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Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services
Bruno Lunenfeld, Professor Emeritus of Endocrinology at Bar-Ilan University, is being recognized as a Giant in our specialty for his work on developing the clinical use and standardization of human menopausal gonadotropin (Pergonal, Merck Serono S.A., Darmstadt, Germany) in the treatment of female and male infertility. His work and contributions have changed our field, were key for the development of the subspecialty of reproductive endocrinology and infertility, and importantly, have changed the lives of so many infertile couples. His is a remarkable story.
Early years: Vienna to London
Bruno was an only child, born in 1927 into a prominent Jewish family living in Vienna, Austria (Figure 1). His father was one of the lawyers to the Habsburg household, managing the House of Habsburg's Austrian finances. Bruno's privileged life came to a halt after the Nazi Party came to power in Germany, and Austria's Chancellor Kurt von Schuschnigg reluctantly signed an Austro-German agreement in 1936. Bruno's father understood the situation. While making plans to leave Austria, he and his brother (Bruno's uncle) were arrested and taken to Dachau, the Nazi's first concentration camp near Munich, before their plan could be carried out. Bruno initially heard that his father had been shot en route to Dachau but then learned some months later that it was his uncle who was killed.
Bruno left Austria after Kristallnacht in 1938 at the age of 11 years as part of the Kindertransport program (“kinder” is German for “children”) (Figure 2). The program was established pursuant to an agreement with the United Kingdom for children to be transported from Germany and Austria to England to be cared for by foster families and other sponsors. Bruno remembers well the tragedies, as well as the many smaller indignities, inflicted on him by the Hitler Youth, such as having his tram ticket stolen and then being forced to walk 6 km home after they cut his shoe laces.
Figure 2Bruno in 1938, age 11 years, around the time of Austrian emigration
On arriving in England, Bruno was taken to a camp in Dovercourt, a small seaside town in Essex, northeast of London. The children had been allowed to take with them only what could fit into a rucksack: Bruno took two books, a compass, and a map of the United Kingdom. His mother had also hidden £10 sterling in his sock, which was quite a lot of money in those days.
Bruno did not want to be placed with a foster family, so he ran away from the camp one night, and used the money hidden in his sock to buy a train ticket to London, where he knew his mother’s brother lived. On arriving in London, he went to the first policeman he saw, as he had been told that the English “bobbies” were very kind and helpful, and explained his situation. The policeman was more than helpful: he took Bruno home, where he and his wife looked after him. They brought Bruno to the cinema to see Tom Sawyer, which Bruno vividly remembers watching from 10 am to 6 pm for four consecutive days–thus giving Bruno valuable lessons in the English language. Shortly thereafter, his uncle, Adolf Hornung, was located at his home in Belsize Park in northwest London (Figure 3).
The Habsburg connection helped Bruno's admission into Seafield Park, a prestigious boys’ boarding school for the Royal Navy. After the school was taken over by the Ministry of Defense and closed following the outbreak of World War II, Bruno attended Wykeham House School until March 1940, when the French military transported him to Palestine, where he was reunited with his parents. His father never spoke about how he managed to reach Palestine, and Bruno never asked, but he believes British intelligence helped his father flee Austria and reunite with his mother in Trieste, Italy, before they left for Palestine.
Choosing medicine
His parents first placed Bruno in a Hebrew school in Tel Aviv, Israel, where he did not do well, as he found Hebrew difficult to learn. After the bombing of Tel Aviv began on September 9, 1940, Bruno’s parents moved him to St George’s, an English boarding school in Jerusalem. It was the death of his best friend from poliomyelitis that influenced Bruno to study medicine.
He finished school in 1945 at a time when there were no medical schools in Palestine, so he enrolled in the British Institute of Sciences to study chemistry. Bruno was eventually accepted to medical school in Geneva, Switzerland, where he received his MD in 1952 and a PhD in 1954 (Figure 4).
Estrogens for the treatment of postmenopausal symptoms
Bruno’s PhD thesis was on the evaluation of an oral estrogen/testosterone preparation made by CIBA, a pharmaceutical company, for the treatment of postmenopausal symptoms. Testosterone was used to protect the uterus from the unopposed estrogen effect, as there were no oral progesterone preparations at the time. The criteria used to select patients required menopause-like symptoms, an atrophic vaginal smear, and a reading of zero estrogens determined by the Brown test (a fluorescent technique that measured estrogen, estradiol, and estriol in a 24-hour urine sample). Bruno’s work represented the first demonstration of the successful oral treatment of postmenopausal symptoms.
