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Giants in Obstetrics and Gynecology Series: A profile of Leon Speroff, MD

      Click Supplemental Materials under article title in Contents at ajog.org
      Dr Leon Speroff, Professor Emeritus and former Chair of Obstetrics and Gynecology at the Oregon Health & Science University School of Medicine and former Arthur H. Bill Professor and Chairman of the Department of Reproductive Biology at the Case Western Reserve University School of Medicine, is being recognized as a Giant in Obstetrics and Gynecology.
      Leon has made seminal contributions to reproductive endocrinology, including key concepts in the regulation of the human menstrual cycle,
      • Speroff L.
      • Vande Wiele R.L.
      Regulation of the human menstrual cycle.
      the role of prostaglandins in ovulation,
      • O'Grady J.P.
      • Caldwell B.V.
      • Auletta F.J.
      • Speroff L.
      The effects of an inhibitor of prostaglandin synthesis (indomethacin) on ovulation, pregnancy, and pseudopregnancy in the rabbit.
      • Caldwell B.V.
      • Auletta F.J.
      • Speroff L.
      Prostaglandins in the control of ovulation, corpus luteum function, and parturition.
      induction of myometrial contractility,
      • Caldwell B.V.
      • Auletta F.J.
      • Speroff L.
      Prostaglandins in the control of ovulation, corpus luteum function, and parturition.
      • Anderson G.G.
      • Hobbins J.C.
      • Speroff L.
      • Caldwell B.V.
      Intravenous prostaglandins E2 and F2 and syntocinon for the induction of term labor.
      • Anderson G.G.
      • Hobbins J.C.
      • Speroff L.
      • Caldwell B.V.
      The use of prostaglandins for the induction of labor.
      induction of labor,
      • Anderson G.G.
      • Hobbins J.C.
      • Speroff L.
      • Caldwell B.V.
      The use of prostaglandins for the induction of labor.
      • Anderson G.G.
      • Hobbins J.C.
      • Speroff L.
      Intravenous prostaglandins E2 and F2 for the induction of term labor.
      • Anderson G.
      • Cordero L.
      • Speroff L.
      • Hobbins J.
      Clinical use of prostaglandins as oxytocin substances.
      and midtrimester termination of pregnancy
      • Anderson G.
      • Cordero L.
      • Speroff L.
      • Hobbins J.
      Clinical use of prostaglandins as oxytocin substances.
      • Anderson G.G.
      • Hobbins J.C.
      • Rajkovic V.
      • Speroff L.
      • Caldwell B.V.
      Midtrimester abortion using intraamniotic prostaglandin F2alpha.
      • Anderson G.G.
      • Hobbins J.C.
      • Speroff L.
      • Caldwell B.V.
      The induction of therapeutic abortion using intravenous prostaglandin F2 alpha.
      in addition to the development of radioimmunoassays for primary prostaglandins and their metabolites.
      • Caldwell B.V.
      • Burstein S.
      • Brock W.A.
      • Speroff L.
      Radioimmunoassay of the F prostaglandins.
      • Zusman R.M.
      • Caldwell B.V.
      • Speroff L.
      • Behrman H.R.
      Radioimmunoassay of the A prostaglandins.
      • Caldwell B.V.
      • Speroff L.
      • Brock W.A.
      • et al.
      Development and application of a radioimmunoassay for F prostaglandins.
      • Haning Jr., R.V.
      • Kieliszek F.X.
      • Alberino S.P.
      • Speroff L.
      A radioimmunoassay for 13, 14-dihydro-15-keto prostaglandin F2alpha with chromatography and internal recovery standard.
      Moreover, he described the role of prostaglandins in endotoxic shock
      • Knox G.E.
      • Caldwell B.V.
      • Ziminski C.M.
      • Hoffman D.C.
      • Speroff L.
      Prevention of endotoxin induced death in rabbits with indomethacin.
      and the use of clomiphene in ovulation induction
      • Gorlitsky G.A.
      • Kase N.G.
      • Speroff L.
      Ovulation and pregnancy rates with clomiphene citrate.
      and made contributions that advanced hormone replacement therapy for perimenopausal women as well as steroid hormones for contraception, which changed the practice of medicine.
      • Rowan J.P.
      “Estrophasic” dosing: a new concept in oral contraceptive therapy.
      • Williams S.R.
      • Frenchek B.
      • Speroff T.
      • Speroff L.
      A study of combined continuous ethinyl estradiol and norethindrone acetate for postmenopausal hormone replacement.
      • Simon J.A.
      • Liu J.H.
      • Speroff L.
      • Shumel B.S.
      • Symons J.P.
      Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy.
      • Speroff L.
      • Rowan J.
      • Symons J.
      • Genant H.
      • Wilborn W.
      The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized controlled trial.
      • Speroff L.
      WHI trial: it's time to be critical!.

