Biomedical Engineering Reference
In-Depth Information
-polypep-
tide subunit that confers biological specifi city to each gonadotrophin. In each case, both subunits
of the mature proteins are glycosylated. Human FSH displays four N-linked (asparagines or Asn-
linked) glycosylation sites, located at positions Asn 52 and 78 of the
heterodimeric hormones containing an identical
α
-polypeptide subunit and a unique
β
α
-subunit and Asn 7 and 24
of the
-subunit. Some 30 per cent of the hormone's overall molecular mass is accounted for by its
carbohydrate component. Structurally, the attached oligosaccharides are heterogeneous in nature,
varying in particular in terms of the content of sialic acid residues and sulfate groups present.
This represents the structural basis of the charge heterogeneity characteristic of this (and other)
gonadotrophins.
The oligosaccharide components play a direct and central role in the biosynthesis, secretion,
serum half-life and potency of the gonadotrophins. The sugar components attached to the
β
-subu-
nits play an important role in dimer assembly and stability, as well as hormone secretion and pos-
sibly signal transduction. The sugars associated with the
α
-subunit, while contributing to dimer
assembly and secretion, appear to play a more prominent role in clearance of the hormone from
circulation.
The functional effects of glycosylation take on added signifi cance in the context of producing
gonadotrophins by recombinant means. As discussed subsequently, several are now produced for
clinical application in recombinant (animal cell line) systems. Although the glycosylation patterns
observed on the recombinant molecules can vary somewhat in composition from those associated
with the native hormone, these slight differences bear no negative infl uence upon their clinical
applicability.
The synthesis and release of both FSH and LH from the pituitary is stimulated by a hypotha-
lamic peptide, gonadotrophin-releasing hormone (also known as gonadorelin, LH-releasing hor-
mone, or LH/FSH-releasing factor).
FSH exhibits a molecular mass of 34 kDa. The
β
α
-subunit gene (containing four exons) is present
gene (three exons) is found on chromosome 11. mRNA coding for
both sununits is translated separately on the rough endoplasmic recticulum, followed by removal of
their signal peptides upon entry into the endoplasmic recticulum. N-linked glycosylation also takes
place, as does intrachain disulfi de bond formation. The
on chromosome 6, and the
β
-subunits combine non-covalently
and appear to be stored in secretory vesicles separately to those containing LH. Although free
α
α
- and
β
-subunits are also found within the pituitary, few
β
-subunits are present in unassociated form.
Such free
-subunits are rapidly degraded.
The major FSH target in the male is the Sertoli cells, found in the walls of the seminiferous
tubules of the testis. They function to anchor and nourish the spermatids, which subsequently are
transformed into spermatozoa during the process of spermatogenesis. Sertoli cells also produce
inhibin (discussed later), which functions as a negative feedback regulator of FSH. The major
physiological effect of FSH in the male is thus sperm cell production.
In the female, FSH mainly targets the granulosa cells of the ovarian follicle (Box 11.4). FSH
exhibits a mitogenic effect upon these cells, stimulating their division and, hence, follicular growth
and development. This activity is enhanced by the paracrine action of locally produced growth
factors. FSH also triggers enzymatic production of glycosaminoglycans, as well as expression
of aromatase and other enzymes involved in oestrogen synthesis. Glycosaminoglycans form an
essential component of the follicular fl uid, and granulosa-cell-derived oestrogens play multiple
roles in sustaining and regulating female reproductive function.
β
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