hCG

hCG shares an identical alpha subunit with LH, FSH and TSH, with specificity conferred by its 145-residue beta subunit. The beta subunit carries a C-terminal peptide extension with four O-linked glycosylation sites, which is why its terminal half-life is roughly 30 hours against LH's 20 to 30 minutes. Functionally it is a long-acting LH: it acts directly on the gonad and does not need the pituitary, which makes it effective even when the hypothalamic-pituitary axis is fully suppressed by exogenous testosterone or anabolic steroids. In men that means maintained intratesticular testosterone, preserved testicular volume and preserved spermatogenesis; in IVF it is the standard trigger for final follicular maturation. Its long duration is also its liability, since prolonged corpus luteum stimulation is the main driver of ovarian hyperstimulation syndrome.

Targets: LH/hCG receptor (LHCGR), Leydig cells, Theca and granulosa cells, Intratesticular testosterone

• · 250 to 500 IU per injection. Coviello's dose-ranging work showed 250 IU every other day fully maintained intratesticular testosterone in men on exogenous testosterone, so higher doses buy nothing but more aromatisation.
• · 1000 to 2500 IU per injection. The role here is to wake the testes up so that the pituitary signal restored by a SERM has something to act on. Doses above 3000 IU tend to desensitise Leydig cells rather than help.
• · 5000 to 10000 IU of urinary hCG, or 250 mcg of recombinant choriogonadotropin alfa (Ovidrel). This is the one context where hCG is genuinely dosed by mass rather than units.
• · 1500 to 2500 IU per injection, usually with recombinant FSH added after several months. This is the evidence-based fertility protocol, not gonadorelin.

Work out your exact syringe units →

• very commonElevated oestradiol— The dominant complaint - water retention, moodiness, nipple sensitivity. Dose-dependent.
• commonGynaecomastia— Downstream of the oestradiol rise, and slow to reverse once established.
• commonAcne and oily skin
• commonInjection-site pain— Subcutaneous is far more comfortable than intramuscular and works just as well.
• commonMood swings or irritability
• uncommonOvarian hyperstimulation syndrome— In women undergoing stimulation. Can be life-threatening; the long half-life is the reason.
• uncommonLeydig cell desensitisation— From sustained high doses, especially above 3000 IU repeatedly.
• rareThromboembolism— Reported in the context of ovarian stimulation.

• Prostate cancer or other androgen-dependent tumours.
• Precocious puberty.
• Known hypersensitivity to hCG.
• Untreated thyroid or adrenal insufficiency in fertility contexts.
• Pregnancy - it will also make any pregnancy test read positive for up to 10 days after a dose, which matters enormously in fertility cycles.

• redundantgonadorelin — Both preserve testicular function on TRT. hCG is the stronger and better-evidenced option; gonadorelin is the pituitary-dependent gentler one.
• synergyfollitropin — The standard combination for restoring spermatogenesis - hCG supplies the LH signal, FSH supplies the Sertoli cell signal.
• cautionAromatase inhibitors such as anastrozole — Frequently added to control hCG-driven oestradiol, but crushing oestradiol causes its own joint, libido and lipid problems. Lower the hCG dose first.
• conflictkisspeptin-54 — Alternative IVF triggers with opposite OHSS profiles; using both is self-defeating.
• synergyTestosterone replacement therapy — The core use case, offsetting exogenous-testosterone-induced testicular shutdown.

• · Total testosterone, free testosterone and oestradiol at baseline and 6 to 8 weeks in - oestradiol via a sensitive LC-MS assay, not the immunoassay.
• · Haematocrit, since hCG-driven testosterone raises it just as injected testosterone does.
• · Semen analysis at 3 and 6 months if fertility is the goal.
• · Testicular volume if maintenance is the goal.

Prescription drug in the US, EU and most of the world. It is not a federally controlled substance - despite frequent claims otherwise, hCG is not scheduled under 21 CFR 1308.13 and is not an anabolic steroid under 21 CFR 1300.01. The FDA has banned over-the-counter hCG weight-loss products, and WADA prohibits it in male athletes.

