GnRH analogue

GnRH analogs , also out of date LHRH analogs , are synthetic analogs of the neurohormone gonadotropin-releasing hormone (GnRH), which are used as drugs to artificially lower the testosterone or estrogen level in the blood . Areas of application are essentially forms of prostate cancer , breast cancer (breast cancer) and endometriosis that can no longer be treated surgically . They are also used to treat idiopathic precocious puberty , in which, as so-called super-agonists, they reduce the release of gonadotropins . In in vitro fertilization, they are used to determine the time of ovulation. They are also widely used in veterinary reproductive medicine.

Pharmacology of GnRH Analogs

Physiologically, GnRH is released in a pulsatile manner from the hypothalamus . For men, it is dispensed approximately every 120 minutes. In women, the interval depends on the cycle phase: in the follicular phase, the drug is released approximately every 90 minutes; in the luteal phase, the intervals are longer. GnRH stimulates the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn stimulate the synthesis of estrogen and testosterone in the gonads (testes and ovaries). FSH and LH are also known as gonadotropins.

GnRH analogues can be used pharmacologically, depending on the type and duration of application, to increase or decrease the release of gonadotropins. An increase in gonadotropin secretion is achieved by a single or pulsatile administration of GnRH agonists. A continuous administration of agonists, on the other hand, initially leads to an initial increase in gonadotropin release. However, within two to three weeks there is a down-regulation of the GnRH receptors in the pituitary gland, causing it to stop releasing FSH and LH. Antagonists, on the other hand, reduce the release of FSH and LH immediately, which means that the effect on hormone release from the gonads occurs more quickly.

As it is with the GnRH analogues to protein compounds, they can not orally administered since they would digested in the gastrointestinal tract. For this reason, they are mostly given by intramuscular or subcutaneous injection. In human medicine there are also preparations for application via the nasal mucosa. Most of the preparations are now administered as a one-, three- or six-month depot . A more recent development is the one- or three-month syringe, which creates a subcutaneous depot in the form of a gel cushion . In veterinary medicine, in addition to injections, depot preparations in the form of so-called hormone chips are also used.

Depending on the effect of the respective substance on the GnRH receptors of the pituitary gland, a distinction is made between GnRH analogues between GnRH agonists and GnRH antagonists.

GnRH agonists

Mechanism of action

In pharmacology, an agonist is an active ingredient which, by binding to a receptor, has the same effect as the body's own ligand . GnRH agonists bind accordingly to the GnRH receptors in the pituitary gland. The mechanism of action lies in a complete down-regulation of the pituitary receptors, which, after an initial brief increase in gonadotropin and thus sex hormone secretion, leads to a complete inhibition of the secretion of sex hormones within about two to three weeks. The use of D-amino acids in position 6 gives the corresponding GnRH analogue greater stability and thus a longer duration of action.

Use in human medicine

Indications

Pharmacologically, GnRH agonists are mainly used to achieve a complete suppression of the secretion of sex hormones. An important indication for this is the inhibition of the hormone-dependent growth of tumors. GnRH agonists are used for palliative treatment of metastatic prostate cancer in men and metastatic breast cancer in women . In women, GnRH agonists are also used to treat endometriosis and to shrink uterine fibroids prior to a scheduled surgical removal. If puberty occurs prematurely ( pubertas praecox ), the administration of GnRH agonists can suppress the secretion of sex hormones by the gonads and prevent the premature completion of growth. Most of the preparations are now administered as a one-, three- or six-month depot . In in vitro fertilization, GnRH agonists are used to suppress the body's own regulation of follicular maturation.

Side effects

All side effects that can occur with the administration of GnRH agonists are due to the suppression of the secretion of the sex hormones. These include climacteric complaints such as disorders of vascular regulation and loss of libido, as well as edema. Long-term administration can lead to osteoporosis, which is why long-term therapy with GnRH agonists is only indicated for life-threatening diseases.

Active ingredients

Structural formula	Active ingredient	indication	Half-life
	Buserelin	Endometriosis, in vitro fertilization	1 - 2 h
	Goserelin	Endometriosis, fibroids	2 - 3 h
	Leuprorelin	Endometriosis, fibroids, breast cancer	3 h
	Nafarelin	Endometriosis, in vitro fertilization	4 h
	Triptorelin	Uterine fibroids, endometriosis, in vitro fertilization	20 min

Use in veterinary medicine

Indications

In veterinary medicine, GnRH agonists are used in different animal species and with different indications.

In order to temporarily suppress the secretion of the sex hormone testosterone in male animals and thus to induce temporary castration, a so-called hormone chip is implanted, from which the active ingredient is continuously released in small amounts over a long period of time. After an initial stimulation of testosterone secretion, spermatogenesis is suppressed after about 2 weeks. Complete infertility is achieved within approximately 6 weeks. Depending on the amount of active ingredient applied, the effect lasts between 6 or 12 months. A depot preparation is approved for use in male dogs and ferrets. In addition to the sterility of dogs, the active ingredient is also used to treat prostate hyperplasia and sexually motivated aggressive behavior, if surgical castration and the associated permanent sterility is not desired. In adrenal gland disease, which is caused by an uncontrolled release of LH in castrated male and female ferrets, LH secretion can be suppressed by implanting such a hormone chip.

