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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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Theca cells Fluid-filled sac
Ovum
Granulosa cell
5 mm
25 mm
Immature follicle
Mature follicle prior to ovulation
HORMONES OF THERAPEUTIC INTEREST 335
In the female, FSH mainly targets the granulosa cells of the ovarian follicle (Box 8.5). 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 (GAGs), as well as expression of aromatase and other enzymes involved in oestrogen synthesis. GAGs form an essential component of the follicular fluid, while granulosa cell-derived oestrogens play multiple roles in sustaining and regulating female reproductive function.
Prior to puberty, serum FSH levels are insufficient to promote follicular recruitment and development. Subsequent to puberty, as a group of follicles begin to develop at the beginning of a cycle, the one that is most responsive to FSH (i.e. displays the lowest FSH threshold) becomes the first to secrete oestrogen. As one effect of oestrogen is to suppress FSH release from the pituitary, blood FSH levels then plateau or decline slightly. This slightly lower FSH concentration is insufficient to sustain growth of follicles of higher FSH thresholds, so they die, leaving only the single oestrogen-producing dominant follicle (Boxes 8.4 and 8.5) to mature and ovulate.
FSH exerts its molecular effects via a specific receptor on the surface of sensitive cells. This receptor contains a characteristic seven transmembrane-spanning regions and is functionally coupled (via membrane-associated G proteins) to adenylate cyclase. This generates the second messenger cAMP. FSH itself can promote increased expression of its own receptor in the short term, although longer-term exposure to elevated FSH levels downregulates receptor numbers. Cloning and analysis of gonadotrophin receptors from several species indicate a high level of homology between the FSH, LH and CG receptors.
LH exhibits a molecular mass of 28.5 kDa. The gene coding for the b-subunit of this glycoprotein hormone is present on human chromosome 19. This subunit exhibits significant amino acid homology to placental CG. Both promote identical biological effects and act via the same 93 kDa cell surface receptor. The LH receptor is present on testicular Leydig cells in males and on female ovarian theca, granulosa, luteal and interstitial cells.
LH promotes synthesis of testosterone, the major male androgen (Box 8.6) by the testicular Leydig cells. FSH sensitizes these cells to the activities of LH, probably by increasing LH receptor numbers on the cell surface. Leydig cells have a limited storage capacity for testosterone (*25 mg), but secrete 5-10 mg of the hormone into the bloodstream daily in young healthy males.
The primary cellular targets of LH in the females are the follicular theca cells, which constitutively express the LH receptor. Under the influence of LH, these cells produce androgens. The androgens (principally testosterone) are then taken up by granulosa cells and converted into oestrogens (Box 8.6) by the already-mentioned aromatase complex. Thus, the follicle represents the major female gonadal endocrine unit, in which granulosa and theca cells cooperate in the synthesis of oestrogens. Physiologically, LH in the female plays a major role in maturation of the dominant follicle and appears central to triggering ovulation.
Pregnant mare serum gonadotrophin (PMSG)
Pregnant mare serum gonadotrophin (PMSG) is a unique member of the gonadotrophin family of hormones. It is synthesized only by pregnant mares (i.e. is not found in other species). Furthermore, it displays both FSH-like and LH-like biological activities.
This glycoprotein hormone is a heterodimer, composed of an a- and b-subunit, and approximately 45% of its molecular mass is carbohydrate. Reported molecular masses range
336 BIOPHARMACEUTICALS
from 52 kDa to 68 kDa, a reflection of the potential variability of the hormone’s carbohydrate content.
PMSG is secreted by cup-shaped outgrowths found in the horn of the uterus of pregnant horses. These equine-specific endometrial cups are of fetal rather than maternal origin. They first become visible around day 40 of gestation, and reach maximum size at about day 70, after which they steadily regress. They synthesize high levels of PMSG and secrete it into the blood, where it is detectable between days 40 and 130 of gestation.
Box 8.6. The androgens and oestrogens
The androgens and oestrogens represent the major male and female sex hormones, respectively. The testicular Leydig cells represent the primary source of androgens in the male, of which testosterone is the major one. Testosterone, in turn, serves as a precursor for two additional steroids: dihydrotestosterone and the oestrogen. These mediate many of its biological effects.
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