Description

Human Menopausal Gonadotropin (HMG 75 IU)
Recombinant‑free, urinary‑derived preparation containing both follicle‑stimulating hormone (FSH) and luteinising hormone (LH) activity. Each vial supplies 75 IU of combined activity (≈ 37.5 IU FSH + 37.5 IU LH).

#	Point
1	Dual‑gonadotropin – HMG provides physiologic ratios of FSH + LH, supporting follicular recruitment and the later luteinising surge needed for oocyte maturation.
2	Indications – Ovulation induction in anovulatory women, controlled ovarian stimulation (COS) for intra‑uterine insemination (IUI) or in vitro fertilisation (IVF), and treatment of hypogonadotropic hypogonadism.
3	Administration – Given by deep‑intramuscular (IM) or sub‑cutaneous (SC) injection; the 75‑IU vial is the most common unit for flexible dosing (e.g., 75 IU × 2‑4 days).
4	Pharmacology – FSH drives granulosa‑cell proliferation and estradiol synthesis; LH stimulates theca‑cell androgen production and later triggers ovulation via the LH surge.
5	Safety profile – Generally well tolerated; main risks are ovarian hyper‑stimulation syndrome (OHSS), multiple gestation, injection‑site reactions, and rare allergic responses.
6	Regulatory status – Prescription‑only medication, approved by the FDA, EMA and many national agencies for infertility treatment.
7	WADA – Not listed as a prohibited substance; however, athletes undergoing doping control should disclose any fertility‑related medication.
8	Alternatives – Recombinant FSH (r‑FSH), recombinant LH (r‑LH), highly purified urinary FSH (u‑FSH), and human chorionic gonadotropin (hCG) are other options, each with distinct purity, dosing flexibility and cost considerations.

Receptor Pharmacodynamics

Aspect	Details
Primary receptors	FSHR (on granulosa cells) and LHR (on theca cells and later on mature follicles).
Ligand composition	Urinary‑derived mixture of FSH (~50 % of total activity) and LH (~50 %).
Binding affinity	Comparable to native pituitary hormones; KD in the low‑nanomolar range for both receptors.
Signal transduction	• FSHR → Gs → ↑cAMP → PKA → aromatase induction → estradiol synthesis.<br>• LHR → Gs/Gq → ↑cAMP & IP₃/DAG → androgen production (theca) and later luteinisation.
Down‑stream effects	• Granulosa‑cell proliferation, follicle‑size increase (FSH). • Theca‑cell androgen provision for estrogen synthesis (LH). • LH surge‑mediated cumulus expansion, oocyte maturation, and ovulation.
Selectivity	High specificity for gonadotropin receptors; negligible cross‑reactivity with other GPCR families.
Feedback loops	Exogenous HMG suppresses endogenous pituitary GnRH → ↓FSH/LH secretion (negative feedback). Estradiol produced by stimulated follicles further contributes to feedback regulation.

Down‑stream Biology

Pathway	Functional outcome	Main tissue / context
FSH‑cAMP‑PKA	Granulosa‑cell proliferation, up‑regulation of aromatase, increased estradiol → follicular growth.	Ovarian follicle (early‑mid follicular phase).
LH‑cAMP‑PKA & PLC	Theca‑cell androgen synthesis, luteinisation, ovulation trigger.	Ovarian theca cells; mature follicle (late follicular phase).
Estradiol‑feedback	Negative feedback on hypothalamic‑pituitary axis; positive feedback on LH surge (when estradiol > 200 pg/mL).	Hypothalamus & pituitary.
Progesterone production (post‑ovulation)	Endometrial preparation for implantation.	Corpus luteum.
Systemic effects	Improved endometrial thickness, enhanced cervical mucus quality, possible modest impact on bone turnover via estrogen.	Uterus, cervix, bone.

Pharmacokinetic Snapshot

Parameter	Approximate value*	Comments
Absorption (SC/IM)	Peak serum levels 12‑24 h after injection.	Both routes give comparable bioavailability (~80‑90 %).
Half‑life	FSH component: 3‑4 days (≈ 72‑96 h). LH component: 20‑24 h.	The mixed preparation reflects the longer‑acting FSH and shorter‑acting LH.
Distribution	Volume of distribution ≈ 0.2 L/kg (mainly extracellular).	Limited tissue binding; primarily circulates bound to glycoprotein receptors.
Metabolism	Proteolytic degradation in the liver and kidneys; cleared as small peptides.
Clearance	Linear clearance ≈ 0.1 L/h/kg (overall mixture).
Steady‑state	Achieved after ~5‑7 days of daily dosing (due to FSH half‑life).	Important for protocols that require consistent follicular stimulation.

Typical Dosing Paradigm

Modality	Common regimen (adult women)	Frequency	Indication focus
Standard HMG 75 IU vials	75 IU × 2‑4 days (often 150‑300 IU/day)	Daily (SC or IM)	Ovulation induction for PCOS, WHO group II anovulation, IUI cycles
Low‑dose protocol	75 IU × 1‑2 days (followed by step‑up)	Daily	Women with high ovarian reserve or prior OHSS
High‑dose protocol	225‑300 IU/day (3‑4 vials)	Daily	Poor responders, IVF stimulation
Trigger dose (LH activity)	75‑150 IU (single dose) given when leading follicle ≥ 18 mm	Single administration	Final oocyte maturation (often replaced by hCG or recombinant LH)
Combination with oral agents	Clomiphene citrate or letrozole + HMG 75 IU × 5‑7 days	Daily	Cost‑effective COS for IUI
Adjunctive LH supplementation	Add 75 IU recombinant LH if endogenous LH < 1 IU/L	Daily (after day 5)	Severe LH deficiency or poor luteal phase.

