madman
Super Moderator
INTRODUCTION
We have the privilege to introduce a groundbreaking advancement in the field of male infertility to the readers of IBJU: the APHRODITE criteria (1), short for “Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function.” Named after the Greek goddess of fertility and procreation, this novel classification system can represent a significant leap forward in our understanding and treatment of male infertility.
The Need for Improved Classification
Male infertility is a complex clinical condition, and thus far, the clinical management of men with reduced fertility and impaired spermatogenesis has been fraught with difficulties and limited advancement (2). This has led to frustration among both clinicians and patients, perpetuating the belief that intracytoplasmic sperm injection (ICSI) is the only solution to provide the couple with a baby without the need to explore the nature or cause of the underlying male infertility (3, 4). The APHRODITE criteria aim to address this gap by providing a structured approach to characterize male infertility in men seeking paternity, particularly those who may benefit from hormonal treatment (1). Importantly, these criteria are not designed for men with established infertility diagnoses, such as varicocele, infection, or obstruction, who would not benefit from hormonal treatment (3).
The Role of Hormones in Spermatogenesis
Understanding the APHRODITE criteria begins with a brief review of human spermatogenesis, a complex process that takes approximately 75 days and is primarily controlled by follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-driven testosterone (5). These hormones are crucial in regulating spermatogenesis, making them central to our approach.
LH and Testosterone
The hypothalamus secretes GnRH, which triggers the pituitary gland to secrete FSH and LH.
In the testicle, key cells for the action of these gonadotropins are the Sertoli and Leydig cells. LH is vital for stimulating testosterone production in Leydig cells, which, in turn, binds to androgen receptors on Sertoli cells, regulating gene transcription and supporting spermatogenesis (5). Testosterone primarily supports the transformation of round spermatids into mature sperm during the late stages of spermatogenesis. Additionally, testosterone aids in transitioning type A to type B spermatogonia and upregulates androgen receptor expression, which improves Sertoli cell function (5).
The Vital Role of FSH
FSH works in synergy with LH and testosterone, acting on Sertoli cells to provide essential metabolic and structural support for spermatogenesis (5). FSH also controls the proliferation, growth, and maturation of Sertoli cells, and it triggers the release of androgen-binding protein. While not indispensable for the completion of spermatogenesis in humans, FSH deficiency markedly reduces sperm quantity (5, 6).
The Underlying Causes of Hypogonadism
Patients with reduced fertility and impaired spermatogenesis may face inadequate testicular stimulation due to deficits in FSH and/or LH production oraction (5). Hypogonadism, characterized primarily by insufficient testosterone production, has various causes,including testicular pathologies, systemic diseases, infections, congenital abnormalities, aging, and poor lifestyle (7). In some instances, the underlying cause remains elusive, and hypogonadism is labeled idiopathic.
The Birth of the APHRODITE Criteria
The APHRODITE criteria emerged from the collaborative efforts of male infertility experts, including andrologists, reproductive urologists, and IVF specialists(1). Inspired by the POSEIDON concept, a stratification system developed for infertile women (8-10), these experts meticulously developed the APHRODITE criteria via an interactive consensus process, relying on clinical patient descriptions and routine laboratory tests, such as semen analysis and hormonal assessment, particularly FSH and testosterone levels (see Table-1) (1). For semen analysis, the WHO framework and reference ranges were applied (11). The FSH levels are grouped as low, normal, or high based on typical reference ranges. For testosterone, 350 ng/dL was the proposed threshold, which is endorsed by most guidelines, and below which the patient is classified as hypogonadal (1).
Stratifying Male Infertility
The APHRODITE criteria categorize male infertility patients into five distinct groups, each with its characteristics and suggested therapeutic management(Figure-1; Table-2).
Aphrodite Group 1: Hypogonadotropic Hypogonadism
This group comprises patients with congenital or acquired hypogonadotropic hypogonadism (12). They present with a hormonal disorder caused by deficient gonadotropin production, which prevents their testicles from producing sperm. Typically, these patients have low FSH, LH, and testosterone levels, usually combined with azoospermia or, less frequently, severe oligozoospermia. Gonadotropin therapy with hCG and FSH can restore spermatogenesis in up to 90 percent of these patients, offering hope for fatherhood (5).
Aphrodite Group 2: Idiopathic Male Infertility
This group predominantly encompasses patients with idiopathic oligozoospermia (≤ 16 million spermatozoa per ml) and select cases of nonobstructive azoospermia (5, 13). These individuals exhibit abnormal semen analysis, a normal physical examination, and normal laboratory results, suggestive of functional hypogonadism. FSH therapy has shown promise in improving semen parameters and pregnancy rates (5), and it might also work in some patients with non-obstructive azoospermia (5).