The story of human menopausal gonadotropin leading to Pergonal for infertility treatment
Bruno injected urine from postmenopausal women, collected before and after treatment with estrogens, into prepuberal mice (often referred to as infantile mice because they have not begun to ovulate). He made the critical and unexpected observation that the urine of postmenopausal women who had not been treated with estrogen would induce ovulation in mice, suggesting that the urine of such women contained a substance that stimulates the gonads (hence, gonadotropins).
Injection with urine, collected from postmenopausal women prior to their treatment with estrogen, caused enlargement of the ovaries and uterus in infantile mice, Bruno found; however, the uterus and ovaries remained infantile in those mice injected with urine collected from women after 60 days of treatment with the estrogen/testosterone combination.
Bruno concluded that the compound detected in menopausal urine that stimulated the mouse uterus and ovaries must be gonadotropin-derived, that postmenopausal women were overproducing gonadotropins, and that the estrogen/testosterone combination was inhibiting gonadotropic secretion.
He had potentially discovered a contraceptive effect but wanted to pursue the fertility aspects of his work.
Building on his observation that postmenopausal women produced gonadotropins in excess, Bruno wanted to purify large quantities of the compound and use it to induce ovulation in amenorrheic women.
and Zondek showed that the blood and urine of postmenopausal women contained gonadotropins. However, because a sufficient amount of gonadotropins could not be obtained from postmenopausal women’s urine, gonadotropins extracted from animal pituitaries and from the pregnant mare’s serum were used to treat patients. These elicited the formation of antibodies that limited their usefulness. Bruno wanted to circumvent this problem by using human gonadotropins.
The Gonadotropin (G)-Club
In 1953, with the help of Professor Hubert de Watteville, Bruno’s PhD supervisor, and a chemist, Dr Rudi Borth, Bruno invited a number of scientists to Geneva to exchange information and coordinate research on gonadotropins. During the meeting, they formed a group called the G-Club. Original club members included Egon Diczfalusy, Jim Brown, and John Loraine (Figure 5, Figure 6). The first collaborative efforts of the G-Club led to two publications.
Photo courtesy of Dr. Bruno Lunenfeld. Left to right, first row: J. H. Gaddum, R. Benz, J. Loraine, A. Mandl, R. Borth, C. Crook; second row: J. Dekansky, E. Diczfalusy, B. Lunenfeld (circled), J. Brown, W. R. Butt; third row: J. A. Strong, S. G. Jonsen, S. L. Steelman, E. T. Bell.
Romero. Profile of Bruno Lunenfeld, MD. Am J Obstet Gynecol 2018.
Piero Donini, a scientist at Serono Pharmacological Institute in Rome, Italy, had previously produced a gonadotropin product: a dose of 25 units was recommended for follicle maturation, ovulation induction, spermatogenesis, corpus luteum insufficiency, etc. Lack of sales and negative results led the company to stop development. Donini had read Bruno’s paper and, in 1957, invited him to Rome. Bruno presented his work to the executive board of Serono, but the board was not enthusiastic. However, the meeting was attended by Francesco Pacelli, who approached Bruno after the meeting to discuss his work and the complicated logistics of collecting and processing large volumes of urine. Pacelli hosted Bruno in Rome for 10 days, and during this time, they discussed the ideas and approach to the generation of postmenopausal gonadotropins. It turned out that Pacelli’s uncle was Pope Pius XII. The Catholic Church arranged to supply large quantities of urine of postmenopausal nuns–this allowed human menopausal gonadotropin (hMG) to be purified and isolated (Figure 7).
By that time, Bruno had returned to Israel as a visiting scientist at the Weizmann Institute of Science and wanted to administer gonadotropins into infertile hypopituitary-hypogonadotropic women with primary amenorrhea who wanted to become pregnant; however, his chief told him to try the preparation on himself first. After his intern injected Bruno with gonadotropin for five days and no side effects appeared, the preparation was deemed safe, and Bruno was allowed to try it in three hypopituitary-hypogonadic, amenorrheic, infertile patients: the first became pregnant and delivered a healthy baby (Figure 8).
L'induction de l'ovulation dans les amenorrhees hypophysaires par un traitement combine de gonadotrophines urinaires menopausiques et de gonadotrophines chorioniques.
It was big news. The other two women also became pregnant, but they both miscarried. Nevertheless, the compound Pergonal was registered in Israel by Teva Pharmaceutical Industries Ltd on behalf of Serono (Figure 9).
Figure 8Introduction of gonadotropins to a patient population
L'induction de l'ovulation dans les amenorrhees hypophysaires par un traitement combine de gonadotrophines urinaires menopausiques et de gonadotrophines chorioniques.
