Gonadotropin-Releasing Hormone Desensitization Preferentially Inhibits Expression of the Luteinizing Hormone β-Subunit Genein Vivo

Abstract

In this study we investigated changes in steady state cytoplasmic mRNA levels for LH subunits in pituitaries of male rats desensitized by continuous infusion of GnRH in vivo. Seven days of GnRH infusion (340 micrograms/day) reduced (P less than 0.01) LH beta mRNA levels in intact adult male rats and prevented the LH beta mRNA rise observed after castration. In contrast, common alpha mRNA doubled (P less than 0.05) in intact rats, and the elevated alpha mRNA after 7 days castration was unchanged. Serum and pituitary LH levels were suppressed below values of intact controls. Fourteen days of GnRH infusion (290 micrograms/day) further reduced LH beta mRNA levels in both intact and castrated male rat pituitaries. alpha mRNA levels in intact rat pituitaries were unchanged by 14 days of GnRH infusion, while in castrated rats there was a 23% (P less than 0.05) decrease, though values were still twice those of intact controls. As at 7 days, serum and pituitary LH were suppressed. Infusion of a superagonist analog (Buserelin) at a dose of 14 micrograms/day for 28 days reduced LH beta mRNA to 15% of intact control values in both castrated and intact rats. Common alpha mRNA was significantly (P less than 0.05) increased in intact rats and reduced by 13% (P less than 0.05) in castrates by superagonist infusion. These results were similar to those produced by 20- to 30-fold higher doses of native GnRH. GnRH and agonist analog effects were specific since no changes were observed in other mRNA species (GH, PRL, actin). These results indicate that in GnRH-desensitized gonadotropes LH beta gene expression is inhibited, and this may largely explain the reduced LH biosynthesis. However, there is a differential effect of continuous GnRH or agonist analog treatment on LH subunit gene expression, with a time-dependent stimulation of common alpha gene expression in intact rats. This may be caused by a stimulatory interaction between GnRH and progestagens at the level of the gonadotrope. Thus, common alpha gene expression is less tightly coupled than that of LH beta to GnRH action.

Alterations in the Postovariectomy Increases in Gonadotropin Secretion in Middle-Aged Persistent-Estrous Rats: Correlation with Pituitary Gonadotropin Subunit Gene Expression

“…Prior to OVX, se rum LH concentrations and pituitary LH contents were similar between these two age groups, while the LHp mRNA expression was significantly lower in middle-aged PE rats. From these data it would appear that LHp mRNA expression is tonically decreased in PE rats, and similar findings have been recently reported in studies on aged fe male rats [17], Hypothalamic secretion o f gonadotropin releasing hormone has been shown to be important in regulating pituitary LHp mRNA expression in which pul satile administration is required [18][19][20][21], Several lines o f evidence have suggested that in middle-aged PE rats, hy pothalamic gonadotropin-releasing hormone pulse fre quency and amplitude are decreased [22,23], and the present findings demonstrating low LHp mRNA expres sion in PE rats would be compatible with this hypothesis. Previous studies have characterized the cyclic changes in pituitary LHp mRNA expression during the estrous cycle, with increased expression beginning early on proestrus afternoon [24], In the present study, the pituitary LHP mRNA expression in young rats at 12.00 h on proestrus (day 0) was significantly greater than that in middle-aged PE females.…”

The GnRH receptor and the response of gonadotrope cells to GnRH pulse frequency code. A story of an atypical adaptation of cell function relying on a lack of receptor homologous desensitization.

“…On the other hand, sustained GnRH causes a more or less rapid depletion of both FSHβ and LHβ mRNA due to transcription arrest associated with transcript degradation. Contrasting with β-counterparts, the α-subunit mRNA levels remain essentially constant or even increases slightly for days [8][9][10]. These observations are consistent with current clinical studies showing that long-term administration of GnRH superagonists readily induced depletion of LH and FSH but increased free α-subunit levels in the serum of treated patients [11].…”

Gonadotropin-releasing hormone and the control of gonadotrope function

“…Indeed, low frequencies in the range one stimulus every two or four hours appear to preferentially increase FSHβ mRNA levels whereas higher frequencies preferentially stimulate LHβ and α subunit mRNA [13,14]. In vivo, permanent exposure to GnRH leads to a more or less rapid depletion of both FSHβ and LHβ mRNA in a manner that suggests a rapid transcription arrest followed by RNA degradation, while the α-subunit mRNA [15][16][17]. The latter data are consistent with current clinical studies showing that long-term administration of GnRH superagonists induces depletion of LH and FSH but increases free α-subunit levels in the serum of treated patients [18].…”