      Speroff L. What have we learned from the WHI? Contemporary OB/GYN. 2007. Available from http://www.modernmedicine.com/modemmedicine/Estrogen/Guest-Editorial-What-have-we-learned-from-the-WHI/ArticleStandard/Article/detail/426598. Accessed on May 18, 2017.

      Leon, with Nathan Kase and Robert Glass, and subsequently with Marc Fritz, wrote the book Clinical Gynecologic Endocrinology and Infertility (Figure 1),
      • Speroff L.
      • Glass R.H.
      • Kase N.G.
      Clinical gynecologic endocrinology and infertility.
      a true medical best-seller, which has been a vademecum and has taught generations of physicians. Now in its eighth edition, the book has been translated into, among other languages, Chinese, Spanish, Italian, Greek, Farsi, Portuguese, Polish, and Turkish. Since the first edition appeared in 1973, the English version of the book has sold nearly 300,000 copies throughout the world.
      Figure thumbnail gr2
      Figure 1A medical best-seller
      Dr Leon Speroff, lead author of the best-seller Clinical Gynecologic Endocrinology and Fertility with Drs Robert Glass and Nathan Kase. This book, now in its eighth edition, expanded from 266 pages to 1,400+ pages, has been translated into more than eight languages, and has sold more than 300,000 copies in English worldwide.
      Romero. Profile of Leon Speroff, MD. Am J Obstet Gynecol 2017.

      Leon’s early life in the Midwest

      Leon was born and raised in Ohio, where he also attended college and medical school. His family came from Macedonia, and his grandparents were mountain people in what is now the northwest corner of Greece. Leon grew up speaking Macedonian and little English until he went to grade school in Lorain. Leon’s father was a barber until he bought a tavern and restaurant in Akron. Leon spent his undergraduate years at Denison University, a liberal arts college in Granville, 30 miles east of Columbus.

      Education in obstetrics and gynecology and steroid hormones

      Leon decided to become a physician in his senior year of college. The Dean of Admissions at the Case Western Reserve University School of Medicine came to Denison to interview Leon and offered him a position at the conclusion of the interview.
      His decision to become an obstetrician was made after he read a book, Childbirth Without Fear,
      • Dick-Read G.
      Childbirth without fear: the principles and practice of natural childbirth.
      about natural childbirth by British obstetrician Grantly Dick-Read. Yale University had the only academic Department of Obstetrics and Gynecology in the United States that promoted natural childbirth, so Leon spent a month as a subintern in New Haven during the summer before his senior year at medical school. Consequently, Yale was the only residency to which he would apply: this proved to be a pivotal decision that influenced the rest of his professional career.
      In the beginning of Leon’s year as chief resident, Nathan Kase brought him into his office and said, “Now, let’s think about what’s going to follow.” Once Leon completed a two-year tour of duty in the U.S. Air Force, Nate helped him arrange to become a Fellow in the steroid training program at the Worcester Foundation for Experimental Biology.
      Following that training, Leon accepted a fellowship with Raymond Vande Wiele at Columbia University. A fascinating observation emerged from that research—mathematical modeling of the hormones produced during the menstrual cycle. Jeff Bogumil, an engineer, and Dr Vande Wiele, using mathematical analyses based on physiologic data pulled from the literature by Leon, predicted that hormones would be secreted in short spurts, a pulsatile manner (Figure 2).
      • Speroff L.
      • Vande Wiele R.L.
      Regulation of the human menstrual cycle.
      • Bogumil R.J.
      • Ferin M.
      • Rootenberg J.
      • Speroff L.
      • Vande Wiele R.L.
      Mathematical studies of the human menstrual cycle. I. Formulation of a mathematical model.
      This was subsequently confirmed by empirical observations by Robert Jaffe at the University of Michigan.
      • Midgley Jr., A.R.
      • Jaffe R.B.
      Regulation of human gonadotropins. X. Episodic fluctuation of LH during the menstrual cycle.
      Figure thumbnail gr3
      Figure 2Toward understanding the endocrinological control of the menstrual cycle
      Romero. Profile of Leon Speroff, MD. Am J Obstet Gynecol 2017.