After the excitement of discovery and success in the treatment of infertility came some disappointments, Bruno told me. The first was a case of hyperstimulation in which the patient presented with a distended abdomen, had a thromboembolic phenomenon, and died; Bruno reported the case in The Lancet.
and the third, corpus luteum insufficiency, which Bruno detected by measuring pregnanediol in urine from a patient treated with Pergonal. Bruno treated what he believed to be a luteal phase defect with injections of progesterone and medroxyprogesterone acetate tablets. Pregnanediol levels increased but the patient aborted, and Bruno realized that the levels he had measured came from the injected compound rather than the corpus luteum. Looking for a progesterone-like preparation that would not metabolize into pregnanediol, he studied dydrogesterone, a “mirror image of progesterone,” which is marketed today in Europe as Duphaston (Abbott Healthcare Products B.V., Weesp, The Netherlands).
However, lacking funds to continue, this aspect of Bruno’s research stopped.
hCG binds to the ovary, hinting about the existence of receptors
From 1962 through 1995, Bruno worked as Head of the Institute of Endocrinology at Tel-Hashomer Hospital (known today as Sheba Medical Center) in Tel Aviv, Israel. The institution served as a World Health Organization (WHO) International Reference Center for Fertility-Promoting Drugs from 1969 through 1992. Bruno joined Bar-Ilan University in 1964, became an associate professor in 1967, professor in 1969, and professor emeritus in 1995.
In the late 1960s, Bruno demonstrated that human chorionic gonadotropin (hCG) labeled with radioactive iodine binds the ovary but disappears from the circulation (Figure 10). He was a close friend with Rosalyn Yalow, a Nobel Laureate for the development of radioimmunoassays, who worked with Bruno in radiolabeling hCG. Dr Yalow taught the team in Israel how to label proteins with radioactive iodine, and Bruno undertook these experiments with the nuclear reactor at Dimona in the Negev Desert. The observation that the ovary would bind radiolabeled hCG suggested the presence of a receptor for this hormone in the ovary, especially in theca cells. Subsequently, luteinizing hormone (LH)
One of Bruno's graphs shows the fate and localization of iodine-labeled hCG in mice. Among all organs examined, only the ovary had the capacity to bind hCG–suggesting active binding sites for hCG and LH in the ovary.
former Chair of Obstetrics and Gynecology and Reproductive Sciences at Harvard University and Dr. Zoltan Petro, a biomedical researcher for Harvard and the University of California at San Diego Medical School. The concept was that follicle-stimulating hormone (FSH) would stimulate granulosa cells to produce aromatase and promote follicular growth and maturation; then, LH would act on theca cells and induce androgen. Androgen would be converted to estrogens by the FSH-induced aromatase. LH would also induce ovulation of the matured follicle and maintain corpus luteum function.
The breakthroughs needed the development of an international standard to measure gonadotropins–in other words, a reference preparation. Bruno was instrumental in developing such a reference preparation to test the potency of hMG. In 1972, he was invited to chair a scientific meeting convened by the WHO in Geneva, Switzerland, at which guidelines for the diagnosis and management of infertile couples were developed, and the effective daily doses of gonadotropin for hypogonadotropic and anovulatory, normogonadotropic patients were defined.
Three years later, Bruno chaired the WHO Expert Committee on Biological Standardization, at which the committee defined the international units for FSH and LH.
A scare that led to the development of recombinant FSH, LH, and hCG
In 1985, three deaths were reported in patients who had been treated with pituitary-derived growth hormone. One cause of death had been confirmed as Creutzfeldt-Jakob disease (CJD) (also known as “mad cow disease,” now known to be caused by prions, misfolded proteins that can cause disease transmitted by meat products).
This led him to contact the Chief Executive Officer of Serono in the United States, and Mr Fabio Bertarelli, the Chief Executive Officer of Serono in Italy, to encourage them to adopt an immune-purification procedure developed by Bruno and his assistant Aliza Eshkol to decrease the risk of CJD.
This also led to a collaboration with Genentech, a company already developing recombinant growth hormone. Eventually, Genentech was bought by Serono and started to work on recombinant FSH.
Through the committee he chaired at WHO, Bruno was familiar with the guidelines for the production of biological proteins by recombinant DNA technology.
He was also aware of the reports of expression of bovine LH by the ovarian cells of Chinese hamsters. At the time, the laboratory of Scott Chappel at Genetech, which Bertarelli had purchased, had identified the coding for the beta subunit of human FSH. All of this led to the production of recombinant FSH, LH, and hCG, which allows the production of pharmacologically active pure hormones with minimal risk of disease transmission through biological contamination.
