A brief history of technical developments in intracytoplasmic sperm injection (ICSI). Dedicated to the memory of J.M. Cummins.

Intracytoplasmic sperm injection (ICSI) is an assisted reproductive technology for treatment of severe male infertility introduced into clinical practice in 1992. This review provides a brief history of the development of ICSI by acknowledging major developments in the field. The review addresses key developments in pre-clinical and early studies, how ICSI compares with in vitro fertilisation, long-term consequences, how the mechanistic approach to ICSI has changed in both manual and semi-automated approaches, and how sperm selection procedures are integrated into ICSI. From the beginnings using animal models in the 1960-1970s, the development of ICSI is a remarkable and transformative success story. Indeed, its broad use (70% of cycles globally) exceeds the need required for treating infertile males, and this remains a controversial issue. There remain questions around the long-term health impacts of ICSI. Furthermore, advances in automation of the ICSI procedure are occurring. An estimated 6million children have been born from the ICSI procedure. With further automation of sperm selection technologies, coupled with automation of the injection procedure, it is likely that the proportion of children born from ICSI will further increase.

Evolution of the WHO "Semen" processing manual from the first (1980) to the sixth edition (2021).

As stated clearly in all editions of the WHO Laboratory Manual for the Examination and Processing of Human Semen, the goal of the manual is to meet the growing needs for the standardization of semen analysis procedures. With constant advances in andrology and reproductive medicine and the advent of sophisticated assisted reproductive technologies for the treatment of infertility, the manual has been continuously updated to meet the need for new, evidence-based, validated tests to not only measure semen and sperm variables but also to provide a functional assessment of spermatozoa. The sixth edition of the WHO manual, launched in 2021, can be freely downloaded from the WHO website, with the hope of gaining wide acceptance and utilization as the essential source of the latest, evidence-based information for laboratory procedures required for the assessment of male reproductive function and health.

The past, present, and future of the semen analysis.

This month's Views and Reviews provides an added perspective to the World Health Organization laboratory manual for the examination and processing of human semen, which was recently published in the 6th edition. The first artice provides a historical context of the prior editions of the World Health Organization manuals and modifications adopted over the years. The next piece then provides additional perspectives on the methodologies used for the performance of semen analysis. The third article then examines some of the new semen analytic technologies and enhancements that have become more common over the years. Finally, the last article proposed where male reproductive testing will head in the coming years with emerging research and technologies.

Historical investigations into varicocele pathophysiology and sperm migration.

Stephenson JD, O'Shaughnessy EJ. Hypospermia and its relationship to varicocele and intrascrotal temperature. Fertil Steril 168;19(1):110-7. "There is a frequently observed, definite relationship between varicocele and hypospermia." Moghissi KS. Human and bovine sperm migration. Fertil Steril 1968;19(1):118-22. "Van Leeuwenhoek's discovery of motile spermatozoa led to the conclusion that their migration was due to their own propellant activity."

[History of spermatozoon and changing views]. / Histoire du spermatozoïde et mobilité des idées.

With Ham, Leeuwenhoek discovered animalcules in human semen in 1677, without theoretical interpretations. Discussions focused on the respective role of ovum and animalcules during two centuries with erroneous doctrines. Modern ideas on status and origin of animalcules are associated with the development of the cell theory. Animalcules became spermatozoa. In 1875, Hertwig observed that the head of spermatozoon becomes a pronucleus and combines with the female pronucleus, thus establishing the concept that fertilization is the conjugation of two cells. During the first half of 20th century, endocrinology and genetics influenced management of infertile couples. Cryopreservation, analyses of ultrastructural morphology improved knowledges of normal and abnormal male gametes. In Vitro Fertilization and more IntraCytoplasmic Sperm Injection opened new views on the role of spermatozoa in human generation. Genetics and procreation were more and more so linked that each perspective of further advances shocked ethical considerations as transgression of natural biology. The future of spermatozoon in human reproductive programs remains a mystery according to, for example, experimental development using stem cell cultures.

