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Molecular basis of gonadotrophin action on human granulosa cell function
E L Yong1, M Turner, D T Baird
1Department of Obstetrics and Gynaecology, National University Hospital, Singapore.
Abstract:
We studied in vitro the effects of Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) on: 1) mature human granulosa cell proliferation and steroidogenesis; 2) intra-cellular second messenger (cAMP) generation, and the effects of cAMP analogues on cell function; and 3) mRNA expression of the rate limiting enzymes for progesterone and oestradiol synthesis namely: Cholesterol side chain cleavage (P450 SCC), Aromatase (P450 Arom); and 4) LH receptor mRNA expression. FSH maintained or stimulated, whereas LH markedly inhibited, basal granulosa cell proliferation. Steroidogenesis (oestradiol and progesterone production) was dose dependently increased by both gonadotrophins; with LH having the greater effect. However, only LH was able to induce maximal progesterone production. FSH generated about ten fold less cAMP than LH; and low and high doses of cAMP analogue were able to mimic FSH and LH effects respectively. Northern analyses showed that both FSH and LH were able to induce maximal P450 Arom mRNA expression, whereas only LH could stimulate maximal P450 SCC mRNA transcription. Maximal P450 Arom mRNA expression was associated with less cAMP generation than for P450 SCC. LH-R mRNA expression was induced by FSH but the strongest stimulatory effect was with LH. These results indicate that: 1) FSH and LH have markedly different effects on mature granulosa cell function; 2) the differential action of FSH and LH are dose dependently mediated through intracellular cAMP; 3) mRNA expression of P450 SCC and P450 Arom are differentially regulated by gonadotrophins and intracellular cAMP; and 4) LH was the most potent inducer of its own receptor mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) impact granulosa cell proliferation and steroidogenesis differently, mediated by intracellular cAMP levels. These hormones differentially regulate key enzyme mRNA for steroid synthesis and their own receptor expression.
Area of Science:
- Reproductive Endocrinology
- Molecular Biology
- Cellular Signaling
Background:
- Granulosa cells are crucial for ovarian function, responding to gonadotropins like FSH and LH.
- Understanding the distinct roles of FSH and LH in granulosa cells is vital for reproductive health research.
Observation:
- FSH and LH exhibit opposing effects on granulosa cell proliferation but both stimulate steroidogenesis.
- Gonadotropin action is mediated by intracellular cyclic AMP (cAMP) generation, with varying potencies.
- Both hormones influence mRNA expression of key steroidogenic enzymes (P450 SCC, P450 Arom) and the LH receptor (LH-R).
Findings:
- FSH and LH exert differential effects on mature human granulosa cell proliferation and function.
- The distinct actions of FSH and LH are dose-dependently mediated via intracellular cAMP.
- FSH and LH differentially regulate mRNA expression of P450 SCC and P450 Arom, influenced by cAMP levels.
- LH is a more potent inducer of its own receptor mRNA expression compared to FSH.
Implications:
- FSH and LH play distinct roles in regulating granulosa cell activity and steroidogenesis.
- Intracellular cAMP is a key mediator of differential gonadotropin signaling in granulosa cells.
- Targeting these pathways could offer new strategies for fertility treatments and reproductive disorder management.