Recombinant FSH

Deep-dive

Recombinant FSH is produced by inserting the human FSH genes into mammalian cells which then secrete the protein. The two long-standing products, follitropin alfa (Gonal-F) and follitropin beta (Puregon, Follistim), are made in Chinese hamster ovary (CHO) cells. The newer follitropin delta (Rekovelle) is made in a human cell line (PER.C6), which gives it a glycosylation pattern closer to native human FSH and a slightly different pharmacokinetic profile. There's also corifollitropin alfa (Elonva), a long-acting modified FSH that can replace the first 7 days of daily injections with a single shot. All of these bind the same FSH receptor. Practically, the meaningful differences are dosing convenience, pen design, and how the dose is calculated, not the underlying biology.

The case for pure FSH over urinary preparations.

HMG (Human Menopausal Gonadotropin) contains both FSH and LH-like activity (mostly via small amounts of hCG). Recombinant FSH is pure FSH. The argument for rFSH is consistency: batch-to-batch potency is identical because it's made in a controlled bioreactor, while urinary HMG depends on what's recovered from postmenopausal donors. The argument against, at least in some IVF settings, is that the LH/hCG content in HMG may improve outcomes. The most recent Cochrane review of 42 trials in 9,606 couples found no overall difference in live birth between rFSH and urinary gonadotropins, but a small advantage for HMG/HP-HMG specifically when compared head-to-head. The differences are small enough that most clinics now choose based on the patient profile, the pen device, and cost rather than blanket preference.

Why FSH matters for men. LH (and its longer-acting analogue, hCG) drives Leydig cells to make testosterone. FSH drives Sertoli cells, which physically support and feed the developing sperm. You can get reasonable testosterone with hCG alone, but quantitatively normal sperm production usually needs FSH as well. In secondary hypogonadism (where the pituitary, not the testes, is the problem), the standard approach is hCG first for 3-6 months, then add rFSH or HMG if sperm don't appear in the ejaculate. A combined analysis of four clinical trials in men with hypogonadotropic hypogonadism found hCG plus rFSH induced spermatogenesis in 84% of patients. A retrospective study of 112 men with congenital hypogonadotropic hypogonadism found rFSH and HMG produced essentially identical spermatogenesis rates (both 85.7%) when added to hCG.

Timeline in men. The full sperm production cycle from spermatogonia to mature sperm is roughly 74 days, and from a fully shut-down state the testes have to rebuild Sertoli cell function first. In a case report of postpubertal hypogonadotropic hypogonadism, 150 IU rFSH three times weekly plus hCG produced first sperm in the ejaculate at 18 weeks and normal concentrations at 24 weeks. In a 2025 retrospective study of 65 men with prepubertal-onset HH, 82% achieved spermatogenesis on hCG plus rFSH, with baseline testicular volume the strongest predictor of success. The pattern is consistent across studies: men with larger baseline testicular volume respond fastest, men with very small testes (under 4 mL) take longer and sometimes need higher FSH doses.

Post-TRT and post-AAS recovery. rFSH sits in the same toolkit as hCG and SERMs (clomiphene, tamoxifen, enclomiphene) for HPG axis restart. A 2016 review on TRT-induced infertility outlines the standard algorithm: stop the suppressive compound, start hCG to wake up Leydig cells, add a SERM to push the pituitary back into producing its own LH and FSH, and add rFSH if FSH stays low and sperm don't return. For men coming off short courses of testosterone or single-compound cycles, hCG and a SERM are usually enough. For men coming off long, heavy AAS use, particularly multi-compound or 19-nor cycles (nandrolone, trenbolone), FSH from an external source is more often necessary because endogenous FSH recovery can lag for many months. rFSH and HMG perform similarly here; the choice is usually cost and pen convenience.

Varicocele and idiopathic male infertility. rFSH has been tested in men with subnormal sperm production not from hypogonadotropic hypogonadism. A randomised trial in 113 infertile men after varicocelectomy compared hCG, HMG, rFSH, and surgery alone over 3 months. Only the rFSH group improved all measured sperm parameters and pushed sperm concentration above 20 million/mL, with a 62.5% pregnancy rate versus 32% for hCG, 57% for HMG, and 0% for surgery alone. A Cochrane review of urinary and recombinant gonadotropins in idiopathic male infertility also found a roughly 4-fold higher spontaneous pregnancy rate per couple within three months of completing therapy compared to placebo. The evidence here is less robust than in HH, but the signal isn't zero.

