HMG

HMG (human menopausal gonadotropin, also called menotropin) is an injectable fertility hormone extracted from the urine of postmenopausal women. It supplies the two gonadotropin signals the pituitary normally sends to the gonads: follicle-stimulating hormone (FSH), which matures eggs and the cells that support sperm development, and luteinizing hormone (LH) activity, which drives the androgen step of steroid production. In highly purified products such as Menopur, most of that LH-type activity is carried by human chorionic gonadotropin (hCG) of placental origin rather than pituitary LH ³.

The concept is older than the modern drug. Avicenna's Canon mentioned urine, a gonadotropin-containing fluid, for stimulating ovulation centuries ago ²¹. Today's HMG is dosed in international units (IU) of FSH bioactivity and comes as a lyophilized powder or a ready-to-use pen, with the two forms shown clinically equivalent ².

The research base is unusually large for a fertility drug, anchored by a Cochrane network of 59 randomized trials covering 18,119 women ¹. HMG is studied mainly for:

• IVF and ICSI ovarian stimulation: the reference gonadotropin in assisted reproduction ¹.
• Ovulation induction: for anovulatory infertility, including PCOS and cycles resistant to oral agents ⁹.
• Male hypogonadotropic hypogonadism: combined with hCG to induce sperm production in gonadotropin-deficient men ⁶.
• Frozen embryo transfer preparation: letrozole plus HMG delivers live-birth rates comparable to hormone-replacement cycles with fewer obstetric complications ¹⁰.

Dosing is set per protocol, not per kilogram of body weight, and every stimulation is titrated against ultrasound and estradiol response ¹¹.

HMG substitutes for the two-hormone drive the pituitary gland normally sends to the gonads, which is why it works when that drive is deficient or when extra follicle growth is the goal.

FSH binds receptors on granulosa cells, the ovarian cells that surround and nurse a growing egg, and on Sertoli cells in the testis. It switches on a cAMP/PKA signaling cascade that drives follicle recruitment, aromatase production, and estradiol synthesis ²⁷. The LH activity in HMG binds a second receptor on theca cells, the ovarian cells that make androgens. Those androgens travel to the granulosa cells, where the enzyme aromatase converts them to estrogen. This two-cell, two-hormone arrangement is the standard model of gonadal steroid production, and HMG delivers both halves at once ³.

Two findings show the components must work together:

• In men, HMG alone did little in gonadotropin-deficient patients. Only when hCG was added did the full sperm-producing epithelium mature ³¹.
• Response tracks receptor status. In infertile men, 11 of 23 with detectable testicular FSH receptors responded to HMG plus hCG, versus 0 of 13 without them ²⁴.

Products are not interchangeable at the signaling level. Two HMG preparations show divergent early intracellular signaling in vitro ³⁴, and granulosa-cell gene expression differs between HMG- and recombinant-FSH-stimulated cycles ³⁵. Even a patient's genetics can matter: GRIA1 gene variants associate with ovarian response in some populations ³⁶.

The headline effect data come from a 2026 Cochrane review of 59 randomized trials. Against recombinant FSH (rFSH), HMG is associated with higher live-birth rates and a lower risk of ovarian hyperstimulation syndrome (OHSS), the main serious complication of stimulation:

• Live birth: rFSH had 17% lower odds of live birth versus HMG or highly purified HMG (OR 0.83), equivalent to about 20% higher odds with HMG. Clinical pregnancy runs in the same direction (OR 0.87) ¹.
• OHSS: rFSH carries 42% higher odds (OR 1.42, 95% CI 1.12-1.80), moderate-certainty evidence ¹.

The picture is not one-sided. A 2:1 combination of recombinant FSH and recombinant LH retrieves about 1.4 more oocytes per cycle and achieves 18% higher clinical pregnancy than highly purified HMG alone in a systematic review ¹⁹. In real-world data, adding HP-hMG to rFSH reaches pregnancy rates comparable to rFSH alone despite worse baseline characteristics, with lower OHSS in frozen-transfer cycles (6.9% vs 13.2%) ²⁰.

