Identification

Name
Follitropin
Accession Number
DB00066  (BTD00099, BTD00064, BIOD00099, BIOD00064, DB09024)
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Hormones
Description

Follitropin is a human follicle stimulating hormone (FSH) preparation of recombinant DNA origin, which consists of two non-covalently linked, non-identical glycoproteins designated as the alpha- and beta- subunits. The alpha- and beta- subunits have 92 and 111 amino acids. The alpha subunit is glycosylated at Asn 51 and Asn 78 while the beta subunit is glycosylated at Asn 7 and Asn 24. Follitropin beta is produced in genetically engineered Chinese hamster cell lines (CHO). The nomenclature “beta” differentiates it from another recombinant human FSH product that was marketed earlier as follitropin alpha. Follitropin is important in the development of follicles produced by the ovaries. Given by subcutaneous injection, it is used in combination with human chorionic gonadotropin (hCG) to assist in ovulation and fertility. Follitropin may also be used to cause the ovary to produce several follicles, which can then be harvested for use in gamete intrafallopian transfer (GIFT) or in vitro fertilization (IVF). Numerous physio-chemical tests and bioassays indicate that follitropin beta and follitropin alpha are indistinguishable. However, a more recent study showed there is may be a slight clinical difference, with the alpha form tending towards a higher pregnancy rate and the beta form tending towards a lower pregnancy rate, but with significantly higher estradiol (E2) levels. Structural analysis shows that the amino acid sequence of follitropin beta is identical to that of natural human follicle stimulating hormone (FSH). Further, the ogliosaccharide side chains are very similar, but not completely identical to that of natural FSH. However, these small differences do not affect the bioactivity compared to natural FSH.

Protein structure
Db00066
Protein chemical formula
C975H1513N267O304S26
Protein average weight
22672.9 Da
Sequences
>Alpha chain
APDVQDCPECTLQENPFFSQPGAPILQCMGCCFSRAYPTPLRSKKTMLVQKNVTSESTCC
VAKSYNRVTVMGGFKVENHTACHCSTCYYHKS
>Beta chain
NSCELTNITIAIEKEECRFCISINTTWCAGYCYTRDLVYKDPARPKIQKTCTFKELVYET
VRVPGCAHHADSLYTYPVATQCHCGKCDSDSTDCTVRGLGPSYCSFGEMKE
Download FASTA Format
Synonyms
  • Follicle stimulating hormone
  • Follitrophin alfa
  • Follitrophin alpha
  • Follitrophin beta
  • Follitropin alfa
  • Follitropin alfa/beta
  • Follitropin alpha
  • Follitropin beta
  • Follitropin delta
  • Follitropin gamma
  • Follotropin recombinant
  • FSH
  • FSH alpha
  • FSH-a
  • FSH-b
  • FSH-beta
  • Recombinant human follicle stimulating hormone beta
  • Recombinant human follicle-stimulating hormone (r-HFSH)
  • rFSH-alpha
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BemfolaInjection, solution225 IU/0.375mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
BemfolaInjection, solution75 IU/0.125mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
BemfolaInjection, solution225 IU/0.375mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
BemfolaInjection, solution300 IU/0.50mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
BemfolaInjection, solution150 IU/0.25mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
BemfolaInjection, solution450 IU/0.75mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
BemfolaInjection, solution150 IU/0.25mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
BemfolaInjection, solution450 IU/0.75mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
BemfolaInjection, solution225 IU/0.375mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
BemfolaInjection, solution300 IU/0.50mlSubcutaneousFinox Biotech Ag2014-03-27Not applicableEu
International/Other Brands
Cinnal-F / Follistim (Organon)
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
PergoverisFollitropin (900 unit) + Lutropin alfa (450 unit)SolutionSubcutaneousEmd Serono, A Division Of Emd Inc., CanadaNot applicableNot applicableCanada
PergoverisFollitropin (150 unit) + Lutropin alfa (75 unit)Kit; Powder, for solutionSubcutaneousEmd Serono, A Division Of Emd Inc., Canada2015-10-22Not applicableCanada
PergoverisFollitropin (450 unit) + Lutropin alfa (225 unit)SolutionSubcutaneousEmd Serono, A Division Of Emd Inc., CanadaNot applicableNot applicableCanada
PergoverisFollitropin (300 unit) + Lutropin alfa (150 unit)SolutionSubcutaneousEmd Serono, A Division Of Emd Inc., CanadaNot applicableNot applicableCanada
Puregon 100 I.U.Follitropin (100 unit) + Sodium Chloride (1 ml)Liquid; Powder, for solutionIntramuscular; SubcutaneousOrganon Canada Ltd Ltee1997-10-082006-08-17Canada
Puregon 50 I.U.Follitropin (50 unit) + Sodium Chloride (1 ml)Liquid; Powder, for solutionIntramuscular; SubcutaneousOrganon Canada Ltd Ltee1997-10-082006-08-17Canada
Categories
UNII
076WHW89TW
CAS number
146479-72-3