Women: IVF stimulation. This is the largest single use case for rFSH. The goal is to grow multiple follicles to retrieval. Conventional dosing with follitropin alfa or beta starts at around 150-225 IU daily and is adjusted by ultrasound and oestradiol response. The newer follitropin delta uses a fixed individualised dose based on AMH and body weight, with no in-cycle adjustment. The ESTHER-1 phase 3 trial and its follow-ups in Japanese and Chinese populations showed individualised follitropin delta was non-inferior to follitropin alfa or beta for ongoing pregnancy and live birth, with roughly half the rate of moderate/severe OHSS in high-AMH women. The takeaway is that for women with high ovarian reserve (high AMH, PCOS phenotype), individualised follitropin delta is meaningfully safer; for women with average or low reserve, the choice between rFSH preparations matters much less. Across the board, live birth rates per fresh cycle with rFSH sit around 23-31%, with cumulative live birth across multiple cycles approaching 60%.

Women: ovulation induction outside IVF. In women who aren't ovulating because of hypothalamic or hypopituitary causes (often from low body fat, overtraining, prolonged stress, or pituitary issues), the natural FSH and LH signal is gone. Pure rFSH alone won't work well here because some LH activity is also needed for normal follicle steroidogenesis. In this setting, HMG (with its LH/hCG content) is usually preferred over pure rFSH. In women with anovulatory PCOS who haven't responded to letrozole or clomiphene, the opposite logic applies: LH is already high, so adding more LH activity via HMG can worsen androgen excess, and pure rFSH is the better choice. Starting doses for ovulation induction are typically 37.5-75 IU daily, much lower than IVF, with the goal of growing a single dominant follicle rather than many.

OHSS, the main risk in women. Ovarian hyperstimulation syndrome happens when the ovaries overrespond and leak fluid into the abdomen and lungs. The trigger for severe OHSS is the hCG given to mature the eggs, not the rFSH itself, but rFSH is what grows the excessive follicle pool that makes OHSS possible. Risk factors are young age, low BMI, PCOS, high AMH (above 3.5 ng/mL or roughly 25 pmol/L), and high antral follicle count. Modern protocols mitigate this with GnRH antagonist suppression, GnRH agonist triggers instead of hCG, freeze-all cycles, and (most recently) AMH-and-weight-based individualised dosing. Severe OHSS still occurs in 1-2% of cycles, and moderate/severe OHSS in around 3-8% under conventional dosing, with rates roughly halved under individualised follitropin delta dosing.

Multiple pregnancy. Rates of twin and higher-order pregnancy are elevated with rFSH. In the original Gonal-F IVF trials, around 40-44% of live births were multiples, though this depends heavily on the number of embryos transferred. Modern single embryo transfer protocols have substantially lowered this rate.

Immunogenicity. Theoretically a concern with any biologic. Anti-FSH antibody formation with follitropin delta across repeated cycles sits around 1%, none of which have shown neutralising capacity, and women with pre-existing antibodies have been treated safely. Allergic reactions including rare anaphylaxis have been reported in postmarketing surveillance of follitropin alfa but are very uncommon.

Older men, older women, and limitations. rFSH only works if there's a functional gonad to stimulate. In primary testicular failure (high baseline FSH and LH, damaged testes from chemo, radiation, mumps, Klinefelter, or simply age), no amount of rFSH will restart sperm production. The same applies to women with premature ovarian insufficiency or significantly diminished ovarian reserve, the eggs aren't there. There's no long-term wellness or anti-ageing use case for rFSH and no data on multi-year continuous use in healthy populations. It's a fertility tool, used in defined cycles.

Dosage:

• Men, adjunct to hCG for spermatogenesis (secondary hypogonadism, post-TRT, post-AAS): 75-150 IU subcutaneous, 2-3 times per week, added to existing hCG (typically 1,500-3,000 IU 2-3x weekly). Standard approach is hCG alone first for 3-6 months, then add rFSH if sperm haven't appeared in the ejaculate. Can go up to 300 IU three times per week if azoospermia persists

• Men, full induction in congenital hypogonadotropic hypogonadism: hCG 1,500-2,000 IU 2-3x weekly plus rFSH 150 IU three times weekly. Continue for at least 6-12 months. Expect testicular volume increase first (over 3-6 months), sperm in the ejaculate second (often 6-12 months in)

