Gonadotropin preparations

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| Synonyms = Gonadotropins; LH; FSH; hCG

| Use = Infertility, hypogonadism

| ATC_prefix = G03GA

| Biological_target = Gonadotropin receptors (LHCGR, FSHR)

| Chemical_class = Glycoproteins

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Gonadotropin preparations are drugs that mimic the physiological effects of gonadotropins, used therapeutically mainly as fertility medication for ovarian hyperstimulation and ovulation induction.{{Citation |title=Gonadotropins |date=2012 |url=http://www.ncbi.nlm.nih.gov/books/NBK548856/ |work=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury |access-date=2023-12-11 |place=Bethesda (MD) |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |pmid=31644163 |archive-date=2023-09-26 |archive-url=https://web.archive.org/web/20230926143518/https://www.ncbi.nlm.nih.gov/books/NBK548856/ |url-status=live }} For example, the so-called menotropins consist of LH and FSH extracted from human urine from menopausal women.{{MeshName|Menotropins}} There are also recombinant variants.{{Medical citation needed|date=December 2022}}

FSH and LH preparations

hMG (human Menopausal Gonadotrophins), FSH and LH prepared from human urine collected from postmenopausal women. First extracted in 1953.Ghumman, Surveen, 2006. Step by Step Ovulation Induction. Anshan Ltd, Kent, United Kingdom. {{ISBN|1-904798-96-9}}. Page 44. 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:{{cite web | url = http://www.mayoclinic.com/health/drug-information/DR600403/DSECTION=side-effects | title = Follicle Stimulating Hormone and Luteinizing Hormone (Intramuscular Route, Subcutaneous Route) | archive-url = https://web.archive.org/web/20131210221628/http://www.mayoclinic.com/health/drug-information/DR600403/DSECTION=side-effects | archive-date=2013-12-10 | work = Mayo Clinic }}

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.{{cite journal | vauthors = Dickey RP, Thornton M, Nichols J, Marshall DC, Fein SH, Nardi RV | title = 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 | journal = Fertility and Sterility | volume = 77 | issue = 6 | pages = 1202–1208 | date = June 2002 | pmid = 12057729 | doi = 10.1016/s0015-0282(02)03131-x | doi-access = free }}

=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{{cite web | title=Gonal-f- follitropin alfa kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae85b9c3-e7eb-4981-a5d9-346050e8f189 | access-date=22 March 2021 | archive-date=1 April 2021 | archive-url=https://web.archive.org/web/20210401041428/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae85b9c3-e7eb-4981-a5d9-346050e8f189 | url-status=live }}

::: Cinnal-f

::: Fertilex

::: Ovaleap

::: Bemfola

:: Generic

::: Follitropin alfa / lutropin alfa combination

:: Brands

::: Pergoveris{{cite web | title=Pergoveris EPAR | website=European Medicines Agency (EMA) | date=25 June 2007 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/pergoveris | access-date=12 October 2024}}

: Follitropin beta

::Generic

::: follitropin beta injection

:: Brands

::: Follistim AQ{{cite web | title=Follistim AQ- follitropin injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=96f11b5d-cc7b-48aa-830a-a28e1962d871 | access-date=22 March 2021 | archive-date=30 March 2021 | archive-url=https://web.archive.org/web/20210330163008/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=96f11b5d-cc7b-48aa-830a-a28e1962d871 | url-status=live }}

::: Puregon

: Follitropin delta

::Generic

::: follitropin delta injection

:: Brands

::: Rekovelle{{cite web | title=Prescription medicines and biologicals: TGA annual summary 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 | access-date=31 March 2024 | archive-date=31 March 2024 | archive-url=https://web.archive.org/web/20240331021323/https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 | url-status=live }}

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.{{cite journal | vauthors = Brinsden P, Akagbosu F, Gibbons LM, Lancaster S, Gourdon D, Engrand P, Loumaye E | title = A comparison of the efficacy and tolerability of two recombinant human follicle-stimulating hormone preparations in patients undergoing in vitro fertilization-embryo transfer | journal = Fertility and Sterility | volume = 73 | issue = 1 | pages = 114–116 | date = January 2000 | pmid = 10632423 | doi = 10.1016/s0015-0282(99)00450-1 | doi-access = free }}{{cite journal | vauthors = Williams RS, Vensel T, Sistrom CL, Kipersztok S, Rhoton-Vlasak A, Drury K | title = Pregnancy rates in varying age groups after in vitro fertilization: a comparison of follitropin alfa (Gonal F) and follitropin beta (Follistim) | journal = American Journal of Obstetrics and Gynecology | volume = 189 | issue = 2 | pages = 342–346 | date = August 2003 | pmid = 14520188 | doi = 10.1067/s0002-9378(03)00728-2 }} 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.{{cite journal | vauthors = Orvieto R, Nahum R, Rabinson J, Ashkenazi J, Anteby EY, Meltcer S | title = Follitropin-alpha (Gonal-F) versus follitropin-beta (Puregon) in controlled ovarian hyperstimulation for in vitro fertilization: is there any difference? | journal = Fertility and Sterility | volume = 91 | issue = 4 Suppl | pages = 1522–1525 | date = April 2009 | pmid = 18851846 | doi = 10.1016/j.fertnstert.2008.08.112 | doi-access = free }}