In horse mares, a short-term implant with the same active ingredient is used to induce ovulation in order to be able to determine the time of covering. 3 to 6 hours after the implantation, maximum active ingredient concentrations are reached, which return to the blood level before the implantation within 24 hours. The short-term increase in FSH and LH secretion induces ovulation within 48 hours.

GnRH analogs are used in reproductive medicine in cattle and pigs for various indications. With the help of the various active ingredients approved for veterinary medicine, oestrus induction and synchronization as well as induction of ovulation can take place. They are also used to treat acycly and follicular cells in cattle.

Active ingredients

Structural formula	Active ingredient	Animal species	indication	Application type	receipt
	Buserelin	Beef, horse, rabbit	Treatment of acyclie, induction of ovulation, improvement of the conception rate	Injection (im, sc, iv)
	Deslorelin	horse	Ovulation Induction	Implant
		Dog, ferret	Temporary sterility (chemical castration) of male dogs	Implant
	Lecirelin	Beef	Acyclie, Ovulation Induction, Improvement in Conception Rate, Follicular Cysts	Injection (im, sc)
		Rabbits	Ovulation induction, improvement of the conception rate	Injection (im, sc)
	Peforelin	pig	Oestrus stimulation	Injection (im, sc)
	Nafarelin	Fish ( salmon-like )	Induction and synchronization of ovulation for the production of fish eggs (no longer permitted in the EU)	Injection (ip)

GnRH antagonists

Mechanism of action

An antagonist is an active ingredient that binds to a receptor without being able to trigger the physiological reaction on it. The receptor is blocked for the binding of the body's own ligand, which has to compete with the antagonistically acting molecules for the receptor binding sites.

GnRH antagonists result from a major modification of the molecular structure. In addition to the amino acids at positions 6 and 10, which are exchanged during the development of agonists, the amino acids at positions 1 to 3 are often exchanged for D-amino acids. A significant increase in the plasma half-life can thus be achieved.

In terms of action, the antagonists differ from the agonists in that they suppress gonadotropin secretion more quickly, without having the disadvantage of the initial increase in secretion triggered by the agonists.

Use in human medicine

Indications

In in-vitro fertilization, GnRH antagonists are used to prevent a premature LH surge in controlled ovarian hyperstimulation. The antagonists are administered together with FSH so that faster growth of the follicles and a shortening of the treatment up to egg retrieval can be achieved.

In men, the GnRH antagonists are used for the palliative therapy of prostate carcinomas, the growth of which is hormone-dependent.

GnRH antagonists are not currently used in veterinary medicine.

Active ingredients

Structural formula	Active ingredient	indication	Half-life
	Cetrorelix	Avoidance of a premature LH surge during in vitro fertilization	12-30 h
	Ganirelix	Avoidance of a premature LH surge during in vitro fertilization	13 h
	Abarelix	Prostate cancer	13-16 days
	Degarelix	Prostate cancer	28 - 43 days

literature

• Claudia Dellas: crash course pharmacology. Urban and Fischer, 2006 Munich ISBN 978-3-437-43181-4 . P. 185

Individual evidence

1. ↑ ^{a b c d e f g h i j k l m} regulation of the formation of sex hormones; Structure and function of gonadotropin releasing hormone and gonadotropins. In: Ernst Mutschler, Gerd Geisslinger, Heyo K. Kroemer, Sabine Menzel, Peter Ruth: Mutschler drug effects: textbook of pharmacology, clinical pharmacology and toxicology. 10th, completely revised and expanded edition, Wissenschaftliche Verlagsgesellschaft, Stuttgart 2013, pp. 404–408.
2. ↑ ^{a b} C Gobello: Effects of GnRH Antagonists vs Agonists in Domestic Carnivores, a Review. In: Reproduction of Domestic Animals. Volume 47 (Suppl. 6), 2012, pp. 373 - 376, doi : 10.1111 / rda.12025 .
3. ↑ Data sheet: Suprelorin 4.7 mg implant for dogs on the Pharmazie.com homepage, accessed on June 15, 2016
4. ↑ Data sheet: Suprelorin 9.4 mg implant for dogs on the Pharmazie.com homepage, accessed on June 15, 2016
5. ↑ M. Renggli, I. Padrutt, E. Michel, IM Reichler: Benign prostatic hyperplasia: therapeutic options in dogs. In: Swiss Archives for Veterinary Medicine (152), pp. 279–284
6. ^ RA Wagner, CA Piché, W. Jöchle, JW Oliver: Clinical and endocrine responses to treatment with deslorelin acetate implants in ferrets with adrenocortical disease. In: American Journal of Veterinary Research. Volume 66 (5), May 2005, pp. 910-914.
7. ↑ J. Handler, K. Arbeiter and W. Jöchle: The influence of breed, breeding management and veterinarian on the timing of ovulation and fertility in mares treated with a GnRH analogue, deslorelin (Ovuplant). In: Pferdeheilkunde 20 (2), 2004, pp. 145–152.
8. ↑ ^{a b c d e f g} S. Goericke-Pesch, A. Wehrend: GnRH agonists in reproductive medicine in small animals - an overview. In: Veterinary practice small animals . Volume 37 (6), 2009, pp. 410-418.
9. ↑ Appendix I of the summary of the product properties for Gonazon on the homepage of the European Medicines Agency (EMA) , accessed on June 15, 2016

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