Population-specific findings:

• Male hypogonadotropic hypogonadism: hCG plus HMG or rFSH produced detectable sperm in the ejaculate in 85.7% of 112 treated men ⁶. In adolescents, hCG/HMG produced faster penile growth at 3 months and higher testosterone at 6-12 months than a GnRH pump ⁷. In an older series, sperm appeared at a mean of about 19 months of therapy ²³, and a case report documents restored spermatogenesis after anabolic-steroid-induced azoospermia ²⁶.
• PCOS resistant to oral agents: step-up HMG produced a dominant follicle in only 28.2% of cycles versus 93.3% after laparoscopic ovarian drilling, so resistant patients often switch strategies ⁹.
• Frozen embryo transfer: letrozole plus HMG matches hormone-replacement therapy for live birth (OR 1.145) while lowering cesarean section (OR 0.619) and gestational diabetes (OR 0.339) rates ¹⁰.
• LH-activity add-ons: adding LH activity does not change blastocyst euploidy (45.8% vs 45.2%) or live-birth rates in unselected patients ⁵.

Published HMG schedules are fixed-dose protocols titrated to response, and no body-weight-based dosing algorithm exists in the literature ¹¹. Representative patterns reported in the documents:

Indication	Route	Representative schedule	Source
IVF/ICSI ovarian stimulation	SC	225 IU daily for the first 5 days, then adjusted to response	2
IVF, predicted poor responder	SC	300 IU daily, fixed	8
Ovulation induction, PCOS step-up	IM/SC	75 IU from cycle day 2, increments from day 9 per follicular response	9
Female hypogonadotropic hypogonadism	SC/IM	Daily HMG plus low-dose hCG 50-300 IU/day	16
Male hypogonadotropic hypogonadism	IM	hCG plus HMG 75 IU once weekly, escalated to twice weekly if sperm output lags	23
Frozen embryo transfer preparation	SC/IM	Letrozole plus HMG in an ovulation-induction cycle	10

A few practical points recur across protocols. Dosing is once daily because the FSH peak arrives about 15-18 hours after injection ¹², and any consistent time of day works since there is no circadian requirement. Female stimulation courses are cycle-bound, typically 10-14 days, and repeat only with a new cycle rather than any on/off pattern ². Male regimens run for months to years: the strongest testicular and penile effects concentrate in the first 3 months ⁷, while sperm appearance averaged about 19 months in one series ²³.

Ovulation induction uses a step-up philosophy: start low, scan follicular growth, and raise the dose only after roughly a week without response, which limits multifollicular growth and OHSS risk ⁹. IVF stimulation starts closer to a fixed dose and adjusts after day 5 ². In every setting the cycle is completed with an hCG trigger of 5,000-10,000 IU once the lead follicle reaches about 17-18 mm (practitioner consensus), with oocyte retrieval roughly 36 hours later ².

HMG comes in two pharmaceutical formats: a lyophilized powder plus diluent, and a ready-to-use liquid prefilled pen that needs no mixing ². The powder dissolves in the sterile 0.9% sodium chloride diluent supplied with the product, and subcutaneous use is the standard route ⁵⁴. Rotate the vial gently to mix; shaking can damage these glycoprotein hormones.

Subcutaneous administration is clinically equivalent to intramuscular ⁵³, and highly purified HMG causes significantly fewer injection-site reactions than older urinary preparations, a real practical difference between products ¹³.

Storage follows the product labeling:

• Unreconstituted powder: refrigerated at 2-8°C or kept at controlled room temperature, protected from light.
• Reconstituted solution: used immediately; single-dose vials are discarded after the dose, while multidose vials hold up to 28 days refrigerated.
• Prefilled pen: refrigerated at 2-8°C, with a 28-day in-use life per manufacturer.
• Never freeze the reconstituted solution, freezing damages the hormones.

Handling matters because the molecule's sugar coating is functional: enzymatic removal of sialic acid inactivates HMG ³⁹. Lot-to-lot consistency is a known analytical challenge as well. Mass-spectrometry analysis shows highly purified HMG carries roughly 20-30% non-gonadotropin protein and a partially oxidized alpha subunit ³, and newer HPLC methods were developed specifically to track batch quality across commercial lots because standard animal bioassays were too variable ²².

The interactive calculator in this section handles dilution math for a protocol dose; the numbers depend on how many vials are dissolved in how much diluent.

