Gonadotropin preparations

Gonadotropin preparations are drugs that mimic the physiological effects of gonadotropins, used therapeutically mainly as fertility medication for ovarian hyperstimulation and ovulation induction.^[1] For example, the so-called menotropins consist of LH and FSH extracted from human urine from menopausal women.^[2] There are also recombinant variants.^{[medical citation needed]}

Gonadotropin preparations
Drug class
Class identifiers
Synonyms	Gonadotropins; LH; FSH; hCG
Use	Infertility, hypogonadism
ATC code	G03GA
Biological target	Gonadotropin receptors (LHCGR, FSHR)
Chemical class	Glycoproteins
Legal status
In Wikidata

FSH and LH preparations

hMG (human Menopausal Gonadotrophins), FSH and LH prepared from human urine collected from postmenopausal women. First extracted in 1953.^[3] Injected intra-muscularily (IM) or subcutaneously (SC).

Generic

menotropins for injections, USP

Brands

• Menopur, 5 mL vials containing 75 IU FSH and 75 IU LH.
• Repronex, vials containing either 75 IU FSH and 75 IU LH, or 150 IU FSH and 150 IU LH.

Common side effects of preparations containing FSH and LH are:^[4]

• Mild bloating
• Pain, swelling, or irritation injection site
• Rash at injection site or other part of body
• Stomach pain or pelvic pain

FSH preparations

Preparations of follicle-stimulating hormone (FSH) mainly include those derived from the urine of menopausal women, as well as recombinant preparations. The recombinant preparations are more pure and more easily administered, but they are more expensive. The urinary preparations are equally effective and less expensive, but are not as convenient to administer as they are available in vials versus injection pens. One study reported that users of the purified urinary FSH preparation Bravelle experienced less injection site pain compared to the recombinant preparation Follistim.^[5]

Urinary preparations

Purified urinary FSH (75 IU FSH and ≤ 2 IU of LH)

Generic

urofollitropin for injection, purified.

Brands

• Bravelle, U.S., (≤ 2 IU LH)
• Metrodin, U.S. and Canada, (≤ 1 IU LH)
• Fertinorm Hp, (Canada)

Highly purified urinary FSH (75 IU FSH and ≤ 0.1 IU LH/1000 IU FSH)

Generic

urofollitropin for injection, (highly) purified.

Brands

Fertinex (≤ 0.1 IU LH/1000 IU FSH)

Recombinant preparations

Follitropin alfa

Generic

Follitropin alfa injection

Brands

Gonal-f^[6][7]

Cinnal-f

Fertilex

Ovaleap^[8][9]

Bemfola^[10]

Follitropin beta

Generic

follitropin beta injection

Brands

Follistim AQ^[11]

Puregon^[12]

Follitropin delta

Generic

follitropin delta injection

Brands

Rekovelle^[13][14]

The package insert for Gonal-f states that based on physio-chemical tests and bioassays that follitropin beta and follitropin alfa are indistinguishable. Two studies showed no difference.^[15][16] However, a more recent study showed there may be a slight clinical difference, with the alfa form tending towards a higher pregnancy rate and the beta form tending towards a lower pregnancy rate, but with significantly higher estradiol (E2) levels.^[17]

The package insert for Puregon states that structural analysis shows that the amino acid sequence of follitropin beta is identical to that of natural human follicle stimulating hormone (hFSH).^[18] Further, the ogliosaccharide side chains are very similar, but not completely identical to that of natural hFSH.^[19] However, these small differences do not affect the bioactivity compared to natural hFSH.^{[medical citation needed]}

Gonal-f was approved for medical use in the European Union in October 1995.^[6]

Puregon was approved for medical use in the European Union in February 1996.^[12]

Rekovelle was approved for medical use in the European Union in December 2016.^[13]

Biosimilars

See also: Biosimilars

Ovaleap was approved for medical use in the European Union in September 2013.^[8] It was approved for medical use in Australia in March 2021.^[9][20]

