FSH (Follitropin)

The pituitary gonadotropin that drives ovarian follicle maturation and Sertoli cell function, licensed in the United States as recombinant follitropin alfa and follitropin beta and as urine-derived menotropins for fertility indications.

Also referenced as: Follicle-Stimulating Hormone, Follitropin, Follitropin Alfa, Follitropin Beta, Urofollitropin, Menotropins, Human Menopausal Gonadotropin, HMG, Gonal-f, Follistim, Menopur

What is FSH (Follitropin)?

Follicle-stimulating hormone is a heterodimeric glycoprotein secreted by anterior pituitary gonadotropes, assembled from the 92-amino-acid alpha subunit shared with LH, TSH, and hCG plus a 111-amino-acid FSH-specific beta subunit, held together non-covalently and N-glycosylated to roughly 30 kDa. The subunit lengths are not an inference — both approved recombinant labels state them outright. It is a glycoprotein rather than a synthetic peptide: licensed material is either extracted from human urine or expressed in Chinese hamster ovary cells, and neither route is reachable by the solid-phase chemistry that produces most compounds in this library.

That manufacturing reality shapes how FSH activity reaches the research market, but it does not keep it out. What is genuinely absent is recombinant follitropin: no research-chemical vendor sells Gonal-f-equivalent or Follistim-equivalent material, because expressing and purifying a correctly paired CHO-cell glycoprotein is not something a peptide house does. What is very much present is HMG — human menopausal gonadotropin, the urine-derived menotropin preparation that carries 75 IU of FSH activity per vial alongside 75 IU of LH activity. HMG 75 IU vials are a routine research-market SKU, carried by multiple vendors tracked here in the same rough price band as mainstream research peptides. So the honest picture is not “FSH is absent from the gray market” but “the gray market carries the urinary, mixed-activity form of it, and none of the recombinant single-hormone products.”

How it works

• FSH receptor agonism on granulosa and Sertoli cells — FSH binds FSHR, a class A G protein–coupled receptor with a large leucine-rich-repeat ectodomain; the 2.9 Å structure of FSH bound to the receptor’s extracellular hormone-binding domain shows the hormone held in a hand-clasp fashion by an elongated, curved receptor across a buried interface of about 2,600 Ų with high charge density (Fan & Hendrickson, Nature, 2005, 433(7023):269–277). Receptor occupancy raises cAMP, activates protein kinase A, phosphorylates CREB, and induces aromatase and StAR in human granulosa cells (Jiang et al., Journal of Clinical Endocrinology & Metabolism, 2015, 100(6):E852–E860)
• A cystine-knot heterodimer, active only when assembled — both chains adopt a central cystine-knot fold from which three beta-hairpins extend, and the two subunits associate very tightly in a head-to-tail arrangement held by non-covalent contacts; the alpha-subunit Asn52 glycan forms an intersubunit hydrogen bond with beta-Tyr58, a plausible mechanism for how that carbohydrate stabilizes the heterodimer (Fox et al., Molecular Endocrinology, 2001, 15(3):378–389). Biological activity is conferred only by the assembled dimer — isolated subunits are not bioactive (Kumar et al., Nature Genetics, 1997, 15(2):201–204)
• Glycosylation sets potency, not just half-life — hypo-glycosylated hFSH21/18 is substantially more effective than fully glycosylated hFSH24 at stimulating cAMP accumulation, PKA activity, CREB phosphorylation, aromatase and StAR expression, and estrogen and progesterone output in human granulosa cells; the physiological glycoform mix shifts with age, with hypo-glycosylated forms declining in older women (Jiang et al., Journal of Clinical Endocrinology & Metabolism, 2015, 100(6):E852–E860)
• Loss-of-function experiments define what FSH is actually required for — Fshb-null female mice are infertile with folliculogenesis blocked before antral follicle formation, while null males remain fertile despite small testes (Kumar et al., Nature Genetics, 1997, 15(2):201–204). The human picture matches: FSH beta-subunit mutations cause delayed puberty and hypogonadism (Layman et al., New England Journal of Medicine, 1997, 337(9):607–611), whereas men homozygous for an inactivating FSHR mutation show variable suppression of spermatogenesis rather than uniform infertility (Tapanainen et al., Nature Genetics, 1997, 15(2):205–206)

Research status

FSH has one of the deepest regulatory and trial records of any hormone in this library — but that depth sits almost entirely inside reproductive medicine, and the areas outside it are either negative, unregistered, or pointed in the opposite direction.

