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. For example, the so-called menotropins consist of LH and FSH extracted from human urine from menopausal women.[1] There are also recombinant variants.

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
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.[2] 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.

The more common side effects of preparations containing FSH and LH are:[3]

• 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.[4]

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.

Dosage

typically 75 - 300, but as high as 600 IU / day

Brands

Fertinex (≤ 0.1 IU LH/1000 IU FSH)

Recombinant preparations

Follitropin alfa

Generic

Follitropin alfa injection

Brands

Gonal-f

Cinnal-f

Fertilex

Ovaleap

Bemfola

Follitropin beta

Generic

follitropin beta injection

Brands

Follistim

Puregon

Follitropin delta

Generic

follitropin delta injection

Brands

Rekovelle

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.[5][6] 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.[7]

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

Gonal-f was approved for use in the European Union in October 1995.[8]

Biosimilars

Bemfola, Ovaleap Ovaleap was approved for use in the European Union in September 2013.[9]

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

Side effects of FSH preparations

Side effects of FSH preparations include:[11]

• 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.[12][13]

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.[14]

In Women: Used to induce final maturation of follicle and subsequent ovulation. Also used for luteal phase support. Typically a single injection of 10,000 international units is used to induce ovulation.

In men: Used to treat select cases of Hypogonadotropic Hypogonadism in adult males.[15] Typical dosages are 500-1000IU three times weekly, or 4,000IU three times weekly for 6-9 months until atrophy is reversed and the dose is reduced to 2,000IU three times weekly.[15] These doses are starting guidelines for treatment, and variable depending on individual response. In off-label use, some urologists prescribe hCG in low doses in combination with Testosterone replacement to preserve fertility.[16]

In male children: Also used to treat prepubertal cryptorchidism not due to anatomical obstruction. therapy is usually administered between ages 4 and 9.[15]

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. Menotropins at the US National Library of Medicine Medical Subject Headings (MeSH)
2. Ghumman, Surveen, 2006. Step by Step Ovulation Induction. Anshan Ltd, Kent, United Kingdom. ISBN 1-904798-96-9. Page 44.
3. Follicle Stimulating Hormone and Luteinizing Hormone (Intramuscular Route, Subcutaneous Route) Side effects. From Mayo Clinic. Last updated: Nov. 1, 2011
4. 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.
5. 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.
6. 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.
7. 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.
8. "Gonal-F EPAR". European Medicines Agency (EMA). Retrieved 2 April 2020.
9. "Ovaleap EPAR". European Medicines Agency (EMA). Retrieved 2 April 2020.
10. "Bemfola EPAR". European Medicines Agency (EMA). Retrieved 2 April 2020.
11. Pharmacy FAQ Archived 2013-12-02 at the Wayback Machine from Regional Fertility Program, Cambrian Wellness Centre. Retrieved December 2013
12. 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.
13. 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.
14. 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.
15. "Pregnyl - FDA prescribing information, side effects and uses". Drugs.com.
16. 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 – via www.auajournals.org.