• Coviello et al. 2005, low-dose hCG maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression, JCEM (trial)
• Pregnyl (chorionic gonadotropin for injection) prescribing information (label)
• Ovidrel (choriogonadotropin alfa) prescribing information (label)
• Bhasin et al. 2018, Endocrine Society clinical practice guideline on testosterone therapy in men with hypogonadism (guideline)

The LH/hCG receptor is a Gs-coupled receptor with a large extracellular leucine-rich repeat domain, and hCG binds it with higher affinity and far greater persistence than LH does. Activation raises cyclic AMP, activates protein kinase A, and phosphorylates steroidogenic acute regulatory protein, which is the rate-limiting step in steroidogenesis - StAR moves cholesterol from the outer to the inner mitochondrial membrane, where CYP11A1 cleaves the side chain and the whole steroid cascade proceeds. In the Leydig cell that ends in testosterone, and the concentration achieved inside the testis is on the order of a hundredfold higher than serum, which is the entire reason intratesticular testosterone matters separately from the number on a blood test. Spermatogenesis depends on that intratesticular concentration, not on serum testosterone, and exogenous testosterone raises the latter while collapsing the former. That single fact explains the whole use case. There are two second-order consequences worth understanding. First, aromatase is expressed in Leydig cells, so driving intratesticular steroidogenesis hard raises oestradiol substantially more than injecting testosterone alone does - men who feel worse on hCG are usually oestrogen-high rather than hCG-intolerant, and halving the dose fixes it far more often than adding an aromatase inhibitor does. Second, the LH/hCG receptor downregulates and uncouples under sustained heavy stimulation, which is why repeated doses above about 3000 IU produce Leydig cell desensitisation and a falling response rather than a rising one. In the ovary, the same receptor on theca and granulosa cells drives final oocyte maturation, and the long half-life that is an advantage in men becomes the liability that produces ovarian hyperstimulation syndrome, because the corpora lutea keep being stimulated for days after they should have been left alone.

Oestradiol is the thing that goes wrong, and it goes wrong quietly - water retention, emotional lability, nipple tenderness, and by the time gynaecomastia is established it does not reverse on its own. The fix is almost always a lower dose. The second failure is dose inflation in restart protocols, where people run 5000 IU every other day on the theory that more signal must mean faster recovery, and instead desensitise the Leydig cell receptor and delay the recovery they are chasing. Anything above about 3000 IU repeatedly is counterproductive. The third is reconstitution damage: hCG is a glycoprotein, not a small rugged peptide, so foaming it by injecting diluent hard into the vial denatures it, and freezing the reconstituted solution destroys activity outright. Add diluent slowly down the glass wall and keep it in the fridge. The fourth is the pregnancy test problem, where a dose makes a test read positive for up to ten days and produces either false hope or a badly timed decision. The fifth, in women, is ovarian hyperstimulation syndrome, which is driven by exactly the long half-life that makes hCG useful in men and can be life-threatening.

• LH/hCG receptor (LHCGR) on Leydig cells — Higher affinity and much longer receptor occupancy than native LH; a specific Kd was not resolved here.

  Gs coupling, cyclic AMP, PKA and StAR phosphorylation, driving cholesterol into the mitochondrion and producing intratesticular testosterone at roughly a hundredfold serum concentrations. Preserves testicular volume and spermatogenesis even under full pituitary suppression.

• LHCGR on ovarian theca and granulosa cells

  Final follicular maturation and luteinisation. This is the ovulation trigger effect, and the prolonged version of it is what drives VEGF release and ovarian hyperstimulation syndrome.

• Leydig cell aromatase (indirect)

  Local conversion of the newly made androgen to oestradiol. The reason hCG raises oestradiol more than equivalent testosterone dosing does, and the source of most of the complaints.

• TSH receptor (weak cross-reactivity)

  Structural homology with TSH means very high hCG concentrations can weakly stimulate the thyroid. Clinically relevant in gestational trophoblastic disease and early pregnancy, essentially irrelevant at TRT-adjunct doses.

• Low-dose hCG dose-ranging study in men with testosterone-induced gonadotropin suppression 2 · 3 weeks · 2005

  Intratesticular testosterone measured by testicular aspiration in men made gonadotropin-suppressed by exogenous testosterone, across hCG doses of 125, 250 and 500 IU every other day. 250 IU every other day maintained intratesticular testosterone at baseline levels, which is where every sensible TRT-adjunct protocol gets its number.

• Concomitant hCG with testosterone replacement to preserve spermatogenesis Observational cohort · 2013

  Semen parameters in hypogonadal men on testosterone replacement with concurrent low-dose hCG. Spermatogenesis was preserved, which is the practical clinical claim rather than the mechanistic one.

