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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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As previously mentioned, hCG exhibits similar biological activities to hLH and is excreted in the urine of pregnant women. Traditionally, hCG from this source has found medical application in humans (as an alternative to hLH; Figure 8.16).
In females, menotrophins and hCG are used for the treatment of anovulatory infertility. This condition is due to insufficient endogenous gonadotrophin production. Menotrophin is administered to stimulate follicular maturation, with subsequent administration of hCG to promote ovulation and corpus luteum formation. Mating at this point should lead to fertilization.
Dosage regimes attempt to mimic as closely as possible normal serum gonadotrophin profiles as they occur during the reproductive cycle of fertile females. This is achieved by monitoring the resultant oestrogen production, or by using ultrasonic equipment to monitor follicular response. Depending upon the basal hormonal status of the female, calculation of the optimal dosage levels can be tricky (treatments are tailored to meet the physiological requirements of individual patients). Over-dosage can, and does, result in multiple follicular development, with consequent risk of multiple pregnancy.
Treatment typically entails daily i.m. administration of gonadotrophin, often for 12 days or more, followed by a single dose of hCG. Alternatively, three equal larger doses of menotrophin may be administered on alternate days, followed by hCG administration 1-2 days after the final menotrophin dose.
Gonadotrophins are also used in assisted reproduction procedures. Here the aim is to administer therapeutic doses of FSH that exceed individual follicular FSH threshold requirements, thus stimulating multiple follicular growth. This, in turn, facilitates harvest of multiple eggs, which are then available for in vitro fertilization (IVF). This technique is often employed when a woman has a blocked fallopian tube, or some other impediment to normal fertilization of the egg by a sperm cell. After treatment, the resultant eggs are collected, incubated in vitro with her partnerís sperm, incubated in culture media until the embryonic blastocyst is formed, and then implanted into the motherís uterus.
FSH and hCG also find application in the treatment of male subfertility or related conditions. Both are administered to males exhibiting hypogonadotrophic hypogonadism to stimulate
342 BIOPHARMACEUTICALS
Table 8.11. Some notable non-gonadal tissues that express functional LH/hCG receptors
Pregnancy/fertility-related tissue Other tissue
Uterus Skin
Cervix Blood vessels
Placenta Adrenal cortex
Oviduct Brain tissue
Fetal membranes Prostate gland
Seminal vesicles Bladder
Sperm cells Monocytes
Breast Macrophages
sperm synthesis and normal sexual function. hCG has found limited application in the treatment of pre-pubertal cryptorchidism (a condition characterized by failure of the testes to descend fully into the scrotum from the abdomen). The ability of this hormone to stimulate testosterone production also caught the attention of some athletes and, as a result, the International Olympic Committee has banned its use.
The LH/hCG cell surface receptor is found in a number of non-gonadal tissues, indicating that these hormones may exert physiologically relevant non-gonadal functions (Table 8.11). In addition, while liver, kidney and muscle cells are devoid of such a receptor, it is expressed by a number of these tissues before birth, hinting at a potential developmental role. Receptor levels in non-gonadal tissues are generally much lower than in gonadal tissue.
Research indicates that hCG probably has a number of pregnancy/non-pregnancy-related non-gonadal functions that may give rise to future additional clinical applications. It appears to promote effects such as increased uterine blood flow and immunosuppression at the maternal-fetal interface. As such, hCG may prove potentially useful in preventing some types of pregnancy loss. Research has also indicated that infusion of hCG into the uterus can counteract prostaglandin-induced uterine contractions. As such, it may prove useful in preventing the onset of premature labour. hCG also exhibits anti-breast cancer activity. Studies in rodents, for example, illustrate that it prevents mammary tumour formation/growth when administered prior or subsequent to various chemical carcinogens.
Recombinant gonadotrophins
Gonadotrophins are now also produced by recombinant DNA technology. The genes or cDNAs coding for gonadotrophins from several species have been identified and expressed in various recombinant host systems, particularly mammalian cell lines. rhFSH produced in CHO cells has proved clinically effective. While exhibiting an amino acid sequence identical to the human molecule, its carbohydrate composition differs slightly. When administered to humans, the preparation is well tolerated and yields no unexpected side effects. It does not elicit an immunological response, and its plasma half-life is similar to the native hormone. rhFSH has proved efficacious in stimulating follicular growth in females suffering from hypogonadotrophic hypogonadism and is effective in the treatment of males suffering from similar conditions. rhFSH was amongst the first biopharmaceutical substances to be approved for general medical
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