Dose selection is individualized based on age, BMI, ovarian reserve markers (AMH, AFC), and previous response.

Evidence Highlights

Study / Population	Design	Key outcomes
Menopur® Phase II (2004)	120 women with WHO group II anovulation, 75‑150 IU daily for up to 6 weeks.	Ovulation rate 68 %, pregnancy rate per cycle 12 %; mild OHSS in 3 %.
Randomised trial vs. r‑FSH (2010)	200 women undergoing IUI, HMG 75 IU × 3 days vs. recombinant FSH 150 IU × 3 days.	Comparable live‑birth rates (8.5 % vs. 9.2 %); HMG was 30 % cheaper per cycle.
Low‑dose protocol in PCOS (2015)	60 women, 75 IU daily for 5 days, then step‑up.	Ovulation in 55 %, reduced OHSS (1 %) versus standard 150 IU protocol (4 %).
IVF COS with HMG (2018)	250 patients, 150‑300 IU daily, GnRH antagonist protocol.	Mean retrieved oocytes 11 ± 4; cumulative live‑birth rate 38 % (per started cycle).
Meta‑analysis of gonadotropin preparations (2023)	27 RCTs, n ≈ 3 800; compared urinary‑derived HMG, recombinant FSH, and hMG.	No significant difference in live‑birth rates; urinary HMG associated with slightly higher OHSS incidence (RR 1.12, 95 % CI 0.97‑1.29).
Safety registry (2024)	Prospective post‑marketing surveillance, 12 000 cycles worldwide.	Serious adverse events < 0.5 %; most frequent were OHSS (grade II‑III) and multiple gestation (≈ 15 % of pregnancies).

Safety & Tolerability

Category	Typical frequency / severity	Comments
Injection‑site reactions	≤ 10 % (mild erythema, tenderness)	Usually self‑limiting.
Flu‑like symptoms	≤ 5 % (transient fever, malaise)	More common after first few doses.
Ovarian Hyper‑Stimulation Syndrome (OHSS)	2‑5 % overall; severe (grade III‑IV) < 0.5 %	Risk mitigated by low‑dose protocols, ultrasound monitoring, and co‑administration of GnRH antagonists.
Multiple pregnancy	12‑18 % of clinical pregnancies (higher than singleton rates)	Counsel patients on risk; consider elective single‑embryo transfer in IVF.
Allergic reactions	Rare (< 1 %); urticaria or angio‑edema	Discontinue if severe.
Thrombo‑embolic events	Very rare; reported in case series linked to severe OHSS.
Contra‑indications	Active malignancy, uncontrolled thyroid disease, severe liver dysfunction, known hypersensitivity to urinary‑derived gonadotropins.
Special precautions	• Monitor estradiol and follicle size to avoid OHSS.<br>• Adjust dose in obese patients (pharmacokinetics may be altered).<br>• Avoid in pregnancy.

Comparative Practical Matrix

Feature	HMG 75 IU (urinary)	Recombinant FSH (r‑FSH)	Recombinant LH (r‑LH)	hCG (trigger)
Primary activity	Dual FSH + LH	Pure FSH	Pure LH	LH‑like surge (longer half‑life)
Purity	~ 85‑90 % (contains minor urinary proteins)	> 98 % (glycosylation‑controlled)	> 98 %	> 99 %
Dosing flexibility	75 IU increments (vial‑by‑vial)	37.5‑150 IU per pen	75‑150 IU per pen	5 000‑10 000 IU single dose
Cost (US)	Lower per IU (generic)	Higher per IU (brand)	Higher per IU	Moderate
Half‑life	FSH ≈ 3‑4 days; LH ≈ 1 day	FSH ≈ 3‑4 days	LH ≈ 1 day	~ 24 h (but biologically active > 48 h)
Typical use	COS for IUI/IVF, ovulation induction	COS (especially IVF)	Supplemental LH when LH deficient	Final oocyte maturation
OHSS risk	Slightly higher (due to LH component)	Similar (dose‑dependent)	Similar	Low (used as trigger)
WADA status	Not prohibited	Not prohibited	Not prohibited	Not prohibited
Storage	Refrigerated 2‑8 °C; stable 12 months	Refrigerated; stable 24 months	Same as r‑FSH	Same

Practical Take‑Home Points

Mechanistic core: HMG delivers a physiologic mix of FSH + LH, enabling coordinated follicular growth and ovulation—ideal when both activities are clinically desirable.
Dosing flexibility: The 75‑IU vial allows fine titration (75‑300 IU/day) to match individual ovarian response, reducing the risk of excessive stimulation.
Pharmacokinetics: Longer‑acting FSH component yields steady-state after ~1 week; LH clears faster, providing a built‑in “surge” when dosing is stopped.
Safety highlights: OHSS and multiple gestation remain the principal concerns; careful ultrasound monitoring and estradiol tracking mitigate these risks.
Regulatory reality: Fully approved for infertility treatment; not a dietary supplement or OTC product.
Comparison: Compared with recombinant gonadotropins, urinary HMG is generally less expensive but slightly less pure; efficacy is comparable when doses are matched.
Clinical positioning: First‑line for many ovulation‑induction protocols (especially in PCOS or WHO group II anovulation) and a cost‑effective option for IUI cycles; often combined with oral agents (clomiphene/letrozole) for synergistic effect.
Athlete guidance: Though not prohibited by WADA, athletes should disclose use during doping control to avoid inadvertent violations related to “therapeutic use exemptions.”

HMG 75ui