Potential regulation of GnRH gene by a steroidogenic factor-1-like protein.

Steroidogenic factor-1 (SF-1) is a member of an orphan nuclear hormone receptor superfamily. It plays a critical role in the development and function of the hypothalamic-pituitary-gonadal and adrenal axis. However, whether SF-1 can regulate transcription of gonadotrophin-releasing hormone (GnRH) gene is not known. To examine this possibility, we first over-expressed SF-1 and found that it not only decreased steady state GnRH messenger ribonucleic acid (mRNA) levels but also reduced its promoter activity in GT1-7 neurons. The inhibitory effect of SF-1 was lost when the 5'-flanking region of GnRH gene containing two distal (-1479 to -1474 bp and -1059 to -1054 bp) hexamers was deleted. Gel mobility shift assays showed that GT1-7 cell nuclear extracts contained a protein that formed a specific complex with synthetic oligonucleotides containing the two distal hexamers or a consensus SF-1 binding sequence. The migration of this complex was, however, slower than the complex formed with MA-10 cell nuclear extracts which were shown to contain a 53 kDa SF-1 protein. The addition of anti-SF-1 antibody supershifted the complex formed with MA-10, but not with GT1-7 cell nuclear extracts. The same antibody, however, detected a 60 kDa protein and immunostained nuclei of GT1-7 neurons. These results are consistent with GT1-7 neurons containing an SF-1-like protein that can bind to the distal hexamer sequences in the 5'-flanking region of rat GnRH gene to inhibit its transcription.

Short term treatment with leuprolide acetate is a successful adjunct to surgical therapy of leiomyomas of the uterus.

Gonadotropin releasing hormone analogs (GnRHa) have been used to induce a reduction in the size of leiomyomas of the uterus after three to six months of therapy. However, none of the studies have noted a significant decrease in size by the first month. Additionally, the results of two reports have suggested long term therapy with GnRHa induced significant aberrations of serum lipoproteins. To evaluate whether or not analog treatment for a short course (two months) would be efficacious, 27 patients with leiomyomas documented by examination of the pelvic area and vaginal ultrasound, who desired to preserve reproductive potential, had myomectomies two and one-half months after commencing depot leuprolide acetate therapy. The reduction in size of the uterus was 35 percent by the first month and the average reduction in the total volume was 44 percent after two months of treatment (474 +/- 364 to 265 +/- 173 milliliters; p less than 0.01). Furthermore, the size of the uterus, determined by examination, decreased significantly from 13.6 +/- 4.0 weeks initially to 10.1 +/- 3.0 weeks preoperatively (p less than 0.0001). Estradiol levels became menopausal by one month of therapy and remained suppressed preoperatively. Menopausal symptoms were well tolerated. Cholesterol, high density lipoprotein, extremely low density lipoprotein and triglyceride levels were not altered by analog treatment, although low density lipoprotein increased from 117 to 130 milligrams per deciliter. A short course of depot leuprolide acetate reduced the size of leiomyomas and surgical tissue planes were preserved, facilitating removal of leiomyomas, and furthermore, there was no significant clinical alteration in lipoprotein or triglyceride levels.