Pharmacology

Indication

In women having been diagnosed with primary ovarian failure, it is used in combination with human chorionic gonadotropin (hCG) to assist in ovulation and fertility. In men with hypogonadotrophic hypogonadism, it is used to induce spermatogenesis. Follitropin may also be used to cause the ovary to produce several follicles, which can then be harvested for use in gamete intrafallopian transfer (GIFT) or in vitro fertilization (IVF).

Structured Indications
Not Available
Pharmacodynamics

Used for the treatment of female infertility, Follitropin beta or follicle stimulating hormone (FSH) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Follitropin beta is the primary hormone responsible for follicular recruitment and development.

Mechanism of action

Follitropin is a recombinant form of endogenous follicle stimulating hormone (FSH). FSH binds to the follicle stimulating hormone receptor which is a G-coupled transmembrane receptor. Binding of the FSH to its receptor seems to induce phosphorylation and activation of the PI3K (Phosphatidylinositol-3-kinase) and Akt signaling pathway, which is known to regulate many other metabolic and related survival/maturation functions in cells.

TargetActionsOrganism
AFollicle-stimulating hormone receptor
agonist
Human
Absorption

The absorption rate is the main driving force behind the pharmokinetics of Follitropin alpha as the rate of absorption was found to be slower than the elimination rate after administration subcutaneously and intramuscularly. The bioavailability is approximately 66-76%. The time to peak after subcutaneous injection in healthy volunteers was 8-16 hours in females and 11-20 hours in males.

Volume of distribution
  • 8 L [female subjects following intravenous administration of a 300 IU dose]
Protein binding
Not Available
Metabolism
Not Available
Route of elimination

Via liver and kidneys.

Half life

Circulation half life of 3-4 hours, elimination half life of 35-40 hours

Clearance
  • 0.01 1*h-1kg-1 [European women with a single intramuscular dose of 300 IU]
  • 0.01 1*h-1kg-1 [Japanese women with a single intramuscular dose of 300 IU]
Toxicity

Headaches, ovarian cysts, nausea and upper respiratory tract infections occurred in more than 10% of women in clinical trials. In men, the most serious adverse events reported were testicular surgery for cryptorchidism which existed prestudy, hemoptysis, an infected pilonidal cyst, and lymphadenopathy associated with an Epstein-Barr viral infection. Other concerns include overstimulation of the ovaries, pulmonary and vascular complications and multiple births. Post-marketing reports revealed hypersensitivity reactions including anaphylactoid reactions and asthma. Follitropin is contraindicated in pregnant women. No studies have been done in nursing mothers.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
No interactions found.
Food Interactions
Not Available