Approved indications. Recombinant follitropin alfa (Gonal-f, initial U.S. approval 1997) is indicated for induction of ovulation and pregnancy in oligo-anovulatory infertile women whose infertility is functional and not due to primary ovarian failure; for development of multiple follicles in ovulatory infertile women in assisted reproductive technology cycles; and for induction of spermatogenesis in infertile men with primary and secondary hypogonadotropic hypogonadism whose infertility is not due to primary testicular failure. Follitropin beta (Follistim AQ, initial U.S. approval 1997) carries the same three-part indication set. Menotropins (Menopur, initial U.S. approval 1975) are indicated for development of multiple follicles and pregnancy in ovulatory women as part of an ART cycle.

Urinary versus recombinant sources. Menotropins — human menopausal gonadotropin, or hMG — are extracted from the urine of postmenopausal women and standardized to 75 International Units of FSH activity and 75 IU of LH activity per vial, with the labeling noting that hCG is detected in the product. Urofollitropin was the purified urinary FSH preparation, sold in the U.S. as Bravelle. Recombinant follitropin alfa and beta are single defined glycoproteins produced in CHO cell lines with no LH activity. On outcomes, this comparison was re-run recently: the Cochrane review was updated in July 2026 and now pools 59 trials in 18,119 women. Against HMG and highly purified HMG, live birth is probably lower with rFSH (OR 0.83, 95% CI 0.73–0.95; 15 studies, 4,793 participants, moderate certainty) and OHSS probably higher (OR 1.42, 95% CI 1.12–1.80; 37 studies, 9,813 participants). Against highly purified urinary FSH there is probably little or no difference in live birth (OR 1.02, 95% CI 0.86–1.21). The 2011 version of the same review, working from 42 trials in 9,606 couples, had reported no overall live-birth difference between rFSH and all other gonadotropins pooled together (OR 0.97, 95% CI 0.87–1.08) — a null that the newer source-specific analysis has now pulled apart (Berkhout et al., Cochrane Database of Systematic Reviews, 2026, CD005354.pub3; van Wely et al., 2011, CD005354.pub2).

Male hypogonadotropic hypogonadism. Warne et al. combined data from four Phase 3, open-label, non-comparative trials in Australia, Europe, Japan, and the United States covering 100 men with complete idiopathic or acquired hypogonadotropic hypogonadism, treated with hCG for three to six months and then with hCG plus recombinant human FSH at 150 IU three times weekly for up to 18 months. Of the 81 men who remained azoospermic but reached normal serum testosterone after hCG pretreatment, 68 (84.0%) achieved spermatogenesis; the authors concluded that r-hFSH with hCG restores fertility in the majority of such men (Fertility and Sterility, 2009, 92(2):594–604). The design was uncontrolled, so the comparison is against natural history rather than a randomized arm.

Idiopathic male infertility — encouraging but thin. Attia et al. identified six randomized trials in 456 men. Live birth was 27% with gonadotropin versus 0% without, but from a single 30-participant study (Peto OR 9.31, 95% CI 1.17–73.75), rated very low quality. Spontaneous pregnancy was 16% versus 7% across five studies in 412 men (Peto OR 4.94, 95% CI 2.13–11.44, I² = 0%), rated moderate quality. No significant difference appeared when ICSI or IUI was performed. The review’s conclusion was that the data are encouraging but insufficient for final conclusions, and that large multi-centre trials are needed (Cochrane Database of Systematic Reviews, 2013, CD005071). Santi et al. reached a similar place from 15 controlled studies (614 men treated, 661 controls), reporting an odds ratio of roughly 4.5 (95% CI 2.17–9.33) for spontaneous pregnancy and 1.60 (95% CI 1.08–2.37) for pregnancy after ART, with improved sperm concentration but no significant increase in testicular volume — while noting that the heterogeneity and high risk of bias limit the strength of the result, that no precise criteria exist to guide FSH administration, and that use in male infertility should therefore be cautious (Endocrine Connections, 2015, 4(3):R46–R58).

