According to data presented at the 119th French Congress of Urology 2025, precise phenotyping of men with hypogonadism or infertility due to idiopathic testicular dysfunction may improve spermatogenesis and guide targeted treatment decisions.

Approximately 3.3 million individuals in France are directly affected by infertility, representing close to 1 in 4 couples. Male factors contribute to approximately 50% of infertility cases and are a contributing factor in nearly 20% of cases.

Charlotte Methorst, MD, urologist and andrologist, was a co-author of the French Urological Association guidelines 2021 on Peyronie disease assessment and treatment. The guideline was published in Prog Urol and presented the framework at the congress. This classification aims to guide treatment decisions in a field where management has been empirical.

“There is a widespread assumption that intracytoplasmic sperm injection can enable a couple to have a baby without explaining the underlying male infertility,” said Sandro Esteves, MD, who led development of the classification. Evidence suggests that therapeutic interventions can improve sperm quantity and quality and overall male health, leading to better reproductive outcomes, even when assisted reproduction remains necessary.

According to the Endocrine Society, the lack of accurate diagnosis in men with idiopathic infertility and subtle endocrine abnormalities remains concerning because spermatogenesis requires the combined action of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the testes. Therefore, additional diagnostic and therapeutic strategies are needed.

Male infertility remains an unmet clinical need and is typically managed empirically. In 2024, an international working group proposed a structured stratification approach for men seeking fertility who may benefit from hormonal therapy.

Hormonal therapy is established in hypogonadotropic hypogonadism (HH), where exogenous gonadotropins restore physiologic stimulation of the testes and spermatogenesis. Data on its role in idiopathic oligozoospermia or nonobstructive azoospermia are mixed, with limited randomized trial evidence.

Unlike ovarian stimulation in assisted reproductive technology, in which gonadotropins are administered regardless of etiology, no standardized approach exists for male infertility. Limited knowledge of idiopathic infertility, potential adverse effects, and insufficiently documented reproductive outcomes limits the widespread use of treatments that do not primarily aim to eliminate the underlying cause.

“The challenge in treating male infertility lies in classification,” Methorst said. “There are varying degrees of hypogonadism.”

In women undergoing ovarian stimulation as part of assisted reproductive treatment, gonadotropins are administered to obtain multiple gametes regardless of the underlying cause of infertility.

In contrast, the treatment of male infertility remains a major unmet need and is often guided by empirical clinical decisions. To address this gap, an international working group in 2024 proposed a new framework to stratify men seeking fatherhood who are most likely to benefit from hormone therapy.

A new classification system, APHRODITE, which involves the management of male patients with hypogonadism and/or infertility due to impaired and idiopathic testicular function, was developed by a consortium of andrologists, reproductive urologists, gynecologists specializing in reproductive medicine, and experts in male infertility.

The classification divides men into five groups, each with specific recommendations with tailored management strategies, and distinguishes functional and relative hypogonadism from classic HH, addressing a clinically relevant intermediate zone.

“Broadly speaking, the challenge in managing infertile men lies in how infertility is classified,” said Methorst.

This reflects the hypogonadism spectrum. Earlier approaches relied on a simplified dichotomy that separated HH, defined by low FSH and testosterone levels, from other forms of hypogonadism characterized by normal or low testosterone and FSH levels between 2 international units (IU)/L and 8 IU/L.

“We had observed for several years the presence of functional hypogonadism, defined by low testosterone and low [FSH] levels ≤ 2 IU/L, as well as relative hypogonadism, characterized by low normal testosterone and [FSH] levels between 2 and 8 IU/L. The terms ‘functional’ and ‘relative’ reflect that, based on sperm analysis, FSH levels > 8 IU/L would typically be expected to explain such impairment,” the speaker explained.

This creates a gray zone for men who are not eugonadal but do not present with overt HH. This intermediate group, corresponding in practice to the APHRODITE 2 and 3 profiles, is where functional assessment becomes most clinically relevant.

Group 1 APHRODITE

HH accounts for 1.9% of azoospermia cases and 1.6% of male infertility cases. Congenital forms are often associated with endocrine or neurologic comorbidities, such as Kallmann syndrome. Genetic mutations involving the DAX1 NR0B1 gene involved in hypothalamic regulation may be present. These patients were directly managed by pediatric endocrinologists for puberty induction.

Acquired HH develops after puberty due to conditions such as pituitary adenoma, anabolic steroid use, pituitary tuberculosis, craniopharyngioma, hemochromatosis, Crohn’s disease, or celiac disease.