Serum testosterone begins to rise within 24 hours of a dose and peaks around 48 to 72 hours, which is why every-other-day and three-times-weekly schedules exist. Because the terminal half-life is roughly 30 hours, repeated dosing accumulates and reaches steady state after about five to six days - the fourth or fifth injection is where the effect settles, not the first. Testicular volume recovers over 4 to 12 weeks in a man who has atrophied on testosterone. Spermatogenesis is the slow one: a full spermatogenic cycle takes roughly 74 days plus epididymal transit, so 3 to 6 months is the honest window before a semen analysis means anything, and men who retest at six weeks and panic are testing too early.

hCG plus recombinant FSH is the properly evidenced fertility combination: hCG supplies the LH signal to the Leydig cell, FSH supplies the Sertoli cell signal, and neither alone reliably restores spermatogenesis in a man who has been suppressed for years. hCG plus testosterone replacement is the core testicular-maintenance use and works well at 250 to 500 IU two or three times a week. hCG plus an aromatase inhibitor is extremely common and mostly a mistake - it treats a dose problem with a second drug, and men who end up with oestradiol in single figures feel considerably worse than men who simply took less hCG. hCG plus gonadorelin is redundant. In a restart, hCG before a SERM is the right sequence, because clomiphene or tamoxifen restore the pituitary signal and there needs to be a responsive testis waiting for it. In IVF, hCG and kisspeptin-54 are competing triggers and combining them destroys the reason to use kisspeptin at all. Note also that hCG is prohibited in male athletes by WADA and is detectable, which matters if you are tested.

Against gonadorelin, hCG is the stronger, better-evidenced and more reliable tool because it does not need a pituitary. Its costs are more oestradiol, a real desensitisation ceiling and, in some jurisdictions, more prescribing friction. Against recombinant LH, hCG is far cheaper and lasts vastly longer, which is why nobody uses recombinant LH outside specialist fertility work. Against recombinant FSH, they are complements rather than alternatives - hCG cannot supply the Sertoli cell signal. Against clomiphene as a way of keeping a man's own axis running, clomiphene works only if the axis is not already suppressed by exogenous testosterone, whereas hCG works regardless. And against the hCG diet, there is nothing to compare: randomised trials found it no better than the starvation diet it was paired with, the FDA has banned over-the-counter hCG weight-loss products, and the Pregnyl label states in capital letters that hCG has no effect on appetite or fat distribution.

$25–$120/month. A 5000 IU vial of compounded or pharmacy hCG has commonly run 30 to 90 dollars, and at 250 to 500 IU three times a week one vial covers roughly three to five weeks, so TRT-adjunct use is cheap. Fertility-dose protocols at 1500 to 2500 IU three times weekly burn through vials far faster and land in the hundreds per month. Ovidrel prefilled syringes are priced per trigger, not per month. Figures are indicative and were not verified in this session.

• ?The pharmacokinetic numbers here are for recombinant choriogonadotropin alfa from the Ovidrel label. Urinary-derived hCG products carry no pharmacokinetic section at all, and whether the two are kinetically equivalent unit-for-unit is not established.
• ?Protein binding is not reported for any hCG product.
• ?The time to steady state of about 6 days is derived from the roughly 30-hour terminal half-life rather than taken from a stated label value.
• ?Participant numbers and exact durations for the Coviello and Hsieh studies were not resolved from the abstracts in this session, so those fields are null rather than estimated.
• ?The 250 IU every-other-day figure comes from a small mechanistic study in healthy young men made suppressed experimentally, not from long-term outcome data in real TRT patients.
• ?Whether hCG preserves fertility as well as it preserves testicular volume over years rather than months is not well characterised.

• Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression Coviello AD, Matsumoto AM, Bremner WJ, Herbst KL, Amory JK, Anawalt BD, Sutton PR, Wright WW, Brown TR, Yan X, Zirkin BR, Jarow JP, Journal of Clinical Endocrinology and Metabolism, 2005 · PMID 15713727

  The study that put an actual number on the dose. It is also unusual for measuring intratesticular testosterone directly by aspiration rather than inferring it from serum, which is why it settled the question.

• 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

  The clinical follow-through: not just intratesticular testosterone but actual semen parameters preserved in men on testosterone replacement.

• OVIDREL (choriogonadotropin alfa) injection - FDA prescribing information DailyMed / FDA

  The only hCG product with a properly characterised pharmacokinetic section: 40 percent subcutaneous bioavailability, 5.9 L steady-state volume of distribution, 0.29 L/h clearance, 29-hour terminal half-life, one tenth excreted in urine.

• PREGNYL (chorionic gonadotropin for injection) - FDA prescribing information DailyMed / FDA

  The urinary-derived product label. Notable for what it lacks - no pharmacokinetic data at all - and for stating in capital letters that hCG has no effect on fat mobilisation, appetite or body fat distribution.

• Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA, Journal of Clinical Endocrinology and Metabolism, 2018 · PMID 29562364

  Sets out the monitoring framework - haematocrit, PSA, symptom review - that applies to anything raising testosterone, including hCG.