Aphrodite Group 3: Biochemical Hypogonadism
This group shares similarities with Group 2 but differs by exhibiting reduced testosterone levels, indicating biochemical hypogonadism (1, 7). Combining hCG with FSH may be beneficial in these patients as hCG boosts intratesticular testosterone production. Some patients with nonobstructive azoospermia fitting this group have experienced improvements in sperm retrieval rates after hormonal treatment (14).
Aphrodite Group 4: Hypergonadotropic Hypogonadism
Group 4 primarily encompasses patients with nonobstructive azoospermia characterized by high FSH and low testosterone levels, indicating hypergonadotropic hypogonadism (7). These individuals have low testicular reserve, making them a challenge to treat (15). Nonetheless, a few observational studies have shown that hormonal treatment improves sperm retrieval rates in some cases (5, 16).
Aphrodite Group 5: Unexplained Male Infertility
The final group consists of patients with unexplained infertility, showing no history of diseases affecting fertility, and also normal semen analysis parameters, physical examination, and laboratory findings. It has been postulated that FSH stimulation might benefit these patients by enhancing spermatogenesis; the hypothesis being that spermatogenesis does not run at its maximum capacity, and additional FSH stimulation could potentially boost spermatogenesis (17). It is noteworthy that in couples attempting natural conception, higher sperm concentrations and total sperm counts are associated with a shorter time to pregnancy (18, 19). However, research is warranted to validate the hypothesis of testicular hyperstimulation.
Challenges and Opportunities
While the existing evidence supports the efficacy of gonadotropin therapy in Aphrodite Groups 1, 2, and 3, the available data remains limited. Larger, well designed studies are necessary to confirm the clinical utility in these groups and to further explore the potential in Groups 4 and 5. Besides gonadotropins, other therapeutic modalities like selective estrogen-receptor modulators and aromatase inhibitors could be explored to modulate reproductive hormones. The APHRODITE criteria have the potential to facilitate communication among clinicians, researchers, and patients and, most importantly, to enhance reproductive outcomes through hormonal therapy. APHRODITE criteria are also suggested to pave the way for future clinical trials of hormonal treatment in male infertility, offering hope to countless couples
CONCLUSIONS
In summary, the APHRODITE criteria significantly advance the stratification and management of male infertility. The criteria provide a clear and well-defined system, classifying patients and promoting communication among healthcare providers, researchers, and patients. Moreover, these criteria open doors to research into new pharmacological interventions and the discovery of novel causes of male infertility.
We have the privilege to introduce a groundbreaking advancement in the field of male infertility to the readers of IBJU: the APHRODITE criteria (1), short for “Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function.” Named after the Greek goddess of fertility and procreation, this novel classification system can represent a significant leap forward in our understanding and treatment of male infertility.
The Need for Improved Classification
Male infertility is a complex clinical condition, and thus far, the clinical management of men with reduced fertility and impaired spermatogenesis has been fraught with difficulties and limited advancement (2). This has led to frustration among both clinicians and patients, perpetuating the belief that intracytoplasmic sperm injection (ICSI) is the only solution to provide the couple with a baby without the need to explore the nature or cause of the underlying male infertility (3, 4). The APHRODITE criteria aim to address this gap by providing a structured approach to characterize male infertility in men seeking paternity, particularly those who may benefit from hormonal treatment (1). Importantly, these criteria are not designed for men with established infertility diagnoses, such as varicocele, infection, or obstruction, who would not benefit from hormonal treatment (3).
The Role of Hormones in Spermatogenesis
Understanding the APHRODITE criteria begins with a brief review of human spermatogenesis, a complex process that takes approximately 75 days and is primarily controlled by follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-driven testosterone (5). These hormones are crucial in regulating spermatogenesis, making them central to our approach.
LH and Testosterone
The hypothalamus secretes GnRH, which triggers the pituitary gland to secrete FSH and LH.
In the testicle, key cells for the action of these gonadotropins are the Sertoli and Leydig cells. LH is vital for stimulating testosterone production in Leydig cells, which, in turn, binds to androgen receptors on Sertoli cells, regulating gene transcription and supporting spermatogenesis (5). Testosterone primarily supports the transformation of round spermatids into mature sperm during the late stages of spermatogenesis. Additionally, testosterone aids in transitioning type A to type B spermatogonia and upregulates androgen receptor expression, which improves Sertoli cell function (5).
The Vital Role of FSH
FSH works in synergy with LH and testosterone, acting on Sertoli cells to provide essential metabolic and structural support for spermatogenesis (5). FSH also controls the proliferation, growth, and maturation of Sertoli cells, and it triggers the release of androgen-binding protein. While not indispensable for the completion of spermatogenesis in humans, FSH deficiency markedly reduces sperm quantity (5, 6).
