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

Eriksson, Kerstin; Wide, Leif

doi:10.1210/jendso/bvaa128

Cited by 3 publications

(2 citation statements)

References 30 publications

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“…Progestins of the levonorgestrel family, commonly used for contraception in women, have a weak androgen effect [ 34 ]. We observed that the glycosylation and glycan modifications of the circulating LH and FSH molecules were of a similar nature in women using such progestins as those found in the present study for women with PCOS [ 35 ]. The progestin-treated women had a significantly increased LHdi serum concentration.…”

Section: Discussionsupporting

confidence: 68%

“…The progestin-treated women had a significantly increased LHdi serum concentration. The mean ratio of the low–N-glycosylated LH and FSH glycoforms, LHdi/FSHtri, was significantly elevated during progestin treatment compared with that of the follicular phase [ 35 ]. Furthermore, progestin treatment induced a significantly increased sialylation of LHdi, LHtri, and FSHtetra and decreased sulfonation of LHdi and LHtri that was similar to the findings for the group of women with PCOS.…”

Section: Discussionmentioning

confidence: 99%

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Low- and Fully N-Glycosylated Gonadotropins Circulating in Women With Polycystic Ovary Syndrome

Wide

Naessén

Sundström‐Poromaa

et al. 2021

Journal of the Endocrine Society

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Context A preponderance of basic luteinizing hormone (LH) molecules having elevated bioactivity was detected in the circulation of women with polycystic ovary syndrome (PCOS). Subsequent studies have shown that both LH and follicle-stimulating hormone (FSH) circulate as glycoforms differing in number of glycans: low-N-glycosylated glycoforms, LHdi and FSHtri, with high in-vitro bioactivity, and fully-glycosylated glycoforms, LHtri and FSHtetra, with high in-vivo bioactivity. Objective Characterize the glycosylation patterns on circulating gonadotropin glycoforms in women with PCOS. Design, Subjects, Main Outcome Measures Serum samples, collected from 8 women with PCOS were included. Concentration, sulfonation and sialylation of each glycoform were determined and compared with values of serum samples from healthy women: 22 women at follicular phase, 16 at mid- cycle and 15 after menopause. Results All the women with PCOS had higher LHdi serum levels compared with those of the follicular phase group. Median LHdi and median LHtri levels were significantly elevated in PCOS women. The percentage of LHdi was increased from 37 to 49 and that of FSHtri was decreased from 41 to 33. The LHdi, LHtri and FSHtetra glycoforms were more sialylated and both LH glycoforms less sulfonated in women with PCOS. Conclusions All women with PCOS had increased serum levels of LHdi, compared with those of follicular phase. The percentage of LHdi was increased and that of FSHtri decreased in women with PCOS. The increased LHdi leads to maintenance of the abnormal early follicular development of the polycystic ovary and the decreased FSHtri contributes to the arrested follicle growth.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Low- and Fully N-Glycosylated Gonadotropins Circulating in Women With Polycystic Ovary Syndrome

Wide

Naessén

Sundström‐Poromaa

et al. 2021

Journal of the Endocrine Society

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Hormonal and Allosteric Regulation of the Luteinizing Hormone/Chorionic Gonadotropin Receptor

Shpakov

2024

Front. Biosci. (Landmark Ed)

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Luteinizing hormone (LH) and human chorionic gonadotropin (CG), like follicle-stimulating hormone, are the most important regulators of the reproductive system. They exert their effect on the cell through the LH/CG receptor (LHCGR), which belongs to the family of G protein-coupled receptors. Binding to gonadotropin induces the interaction of LHCGR with various types of heterotrimeric G proteins (Gs, Gq/11, Gi) and β-arrestins, which leads to stimulation (Gs) or inhibition (Gi) of cyclic adenosine monophosphate-dependent cascades, activation of the phospholipase pathway (Gq/11), and also to the formation of signalosomes that mediate the stimulation of mitogen-activated protein kinases (β-arrestins). The efficiency and selectivity of activation of intracellular cascades by different gonadotropins varies, which is due to differences in their interaction with the ligand-binding site of LHCGR. Gonadotropin signaling largely depends on the status of N- and O-glycosylation of LH and CG, on the formation of homo- and heterodimeric receptor complexes, on the cell-specific microenvironment of LHCGR and the presence of autoantibodies to it, and allosteric mechanisms are important in the implementation of these influences, which is due to the multiplicity of allosteric sites in different loci of the LHCGR. The development of low-molecular-weight allosteric regulators of LHCGR with different profiles of pharmacological activity, which can be used in medicine for the correction of reproductive disorders and in assisted reproductive technologies, is promising. These and other issues regarding the hormonal and allosteric regulation of LHCGR are summarized and discussed in this review.

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Multiple mechanisms of allosteric regulation of the luteninizing hormone receptor

Shpakov,

Derkach

2024

Uspehi fiziologičeskih nauk

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The regulatory effects of luteinizing hormone (LH) and chorionic gonadotropin (CG) are realized through the activation of the G-protein coupled LH/CG receptor (LH/CG-R). The result of this is the activation of various types of G proteins, which leads to stimulation (Gs) or inhibition (Gi) of the cAMP-dependent pathway and stimulation of calcium signaling (Gq/11, Gi), and the recruitment of β-arrestins, which prevent G protein signaling through receptor internalization and downregulation, but can also activate the mitogen-activated protein kinase cascade. Despite a certain similarity in the effects of LH and CG, there are differences between them both in efficiency and in the pattern of regulation of LH/CG-R. This is a consequence of differences in the affinity of LH and CG to the orthosteric site of the receptor, as well as differences at the level of allosteric regulation of the receptor, which is due to the presence of a C-terminal extension in the β-subunit of CG, including sites for O-glycosylation, and the variability of N-glycosylation of α- and β-subunits of gonadotropins. Moreover, the number of N-glycans, the degree of their branching and charge differ, which leads to different efficiency of activation of intracellular cascades, affecting the physiological response of the reproductive system to gonadotropins. Of great importance is the formation of homodi(oligo)meric complexes of LH/CG-R and its heterocomplexes with the follicle-stimulating hormone receptor, where protomers allosterically influence the efficiency of LH/CG-R activation and the bias of signal transduction. Taking into account the large number of allosteric sites in LH/CG-R, the development of low-molecular allosteric regulators is underway, including agonists based on thieno[2,3-d]-pyrimidine and peptides derived from the cytoplasmic loops of LH/CG-R. These regulators can become prototypes of drugs for correcting the functions of the reproductive system. This review is devoted to the analysis of data on the similarities and differences in the signaling and physiological effects of gonadotropins with LH activity, the role of allosteric mechanisms in this, and the prospects for creating allosteric regulators of LH/CG-R.

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

Cited by 3 publications

References 30 publications

Low- and Fully N-Glycosylated Gonadotropins Circulating in Women With Polycystic Ovary Syndrome

Low- and Fully N-Glycosylated Gonadotropins Circulating in Women With Polycystic Ovary Syndrome

Hormonal and Allosteric Regulation of the Luteinizing Hormone/Chorionic Gonadotropin Receptor

Multiple mechanisms of allosteric regulation of the luteninizing hormone receptor

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