The human female reproductive (ovarian) cycle is initiated and regulated by gonadotrophic hormones. Day 1 of the cycle is characterized by commencement of menstruation: the discharge of fragments of the endometrium (wall of the womb) from the body, signifying fertilization has not occurred in the last cycle. At this stage, plasma levels of FSH and LH are low, but these begin to increase slowly over the subsequent 10-14 days.
During the first phase of the cycle, a group of follicles (each of which houses an egg) begins to develop and grow, largely under the influence of FSH. Shortly thereafter, a single dominant follicle normally emerges and the remainder regress. The growing follicle begins to synthesize oestrogens, which, in turn, trigger a surge in LH secretion at the cycle midpoint (day 14). A combination of elevated FSH and LH levels (along with additional factors such as prostaglan-din F2a) promotes follicular rupture. This releases the egg cell (ovulation) and converts the follicle into the progesterone-secreting follicular remnant: the corpus luteum. Release of the egg marks the end of the first half (follicular phase) of the cycle and the commencement of the second (luteal) phase.
In the absence of fertilization subsequent to ovulation, the maximum life span of the corpus luteum is 14 days, during which time it steadily regresses. This, in turn, promotes slowly decreasing levels of corpus luteum hormones, i.e. oestrogen and progesterone. Progesterone normally serves to prepare (thicken) the lining of the womb for implantation of an embryo should fertilization occur. Withdrawal of hormonal support as the corpus luteum regresses results in the shedding of the endometrial tissue, which marks commencement of the next cycle. However, if ovulation is followed by fertilization, then the corpus luteum does not regress but is maintained by hCG, synthesized in the placenta of pregnant females (Figure 11.B1).
heterodimeric hormones containing an identical a-polypeptide subunit and a unique Polypeptide subunit that confers biological specificity 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 a-subunit and Asn 7 and 24 of the P-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 a-subu-nits play an important role in dimer assembly and stability, as well as hormone secretion and possibly signal transduction. The sugars associated with the P-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 significance 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 influence 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 hormone, or LH/FSH-releasing factor).
FSH exhibits a molecular mass of 34 kDa. The a-subunit gene (containing four exons) is present on chromosome 6, and the P 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 disulfide bond formation. The a- and P-subunits combine non-covalently and appear to be stored in secretory vesicles separately to those containing LH. Although free a-subunits are also found within the pituitary, few P-subunits are present in unassociated form. Such free P-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 fluid, and granulosa-cell-derived oestrogens play multiple roles in sustaining and regulating female reproductive function.
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