Gonadotropin preparations explained

Synonyms:Gonadotropins; LH; FSH; hCG
Use:Infertility, hypogonadism
Atc Prefix:G03GA
Biological Target:Gonadotropin receptors (LHCGR, FSHR)
Chemical Class:Glycoproteins

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

FSH and LH preparations

hMG (human Menopausal Gonadotrophins), FSH and LH prepared from human urine collected from postmenopausal women. First extracted in 1953.[1] Injected intra-muscularily (IM) or subcutaneously (SC).

Generic

menotropins for injections, USP

Brands

Common side effects of preparations containing FSH and LH are:[2]

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.[3]

Urinary preparations

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

Generic

urofollitropin for injection, purified.

Brands

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[4]

Cinnal-f

Fertilex

Ovaleap

Bemfola

Follitropin beta

Generic

follitropin beta injection

Brands

Follistim AQ[5]

Puregon

Follitropin delta

Generic

follitropin delta injection

Brands

Rekovelle[6]

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.[7] [8] 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.[9]

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).[10] Further, the ogliosaccharide side chains are very similar, but not completely identical to that of natural hFSH.[11] However, these small differences do not affect the bioactivity compared to natural hFSH.

Gonal-f was approved for medical use in the European Union in October 1995.[12]

Puregon was approved for medical use in the European Union in February 1996.[13]

Rekovelle was approved for medical use in the European Union in December 2016.[14]

Biosimilars

See also: Biosimilars.

Ovaleap was approved for medical use in the European Union in September 2013.[15] It was approved for medical use in Australia in March 2021.[16] [17]

Bemfola was approved for medical use in the European Union in March 2014.[18]

Side effects of FSH preparations

Side effects of FSH preparations include:[19]

FSH analogues

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.[20] [21]

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.[22]

In Women:Used to induce final maturation of follicle and subsequent ovulation. Also used for luteal phase support.

In men:Used to treat select cases of Hypogonadotropic Hypogonadism in adult males.[23] In off-label use, some urologists prescribe hCG in low doses in combination with testosterone replacement to preserve fertility.[24]

In male children: Also used to treat prepubertal cryptorchidism not due to anatomical obstruction. Therapy is usually administered between ages 4 and 9.[23]

Urinary preparations

Derived from the urine of pregnant women.

Generic

(human) chorionic gonadotropin for injection, USP

Brands

Recombinant preparations

Generic

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

Brands

Ovidrel

Notes and References

  1. Ghumman, Surveen, 2006. Step by Step Ovulation Induction. Anshan Ltd, Kent, United Kingdom. . Page 44.
  2. http://www.mayoclinic.com/health/drug-information/DR600403/DSECTION=side-effects Follicle Stimulating Hormone and Luteinizing Hormone (Intramuscular Route, Subcutaneous Route)
  3. 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 . 10.1016/s0015-0282(02)03131-x. 12057729 . free .
  4. Web site: Gonal-f- follitropin alfa kit . DailyMed . 22 March 2021 . 1 April 2021 . https://web.archive.org/web/20210401041428/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae85b9c3-e7eb-4981-a5d9-346050e8f189 . live .
  5. Web site: Follistim AQ- follitropin injection, solution . DailyMed . 22 March 2021 . 30 March 2021 . https://web.archive.org/web/20210330163008/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=96f11b5d-cc7b-48aa-830a-a28e1962d871 . live .
  6. Web site: Prescription medicines and biologicals: TGA annual summary 2017 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 31 March 2024 . 31 March 2024 . https://web.archive.org/web/20240331021323/https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 . live .
  7. 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 . 10.1016/s0015-0282(99)00450-1. 10632423 . free .
  8. Williams . R. Stan . etal . 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 . 10.1067/s0002-9378(03)00728-2. 14520188 .
  9. 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 . 10.1016/j.fertnstert.2008.08.112 . 18851846 . free .
  10. 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 . en . 23 . 6 . 706–716 . 10.1177/1933719115607992 . 26446000 . 6023362 . 1933-7205.
  11. Belorkar . Seema A. . Gupta . A. K. . 2016-10-03 . Oligosaccharides: a boon from nature's desk . AMB Express . 6 . 1 . 82 . 10.1186/s13568-016-0253-5 . 2191-0855 . 5047869 . 27699701 . free .
  12. Web site: Gonal-f EPAR . European Medicines Agency (EMA) . 17 September 2018 . 2 April 2020 . 1 July 2020 . https://web.archive.org/web/20200701090155/https://www.ema.europa.eu/en/medicines/human/EPAR/gonal-f . live .
  13. Web site: Puregon EPAR . European Medicines Agency (EMA) . 17 September 2018 . 22 March 2021 . 8 March 2021 . https://web.archive.org/web/20210308081653/https://www.ema.europa.eu/en/medicines/human/EPAR/puregon . live .
  14. Web site: Rekovelle EPAR . European Medicines Agency (EMA) . 17 September 2018 . 22 March 2021 . 1 July 2020 . https://web.archive.org/web/20200701090307/https://www.ema.europa.eu/en/medicines/human/EPAR/rekovelle . live .
  15. Web site: Ovaleap EPAR . European Medicines Agency (EMA) . 17 September 2018 . 2 April 2020 . 23 September 2020 . https://web.archive.org/web/20200923142241/https://www.ema.europa.eu/en/medicines/human/EPAR/ovaleap . live .
  16. Web site: AusPAR: Follitropin alfa . Therapeutic Goods Administration (TGA) . 19 May 2021 . 12 June 2021 . 20 May 2021 . https://web.archive.org/web/20210520180119/https://www.tga.gov.au/auspar/auspar-follitropin-alfa . live .
  17. https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=366B4AEAF4C9C6FFCA258694003CAF80&agid=(PrintDetailsPublic)&actionid=1{{Dead link|date=January 2023 |bot=InternetArchiveBot |fix-attempted=yes }}
  18. Web site: Bemfola EPAR . European Medicines Agency (EMA) . 17 September 2018 . 2 April 2020 . 28 October 2020 . https://web.archive.org/web/20201028131041/https://www.ema.europa.eu/en/medicines/human/EPAR/bemfola . live .
  19. http://www.regionalfertilityprogram.ca/index.php Pharmacy FAQ
  20. Koper . N. P. . etal . 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 . 10.1016/j.fertnstert.2008.07.864. free .
  21. 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. 10.1093/humrep/dep291 . 19684043 . 2777786.
  22. Hervé . V . Roy . F . Bertin . J . Guillou . F . Maurel . MC . 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 . January 2004 . 145 . 1 . 294–303 . 10.1210/en.2003-0595 . 14525910. free .
  23. Web site: Pregnyl - FDA prescribing information, side effects and uses. Drugs.com. 2018-07-23. 2018-07-24. https://web.archive.org/web/20180724032302/https://www.drugs.com/pro/pregnyl.html. live.
  24. Concomitant Intramuscular Human Chorionic Gonadotropin Preserves Spermatogenesis in Men Undergoing Testosterone Replacement Therapy. Tung-Chin. Hsieh. Alexander W.. Pastuszak. Kathleen. Hwang. Larry I.. Lipshultz. February 20, 2013. The Journal of Urology. 189. 2. 647–650. 10.1016/j.juro.2012.09.043. 23260550. www.auajournals.org. March 20, 2020. March 20, 2020. https://web.archive.org/web/20200320231454/https://www.auajournals.org/doi/abs/10.1016/j.juro.2012.09.043. live.

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