Bemfola was approved for medical use in the European Union in March 2014.^[10]

Side effects of FSH preparations

Side effects of FSH preparations include:^{[21][medical citation needed]}

• Local irritation at the injection site
• Feeling of fullness, bloating, and tenderness in the lower abdomen due to increasing size of the ovaries.
• Mood swings
• Fatigue

FSH analogues

Corifollitropin alfa

Merck received approval on February 15, 2010, from the European Commission for ELONVA (corifollitropin alfa) a long lasting single injection fusion protein lacking LH activity. Only one injection is required for the first seven days, replacing the first seven daily injections of conventional FSH. Initial results demonstrates similar pregnancy rates as daily recombinant FSH injections.^[22][23]

LH (Luteinizing hormone) preparations

Prepared from recombinant DNA.

Generic

lutropin alfa for injection

Brands

Luveris

hCG preparations

Human chorionic gonadotropin (hCG) can be recovered from the urine of pregnant women or be produced from recombinant DNA. It acts similarly to LH, but the larger supply makes it less costly; it also has a longer half-life. In veterinary medicine, equine chorionic gonadotropin (eCG) extracted from pregnant mare serum is used instead on a variety of mammals, sometimes eliciting an immune response in non-horse species.^[24]

In Women: Used to induce final maturation of follicle and subsequent ovulation.^{[medical citation needed]} Also used for luteal phase support.^{[medical citation needed]}

In men: Used to treat select cases of Hypogonadotropic Hypogonadism in adult males.^[25] In off-label use, some urologists prescribe hCG in low doses in combination with testosterone replacement to preserve fertility.^[26]

In male children: Also used to treat prepubertal cryptorchidism not due to anatomical obstruction. Therapy is usually administered between ages 4 and 9.^[25]

Urinary preparations

Derived from the urine of pregnant women.

Generic

(human) chorionic gonadotropin for injection, USP

Brands

• Pregnyl (Merck/Schering-Plough)
• Follutein
• Profasi
• Novarel

Recombinant preparations

Generic

choriogonadotropin alfa for injection (recombinant human Chorionic Gonadotropin, r-hCG).

