Human Chorionic Gonadotropin-Based Clinical Treatments for Infertile Men with Non-Obstructive Azoospermia

A narrative review argues hCG may treat more azoospermia subtypes than currently accepted, introducing the unvalidated "APHRODITE criteria" to guide patient selection.

Journal: Andrology | Published: 2025-02-04 | Type: Narrative Review | PMID: 39901824 Authors: Esteves SC, Viana MC, Achermann APP, Santi D (ANDROFERT Andrology Clinic, Campinas, Brazil; University of Modena, Italy) Funding/COI: Not listed. Esteves is based at ANDROFERT, a private fertility clinic with a financial interest in expanded treatment indications.

Summary

HCG mimics luteinizing hormone (LH), stimulating Leydig cells to produce intratesticular testosterone — the key driver of sperm production. For men with hypogonadotropic hypogonadism (low gonadotropins from the pituitary), HCG reliably restores spermatogenesis; that much is established. What this review argues — more hopefully than the evidence fully supports — is that HCG may also benefit men with other forms of non-obstructive azoospermia (NOA), where sperm production fails despite normal or high gonadotropin levels. The authors introduce the APHRODITE criteria, a proposed patient stratification framework, as a tool for identifying who might respond.

Claims

• HCG effectively restores spermatogenesis in pre-testicular NOA (hypogonadotropic hypogonadism); this is described as established
• Evidence for HCG in testicular NOA (primary spermatogenic failure) is characterized as accumulating but not conclusive
• LH activity — via HCG — is positioned as critical even in forms of NOA not classically treated with gonadotropins
• The APHRODITE criteria (clinical and laboratory indicators) are proposed as a novel framework to select patients for HCG therapy
• Optimal dosages and treatment durations remain undefined; the authors call for further research

Study Quality

This is a narrative review, the lowest tier of secondary evidence. Narrative reviews do not employ systematic search protocols or pre-registered inclusion criteria, which means the authors selected the studies they found most relevant — a process vulnerable to confirmation bias. No PRISMA flowchart, no quality scoring of included studies, no pooled effect sizes. There are no original data here, and the abstract offers no specific quantitative findings from the reviewed literature. The APHRODITE criteria are introduced as novel, which means they have not been externally validated in a prospective cohort.

The authors are clinicians at a private fertility clinic, and expanded HCG indications would directly expand their practice's treatment repertoire. The absence of any listed funding or COI disclosure is not reassurance — it is a gap.

Red Flags

• Narrative review design: cherry-picking risk is real and unmitigated by methodology
• No funding or COI disclosed despite lead author's affiliation with a commercial fertility clinic (ANDROFERT)
• APHRODITE criteria are novel and unvalidated — named frameworks that debut in the same paper proposing their use warrant skepticism
• Abstract contains no hard numbers: no sample sizes from reviewed studies, no reported effect sizes, no statistical outcomes
• "Accumulating evidence suggests promising venues" is the authors' characterization, not a quantified finding
• The ongoing debate about HCG in non-hypogonadotropic NOA is acknowledged but the review appears to lean toward optimism without resolving it

Strengths

• Covers molecular mechanisms of HCG/LH action in spermatogenesis in useful detail
• Addresses a genuinely contested clinical question where practicing urologists lack clear guidance
• Includes multiple NOA subtypes rather than collapsing them into a single category
• Authors are credentialed specialists in male infertility with substantial publication records in this area

Verdict

This paper is advocacy dressed as review. The underlying clinical question — whether HCG has a role in NOA beyond hypogonadotropic hypogonadism — is legitimate and underexplored. But a narrative review from authors at a private fertility clinic, with no disclosed COI, no systematic methodology, and no hard numbers, cannot settle that debate. The APHRODITE criteria may eventually prove useful; right now they are a hypothesis. Read this for background on the molecular rationale and to understand the state of clinical uncertainty. Do not read it as evidence that HCG works broadly for NOA.