Programs that stalled, or that stopped at the U.S. border. Corifollitropin alfa, a long-acting FSH carrying hCG’s C-terminal peptide, has been authorised in the European Union as Elonva since 25 January 2010, where a single dose covers seven days — but it has never been approved in the United States, and no corifollitropin application appears in FDA’s Drugs@FDA records at all. Follitropin delta, expressed in a human cell line and dosed by mass with individualization based on anti-Müllerian hormone and body weight, met its co-primary endpoints of ongoing pregnancy rate and ongoing implantation rate against conventional follitropin alfa in the 1,329-patient ESTHER-1 trial — a non-inferiority result at a −8.0% margin, not a superiority one (Nyboe Andersen et al., Fertility and Sterility, 2017, 107(2):387–396.e4). It has been authorised in the EU as Rekovelle since 12 December 2016 but likewise has no U.S. application on file. The 2026 Cochrane update now pools three to four trials against it and finds probably little or no difference in live birth versus conventional rFSH, with OHSS probably higher on rFSH (OR 1.62, 95% CI 1.18–2.23). Bravelle, the urinary urofollitropin product, was voluntarily recalled by Ferring for subpotency — FDA’s enforcement record shows the recall initiated 9 September 2015 covering 32,341 vials distributed nationwide, classified Class III on 14 October 2015 — and FDA product records now list the 75 IU vial as discontinued.

The bone and fat literature runs the other way. Sun et al. reported that neither FSHβ-null nor FSHR-null mice lose bone despite severe hypogonadism, that bone mass is increased in haploinsufficient FSHβ+/− mice with normal ovarian function, and that FSH acts on Gi2α-coupled receptors on osteoclasts and their precursors to enhance osteoclast formation and function (Cell, 2006, 125(2):247–260). Liu et al. later showed that a polyclonal antibody against the FSH beta subunit induced beiging of white adipose tissue, activated brown fat, and sharply reduced adiposity in mice (Nature, 2017, 546(7656):107–112). Both lines argue for blocking FSH rather than administering it, both remain preclinical, and no human trial of FSH blockade appears in the registry.

Trial registry picture. ClinicalTrials.gov lists 382 studies naming follitropin as an intervention (August 2026), distributed as roughly 227 under infertility, 25 under polycystic ovary syndrome, 11 under hypogonadotropic hypogonadism, 10 under male infertility, six under obesity, and none under osteoporosis. By phase there are about 91 Phase 4, 68 Phase 3, and 41 Phase 2 records — the profile of a mature reproductive-medicine portfolio rather than an exploratory one. The obesity-tagged records are studies of ovarian stimulation in patients with obesity and of FSH physiology after menopause, not tests of FSH as a weight intervention.