References

General References
  1. Goa KL, Wagstaff AJ: Follitropin alpha in infertility: a review. BioDrugs. 1998 Mar;9(3):235-60. [PubMed:18020563]
External Links
UniProt
P01225
Genbank
M16647
PubChem Substance
46508818
ChEMBL
CHEMBL1201692
Therapeutic Targets Database
DAP001028
PharmGKB
PA449693
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Follicle-stimulating_hormone
ATC Codes
G03GA05 — Follitropin alfaG03GA06 — Follitropin beta
AHFS Codes
  • 68:18.00 — Gonadotropins
FDA label
Download (468 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingTreatmentProgesterone Resistance1
1CompletedNot AvailableHealthy Volunteers1
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentBioequivalence1
1, 2Enrolling by InvitationTreatmentFemale Infertility Due to Diminished Ovarian Reserve1
2CompletedTreatmentAssisted Reproductive Technology therapy / Infertilities1
2CompletedTreatmentControlled Ovarian Stimulation1
2CompletedTreatmentFertilization1
2CompletedTreatmentInfertilities4
2TerminatedTreatmentHypogonadism / Olfacto genital dysplasia1
2TerminatedTreatmentOvulation induction therapy2
2Unknown StatusTreatmentInfertilities1
2Unknown StatusTreatmentPolycystic Ovaries Syndrome1
2, 3CompletedTreatmentMale Infertility1
3CompletedNot AvailableInfertilities1
3CompletedTreatmentAnovulatory cycle2
3CompletedTreatmentAnovulatory cycle / Hypothalamic-pituitary Dysfunction / Oligo-ovulation / Polycystic Ovarian Syndrome1
3CompletedTreatmentAnovulatory cycle / Infertilities1
3CompletedTreatmentAssisted Reproductive Techniques / Reproductive Technology, Assisted1
3CompletedTreatmentHypogonadism1
3CompletedTreatmentIn-Vitro Fertilization / Infertilities / Ovulation induction therapy1
3CompletedTreatmentInfertilities11
3CompletedTreatmentInfertilities / Ovulation induction therapy2
3Not Yet RecruitingTreatmentInfertility, Female / Polycystic Ovaries Syndrome1
3RecruitingTreatmentControlled Ovarian Simulation1
3RecruitingTreatmentInfertilities1
3RecruitingTreatmentInfertility, Female1
3TerminatedSupportive CareFertility / Follicle Stimulating Hormone Deficiency / Infertilities1
3WithdrawnTreatmentInfertilities1
4Active Not RecruitingTreatmentInfertilities1
4CompletedNot AvailableInfertilities1
4CompletedNot AvailableInfertilities / Premature Ovarian Failure (POF)1
4CompletedPreventionInfertilities1
4CompletedTreatmentAssisted Reproductive Technology therapy / Infertilities1
4CompletedTreatmentInfertile Women Undergoing Assisted Reproductive Technology (ART)1
4CompletedTreatmentInfertilities9
4CompletedTreatmentInfertilities / Polycystic Ovarian Syndrome1
4CompletedTreatmentInvitro Fertilization1
4CompletedTreatmentOvulation induction therapy1
4CompletedTreatmentSubfertility1
4Not Yet RecruitingTreatmentInfertilities2
4Not Yet RecruitingTreatmentInfertility, Female1
4Not Yet RecruitingTreatmentMale Infertility / Varicoceles1
4RecruitingSupportive CareAssisted Reproductive Technology therapy / Infertilities1
4RecruitingTreatmentEgg Donation1
4RecruitingTreatmentInfertilities2
4RecruitingTreatmentInfertility, Female2
4RecruitingTreatmentReproductive Techniques, Assisted1
4TerminatedTreatmentAssisted Reproductive Technology therapy2
4TerminatedTreatmentAssisted Reproductive Technology therapy / Intracytoplasmic Sperm Injection1
4TerminatedTreatmentAssisted Reproductive Technology therapy / Ovulation induction therapy1
4TerminatedTreatmentIdiopathic Hypogonadotropic Hypogonadism1
4TerminatedTreatmentInfertilities / Monofollicular Development1
4TerminatedTreatmentPatients for In Vitro Fertilization(IVF)Treatment1
4Unknown StatusTreatmentAneuploidy / Blastocyst Disintegration / Chemical Pregnancy / Complication of Implant / Embryo/Fetus Death1
4Unknown StatusTreatmentFemale Reproductive Problem / Infertilities1
4Unknown StatusTreatmentInfertilities2
Not AvailableActive Not RecruitingNot AvailableOocytes / Pregnancy Rate1
Not AvailableCompletedNot AvailableAnovulatory cycle1
Not AvailableCompletedNot AvailableAssisted Reproductive Technology therapy1
Not AvailableCompletedNot AvailableFertilization in Vitro1
Not AvailableCompletedNot AvailableInfertilities2
Not AvailableCompletedNot AvailableInfertility, Subfertility1
Not AvailableCompletedNot AvailableMultifollicular Stimulation1
Not AvailableCompletedNot AvailableNeonates / Pregnancy2
Not AvailableCompletedNot AvailableOvulation induction therapy1
Not AvailableCompletedNot AvailablePolycystic Ovaries Syndrome1
Not AvailableCompletedNot AvailablePregnancy1
Not AvailableCompletedScreeningPolycystic Ovaries Syndrome1
Not AvailableCompletedTreatmentCompare Pregnancy Rates Between FSH Stimulation and FSH and / GnRH Antagonist1
Not AvailableCompletedTreatmentIdiopathic Hypogonadotropic Hypogonadism1
Not AvailableCompletedTreatmentInfertilities2
Not AvailableCompletedTreatmentSubfertility1
Not AvailableEnrolling by InvitationTreatmentInfertilities1
Not AvailableNot Yet RecruitingTreatmentInfertilities2
Not AvailableRecruitingNot AvailableInfertilities2
Not AvailableRecruitingTreatmentFertility / Infertilities1
Not AvailableTerminatedNot AvailableInfertilities1
Not AvailableTerminatedNot AvailableMultifollicular Stimulation1
Not AvailableUnknown StatusNot AvailableGalactose intolerance / Premature Ovarian Failure (POF)1
Not AvailableUnknown StatusNot AvailableSubfertility1
Not AvailableUnknown StatusTreatmentComplications Associated With Artificial Fertilization / Female Infertility Due to Nonimplantation of Ovum1
Not AvailableUnknown StatusTreatmentInfertility, Female1