The Underlying Causes of Hypogonadism
Patients with reduced fertility and impaired spermatogenesis may face inadequate testicular stimulation due to deficits in FSH and/or LH production oraction (5). Hypogonadism, characterized primarily by insufficient testosterone production, has various causes,including testicular pathologies, systemic diseases, infections, congenital abnormalities, aging, and poor lifestyle (7). In some instances, the underlying cause remains elusive, and hypogonadism is labeled idiopathic.
The Birth of the APHRODITE Criteria
The APHRODITE criteria emerged from the collaborative efforts of male infertility experts, including andrologists, reproductive urologists, and IVF specialists(1). Inspired by the POSEIDON concept, a stratification system developed for infertile women (8-10), these experts meticulously developed the APHRODITE criteria via an interactive consensus process, relying on clinical patient descriptions and routine laboratory tests, such as semen analysis and hormonal assessment, particularly FSH and testosterone levels (see Table-1) (1). For semen analysis, the WHO framework and reference ranges were applied (11). The FSH levels are grouped as low, normal, or high based on typical reference ranges. For testosterone, 350 ng/dL was the proposed threshold, which is endorsed by most guidelines, and below which the patient is classified as hypogonadal (1).
Stratifying Male Infertility
The APHRODITE criteria categorize male infertility patients into five distinct groups, each with its characteristics and suggested therapeutic management(Figure-1; Table-2).
Aphrodite Group 1: Hypogonadotropic Hypogonadism
This group comprises patients with congenital or acquired hypogonadotropic hypogonadism (12). They present with a hormonal disorder caused by deficient gonadotropin production, which prevents their testicles from producing sperm. Typically, these patients have low FSH, LH, and testosterone levels, usually combined with azoospermia or, less frequently, severe oligozoospermia. Gonadotropin therapy with hCG and FSH can restore spermatogenesis in up to 90 percent of these patients, offering hope for fatherhood (5).
Aphrodite Group 2: Idiopathic Male Infertility
This group predominantly encompasses patients with idiopathic oligozoospermia (≤ 16 million spermatozoa per ml) and select cases of nonobstructive azoospermia (5, 13). These individuals exhibit abnormal semen analysis, a normal physical examination, and normal laboratory results, suggestive of functional hypogonadism. FSH therapy has shown promise in improving semen parameters and pregnancy rates (5), and it might also work in some patients with non-obstructive azoospermia (5).
Aphrodite Group 3: Biochemical Hypogonadism
This group shares similarities with Group 2 but differs by exhibiting reduced testosterone levels, indicating biochemical hypogonadism (1, 7). Combining hCG with FSH may be beneficial in these patients as hCG boosts intratesticular testosterone production. Some patients with nonobstructive azoospermia fitting this group have experienced improvements in sperm retrieval rates after hormonal treatment (14).
Aphrodite Group 4: Hypergonadotropic Hypogonadism
Group 4 primarily encompasses patients with nonobstructive azoospermia characterized by high FSH and low testosterone levels, indicating hypergonadotropic hypogonadism (7). These individuals have low testicular reserve, making them a challenge to treat (15). Nonetheless, a few observational studies have shown that hormonal treatment improves sperm retrieval rates in some cases (5, 16).
Aphrodite Group 5: Unexplained Male Infertility
The final group consists of patients with unexplained infertility, showing no history of diseases affecting fertility, and also normal semen analysis parameters, physical examination, and laboratory findings. It has been postulated that FSH stimulation might benefit these patients by enhancing spermatogenesis; the hypothesis being that spermatogenesis does not run at its maximum capacity, and additional FSH stimulation could potentially boost spermatogenesis (17). It is noteworthy that in couples attempting natural conception, higher sperm concentrations and total sperm counts are associated with a shorter time to pregnancy (18, 19). However, research is warranted to validate the hypothesis of testicular hyperstimulation.
Challenges and Opportunities
While the existing evidence supports the efficacy of gonadotropin therapy in Aphrodite Groups 1, 2, and 3, the available data remains limited. Larger, well designed studies are necessary to confirm the clinical utility in these groups and to further explore the potential in Groups 4 and 5. Besides gonadotropins, other therapeutic modalities like selective estrogen-receptor modulators and aromatase inhibitors could be explored to modulate reproductive hormones. The APHRODITE criteria have the potential to facilitate communication among clinicians, researchers, and patients and, most importantly, to enhance reproductive outcomes through hormonal therapy. APHRODITE criteria are also suggested to pave the way for future clinical trials of hormonal treatment in male infertility, offering hope to countless couples
CONCLUSIONS
In summary, the APHRODITE criteria significantly advance the stratification and management of male infertility. The criteria provide a clear and well-defined system, classifying patients and promoting communication among healthcare providers, researchers, and patients. Moreover, these criteria open doors to research into new pharmacological interventions and the discovery of novel causes of male infertility.