[Men as a medical role. A blind spot in science]. / Der Mann als medizinisches Wissensobjekt: Ein blinder Fleck in der Wissenschaftsgeschichte.

While historians of science have demonstrated that in the late eighteenth century the emergence of the human sciences went along with the sexualization and medicalization of women, they paid almost no attention to the development of a medical knowledge on male (in)fertility. This paper argues that in the early twentieth century, the scientific investigation of the male role in reproduction was due to the rise of eugenics and the racial sciences. In order to illustrate this relation, I will discuss how in the context of the Nazi population and racial policy new research outcomes in the field of male (in)fertiliy research were achieved. More generally, I want to show that the transformation of man into a reproductive being and an object of medical knowledge is not only relevant for the history of reproductive medicine, but also for the history of the human sciences in the twentieth century.

George Washington's infertility: why was the father of our country never a father?

George Washington was the single most important figure in the founding of the United States of America. Numerous biographies of Washington have been written and his name is honored in countless ways, including as the name of the United States' capital. Washington has become so idealized in U.S. consciousness that it is easy to lose sight of his failings and disappointments. Undoubtedly, one of his most personal sorrows was his inability to have a child with his wife Martha. As the historian W.S. Randall puts it, "He was content with Martha, but mystified why, year after year, he and Martha could produce no Washington heir." In this article, George and Martha Washington's inability to have children is discussed, and it is suggested that George was the likely source of the couple's infertility. The author also speculates as to the cause of Washington's infertility and its effect on the course of American history. Frank discussion of Washington's infertility might provide some comfort to men struggling with infertility today.

Varicocele and male fertility.

Over the past 25 years the association of varicocele with male subfertility has been repeatedly demonstrated and the beneficial effect of varicocele ligation in infertile men with oligoasthenospermia has been documented. Since the precise mechanisms by which a varicocele affects spermatogenesis are still unclear, the proper approach to the management of "asymptomatic" varicoceles is controversial.

[Statistical analysis of 100 recent cases of sterile couples. (1948)]. / Causas error en estadísticas de parejas estériles. Estudio analítico de 100 casos.

A statistical analysis of 100 recent cases of sterile couples, studied from February through December, 5945, is made. The management of the study is described. Sterility causes are classified under four groups: hormonal factor; tubal factor; cervical spermatic factor; spermatic (pure) factor. Every group has two subgroups: serious and not serious. The serious case is incurable or very difficult to treat (examples: azoospermia, bilateral absence or tubal obstruction, nonovulatory menstruation). Other doctor-referred cases (difficult): 61. Doctors' own wives: 15. Serious cases: 65 with three pregnancies (4.56 per cent). Not serious cases: 24, with ten pregnancies (41.8 per cent). Total number of cases finished: 89, with 13 pregnancies (14.5 per cent). Study discontinued: eleven. The last total rate (14.5 per cent) is erroneous because there is an absolute difference between the "serious cases", and the "not serious cases." In Mexico the "sterility specialist" has many "serious cases", and for this reason the rate of successful cases is low.

[Could phimosis have been the cause of sexual difficulties and delayed fertility of Louis XVI (1754-1793)?]. / Le phimosis de Louis XVI (1754-1793) aurait-il été à l'origine de ses difficultés sexuelles et de sa fécondité retardée?

The great majority of historians agree that the marriage of Louis XVI and Marie-Antoinette was only consumated seven years after the official ceremony. This delay could have been due to a genital malformation (phimosis) of Louis XVI, a strict religious education, a traumatic childhood and the young age of the two spouses, factors that may have inhibited their sexuality. In this article, the authors try to determine whether Louis XVI was able to overcome his sexual difficulties following an operation (circumcision) or as a result of spontaneous cure.

[Hypospadia and infertility of Henry II of France (1519-1559)]. / Die Hypospadie und Infertilität von Heinrich II von Frankreich (1519-1559).

