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2012 ; 11
(1
): 11-25
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Gonadotropin stimulation: past, present and future
#MMPMID29699102
Lunenfeld B
Reprod Med Biol
2012[Jan]; 11
(1
): 11-25
PMID29699102
show ga
Gonadotropin therapy is so central to infertility treatment that it is easy to
overlook the considerable discovery and research that preceded production of the
effective and safe products available today. The history underpinning this
development spans over 300 years and provides a splendid example of how basic
animal experimentation and technological advances have progressed to clinical
application. Following the discovery of germ cells in 1677 and realizing, in
1870, that fertilization involved the merging of two cell nuclei, one from the
egg and one from sperm, it took another 40 years to discover the interplay
between hypothalamus, pituitary and gonads. The potential roles of gonadotropin
regulation were discovered in 1927. Gonadotropin, such as pregnant mare serum
gonadotropin (PMSG), was first introduced for ovarian stimulation in 1930.
However, use of PMSG leads to antibody formation, and had to be withdrawn.
Following withdrawal of PMSG, human pituitary gonadotropin (HPG) and urinary
menopausal gonadotropin (hMG) appeared on the market, and 50 years ago the first
child was delivered by our group in 1961 and opened the path to controlled
ovarian stimulation. HPG produced good results, but its use came to an end in the
late 1980s when it was linked to the development of Creutzfeldt-Jakob disease
(CJD). HMG preparations containing a high percentage of unknown urinary proteins,
making quality control almost impossible, were then the only gonadotropins
remaining on the market. With the availability of hMG, clomiphene citrate, ergot
derivatives, GnRH agonists and antagonists, as well as metformin, algorithms were
developed for their optimal utilization and were used for the next four decades.
Following the first human IVF baby in 1978 and ICSI in 1991, such procedures
became standard practice. The main agents for controlled ovarian stimulation for
IVF were gonadotropins and GnRH analogues, with batch to batch consistent
gonadotropic preparations; methods could be developed to predict and select the
correct dose and the optimal protocol for each patient. We are now seeing the
appearance of gonadotropin with sustained action and orally active GnRH analogues
as well as orally active molecules capable to stimulate follicle growth and
inducing ovulation. These new developments may one day remove the need for the
classical gonadotropin in clinical work.
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