Ragoobir, Jennifer; (1999) Lipoproteins and Progesterone biosynthesis in the human ovary. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The highly vascularised ovarian luteal tissue is exposed to high-density lipoproteins (HDLs), and low-density lipoproteins (LDLs) in vivo. LDLs have been shown to stimulate human ovarian steroidogenesis, however the effects of HDLs on progesterone production remain unclear. The present study investigates a role for HDLs in progesterone synthesis by human granulosa-lutein cells, and assesses the effects of lipoprotein oxidation on the steroidogenic responses to HDLs and LDLs. Human follicular fluid contained HDLs with a lower cholesterol content, and a lower proportion of apolipoprotein E containing particles compared to plasma HDLs. Despite these differences, HDLs (intrafollicular fluid and plasma), and LDLs significantly stimulated progesterone production by granulosa-lutein cells. The progesterone responses to HDLs and LDLs were unaffected by protein kinase C down-regulation. However, HDLs and LDLs increased cAMP accumulation, and synergised with maximally effective concentrations of hCG and dibutyryl cAMP to increase progesterone production by granulosa-lutein cells over 24h. The HDL/LDL-hCG interactions required 24h incubation regardless of whether cells were exposed simultaneously, or in sequence to hCG and HDL/LDL. At equal cholesterol content, HDLs increased progesterone production to a greater extent that LDLs, suggesting that the progesterone response to HDLs may involve mechanisms other than cholesterol delivery. In keeping with this proposal, HDLs interacted synergistically with maximally effective concentrations of 22R- hydroxycholesterol. Moreover, increased concentrations of prostaglandin E2, cAMP and progesterone by granulosa-lutein cells, in response to HDLs, were abolished in the presence of a prostaglandin H synthase inhibitor. Human follicular fluids contained oxidatively modified HDL, despite having high antioxidant concentrations. Regarding the consequence of lipoprotein oxidation, lipoproteins oxidised in vitro, did not interact synergistically with hCG to increase progesterone production. Moreover, the effects of oxidised lipoproteins were unaffected by leucocyte-depletion of granulosa-lutein cells. While native HDLs and LDLs support progesterone production in vitro, the physiological significance of native and oxidised lipoproteins in vivo, remains to be elucidated.

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