The impact of Bruno’s discoveries in reproductive endocrinology
It is difficult to overstate the impact of Bruno’s contributions to our field. He (1) identified that a combination of estrogens and testosterone was effective in treating postmenopausal symptoms; (2) discovered that the urine of postmenopausal women contains high concentrations of gonadotropins, and capitalized on this observation to purify hMG as a therapeutic tool for the treatment of infertility; (3) made the seminal observation that the ovary would bind radiolabeled hCG, paving the way for the 2-cell, 2-gonadotropin theory of follicular development proposed by Ken Ryan; (4) generated the first international preparation of gonadotropins; and (5) made possible the subsequent development of recombinant FSH, LH, and hCG, which are in clinical use today.
The birth of the International Society for the Study of the Aging Male
In 1995, Bruno became Professor Emeritus of Endocrinology at Bar-Ilan University, yet he wanted to remain active. Upon realizing that men had many of the same problems as postmenopausal women as they age, such as loss of sleep and concentration, he turned his attention to the study of the aging male.
Bruno founded the International Society for the Study of the Aging Male, and, in collaboration with WHO, organized the first, second, and third World Congresses on the Aging Male held in Geneva. He also founded a journal, The Aging Male, for which he has been Editor-in-Chief since 2002 (Figure 11).
Figure 11A multidisciplinary quarterly covering all aspects of male health throughout the aging process
Bruno had two sons with his first wife Susanne (Suzi), who he met on New Year’s Eve during a ski vacation in Argentière (France) in 1946. She was a political science student and interpreter at the University of Geneva. They married six years later, and she sadly succumbed to breast cancer in 1995. Bruno met his second wife Pnina when, working with the pharmaceutical company Teva, she tried to sell him the very infertility drug he had helped develop. When they married, she was General Manager of GenMedics Israel.
Having been an only child, it gives Bruno great joy to have a large family: he has eight grandchildren, five through his second wife, and five great-grandchildren (Figure 12). A particular source of pride for Bruno is that his elder son, Eitan, is the Dr Morrie Gelfand Professor and Chair of Obstetrics and Gynecology at Ben-Gurion University of the Negev/Soroka Medical Center in Be’er Sheva, Israel; Co-Chair and Founder of the Center for Advanced Research and Education in Reproduction at Ben-Gurion University of the Negev; and past president of the Israeli Association of Obstetrics and Gynecology. His younger son, Yoram, who studied economics, is a prominent, successful real estate professional and manages the family’s properties in Austria and Israel.
After begrudgingly taking piano lessons as a child, Bruno lost interest in music after his piano teacher passed away. But now his life is again filled with music, as his wife loves classical, and has made Bruno an opera lover. He likes music that has a story, and so it was perhaps predictable that he would fall in love with Richard Wagner’s operas, which the composer described as “music dramas,” and for which Wagner wrote the librettos. Bruno had the rare privilege of being invited to the Bayreuth Festival for many years by Wagner's grandson, Wolfgang Wagner, the festival's long-time director from 1951 to 2008. The month-long festival is held annually, and Wagner’s operas are performed in the opera house Wagner designed. The festival has been sold out since it was inaugurated in 1876, and the waiting list for a ticket is several years long.
Bruno has always read when he had the time. As a child, he loved Karl May’s adventure stories about the American Old West. After reuniting with his parents in Palestine, his father introduced him to the German classics: Schiller, Goethe, Heine. He also likes history and historical/political thrillers such as Phillip Kerr’s Berlin Noire. His favorite poems are “Das Lied von der Glocke” (“Song of the Bell”) and “Die Bürgschaft” (“The Pledge”) by Schiller. He loves the television series The Americans, and among his favorite movies are Fargo and The White Ribbon.
At the age of 91 years, Bruno, an ardent believer in the “use it or lose it” philosophy, remains physically and mentally active. He spends two-thirds of his time in Florida, swims most days, and reads at least four articles a week as Editor-in-Chief of The Aging Male. Bruno used to sail most weekends, and now likes to cruise, travel, and enjoy nature as well as visit art galleries and museums.
In closing
This piece is based on several two-hour conversations I had with Bruno. At the end of every exchange, Bruno's energy and love for life left me feeling inspired, optimistic, and ready to take on greater challenges. Bruno's charisma is contagious, his achievements inspiring, and his life an example for us all.
To Bruno, success means achieving one’s goals. After living through the Holocaust, the genocide that destroyed six million Jewish lives, and World War II, during which several million more men and women were lost, it is fitting that Bruno found a way to make new life possible. Measured by that goal, he has had much success in his long life: that success has made him a “Giant” in our specialty.
References
De Watteville H.
Lunenfeld B.
Clinical and cytological effects of a combined estrogen and androgen treatment in the menopausal syndrome.
Schweiz Med Wochenschr.1953; 83 ([in undetermined language]): 14-18
L'induction de l'ovulation dans les amenorrhees hypophysaires par un traitement combine de gonadotrophines urinaires menopausiques et de gonadotrophines chorioniques.
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