Common dosage forms

• Recombinant lyophilized vials — Gonal-f as multi-dose vials of 450 IU and 1,050 IU, and Gonal-f RFF as a 75 IU single-dose vial, reconstituted before subcutaneous injection.
• Recombinant prefilled multi-dose pens — Gonal-f RFF Redi-ject in 300 IU/0.5 mL, 450 IU/0.75 mL, and 900 IU/1.5 mL presentations, with a 150 IU/0.25 mL presentation also listed in FDA product records.
• Recombinant cartridges for a reusable pen — Follistim AQ at 300 IU/0.36 mL, 600 IU/0.72 mL, and 900 IU/1.08 mL, delivered through the Follistim Pen.
• Urinary lyophilized vials — Menopur, each vial standardized to 75 IU of FSH activity and 75 IU of LH activity, reconstituted with sterile 0.9% sodium chloride. Bravelle used the same 75 IU per-vial format before its U.S. withdrawal.
• Mass-dosed presentation outside the U.S. — follitropin delta is supplied as a prefilled pen dosed in micrograms rather than International Units, so its numbers are not comparable to IU-labeled products.
• Research-market HMG vials — the form FSH activity actually takes in research catalogs is HMG 75 IU: a lyophilized menotropin vial mirroring the licensed Menopur format, carrying LH activity alongside the FSH and sold without the bioassay standardization, WHO reference calibration, or lot-release testing that define the licensed product.
• Laboratory reagent grade — native and recombinant FSH protein sold by life-science suppliers in microgram quantities as assay standards and cell-culture reagent. This is bench material for in vitro work, and it is the only route by which genuine recombinant follitropin reaches the bench outside the prescription channel.

Key considerations

• Prescription biologic, not a research compound. Every U.S. FSH product is prescription-only and, since March 23, 2020, licensed under the Public Health Service Act rather than approved as an NDA: FDA records now list Gonal-f as BLA 020378, Gonal-f RFF as BLA 021765, Gonal-f RFF Redi-ject as BLA 021684, Follistim AQ as BLA 021211, and Menopur as BLA 021663. No follitropin biosimilar is approved in the United States — every follitropin application on file belongs to one of the two originator sponsors — even though the European market has biosimilars established enough that the 2026 Cochrane review pools eight trials against them. The compounding exemptions that apply to small-molecule drugs do not extend to licensed biologics.
• Potency here is a bioassay number, not a purity number. FSH is dosed in International Units traceable to WHO reference standards — the menotropin label cites the Fourth International Standard for Urinary FSH and Urinary LH — and the recombinant and menotropin labels alike define biological activity by an in vivo rat ovarian weight assay, the method introduced by Steelman and Pohley in 1953 (Endocrinology, 53(6):604–616). Because activity depends on correct subunit pairing and glycoform composition, a mass-and-purity certificate of the kind issued for synthetic peptides demonstrates nothing about biological potency. This is the sharpest practical point on the page: an HMG 75 IU research vial states an IU number that only a rat bioassay could substantiate, and the certificates circulating in that market do not run one. The 2015 Bravelle recall shows that potency can fail even inside a licensed supply chain that does.
• Urinary and recombinant material differ in composition, and the outcome data now favor the urinary side. Menotropins carry both FSH and LH activity plus detectable hCG; recombinant follitropins are single glycoproteins with no LH activity. The 2026 Cochrane update finds live birth probably lower and OHSS probably higher with rFSH than with HMG/HP-HMG, and little or no difference against highly purified urinary FSH — so a blanket claim that recombinant is superior inverts the current evidence rather than merely overstating it.
• Naming confusions are unusually dense. Follistim (follitropin beta) is not follistatin, an unrelated activin-binding protein sold in the research market as Follistatin-344. Urofollitropin is urine-derived FSH, while follitropin alfa and beta are recombinant. Menotropins and hMG are not pure FSH — an HMG vial delivers roughly equal FSH and LH activity, so it is not a substitute for an FSH-only product and will not reproduce an FSH-only protocol. Follitropin delta is dosed in micrograms rather than IU, so a small-looking number is not a small dose. And FSH the hormone should not be conflated with FSHR, its receptor, or with the unrelated “FSHD” abbreviation used for facioscapulohumeral muscular dystrophy in the literature.
• Labeled safety signals belong to ovarian stimulation as a procedure. Approved labeling describes ovarian hyperstimulation syndrome with rapid fluid accumulation in the peritoneal cavity and thorax, thromboembolic events including pulmonary embolism and cerebral vascular occlusion (stroke), serious pulmonary conditions such as acute respiratory distress syndrome, ovarian torsion, ectopic pregnancy and spontaneous abortion, rare reports of ovarian neoplasms, and multiple births in 20% of live births after ovulation induction and 35.1% after ART.