Effects of 17β-oestradiol and norethisterone acetate on sulfonation and sialylation of gonadotrophins in post-menopausal women

Abstract

BackgroundThe number of terminal sialic acid and sulfonated N-acetylgalactosamine (SO3-GalNAc) on gonadotrophins in serum varies during the menstrual cycle and changes at menopause, suggesting that gonadal steroids modify their oligosaccharide synthesis. Our objective was to determine the effects of 17β-oestradiol (E2) and a progestogen, norethisterone acetate (NETA), on the sulfonation and sialylation of gonadotrophins in post-menopausal women.MethodsSerum samples were obtained from eight post-menopausal women treated with 20 mg E2 implants every 6 months, from four women who in addition were treated daily with 5 mg NETA orally for a 2-week period, and from four women who got this NETA treatment during a 4-week period. Sera from 11 non-treated post-menopausal women served as a reference group. The gonadotrophin serum concentrations, the number of SO3-GalNAc and sialic acid residues per serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) molecule, and the distributions of molecules with 0-1-2-3-4 sulfonated residues were measured.ResultsThe E2-treated post-menopausal women had considerably less (P < 0.001) sialic acid and slightly more (P < 0.01) SO3-GalNAc per serum LH and FSH molecule than the non-treated. Two weeks of NETA treatment increased the sulfonation of LH (P < 0.01) and FSH (P < 0.05) concomitantly with decreased (P < 0.05) sialylation of LH.ConclusionThe primary effect of E2 treatment was a decrease in sialylation and, due to competition for the same substrate, a secondary and consequentially minor increase in sulfonation of LH and FSH. The primary effect of the NETA therapy was an increase in the sulfonation of LH and FSH concomitantly with secondary and consequentially decreases in sialylation of LH.

Gonadotropin Glycoforms Circulating in Women Using Progestins of the Levonorgestrel Family for Contraception

“…The progestin+EE treatment decreased the mean levels of FSHtri, FSHtetra, and LHtri compared with the mean values of the follicular phase and decreased the sialylation of FSHtri. The decreased sialylation of FSH by the EE treatment is in agreement with previously observed effects of 17β-estradiol in postmenopausal women [ 31 ]. The low degree of sialylation of FSHtri molecules during the 28-day treatment cycle is expected to contribute to the low mean serum level of the FSHtri glycoform during this treatment.…”

Dynamic changes in glycosylation and glycan composition of serum FSH and LH during natural ovarian stimulation

“…Administration of 17β-oestradiol and progestogen preparations to postmenopausal women has been shown to change the contents of SA and SU residues per molecule on both FSH and LH in serum (40). This suggested steroid effects on the enzymes in the trans-Golgi of the pituitary gonadotrophin-producing cells.…”

What is the Clinical Relevance of Follicle-Stimulating Hormone Isoforms in Fertility Treatment?

“…29 Recent studies have shown that estradiol administered to postmenopausal women shifts pituitary FSH release to more basic FSH isoforms compared with non-treated women. 28 Thus, in addition to the fine-tuned interplay between the selected developing follicle and pituitary release of gonadotrophins, it appears that the follicle is capable also of directing the isoform profile released.…”

“…The selected follicle vastly increases its capacity to produce estradiol; shortly after selection, .90% of the estradiol present in the body is derived from this follicle. 28 Recent evidence suggests that the estradiol secreted by this follicle plays an important role in directing the pituitary output of FSH isoforms. 28 Pituitary expression of different glycosyl transferases, including 2,3 α-sialyltransferase (an enzyme that catalyses the incorporation of sialic acid residues into sugar residues attached to the FSH molecule), is down-regulated by estradiol.…”

“…28 Recent evidence suggests that the estradiol secreted by this follicle plays an important role in directing the pituitary output of FSH isoforms. 28 Pituitary expression of different glycosyl transferases, including 2,3 α-sialyltransferase (an enzyme that catalyses the incorporation of sialic acid residues into sugar residues attached to the FSH molecule), is down-regulated by estradiol. 29 Recent studies have shown that estradiol administered to postmenopausal women shifts pituitary FSH release to more basic FSH isoforms compared with non-treated women.…”