Pharmacoeconomics

Manufacturers
  • Organon usa inc
  • Emd serono inc
Packagers
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous150 IU/0.25ml
Injection, solutionSubcutaneous225 IU/0.375ml
Injection, solutionSubcutaneous300 IU/0.50ml
Injection, solutionSubcutaneous450 IU/0.75ml
Injection, solutionSubcutaneous75 IU/0.125ml
Injection, solutionIntramuscular; Subcutaneous150 [iU]/.5mL
Injection, solutionIntramuscular; Subcutaneous75 [iU]/.5mL
Injection, solutionSubcutaneous350 [iU]/.42mL
Injection, solutionSubcutaneous650 [iU]/.78mL
Injection, solutionSubcutaneous975 [iU]/1.17mL
Injection, powder, for solutionSubcutaneous1050 IU/1.75ml
Injection, powder, for solutionSubcutaneous300 IU/0.5ml
Injection, powder, for solutionSubcutaneous450 IU/0.75ml
Injection, powder, for solutionSubcutaneous75 IU
Injection, solutionSubcutaneous300 IU/0.5ml
Injection, solutionSubcutaneous900 IU/1.5ml
Powder, for solutionIntramuscular; Subcutaneous1200 unit
Powder, for solutionIntramuscular; Subcutaneous150 unit
Powder, for solutionIntramuscular; Subcutaneous33 mcg
Powder, for solutionIntramuscular; Subcutaneous37.5 unit
Powder, for solutionIntramuscular; Subcutaneous5.5 mcg
Powder, for solutionIntramuscular; Subcutaneous75 unit
Powder, for solutionIntramuscular; Subcutaneous77 mcg
SolutionSubcutaneous300 unit
SolutionSubcutaneous450 unit
SolutionSubcutaneous900 unit
KitSubcutaneous
Injection, solutionSubcutaneous300 [iU]/.5mL
Injection, solutionSubcutaneous450 [iU]/.75mL
Injection, solutionSubcutaneous900 [iU]/1.5mL
Kit; powder, for solutionSubcutaneous
SolutionSubcutaneous
Injection, solutionIntramuscular; Subcutaneous100 IU/0.5mL
Injection, solutionIntramuscular; Subcutaneous150 IU/0.5mL
Injection, solutionIntramuscular; Subcutaneous200 IU/0.5mL
Injection, solutionIntramuscular; Subcutaneous225 IU/0.5mL
Injection, solutionIntramuscular; Subcutaneous50 IU/0.5mL
Injection, solutionIntramuscular; Subcutaneous75 IU/0.5mL
Injection, solutionSubcutaneous150 IU/0.18mL
Injection, solutionSubcutaneous300 IU/0.36mL
Injection, solutionSubcutaneous600 IU/0.72mL
Injection, solutionSubcutaneous900 IU/1.08mL
SolutionIntramuscular; Subcutaneous100 unit
SolutionIntramuscular; Subcutaneous50 unit
SolutionSubcutaneous833 unit
SolutionSubcutaneous737 unit
Liquid; powder, for solutionIntramuscular; Subcutaneous
Prices
Unit descriptionCostUnit
Gonal-f rff 900 unit pen1409.62USD ml
Follistim AQ 900unt/1.08ml Solution 1 Cartridge = 1.17ml1366.71USD cartridge
Follistim AQ 600unt/0.72ml Solution 0.78ml Cartridge911.14USD cartridge
Gonal-f 450 unit Solution Vial733.0USD vial
Gonal-f rff 450 unit pen704.81USD pen
Gonal-f rff 300 unit pen469.87USD pen
Follistim AQ 300unt/0.36ml Solution 0.42ml Cartridge455.57USD cartridge
Follistim aq 300 unit cartridge438.05USD cartridge
Follistim aq 150 unit vial219.02USD vial
Gonal-f rff 75 unit vial117.47USD vial
Follistim aq 75 unit vial109.51USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5270057No1994-03-202011-03-20Us
CA2037884No2003-10-212011-03-08Canada
US7563763No1999-08-232019-08-23Us
US5929028No1998-01-142018-01-14Us
US7446090No1999-08-232019-08-23Us
US7741268No2004-04-022024-04-02Us

