Low-glycosylated forms of both FSH and LH play major roles in the natural ovarian stimulation

Abstract

BackgroundThe natural ovarian stimulation is mediated by four gonadotrophin glycoforms: FSHtri with three, FSHtetra with four, LHdi with two, and LHtri with three N-glycans. The aim of the study was to determine the serum concentrations of the four glycoforms and their contents of anionic monosaccharides (AMS), i.e. sialic acid (SA) and sulfonated N-acetylgalactosamine (SU) residues throughout the menstrual cycle.MethodsSerum samples were collected from 78 healthy women with regular menstrual cycles. The serum glycoform molecules were identified by their distributions at electrophoreses. Analyses were also performed after removal of terminal SA. The hormones were measured with time-resolved sandwich fluoroimmunoassays.ResultsThe concentration profiles of the four glycoforms were markedly different. FSHtri, which had a 3-fold higher biopotency than FSHtetra, had peak levels on cycle day 5 and at midcycle and nadirs on cycle days 9 and 21–23. FSHtetra had a raised level on cycle days 5–12, followed by a decrease. LHdi and LHtri had similar patterns, but the peak/nadir ratio was much more pronounced for LHdi than for LHtri, 18 versus 4. The numbers of SA residues per molecule were at a maximum around midcycle when the corresponding numbers of SU were at a minimum. The SU/SA ratio was at a minimum on cycle day 12.ConclusionThe results indicate that the LHdi and the FSHtri molecules play major roles in the natural ovarian stimulation. The SU/SA ratios per molecule favoured a prolonged circulatory half-life of all glycoforms at the midcycle phase. The observations may lead to more successful inductions of ovulation in anovulatory women.

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

“…A reference group of follicular phase values from normal menstrual cycles comprised the results of analyses of one serum sample from each of 26 medical students taken on days 1 to 11 of the cycle. This follicular phase group was derived from a previously reported study on 78 healthy medical students having normal menstrual cycles [ 11 ]. The follicular phase serum samples were obtained in parallel with those of the present study and the analytical methods used were identical.…”

“…We have found that all 3 pituitary glycoprotein hormones, FSH, luteinizing hormone (LH), and thyrotropin (thyroid-stimulating hormone; TSH) circulate in blood as low-N-glycosylated and fully N-glycosylated forms differing in total number of glycans: FSHtri and FSHtetra; LHdi and LHtri; and TSHdi and TSHtri, respectively [ 10 ]. The low N-glycosylated forms of both FSH and LH play major roles in the natural ovarian stimulation [ 11 ]. The degrees of sialylation and sulfonation of the N-glycans differ with the phases of the menstrual cycle, after menopause, and in women with polycystic ovary syndrome [ 11 , 12 ].…”

“…The low N-glycosylated forms of both FSH and LH play major roles in the natural ovarian stimulation [ 11 ]. The degrees of sialylation and sulfonation of the N-glycans differ with the phases of the menstrual cycle, after menopause, and in women with polycystic ovary syndrome [ 11 , 12 ]. The low-N-glycosylated forms of FSH, LH, and TSH are less sialylated and such molecules exhibit a higher bioactivity at the target cells compared with the more sialylated fully N-glycosylated forms [ 13-24 ].…”

New Human Follitropin Preparations: How Glycan Structural Differences May Affect Biochemical and Biological Function and Clinical Effect

“…Ironically, in the endeavor to reach the high bar, the physiological is subverted. That is because glycosylation of the naturally occurring FSH secreted from the pituitary is complex and varies with age and menstrual cycle stage ( 86 , 93 ). Capitalizing on this observation, attempts are underway to specifically and intentionally prepare recombinant preparations of FSH that represent FSH glycoforms predominantly observed in younger women ( 77 ).…”

Discovery and Preclinical Development of Orally Active Small Molecules that Exhibit Highly Selective Follicle Stimulating Hormone Receptor Agonism

“…Orally active gonadotropin agonists are anticipated to provide measurable benefits for patients that include: a) faster elimination of small molecules from blood (predicted 5–9 h) than injectable high sialic acid-glycosylated gonadotropins (9–24 h) ( le Contonnec et al, 1994 ; Wide and Eriksson, 2013 ; Bousfield et al, 2018 ; Wide and Eriksson, 2018 ; Riccetti et al, 2019 ) or clomiphene (72 + h ) ( Ghobadi et al, 2009 ); b) greater predictability of individual patient responses to the same molecule as patients transition from low dose, low complexity OI-IUI cycles into higher dose, COS-IVF cycles; c) direct action of FSHR-AA on FSHR, compared to CC and aromatase inhibitors which depend on the integrity of the hypothalamic-pituitary-ovarian axis; d) absence of compromise to endometrial implantation when compared to CC ( Chen et al, 2016 ; Mehdinejadiani et al, 2019 ) and e) small molecule gonadotropin agonists work at the FSH receptor independent of the glycosylation of endogenous FSH that varies over the menstrual cycle ( Bousfield et al, 2018 ; Wide and Eriksson, 2018 ) and among glycoprotein hormone preparations of FSH ( Wide and Eriksson, 2013 ; Riccetti et al, 2019 ). It is anticipated that these benefits can deliver improvements in stimulation outcomes and as a result, reduced time for patients to achieve a live birth.…”