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In addition to GnRH, several other effector molecules modulate secretion of gonadotrophins. These include not only inhibins and activins, but also gonadal steroids. All of these combine via complex feedback loops to modulate gonadotrophin production and, hence, reproductive function (Figure 8.15).
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Figure 8.15. Inter-relationships between various hormones regulating reproductive function in the male and female. Particular emphasis is placed upon the regulatory effect many have on the production levels of additional reproductive hormones
Medical and veterinary applications of gonadotrophins
Because of their central role in maintaining reproductive function, the therapeutic potential of gonadotrophins in treating subfertility and some forms of infertility was obvious (Table 8.10). Gonadotrophins are also used to induce a superovulatory response in various animal species, as outlined later. The market for these hormones, while modest by pharmaceutical standards, is,
Table 8.10. Overview of gonadotrophin and related preparations used (or of potential use) in human and veterinary medicine. See text for details of each
Hormonal Source Description/activity
Menotrophin Urine of post-menopausal women Contains FSH with some LH activity.
Used to induce human follicular
P-FSH Porcine pituitary extract Enriched FSH extract. Contains
lower levels of LH and other
pituitary proteins. Used to induce
superovulatory response in animals
r-FSH Mainly recombinant mammalian Purified FSH (human or animal) used
production systems, notably to treat human sub-fertility or
CHO cell lines induction of superovulation in
P-LH Porcine pituitary extract Used to induce ovulation in super
r-LH Mammalian cell production systems, Used to induce ovulation in super-
e.g. CHO cell lines ovulated animals
hCG Urine of pregnant females Enriched hCG preparations, used
instead of LH in human medicine
PMSG Serum of pregnant mares Exhibits both FSH- and LH-like
biological activities---used to
Inhibins Produced by gonads. rDNA technology Inhibits FSH secretion
only source of large quantities Tumour suppressor
Activins Produced by gonads. rDNA technology Stimulates FSH secretion
only source of large quantities
GnRH Produced by hypothalmus. Therapeutic Stimulates synthesis and secretion of
product, manufactured by direct FSH and LH
none the less substantial. By the late 1990s the annual human market stood at about $250 million, of which the USA accounted for *$110 million, Europe *$90 million and Japan $50 million.
Sources and medical uses of FSH, LH and hCG
While the human pituitary is the obvious source of human gonadotrophins, it also constitutes an impractical source of medically useful quantities of these hormones. However, the urine of post-menopausal women does contain both FSH and LH activity. Up until relatively recently this has served as the major source, particularly of FSH, used medically.
Menotrophin (human menopausal gonadotrophin, HMG) is the name given to FSH-enriched extracts from human urine. Such preparations contain variable levels of LH activity, as well as various other proteins normally present in urine. As much as 2.51 of urine may be required to produce one dose (75 IU, *7.5mg) of human FSH (hFSH).
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Figure 8.16. Overview of the procedure by which hCG may be purified from the urine of pregnant females at laboratory scale. Production-scale systems would be at least partially based upon such a purification strategy. Although initial concentration steps could involve precipitation, the use of ultrafiltration would now be more common