences in steroidogenesis between PCOS brothers and control men. WIDER IMPLICATIONS OF THE FINDINGS Decreased ACTH-stimulated Δ17Preg/Δ17Prog and ΔDHEA/ΔAD responses suggested increased adrenal 3β-hydroxysteroid dehydrogenase activity in the brothers. Decreased Δ17Prog/ΔAD and increased ΔAD/ΔT responses to GnRH agonist stimulation suggested increased gonadal 17,20-lyase and decreased gonadal 17β-hydroxysteroid dehydrogenase activity in the brothers. Increased LH and FSH responses to GnRH agonist stimulation suggested neuroendocrine alterations in the regulation of gonadotrophin secretion similar to those in their proband sisters. These changes in PCOS brothers may reflect the impact of PCOS susceptibility genes and/or programming effects of the intrauterine environment.

KW - male phenotype

KW - polycystic ovary syndrome

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