Andrology: The Male Factor

Antti Perheentupa, MD, PhD

The clinical significance of the male factor in infertility has been well-recognized for years. Approximately 50% of the infertility in couples is considered to be caused at least to some degree by the male. Alarming findings of the globally decreasing semen quality have further highlighted the importance of andrology as a field of research as well as clinical specialty. The development of intracytoplasmic sperm injection (ICSI) in 1992 was for several years considered to largely solve the challenges of male infertility.[1] In retrospect, although completely new groups of infertile men could be treated effectively with this method, the research activity in andrology became focused less on improving male fertility as a result. Recent years have witnessed the elevated appreciation of the male factor. In addition to basic research advancing our understanding of spermatogenesis, the event of paramount importance in male fertility, new methods are being employed to further develop the diagnosis of male infertility as well as the treatment. This issue of Seminars in Reproductive Medicine is dedicated to andrology, a selection of seven reviews covering some of the highlights of the advances in this important specialty.

Small non-coding RNAs (sncRNAs) regulate activities in both somatic and germ cells. miRNAs are well conserved among species and their expression is specific to different cell types, developmental stage, as well as disease type.[2] They are involved in multiple physiological events as well as different diseases.[3] On the other hand, PIWI-interacting RNAs (piRNAs) are predominantly expressed in the male germline. The article by professor Kotaja's group reviews the complex roles of the sncRNAs in spermatogenesis.[4] The animal models have shown that these sncRNAs play a critical role in male germ cell maturation, and abnormalities may lead to compromised male fertility. Even if currently most of the findings appear to be of largely basic science interest, the sncRNAs may well find clinical use as indicators and/or markers of male infertility, male reproductive disorders, and even assist in predicting the outcome of medically assisted reproduction.

Multiple studies have displayed alarming findings suggesting deteriorating male fertility in the form of decreasing quality of semen.[5] The possible role of environmental factors in this alarming development is discussed in detail in the review by Toppari et al.[6] In addition to reviewing the endocrine disrupting chemicals, this seminar importantly discusses the sensitive developmental stages in individual male development (fetal, mini-puberty, and puberty), which may determine the spermatogenic capacity irrespective of exposures in adulthood. Several chemicals have been banned and the monitoring has been improved; however, more reliable research data are essential to ensure appropriate regulation and monitoring of a vast array of chemicals to ensure that the fertility of men and women as well as all other species is not irreversibly endangered.

Sperm DNA fragmentation is clearly among the hottest topics in andrology at the moment. The association with poor fertility, risk of miscarriage, and lack of success in treatments with assisted reproductive techniques is apparent. When should DNA fragmentation be measured? How can it be effectively treated, and should it affect the infertility treatment choices? What do the different methods in evaluating DNA fragmentation actually test? Moller Nielsen et al review the available methods to measure sperm DNA fragmentation, how the results should be interpreted, and importantly what can be done to minimize the detrimental effect of fragmentation and how to avoid the negative consequences.[7] The possibility of transgenerational effects of this phenomenon is discussed.

Nearly all infertility treatments targeting women are employing gonadotropins, follicle-stimulating hormone (FSH), as well as luteinizing hormone/human chorionic gonadotropin. However, the use of FSH in the treatment of male infertility has been far more limited and the doses used could be rather considered replacement than pharmacology in dosing. In their article, Romeo et al[8] review, in addition to summarizing the use of gonadotropins in IVF stimulation, the data supporting the use of FSH in treating male infertility. FSH has a clear role in the treatment of azoospermia in men with hypogonadotropic hypogonadism. However, the potential effect of improving semen quality with FSH in cases when no apparent etiology can be identified is far less obvious. The current knowledge as well as gaps in our knowledge on FSH treatment are covered in this Seminar.

Nonobstructive azoospermia (NOA) is the most severe form of male infertility. Microscopic testicular sperm extraction (micro-TESE) has been proven to be the most effective method of retrieving sperm from the testis. Several details need to be optimized to have a high-quality setup. As this method is employed in men with NOA with a heterogenous etiology, the sperm retrieval rates and the importance of preoperative optimization may be variable. It is important to counsel each patient accordingly. A comprehensive overview by Brant and Schlegel gives an update on these important details so that the vast experience of the original developer of this effective method may benefit all who take part in the treatment of these challenging cases of male infertility.[9]

Following its invention, intracytoplasmic sperm injection has gained widespread use in assisted reproduction. It is clear that this method of fertilization is very effective in treating severe male factor infertility. With ICSI it has become apparent that it is more about the quality than just the quantity, and accumulating evidence clearly shows that choosing the best possible sperm to fertilize the egg is highly important. Gallagher et al[10] not only review the available methods of choosing the best sperm but also discuss the importance of optimizing the important lifestyle factors of the male sufficiently early prior to the fertility treatment.

Although this issue is almost exclusively dedicated to challenges in male fertility and infertility, it seems appropriate to also include the status quo of the development of new male contraceptive methods. While women clearly carry most of the responsibility for avoiding unwanted pregnancies, it has become obvious that men are willing and should have more options to take part in contraceptive practices. We have waited long for a clinically acceptable hormonal contraceptive for men; however, other methods are being pursued. Professor Amory reviews the different options that are being developed to solve this challenge, which can at least to some degree be considered a gender equality issue.[11]

It is clear that there remain significant gaps in our understanding in the field of andrology. I hope that the readers with academic as well as clinical background find the articles included in this issue interesting. Andrology deserves more high-quality basic as well as clinical research to fill the existing gaps and to improve the care of male reproductive health. Do not forget the father, as Gallagher et al remind us.[10] Let us remember to involve the male partners in the process of infertility workup as well as treatments. Even when there is a female etiology, the best sperm should be made available for the fertility treatments.

Publication History

Article published online:
18 March 2024

• References

• 1 Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992; 340 (8810): 17-18
• 2 Soumillon M, Necsulea A, Weier M. et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep 2013; 3 (06) 2179-2190
• 3 Bartel DP. Metazoan microRNAs. Cell 2018; 173 (01) 20-51
• 4 Olotum O, Ammar A, Kotaja N. Small non-coding RNAs in male reproduction. Semin Reprod Med 2024; 41 (06) 213-225
• 5 Levine H, Jørgensen N, Martino-Andrade A. et al. Temporal trends in sperm count: a systematic review and meta-regression analysis of samples collected globally in the 20th and 21st centuries. Hum Reprod Update 2023; 29 (02) 157-176
• 6 Toppari J, Virtanen H, Rodprasert W. Deteriorating semen quality – the role of the environment. Semin Reprod Med 2024; 41 (06) 226-240
• 7 Moller Nielsen JL, Majzoub A, Esteves S, Humaidan P. Unraveling the impact of sperm DNA fragmentation on reproductive outcomes. Semin Reprod Med 2024; 41 (06) 241-257
• 8 Romeo M, Simoni M, La Marca A, Santi D. Gonadotropins in the management of couple infertility: toward the rational use of an empirical therapy. Semin Reprod Med 2024; 41 (06) 258-266
• 9 Brant A, Schlegel P. Micro-TESE. Semin Reprod Med 2024; 41 (06) 267-272
• 10 Gallagher MT, Krasauskaite I, Kirkman-Brown JC. Only the best of the bunch – sperm preparation is not just about numbers. Semin Reprod Med 2024; 41 (06) 273-278
• 11 Amory J. Male contraception. Semin Reprod Med 2024; 41 (06) 279-286