Follitropin alfa/beta

Follitropin is recombinant human FSH, a heterodimer of a 92-residue alpha subunit shared with LH, hCG and TSH and a 111-residue beta subunit that gives FSH its specificity. Alfa and beta differ only in glycosylation pattern from their respective cell lines and are clinically equivalent; follitropin delta (Rekovelle) is a newer human-cell-line product dosed by body weight and AMH rather than in international units. In women it recruits a cohort of follicles that would otherwise undergo atresia, which is the entire basis of controlled ovarian stimulation. In men with hypogonadotropic hypogonadism it supplies the Sertoli cell signal that hCG alone cannot, and the combination is what actually produces sperm - typically over 6 to 24 months, which is far slower than most people expect.

Targets: FSH receptor (FSHR), Granulosa cells, Sertoli cells, Follicular recruitment, Spermatogenesis

• · 150 to 300 IU daily for most patients, with 450 IU used in poor responders and 75 to 150 IU in women at high risk of hyperstimulation. Dosing is individualised on antral follicle count, AMH and age - a single number is meaningless here.
• · 75 to 150 IU daily, increased by 37.5 IU increments no more often than every 7 days. The goal is one dominant follicle, not many, so this is deliberately slower and gentler than an IVF protocol.
• · 75 to 150 IU three times weekly alongside hCG. Expect 6 to 24 months before meaningful sperm counts, and longer in men who never went through normal puberty.

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• very commonInjection-site reaction
• very commonAbdominal bloating and pelvic discomfort— From ovarian enlargement; expected during stimulation.
• commonHeadache
• commonOvarian cysts— Usually resolve spontaneously.
• commonMultiple pregnancy— Roughly 10 to 30 percent in stimulated cycles, with all the obstetric risk that carries.
• uncommonOvarian hyperstimulation syndrome— The defining risk of gonadotropin stimulation. Severe OHSS can cause ascites, thrombosis and renal failure and needs urgent care.
• uncommonGynaecomastia in men— Usually from the accompanying hCG rather than FSH itself.
• rareThromboembolism— Associated with OHSS and with pregnancy.

• Primary ovarian failure or primary testicular failure - there is no receptor-bearing tissue left to stimulate.
• Uncontrolled thyroid or adrenal dysfunction.
• Untreated pituitary or hypothalamic tumour.
• Hormone-dependent tumours of the ovary, uterus, breast, prostate or testis.
• Undiagnosed abnormal uterine bleeding.
• Ovarian cysts or enlargement not due to polycystic ovary syndrome.
• Pregnancy.

• synergyhcg — The standard pairing - FSH for follicular or Sertoli cell stimulation, hCG for the LH signal and for triggering.
• synergycetrorelix — The antagonist IVF protocol, preventing a premature LH surge during FSH stimulation.
• synergyganirelix — Same role as cetrorelix in the antagonist protocol.
• synergyClomiphene or letrozole — Frequently combined in mild-stimulation protocols to reduce the total gonadotropin dose.

• · Transvaginal ultrasound follicle counts and sizes every 2 to 3 days during stimulation.
• · Serum oestradiol through the stimulation phase - a steep rise flags hyperstimulation risk.
• · Cancel or coast the cycle rather than trigger if oestradiol and follicle numbers cross the unit's OHSS threshold.
• · In men, semen analysis every 3 months and serum testosterone.

Prescription drug worldwide, with several biosimilars now available.

• Gonal-f (follitropin alfa) prescribing information (label)
• Follistim AQ (follitropin beta) prescribing information (label)
• Practice Committee of ASRM, guidance on gonadotropin use and prevention of ovarian hyperstimulation syndrome (guideline)

The FSH receptor is Gs-coupled and sits on granulosa cells in the ovary and Sertoli cells in the testis, and the two jobs it does are quite different in character. In the ovary, FSH receptor activation raises cyclic AMP and PKA activity, which drives granulosa cell proliferation and, critically, upregulates aromatase (CYP19A1) so that androgen from the neighbouring theca cell is converted to oestradiol. That is the two-cell two-gonadotropin model, and it explains why FSH alone raises oestradiol: you are not adding oestrogen, you are building the machinery that makes it. FSH also upregulates LH receptors on granulosa cells as follicles mature, which is what makes those follicles competent to respond to an ovulatory trigger later - so FSH is preparing the ground for the hCG or agonist trigger that follows. Controlled ovarian stimulation works by keeping FSH above the threshold for follicular recruitment for longer than the natural cycle does, rescuing follicles that would otherwise undergo atresia and producing a cohort rather than a single dominant follicle. In the testis, the same receptor on Sertoli cells supports spermatogenesis, and this is the arm that hCG cannot supply - which is precisely why male fertility restoration protocols add recombinant FSH to hCG after several months when sperm counts stay low. Two practical pharmacokinetic points follow from the label. Bioavailability is 66 percent but with a standard deviation of 39 percent, so identical doses produce very different exposures. And with a 24 to 41 hour terminal half-life on daily dosing, the drug accumulates and reaches steady state after about five to seven days, which is why the ovarian response builds through a stimulation cycle rather than appearing at once.

