Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex
Jukka Kero, Matti Poutanen, Fu-Ping Zhang, Nafis Rahman, Anne Marie McNicol, John H. Nilson, Ruth A. Keri, Ilpo T. Huhtaniemi
Jukka Kero, Matti Poutanen, Fu-Ping Zhang, Nafis Rahman, Anne Marie McNicol, John H. Nilson, Ruth A. Keri, Ilpo T. Huhtaniemi
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Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex

Abstract

Transgenic (TG) female mice expressing bLHβ-CTP (a chimeric protein derived from the β-subunit of bovine luteinizing hormone [LH] and a fragment of the β-subunit of human chorionic gonadotropin [hCG]) exhibit elevated serum LH, infertility, polycystic ovaries, and ovarian tumors. In humans, increased LH secretion also occurs in infertility and polycystic ovarian syndrome, often concomitant with adrenocortical dysfunction. We therefore investigated adrenal function in LH overexpressing bLHβ-CTP female mice. The size of their adrenals was increased by 80% with histological signs of cortical stimulation. Furthermore, adrenal steroid production was increased, with up to 14-fold elevated serum corticosterone. Primary adrenal cells from TG and control females responded similarly to ACTH stimulation, but, surprisingly, the TG adrenals responded to hCG with significantly increased cAMP, progesterone, and corticosterone production. LH receptor (LHR) expression and activity were also elevated in adrenals from female TG mice, but gonadectomized TG females showed no increase in corticosterone, suggesting that the dysfunctional ovaries of the intact TG females promote adrenocortical hyperfunction. We suggest that, in intact TG females, enhanced ovarian estrogen synthesis causes increased secretion of prolactin (PRL), which elevates LHR expression. Chronically elevated serum LH, augmented by enhanced PRL production, induces functional LHR expression in mouse adrenal cortex, leading to elevated, LH-dependent, corticosterone production. Thus, besides polycystic ovaries, the bLHβ-CTP mice provide a useful model for studying human disorders related to elevated LH secretion and adrenocortical hyperfunction.

Authors

Jukka Kero, Matti Poutanen, Fu-Ping Zhang, Nafis Rahman, Anne Marie McNicol, John H. Nilson, Ruth A. Keri, Ilpo T. Huhtaniemi

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Age-dependent upregulation of LHR mRNA expression occurs in bLHβ-CTP fem...
Age-dependent upregulation of LHR mRNA expression occurs in bLHβ-CTP female mice, but not in control or gonadectomized TG or non-TG mice. Northern hybridization analysis for LHR mRNA was carried out using total RNA (20 μg/lane) isolated from adrenal glands of nontransgenic and bLHβ-CTP female mice, at ages 1, 3, and 5 months. RNAs from kidney and testis were used as negative and positive controls, respectively. The molecular sizes of the major LHR mRNA transcripts, as well as the location of the 28 S and 18 S ribosomal RNAs, are indicated. (a) In 3- and 5-month-old bLHβ-CTP female adrenals, a clear hybridization signal with LHR cRNA probe can be seen. (b) Hybridization between LHR cRNA probe and adrenal gland RNA from 5-month-old gonadectomized and nongonadectomized bLHβ-CTP and non-TG mice. (Below a and b, ethidium bromide staining of 28 S ribosomal RNA, used as loading control, is shown.)