• Women, ovulation induction (hypothalamic causes, clomiphene/letrozole failure): typically starting at 37.5-75 IU subcutaneous daily, titrated by ultrasound and oestradiol monitoring. In women with PCOS, lower starting doses (37.5 IU) due to higher OHSS risk. Clinic-managed, not a self-administered protocol

• Women, IVF stimulation, conventional dosing (follitropin alfa/beta): 150-300 IU daily for 7-12 days as part of a long agonist, short, or antagonist protocol. Dose adjusted by response. Clinic-managed

• Women, IVF stimulation, individualised dosing (follitropin delta): fixed dose calculated from AMH and body weight, typically 6-12 µg daily with no in-cycle adjustment. The minimum is 6 µg, maximum 12 µg in most protocols. Best evidence for safety advantage in high-AMH women

• Women, long-acting (corifollitropin alfa): single 100 or 150 µg subcutaneous injection replacing the first 7 days of daily rFSH, followed by daily rFSH from day 8 if more stimulation is needed

• Injection method: subcutaneous in the belly fat or thigh. Modern preparations come in pre-filled multi-dose pens (Gonal-F Pen, Puregon Pen, Rekovelle Pen) that make self-injection straightforward. Refrigerated, used within the timeframe on the label

• Practical note for men: rFSH and HMG are roughly interchangeable as the FSH source. rFSH is purer and the pen devices are more convenient. HMG is cheaper per IU and has the small LH/hCG component built in. If you're already on hCG, the LH component of HMG is largely redundant, so rFSH is the cleaner choice. If you're not on hCG, HMG is the better single product

Here's what you can expect:

Side effects & risks:

• Injection site reactions. Mild redness, soreness, or bruising. Subcutaneous injection with pen devices is generally well-tolerated

• Headaches, bloating, fatigue, mood changes. Common at therapeutic doses in both sexes, usually mild and resolve when treatment stops

• Ovarian hyperstimulation syndrome (women). The serious risk specific to women. Symptoms: severe abdominal pain, bloating, rapid weight gain, nausea, vomiting, shortness of breath. Develops 7-10 days after trigger. Higher risk in women under 35, low BMI, PCOS, high AMH, high antral follicle count. Modern protocols (antagonist suppression, agonist triggers, freeze-all, AMH-based individualised dosing) have substantially reduced severe OHSS rates but it still occurs

• Multiple pregnancy. Real risk in women because rFSH can recruit more than one follicle. Twin and triplet pregnancy rates are higher than baseline. Modern protocols mitigate with careful monitoring, conservative dosing in ovulation induction, and single embryo transfer in IVF

• Ovarian torsion (women). Rare but documented. Enlarged ovaries during stimulation can twist on their pedicle. Sudden severe one-sided pelvic pain needs immediate evaluation

• Thromboembolism (women). Mainly in the setting of severe OHSS, where haemoconcentration and inflammatory mediators raise clotting risk. Rare at standard doses

• Estradiol elevation and gynecomastia (men). Possible because rFSH stimulation supports Sertoli cell aromatase activity, and if you're stacking with hCG that drives testosterone which converts to estradiol. Less of a concern than with high-dose hCG monotherapy, but worth tracking

• Allergic reactions. Rare. Mostly mild local reactions; anaphylaxis has been reported in postmarketing surveillance of follitropin alfa but is exceedingly uncommon. Anti-FSH antibodies form in around 1% of users with repeated cycles, none neutralising in the available data

• Transient liver enzyme abnormalities. Reported in some users, particularly in the setting of OHSS. Usually self-limiting

• Underlying contraindications: primary ovarian failure, primary testicular failure (it won't work), uncontrolled thyroid or adrenal dysfunction, pituitary or hypothalamic tumours unless treated, undiagnosed vaginal bleeding, ovarian cysts or enlargement not from PCOS, pregnancy, hormone-sensitive tumours of the reproductive tract

• Quality and sourcing. Pharmaceutical rFSH (Gonal-F, Puregon, Follistim, Rekovelle, Bemfola, Ovaleap) is highly characterised and reliably potent. The pen-based delivery means dose accuracy is much better than reconstituted vials. Research-grade or underground FSH varies wildly in actual potency and sterility, and as a protein it degrades easily with heat, light, and time. Sourcing matters more here than for small-molecule drugs