Brands

Ovidrel

References

1. "Gonadotropins", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID 31644163, retrieved 2023-12-11
2. Menotropins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
3. Ghumman, Surveen, 2006. Step by Step Ovulation Induction. Anshan Ltd, Kent, United Kingdom. ISBN 1-904798-96-9. Page 44.
4. Follicle Stimulating Hormone and Luteinizing Hormone (Intramuscular Route, Subcutaneous Route) 2013-12-10 at the Wayback Machine Side effects. From Mayo Clinic. Last updated: Nov. 1, 2011
5. Dickey, RP; Thornton, M; Nichols, J; Marshall, DC; Fein, SH; Nardi, RV (Jun 2002). "Comparison of the efficacy and safety of a highly purified human follicle-stimulating hormone (Bravelle) and recombinant follitropin-beta for in vitro fertilization: a prospective, randomized study". Fertility and Sterility. 77 (6): 1202–8. doi:10.1016/s0015-0282(02)03131-x. PMID 12057729.
6. "Gonal-f EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 1 July 2020. Retrieved 2 April 2020.
7. "Gonal-f- follitropin alfa kit". DailyMed. from the original on 1 April 2021. Retrieved 22 March 2021.
8. "Ovaleap EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 23 September 2020. Retrieved 2 April 2020.
9. "AusPAR: Follitropin alfa". Therapeutic Goods Administration (TGA). 19 May 2021. from the original on 20 May 2021. Retrieved 12 June 2021.
10. "Bemfola EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 28 October 2020. Retrieved 2 April 2020.
11. "Follistim AQ- follitropin injection, solution". DailyMed. from the original on 30 March 2021. Retrieved 22 March 2021.
12. "Puregon EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 8 March 2021. Retrieved 22 March 2021.
13. "Rekovelle EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 1 July 2020. Retrieved 22 March 2021.
14. "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
15. Brinsden, Peter; Akagbosu, Fidelis; Gibbons, Lisa M; Lancaster, Susan; Gourdon, Dominique; Engrand, Patrick; Loumaye, Ernest (2000). "A comparison of the efficacy and tolerability of two recombinant human follicle-stimulating hormone preparations in patients undergoing in vitro fertilization-embryo transfer". Fertility and Sterility. 73 (1): 114–116. doi:10.1016/s0015-0282(99)00450-1. PMID 10632423.
16. Williams, R. Stan; et al. (2003). "Pregnancy rates in varying age groups after in vitro fertilization: a comparison of follitropin alfa (Gonal F) and follitropin beta (Follistim)". American Journal of Obstetrics and Gynecology. 189 (2): 342–346. doi:10.1067/s0002-9378(03)00728-2. PMID 14520188.
17. Orvieto, R; Nahum, R; Rabinson, J; Ashkenazi, J; Anteby, EY; Meltcer, S (Apr 2009). "Follitropin-alpha (Gonal-F) versus follitropin-beta (Puregon) in controlled ovarian hyperstimulation for in vitro fertilization: is there any difference?". Fertility and Sterility. 91 (4 Suppl): 1522–5. doi:10.1016/j.fertnstert.2008.08.112. PMID 18851846.
18. Smitz, Johan; Wolfenson, Claudio; Chappel, Scott; Ruman, Jane (2016-06-01). "Follicle-Stimulating Hormone: A Review of Form and Function in the Treatment of Infertility". Reproductive Sciences. 23 (6): 706–716. doi:10.1177/1933719115607992. ISSN 1933-7205. PMID 26446000. S2CID 6023362.
19. Belorkar, Seema A.; Gupta, A. K. (2016-10-03). "Oligosaccharides: a boon from nature's desk". AMB Express. 6 (1): 82. doi:10.1186/s13568-016-0253-5. ISSN 2191-0855. PMC 5047869. PMID 27699701.
20. https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=366B4AEAF4C9C6FFCA258694003CAF80&agid=(PrintDetailsPublic)&actionid=1^{[permanent dead link] [bare URL PDF]}
21. Pharmacy FAQ 2013-12-02 at the Wayback Machine from Regional Fertility Program, Cambrian Wellness Centre. Retrieved December 2013
22. Koper, N. P.; et al. (2008). "Corifollitropin alfa demonstrates similar pregnancy rates as compared to daily recombinant FSH treatment in a controlled ovarian stimulation regimen for IVF/ICSI". Fertility and Sterility. 90: S75. doi:10.1016/j.fertnstert.2008.07.864.
23. Devroey, P; Boostanfar, R; Koper, NP; Mannaerts, BM; Ijzerman-Boon, PC; Fauser, BC (2009). "A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol". Human Reproduction. 24 (12): 3063–72. doi:10.1093/humrep/dep291. PMC 2777786. PMID 19684043.
24. Hervé, V; Roy, F; Bertin, J; Guillou, F; Maurel, MC (January 2004). "Antiequine chorionic gonadotropin (eCG) antibodies generated in goats treated with eCG for the induction of ovulation modulate the luteinizing hormone and follicle-stimulating hormone bioactivities of eCG differently". Endocrinology. 145 (1): 294–303. doi:10.1210/en.2003-0595. PMID 14525910.
25. "Pregnyl - FDA prescribing information, side effects and uses". Drugs.com. from the original on 2018-07-24. Retrieved 2018-07-23.
26. Hsieh, Tung-Chin; Pastuszak, Alexander W.; Hwang, Kathleen; Lipshultz, Larry I. (February 20, 2013). "Concomitant Intramuscular Human Chorionic Gonadotropin Preserves Spermatogenesis in Men Undergoing Testosterone Replacement Therapy". The Journal of Urology. 189 (2): 647–650. doi:10.1016/j.juro.2012.09.043. PMID 23260550. from the original on March 20, 2020. Retrieved March 20, 2020 – via www.auajournals.org.