Over-response is the thing that hurts people. Too high a starting dose in a woman with high AMH and a high antral follicle count produces a large follicular cohort, a steeply climbing oestradiol and a real risk of ovarian hyperstimulation syndrome, which in its severe form causes third-spacing, haemoconcentration, thrombosis and occasionally death. This is why AMH and antral follicle count before starting are worth more than any dosing table, and why the modern answer to an over-response is a GnRH agonist trigger and a freeze-all rather than pressing on with hCG. Under-response is the other failure and is less dangerous but more common in older women and those with diminished reserve, and it is not usually fixed by simply going higher. Multiple pregnancy is a genuine risk in ovulation induction cycles where all mature follicles remain in play. Practically, the 66 percent bioavailability with a 39 percent standard deviation means dose-response is only loosely predictable between individuals, so monitoring is not optional. Pen devices reduce dosing errors substantially compared with vials and syringes.

• FSH receptor (FSHR) on ovarian granulosa cells — Physiological FSH receptor agonism; specific affinity values were not resolved here.

  Gs coupling, cyclic AMP and PKA signalling, granulosa proliferation and aromatase upregulation. Produces multifollicular recruitment and rising oestradiol, and upregulates granulosa LH receptors so the follicles can respond to a trigger.

• FSH receptor on testicular Sertoli cells

  Supports spermatogenesis. The arm hCG does not supply, and the reason the evidence-based male fertility protocol is hCG plus FSH rather than hCG alone.

• Aromatase (CYP19A1), indirect

  Upregulated in granulosa cells. The mechanistic reason oestradiol climbs steeply during stimulation and the reason oestradiol is the monitoring marker.

Follicular recruitment begins within days of starting daily injections, and with a 24 to 41 hour terminal half-life the drug accumulates to steady state over about five to seven days - which is precisely when the follicular cohort becomes visible on ultrasound. A typical stimulation phase runs 8 to 12 days to the trigger. Oestradiol climbs through that period and is the day-to-day steering signal. Retrieval follows 34 to 36 hours after the trigger. In male use the timescale is entirely different: spermatogenesis takes roughly 74 days plus epididymal transit, so meaningful semen changes take 3 to 6 months and full assessment takes 6 to 12 months. Judging male FSH therapy at six weeks is judging it far too early.

In female fertility, follitropin is the stimulation backbone and everything else in the cycle is built around it: a GnRH antagonist such as cetrorelix or ganirelix added mid-stimulation to prevent a premature LH surge, then a trigger with hCG, a GnRH agonist, or in trial settings kisspeptin-54, then luteal progesterone support. Human menopausal gonadotropin is sometimes used instead of or alongside pure FSH to supply LH activity, which matters in women with profound hypogonadotropic hypogonadism where there is no endogenous LH at all. In male fertility, the established combination is hCG first for several months to restore intratesticular testosterone, with recombinant FSH added if sperm counts remain low - not the other way round, and not FSH alone. Adding an aromatase inhibitor is sometimes done in male protocols to manage oestradiol, and the same warning applies as with hCG: lower the driving dose before crushing oestrogen.

Against urinary-derived FSH and human menopausal gonadotropin, recombinant follitropin is more consistent batch to batch and contains no LH activity, which is an advantage when you want pure FSH and a disadvantage in women with no endogenous LH at all - hence menotropins retaining a role. Follitropin alfa and follitropin beta differ in glycosylation and manufacturing but are clinically interchangeable in practice. Against hCG, this is a complement rather than an alternative: hCG is the LH signal and FSH is the Sertoli or granulosa signal, and neither substitutes for the other. Against clomiphene for ovulation induction, injectable FSH is far more powerful, far more expensive and carries much higher multiple-pregnancy and OHSS risk, which is why clomiphene or letrozole remain first-line in simple anovulation and gonadotropins are reserved for when those fail.

$1500–$5000/month. Recombinant FSH is the most expensive component of an IVF cycle by a wide margin. US pricing has commonly run 60 to 100 dollars per 75 IU, and a stimulation cycle using 150 to 300 IU daily for 8 to 12 days lands in the low-to-mid thousands. Biosimilars have brought this down somewhat. Male fertility protocols run at lower daily doses but for many months, which accumulates. Figures are indicative and were not verified in this session.

• ?Protein binding is not reported for follitropin alfa.
• ?Metabolism is explicitly stated as not studied in humans in the label, so any specific claim about its metabolic fate goes beyond the regulatory record.
• ?The tmax figure of 14 hours is the midpoint of the label's 8 to 20 hour range, which varies by population.
• ?The 66 percent bioavailability carries a standard deviation of 39 percent, which is so wide that the central value should not be used to predict an individual's exposure.
• ?The time to steady state of 5 days is inferred from the terminal half-life and the label's note that steady state was measured after the seventh daily dose.
• ?No specific registration trials are listed here because follitropin's approval rests on a large and old body of fertility trial evidence that I did not resolve to individual named studies in this session.
• ?Follitropin beta and biosimilar products have their own labels and pharmacokinetic data that were not reviewed here; the numbers on this page are for follitropin alfa specifically.
• ?Cost figures are indicative and were not verified in this session.

• GONAL-F (follitropin alfa for injection) - FDA prescribing information DailyMed / FDA

  Source of the 66 plus or minus 39 percent bioavailability, the 8 to 20 hour tmax, the 10 L volume of distribution, 0.7 to 0.9 L/h apparent clearance, the 24 to 41 hour terminal half-life, and the label's admission that metabolism has not been studied in humans.

• Gonadotrophin-releasing hormone antagonists for assisted reproductive technology Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ, Cochrane Database of Systematic Reviews, 2016 · PMID 27126581

  Included because follitropin is always given inside a protocol, and this review defines the protocol architecture - antagonist versus agonist - that determines how it is used.

• Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI, The Journal of Urology, 2013 · PMID 23260550

  Context for the male use case. hCG handles the Leydig cell; FSH is what gets added when hCG alone does not restore spermatogenesis.