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).{{cite journal | vauthors = Smitz J, Wolfenson C, Chappel S, Ruman J | title = Follicle-Stimulating Hormone: A Review of Form and Function in the Treatment of Infertility | journal = Reproductive Sciences | volume = 23 | issue = 6 | pages = 706–716 | date = June 2016 | pmid = 26446000 | doi = 10.1177/1933719115607992 | s2cid = 6023362 }} Further, the ogliosaccharide side chains are very similar, but not completely identical to that of natural hFSH.{{cite journal | vauthors = Belorkar SA, Gupta AK | title = Oligosaccharides: a boon from nature's desk | journal = AMB Express | volume = 6 | issue = 1 | pages = 82 | date = December 2016 | pmid = 27699701 | pmc = 5047869 | doi = 10.1186/s13568-016-0253-5 | doi-access = free }} However, these small differences do not affect the bioactivity compared to natural hFSH.{{Medical citation needed|date=December 2022}}

Gonal-f was approved for medical use in the European Union in October 1995.{{cite web | title=Gonal-f EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/gonal-f | access-date=2 April 2020 | archive-date=1 July 2020 | archive-url=https://web.archive.org/web/20200701090155/https://www.ema.europa.eu/en/medicines/human/EPAR/gonal-f | url-status=live }}

Puregon was approved for medical use in the European Union in February 1996.{{cite web | title=Puregon EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/puregon | access-date=22 March 2021 | archive-date=8 March 2021 | archive-url=https://web.archive.org/web/20210308081653/https://www.ema.europa.eu/en/medicines/human/EPAR/puregon | url-status=live }}

Rekovelle was approved for medical use in the European Union in December 2016.{{cite web | title=Rekovelle EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/rekovelle | access-date=22 March 2021 | archive-date=1 July 2020 | archive-url=https://web.archive.org/web/20200701090307/https://www.ema.europa.eu/en/medicines/human/EPAR/rekovelle | url-status=live }}

==Biosimilars==

Ovaleap was approved for medical use in the European Union in September 2013.{{cite web | title=Ovaleap EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ovaleap | access-date=2 April 2020 | archive-date=23 September 2020 | archive-url=https://web.archive.org/web/20200923142241/https://www.ema.europa.eu/en/medicines/human/EPAR/ovaleap | url-status=live }} It was approved for medical use in Australia in March 2021.{{cite web | title=AusPAR: Follitropin alfa | website=Therapeutic Goods Administration (TGA) | date=19 May 2021 | url=https://www.tga.gov.au/auspar/auspar-follitropin-alfa | access-date=12 June 2021 | archive-date=20 May 2021 | archive-url=https://web.archive.org/web/20210520180119/https://www.tga.gov.au/auspar/auspar-follitropin-alfa | url-status=live }}

Bemfola was approved for medical use in the European Union in March 2014.{{cite web | title=Bemfola EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/bemfola | access-date=2 April 2020 | archive-date=28 October 2020 | archive-url=https://web.archive.org/web/20201028131041/https://www.ema.europa.eu/en/medicines/human/EPAR/bemfola | url-status=live }}

=Side effects of FSH preparations=

Side effects of FSH preparations include:{{cite web | url = http://www.regionalfertilityprogram.ca/index.php | title = Pharmacy FAQ | archive-url = https://web.archive.org/web/20131202010951/http://www.regionalfertilityprogram.ca/index.php |archive-date=2013-12-02 | work = from Regional Fertility Program, Cambrian Wellness Centre. }}{{Medical citation needed|date=December 2022}}

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

{{visible anchor|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.{{cite journal | vauthors = Koper NP, Boostanfar R, Devroey P, Fauser BC, IJzerman-Boon PC, Mannaerts BM | year = 2008| title = Corifollitropin alfa demonstrates similar pregnancy rates as compared to daily recombinant FSH treatment in a controlled ovarian stimulation regimen for IVF/ICSI | journal = Fertility and Sterility | volume = 90 | page = S75 | doi=10.1016/j.fertnstert.2008.07.864| doi-access = free }}{{cite journal | vauthors = Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC | title = 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 | journal = Human Reproduction | volume = 24 | issue = 12 | pages = 3063–3072 | date = December 2009 | pmid = 19684043 | pmc = 2777786 | doi = 10.1093/humrep/dep291 }}

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.{{cite journal | vauthors = Hervé V, Roy F, Bertin J, Guillou F, Maurel MC | title = 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 | journal = Endocrinology | volume = 145 | issue = 1 | pages = 294–303 | date = January 2004 | pmid = 14525910 | doi = 10.1210/en.2003-0595 | doi-access = free }}

In Women:

Used to induce final maturation of follicle and subsequent ovulation.{{Medical citation needed|date=December 2022}} Also used for luteal phase support.{{Medical citation needed|date=December 2022}}

In men:

Used to treat select cases of Hypogonadotropic Hypogonadism in adult males.{{Cite web|url=https://www.drugs.com/pro/pregnyl.html|title=Pregnyl - FDA prescribing information, side effects and uses|website=Drugs.com|access-date=2018-07-23|archive-date=2018-07-24|archive-url=https://web.archive.org/web/20180724032302/https://www.drugs.com/pro/pregnyl.html|url-status=live}} In off-label use, some urologists prescribe hCG in low doses in combination with testosterone replacement to preserve fertility.{{cite journal | vauthors = Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI | title = Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy | journal = The Journal of Urology | volume = 189 | issue = 2 | pages = 647–650 | date = February 2013 | pmid = 23260550 | doi = 10.1016/j.juro.2012.09.043 | url = https://www.auajournals.org/doi/abs/10.1016/j.juro.2012.09.043 | access-date = March 20, 2020 | url-status = live | archive-url = https://web.archive.org/web/20200320231454/https://www.auajournals.org/doi/abs/10.1016/j.juro.2012.09.043 | archive-date = March 20, 2020 }}

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