The APHRODITE criteria—short for “Addressing Male Patients With Hypogonadism and/or Infertility Owing to Altered, Idiopathic Testicular Function”—present a novel system for describing and managing male infertility, particularly in hypogonadal males with idiopathic infertility.¹ Named after the Greek goddess of fertility and male sexuality, these criteria offer a structured framework that uses clinical characteristics, hormone levels, and semen analysis to categorize patients. The classification includes 5 distinct groups, each posing unique therapeutic challenges and opportunities, with hormonal treatments showing promise in improving spermatogenesis. While more research is required to establish the full potential of this approach, the APHRODITE criteria represent an essential first step aimed at enhancing communication between health care providers and paving the way for novel treatments for male infertility.

The Need for Improved Classification

Male infertility has long been a source of frustration for both patients and clinicians, particularly in cases of idiopathic infertility where progress has been limited. Many practitioners resort to intracytoplasmic sperm injection as the primary solution, often without exploring other treatment options.² The APHRODITE criteria aim to change this paradigm by offering a more systematic and detailed approach to classifying and treating men with infertility and hypogonadism, specifically those who may benefit from hormonal interventions.

Hormonal Regulation of Spermatogenesis

Understanding the APHRODITE criteria requires a basic knowledge of spermatogenesis—the intricate process that takes approximately 75 days by which sperm is produced. This process is primarily regulated by follicle-stimulating hormone (FSH) and luteinizing hormone (LH)–mediated testosterone production.³ These hormones are crucial in regulating spermatogenesis and form the foundation of the APHRODITE classification system.

The Role of LH, Testosterone, and FSH in Sperm Production

Gonadotropin-releasing hormone, secreted by the hypothalamus, signals the pituitary to release FSH and LH, which act on Sertoli and Leydig cells in the testes. LH is crucial for stimulating testosterone production in Leydig cells, while testosterone, in turn, activates androgen receptors on Sertoli cells to support spermatogenesis. Testosterone is particularly critical in the final phases of spermatogenesis, transforming round spermatids into mature sperm. FSH works in tandem with testosterone and LH, acting on Sertoli cells to ensure proper support for sperm production.³

Hypogonadism and Infertility

Many cases of male infertility arise from inadequate testicular stimulation due to insufficient FSH and/or LH production or action.⁴ Hypogonadism, characterized by deficient gonadal function—typically associated with low testosterone production—can result from various factors, including testicular disease, systemic illnesses, infections, congenital abnormalities, aging, or poor lifestyle choices.¹ The condition is classified as idiopathic when no underlying cause is identified. Despite the complexity, hypogonadism is often treatable, potentially allowing for the improvement of testicular function.

Breaking Down the APHRODITE Criteria

Developed through a collaborative effort among experts in male infertility, the APHRODITE criteria build upon concepts from the POSEIDON criteria for female infertility.^1,5 The system relies on clinical characteristics and routine lab tests, such as semen analysis and hormonal assessments, with a focus on FSH and testosterone levels (Table 1).¹ It classifies male infertility into 5 groups, each with specific treatment recommendations and endpoints (Figure; Table 2).¹

Table 1. Laboratory Tests and Interpretation According to the APHRODITE Criteria

Table 2. Characteristics of the 5 APHRODITE Groups

Group 1: Hypogonadotropic Hypogonadism

Patients in this group present with low FSH, LH, and testosterone levels, often associated with azoospermia.⁶ Typically caused by congenital or acquired conditions affecting gonadotropin secretion, these patients can benefit from gonadotropin therapy (human chorionic gonadotropin and FSH), which may restore spermatogenesis in up to 90% of cases.⁶

Group 2: Idiopathic Male Infertility

This group primarily includes men with idiopathic oligozoospermia and certain cases of idiopathic nonobstructive azoospermia.^1,3,7 Despite normal physical exams and lab results, these patients show signs of functional hypogonadism. FSH therapy has demonstrated effectiveness³ and is recognized by the AUA/American Society for Reproductive Medicine guidelines as a valid medical intervention to be considered in men with idiopathic infertility for enhancing spermatogenesis and improving pregnancy prospects.⁸

Group 3: Biochemical Hypogonadism

Biochemical hypogonadism, characterized by low testosterone levels, distinguishes these patients from those in Group 2. Hormonal therapy combining human chorionic gonadotropin—to boost intratesticular testosterone production—with FSH is suggested to help enhance spermatogenesis.^1,3 Patients with nonobstructive azoospermia in this group have shown improvements in sperm retrieval rates after treatment.⁹

Group 4: Hypergonadotropic Hypogonadism

Patients in this group exhibit high FSH and low or compensated testosterone levels, indicating diminished testicular reserve.⁷ Although more challenging, some evidence suggests hormonal therapy may improve sperm retrieval outcomes in certain cases.^3,9

Group 5: Unexplained Male Infertility

This group includes men with normal semen analysis, hormone levels, and physical exams (along with unremarkable findings in the female partner’s evaluation) who remain infertile for unknown reasons. It is hypothesized that FSH stimulation could enhance sperm production in these patients by optimizing spermatogenesis, which may not be functioning at its full capacity. While further research is needed to validate this approach, it is well-known that higher sperm counts are associated with a shorter time to natural conception,¹⁰ thereby providing a rationale for the potential benefit of FSH therapy to boost spermatogenesis.

Challenges and Future Directions

While initial data support the effectiveness of gonadotropin therapy in Groups 1, 2, and 3, further studies are needed to establish broader applications. Additionally, alternative treatments using selective estrogen receptor modulators and aromatase inhibitors—alone or combined with gonadotropins—could be explored to enhance reproductive hormone balance. The APHRODITE criteria may significantly advance classifying and treating male infertility, fostering clearer communication among clinicians, researchers, and patients. By guiding future clinical trials, these criteria can also offer hope to countless couples seeking new treatment avenues for infertility.

Author’s Note

I am deeply honored to have been part of the distinguished panel that developed the APHRODITE criteria. I also want to express my heartfelt gratitude to the AUA for granting me an invaluable opportunity nearly 30 years ago after completing my urology residency as one of the first international scholars from South America in the AUA/Confederación Americana de Urología exchange program. The knowledge and insight I gained through this program and the subsequent fellowship at the Glickman Urological and Kidney Institute at the Cleveland Clinic have shaped my clinical expertise and academic journey in male infertility and reproductive medicine. This experience has laid the foundation for my contributions to the field, and I remain deeply thankful for these early opportunities that continue to influence my work today.

Acknowledgments

The author thanks Chloé Xilinas and Josefina Zamarbide from MedEA for their help with the artwork.