Gonadotropins are glycoprotein hormones, so they are not metabolized through liver enzyme pathways. Most interactions are pharmacodynamic: they change what the hormones do rather than how they are processed.

hCG. An hCG trigger completes every stimulation cycle, but hCG exposure also drives OHSS risk. Commercial highly purified HMG already contains hCG, with beta-hCG making up 18-47% of gonadotropin content, and it accumulates with daily dosing ³. Endogenous hCG from an unrecognized early pregnancy can cause severe OHSS even without any trigger injection; one case produced pleural effusions at a peak estradiol of only 279 pg/mL ¹⁴. Research practice is a negative serum pregnancy test before every stimulation start.

GnRH agents. Adding GnRH-agonist downregulation to HMG raised IVF pregnancy rates from 7% to 15% versus HMG alone, mainly by preventing premature LH surges, at the cost of higher hyperstimulation risk ⁴². GnRH antagonists are co-administered for the same purpose with no pharmacokinetic interaction.

Oral ovulation inducers.

• Letrozole plus HMG is a first-line induction pairing. The aromatase inhibitor suppresses estrogen feedback so lower gonadotropin doses work. When this pairing fails, the data favor switching strategy over escalating HMG: step-up HMG alone produced dominant follicles in only 28.2% of cycles versus 93.3% after laparoscopic ovarian drilling ⁹.
• Clomiphene followed by HMG is a long-established sequential pairing that reduces the total HMG dose needed. Community protocols note that it recruits multiple follicles, so multiple-pregnancy and OHSS risks remain and serial ultrasound monitoring applies.

Recombinant gonadotropins. Adding rFSH to HP-hMG matches rFSH-alone pregnancy rates despite worse prognostic features, with lower OHSS among frozen-transfer patients (6.9% vs 13.2%) ²⁰. Against a 2:1 rFSH:rLH combination, HP-hMG alone retrieves about 1.4 fewer oocytes per cycle ¹⁹.

Supplements. Alpha-lipoic acid added to letrozole improved ovulation per cycle from 71.9% to 92.2% in one RCT, with a favorable safety signal ⁴⁹. High-dose green tea extract (EGCG) strongly inhibited endometrial blood vessel growth in HMG/hCG-stimulated mice, so the peri-implantation window appears sensitive to antiangiogenic supplements ³⁸. Testosterone pretreatment did not improve pregnancy in diminished ovarian reserve patients stimulated with 300 IU/day HP-hMG (RR 1.05) ⁸.

Clotting and valves. HMG stimulation is associated with arterial and venous thrombosis, including a reported bioprosthetic heart valve thrombosis during IVF ¹⁵. The hyperestrogenic state of stimulation raises clotting risk, so anticoagulated patients need consistent monitoring and valve patients need cardiology clearance.

HMG is almost never studied alone in male indications and is routinely combined in female stimulation, so combination design is a core part of the literature.

HMG + hCG is the reference combination for male hypogonadotropic hypogonadism. The hCG supplies the Leydig-cell LH signal while HMG supplies the FSH signal for sperm development; without both, gonadotropin-deficient men do not complete sperm maturation ³¹. Together they produce spermatogenesis in 85.7% of congenital hypogonadotropic hypogonadism patients ⁶, and this pairing restored spermatogenesis in a case of anabolic-steroid-induced azoospermia ²⁶.

HMG + rFSH adds LH activity to a recombinant FSH backbone. Real-world data show comparable pregnancy across combinations, with lower OHSS in frozen-transfer cycles when HP-hMG is added (6.9% vs 13.2%) ²⁰.

HMG + letrozole is the principal oral-plus-gonadotropin stack for ovulation induction and frozen-transfer preparation, with live-birth rates comparable to hormone-replacement therapy and lower cesarean and gestational diabetes rates ¹⁰. In minimal-stimulation IVF, clomiphene plus low-dose gonadotropins (at most 150 IU/day) reached a live-birth rate of 58.2% in one retrospective cohort ⁴¹.

What the data argue against is triple-stacking LH activity: HMG already carries hCG that accumulates with daily dosing ³, and adding further LH/hCG sources raises OHSS risk without benefit. HMG versus low-dose hCG as the LH supplement gives comparable live-birth rates, so research protocols generally pick one rather than both ³⁰.