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)55 °CForastieri, H., Ingham, K.C. J. Biol. Chem. 257:7976-7981 (1982)
hydrophobicity-0.330Not Available
isoelectric point7.50Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
G-protein coupled peptide receptor activity
Specific Function
Receptor for follicle-stimulating hormone. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Induces cAMP production through the activation of PI3K-AKT and S...
Gene Name
FSHR
Uniprot ID
P23945
Uniprot Name
Follicle-stimulating hormone receptor
Molecular Weight
78264.07 Da
References
  1. Layman LC: Mutations in the follicle-stimulating hormone-beta (FSH beta) and FSH receptor genes in mice and humans. Semin Reprod Med. 2000;18(1):5-10. [PubMed:11299519]
  2. Leng N, Dattatreyamurty B, Reichert LE Jr: Identification of amino acid residues 300-315 of the rat FSH receptor as a hormone binding domain: evidence for its interaction with specific regions of FSH beta-subunit. Biochem Biophys Res Commun. 1995 May 16;210(2):392-9. [PubMed:7755615]
  3. Santa Coloma TA, Dattatreyamurty B, Reichert LE Jr: A synthetic peptide corresponding to human FSH beta-subunit 33-53 binds to FSH receptor, stimulates basal estradiol biosynthesis, and is a partial antagonist of FSH. Biochemistry. 1990 Feb 6;29(5):1194-200. [PubMed:2108722]
  4. Dattatreyamurty B, Reichert LE Jr: Identification of regions of the follitropin (FSH) beta-subunit that interact with the N-terminus region (residues 9-30) of the FSH receptor. Mol Cell Endocrinol. 1993 May;93(1):39-46. [PubMed:8319832]
  5. Lindau-Shepard B, Roth KE, Dias JA: Identification of amino acids in the C-terminal region of human follicle-stimulating hormone (FSH) beta-subunit involved in binding to human FSH receptor. Endocrinology. 1994 Sep;135(3):1235-40. [PubMed:8070368]
  6. Goa KL, Wagstaff AJ: Follitropin alpha in infertility: a review. BioDrugs. 1998 Mar;9(3):235-60. [PubMed:18020563]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on January 14, 2018 10:04