This condition is characterized by deficient FSH and LH levels, resulting in reduced testosterone levels and impaired spermatogenesis.

Treatment consisted of FSH combined with human chorionic gonadotropin (hCG), adjusted according to the etiology of HH.

Group 2 APHRODITE

Semen analysis parameters were low, showing oligospermia or azoospermia without an identifiable cause, serum FSH levels were normal (> 2 IU/L but < 8 IU/L), and total testosterone levels were normal (5-6 ng/mL). Hormonal assays do not reflect impaired spermatogenesis.

Subtle impairment in sperm production was not detected by standard hormone assays. “This reflects relative hypogonadism,” said Methorst. “Given the sperm parameters, higher gonadotropin levels would be expected to support greater spermatogenesis.”

This pattern lies within a gray zone of relative hypogonadism, affecting an estimated 15%-60% of patients. As testosterone levels are preserved, meta-analyses support treatment with FSH. Four meta-analyses reported improvements in sperm parameters, pregnancy rates, and live birth rates.

Treatment consisted of FSH alone.

Group 3 APHRODITE

Semen parameters are reduced, including oligoasthenoteratospermia with or without azoospermia without an identifiable cause. FSH levels are within the normal range, while total testosterone is reduced. This pattern reflects functional hypogonadism, with testosterone levels around 2-3 ng/mL and FSH levels > 2 IU/L but < 8 IU/L.

Patients in this group account for about 20% of men with infertility. In this setting, higher gonadotropin levels are expected to support spermatogenesis and testosterone production. “However, this increase is not present, which places these men in the gray area of hypogonadism.”

Treatment relies on the administration of gonadotropins, beginning with an LH effect via the injection of moderate doses of hCG, adjusted according to testicular volume. An FSH protocol may be added, with adjustments made on a case-by-case basis; it is a highly customized approach.

Treatment consisted of hCG with or without FSH.

Group 4 APHRODITE

Semen parameters are markedly reduced, including severe oligospermia or azoospermia, with normal to high FSH levels and reduced or normal testosterone.

Patients in this group represent approximately 10% of infertile men and include patients with conditions such as Klinefelter syndrome, bilateral cryptorchidism, chemotherapy, and postinfectious or idiopathic orchitis. Management remains challenging because evidence is limited and the response to hormonal therapy is often modest.

No standard protocol has been established yet. The current practice is to initiate treatment with hCG to increase testosterone levels required for spermatogenesis and restore FSH receptor sensitivity. FSH can then be added on the basis of individual response. In cases of azoospermia, testicular biopsy should be considered for sperm retrieval.

Treatment consisted of hCG with or without FSH, with close monitoring.

Group 5 APHRODITE or Idiopathic Infertility

This group includes unexplained male infertility in an infertile couple. “These are the most difficult cases to interpret, and it is a diagnosis of exclusion: the spermogram is normal, the serum levels of FSH and testosterone are normal, but the couple remain infertile,” said Methorst.

Environmental factors may contribute to this, including toxin exposure, heat, smoking, chronic stress, and endocrine disruptors. This highlights the limitations of standard diagnostic tools and suggests subtle dysfunction not detected by routine testing.

Advanced assessments include sperm DNA fragmentation, capacitation testing, oxidative stress analysis, and acrosome reaction evaluation. Elevated sperm DNA fragmentation is often observed.

FSH treatment has been explored with some evidence of benefit. Additional approaches to reduce DNA fragmentation include antioxidants and lifestyle changes, such as weight loss, smoking cessation, and treatment of varicocele.

This group is approximately 15% of men with infertility, and clear conclusions on management remain limited.

Treatment consisted of individualized FSH administration based on patient context.

“Improved stratification now allows more targeted care for selected patients,” said Methorst.

Testosterone levels vary widely and should not be interpreted in isolation. A level of 2-3 ng/mL in a 25-year-old man cannot be considered normal without a clinical context. The key is to stratify correctly, considering “normal” testosterone interpretation compared with age and overall presentation within a broader context.

“In practice, those who benefit most from this classification are men in APHRODITE groups 2 and 3, within the gray zone of hypogonadism. In these men, treatment with FSH can improve sperm parameters and may support obtaining a positive testicular biopsy. These are the patients we can truly help,” Methorst concluded.

Methorst reported having relationships with Besins Healthcare, Organon, Theramex, Institut Biochimique SA, Ipsen, Servier, Astellas, Effik, and Kranus Health.

This story was translated from Medscape’s French edition.