Structural differences matter when switching stacks. A 2:1 rFSH:rLH combination retrieves about 1.4 more oocytes per cycle than HP-hMG alone and achieves higher clinical pregnancy ¹⁹, which is why some researchers favor it when oocyte yield is the priority.

HMG is an FDA-approved prescription fertility medicine. The US reference product, Menopur, is approved for ovulation induction and controlled ovarian stimulation in assisted reproduction ⁵⁴. In 2026 a randomized non-inferiority trial across 19 US centers established the prefilled pen as equivalent to the approved powder (ongoing pregnancy 45.0% vs 42.7%) ², building on a 2021 bioequivalence study ¹².

It is not scheduled under the Controlled Substances Act and is not a DEA-controlled substance, but it is available only by prescription. Compounded menotropin from 503A/503B pharmacies sits outside the FDA-approval pathway, with no bioequivalence requirement against the reference product, which matters for a batch-variable urinary glycoprotein ³.

Internationally, menotropin is marketed in Europe as Menopur and Menogon with member-state marketing authorizations, and the UK and Australia list it as an approved prescription medicine for the same infertility indications. Regional products are not identical: mass-spectrometry comparisons found imported recombinant gonadotropins above 98.55% purity for the principal component, while some domestic Chinese HMG products are FSH-dominant with small hCG and minimal LH ²⁹. Personal import of unapproved biologics generally requires a prescription and cold-chain handling.

For athletes, the World Anti-Doping Agency prohibits gonadotropins and their releasing factors under category S2 in male athletes at all times, in and out of competition. The rationale is grounded in real male hormonal effects: HMG plus hCG demonstrably raises testosterone and restores sperm production in gonadotropin-deficient men ⁶.

The most common adverse events in a 254-woman trial were nausea (8.7%) and headache (5.1%) ¹⁸. Injection-site discomfort is the most frequent local effect, and highly purified HMG causes significantly fewer site reactions than older urinary preparations ¹³.

The dominant serious risk is ovarian hyperstimulation syndrome (OHSS).

• Frequency: early OHSS ran 3.5% in the pen-versus-powder RCT ², and follicle-count criteria flag about 19.8% of HP-hMG cycles as high-risk ⁴.
• Comparative risk: rFSH carries 42% higher OHSS odds than HMG/HP-hMG (OR 1.42), so HMG-containing regimens are the lower-risk choice on this axis ¹.
• Atypical presentations occur: severe OHSS with isolated pleural effusion developed with 17 follicles but a peak estradiol of only 279 pg/mL, driven by endogenous pregnancy hCG with no trigger at all. Low estrogen does not rule the syndrome out ¹⁴.
• Multiple gestation is an inherent risk of gonadotropin stimulation, with a historical septuplet case despite intensive monitoring ⁴⁵; modern single-embryo-transfer practice limits this.
• Ovarian torsion is a rare complication of enlarged stimulated ovaries; acute unilateral pelvic pain, often with nausea, warrants immediate imaging and surgical evaluation (practitioner consensus).

Thrombosis is the other serious axis. Arterial and venous events are documented during HMG stimulation, including a reported bioprosthetic mitral valve thrombosis ¹⁵. A hypercoagulable state or prosthetic valve is therefore a contraindication, and research protocols exclude early pregnancy before any luteal-phase or random-start cycle ¹⁴. Sex-hormone-dependent malignancies are standard exclusions.

Long-term questions remain open. An older observational study raised the question of epithelial ovarian cancer after gonadotropin exposure, with residual confounding likely and no modern confirmation ²⁸. Batch variability and the roughly 20-30% non-gonadotropin protein content of urinary products keep immunogenicity questions alive ³. Unpredictable hyperresponse is also documented: 55 oocytes retrieved after long-term hormonal-contraceptive use despite suppressed reserve markers ⁴⁷.

Monitoring is the backbone of risk control: estradiol from day 5 every 1-3 days, follicular ultrasound at each visit, a negative pregnancy test before every cycle start, and post-trigger surveillance of weight, abdominal girth, and breathing for one to two weeks ¹⁴.

Luteal-phase support with progesterone typically follows oocyte retrieval or embryo transfer in HMG-stimulated cycles (practitioner consensus); one trial used a weekly progesterone vaginal ring from the day after retrieval for up to 10 weeks ¹⁸.