Henry II (1519-1559) of France was the second son of Francis I (1494-1547) and Claude de France (1498-1524) born in 1519 in St. Germain-en-Laye. After his older brother's and his father's death in 1547, he was anointed the French king in Reims. In 1533 already, as a 14-year-old boy, for reasons of state, he was married to the same aged Catherine de Medici (1519-1589), as her uncle was Pope Clement VII (1478-1534). The marriage remained childless for 11 years since Henry, due to a distinct hypospadia and a completely sexually inexperienced wife was unable to conceive children with her. His existing liaison to Diane de Poitiers (1499-1566) - a 19-year-older maid of honor of his father Francis I from 1537 until his death - influenced his sexual life immensely.The blame for the childless marriage was placed primarily on his wife, as Henry had become father of an illegitimate daughter with a mistress. Catherine then underwent all possible medical and alchemical procedures to finally give birth to the hoped Dauphin. Ironically, her rival for the favor of her husband, Diane de Poitiers was one of her greatest allies. She made clear that the cause lay with Henry and not with his wife. This was confirmed by the added solid physician Jean Fernel (1497-1558). His treatment of Henry and the simultaneous training of the unexperienced Catherine by Diane de Poitiers led to success.The result was the birth of Francis II (1544-1560) in 1544, the first of 10 children in 12 years. Thus, the dynasty was saved. After the death of Henry in a tragic tournament accident in 1559, three of his sons became kings of France. But the line of Valois remained without further descendants and was continued by Henry IV, the first Bourbon king in 1589.

Tales of healthy men: male reproductive bodies in biomedicine from 'Lebensborn' to sperm banks.

Using the example of 'sperm tales', borne out of the biomedical technologies that went hand in hand with the establishment of the 'science of man' (andrology), the article engages with the epistemic evolution of interrelated biomedical theories and concepts of what constitutes a 'healthy' reproductive male body. The article asks: how has the normative ideal male body been either perpetuated or interrogated through these tales of male reproduction at the interface between scientific and medical technologies? And how were changes to the normalization of male bodies central to clinical practices and cultural understandings of health and illness? With many aspects of the medical history of male reproduction in the 20th century still unexplored, this article will focus on the growing intervention of biomedicine to 'treat' male infertility by way of the classification, standardization and normalization of male corporeality, focusing in particular on the representation and construction of men and the male body, as reflected in medical science and practice from the second half of the 20th century onwards in Germany. The article analyses the rise in importance of sperm in biomedical investigation, including a consideration of the construction of infertility as the defining force behind concepts of 'healthy men', and examines the related conceptualization of male reproductive bodies at the crossroad between 'healthy' and 'normal'. It is argued that the ideal of male reproduction as being inherently healthy has lost ground. By the late 20th century, male bodies have become vulnerable, at least as represented in medical science and technology.

Henry VIII, McLeod syndrome and Jacquetta's curse.

The mental decline of King Henry VIII from being a jovial, charismatic and athletic young man into an increasingly paranoid, brutal tyrant in later life, ever more concerned at his lack of one or more male heirs, has attracted many medical diagnostic theories. Previous hypotheses have included diabetes, syphilis and hypothyroidism, among others. However, these inadequately explain Henry's failure to produce a male heir, despite multiple pairings. The latest postulated diagnoses for Henry are the coexistence of both Kell blood group antigenicity (possibly inherited from Jacquetta Woodville, Henry's maternal great grandmother) causing related impaired fertility, and McLeod syndrome, causing psychotic changes. As the mutated McLeod protein of the syndrome significantly reduces the expression, effectively inactivating the Kell antigen, we critically review this theory, examining in detail the pathophysiology of these conditions and assessing the genealogy of Henry VIII and its effect in subsequent generations.

Development and current applications of assisted fertilization.

Since the very early establishment of in vitro insemination, it became clear that one of the limiting steps is the achievement of fertilization. Among the different assisted fertilization methods, intracytoplasmic sperm injection emerged as the ultimate technique to allow fertilization with ejaculated, epididymal, and testicular spermatozoa. This work describes the early steps that brought forth the development of intracytoplasmic sperm injection and its role in assisted reproductive techniques. The current methods to select the preferential male gamete will be elucidated and the concerns related to the offspring of severe male factor couples will be discussed.