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The functional effects of glycosylation take on added significance in the context of producing gonadotrophins by recombinant means. As subsequently discussed, several are now produced for clinical application in recombinant (animal cell line) systems. While 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 hypothalmic peptide, gonadotrophin-releasing hormone (GnRH, also known as gonadorelin, luteinizing hormone-releasing hormone (LHRH), 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, while the b 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 intra-chain disulphide bond formation. The a- and b-subunits combine non-covalently and appear to be stored in secretory vesicles, separately to those containing LH. While free a-subunits are also found
HORMONES OF THERAPEUTIC INTEREST 333
Box 8.4. An overview of the female reproductive cycle
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 that 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 prostaglandin F2a) promotes follicular rupture. This releases the egg cell (ovulation) and converts the follicle into the progesterone-secreting follicular reminant, the corpus luteum (CL). 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 CL hormones — 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 CL regresses results in the shedding of the endometrial tissue, which marks commencement of the next cycle. However, if ovulation is followed by fertilization, the CL does not regress but is maintained by hCG, synthesized in the placenta of pregnant females.
Changes in plasma FSH (a) and LH (b) levels during the reproductive cycle of a healthy human female. Reproduced by permission of John Wiley & Sons Ltd from Walsh & Headon (1994)
within the pituitary, few b-subunits are present in unassociated form. Such free b-subunits are rapidly degraded.
The major FSH target in the male are the Sertoli cells, found in the walls of the seminiferous tubules of the testis. They function to anchor and nourish the spermatids, which are subsequently 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.
Box 8.5. Female follicular structure
The major female reproductive organs are a pair of ovaries, situated in the lower abdomen. At birth, each ovary houses approximately 1 million immature follicles. Each follicle is composed of an egg cell (ovum) surrounded by two layers of cells; an inner layer of granulosa cells and an outer layer of theca cells. During the follicular phase of the female reproductive cycle (Box 8.3), a group of follicles (ca. 20), approximately 5 mm in diameter, are recruited by FSH (i.e. they begin to grow). FSH targets the granulosa cells, prompting them to synthesize oestrogen. The dominant follicle continues to grow to a diameter of 20-25 mm. At this stage, it contains a fluid-filled cavity with the ovum attached to one side. Ovulation is characterized by bursting of the follicle and release of the ovum.
Typically, 400 follicles will mature and fully ovulate during an average woman’s reproductive lifetime. The remaining 99.98% of her follicles begin to develop but regress due to inadequate FSH stimulation. The molecular detail of how FSH (and LH) promote follicular growth is described in the main body of the text.