      Academic career and authorship in reproductive endocrinology

      Leon intended to spend two years at Columbia University, but after his first year, Nate, who had become Chair at Yale in 1969, asked Leon to return, which he did during the summer of 1970. He went on to gain national and international stature because of his clarity of thought, eloquence, and impeccably delivered lectures in reproductive endocrinology. Leon became director of the residency program and, eventually, vice chairman of the department.
      One day, Robert Glass stopped Leon in the corridor and asked, “Nate and I are writing a book on endocrinology. Would you like to join us?”
      Leon jumped at the chance, met with Bob and Nate, and asked, “Well, what have you done so far?”
      They replied, “Nothing.” So Leon took over the project, wrote most of the book, and became the first author of what would be Clinical Gynecologic Endocrinology and Infertility.
      • Speroff L.
      • Glass R.H.
      • Kase N.G.
      Clinical gynecologic endocrinology and infertility.
      The first edition was published in 1973; the price was $17 for a book of 266 pages.

      Research in prostaglandins and editor of Prostaglandins

      Leon’s research at Yale focused on prostaglandins. He recruited Burt Caldwell from the Worcester Foundation to develop radioimmunoassays for prostaglandins, assembled a team that explored the role of prostaglandins in every facet of reproduction, and founded the journal Prostaglandins, which he edited with Burt Caldwell and Gerry Anderson. John Hobbins and Harold Behrman also became important members of the team.
      The result was an extremely prolific period of applied research in which the team published extensively on the role of prostaglandins in ovulation,
      • O'Grady J.P.
      • Caldwell B.V.
      • Auletta F.J.
      • Speroff L.
      The effects of an inhibitor of prostaglandin synthesis (indomethacin) on ovulation, pregnancy, and pseudopregnancy in the rabbit.
      • Caldwell B.V.
      • Auletta F.J.
      • Speroff L.
      Prostaglandins in the control of ovulation, corpus luteum function, and parturition.
      luteolysis,
      • Anderson G.G.
      • Hobbins J.C.
      • Speroff L.
      • Caldwell B.V.
      The induction of therapeutic abortion using intravenous prostaglandin F2 alpha.
      and midtrimester termination of pregnancy
      • Anderson G.G.
      • Hobbins J.C.
      • Speroff L.
      • Caldwell B.V.
      The induction of therapeutic abortion using intravenous prostaglandin F2 alpha.
      as well as induction of labor (Figure 3)
      • Anderson G.G.
      • Hobbins J.C.
      • Speroff L.
      • Caldwell B.V.
      Intravenous prostaglandins E2 and F2 and syntocinon for the induction of term labor.
      • Anderson G.G.
      • Hobbins J.C.
      • Speroff L.
      Intravenous prostaglandins E2 and F2 for the induction of term labor.
      and the role of prostaglandins as a cause of preeclampsia,
      • Speroff L.
      Toxemia of pregnancy. Mechanism and therapeutic management.
      which was validated many years later by the demonstration that aspirin (which blocks prostaglandin production) reduces the frequency of preterm preeclampsia.
      Figure thumbnail gr4
      Figure 3A seminal report on prostaglandins
      Romero. Profile of Leon Speroff, MD. Am J Obstet Gynecol 2017.
      Leon and his group were the first to demonstrate that indomethacin prevents ovulation in the rabbit,
      • O'Grady J.P.
      • Caldwell B.V.
      • Auletta F.J.
      • Speroff L.
      The effects of an inhibitor of prostaglandin synthesis (indomethacin) on ovulation, pregnancy, and pseudopregnancy in the rabbit.
      and he was the first to report that prostaglandins increase the production of progesterone by the corpus luteum.
      • Speroff L.
      • Ramwell P.W.
      Prostaglandin stimulation of in vitro progesterone synthesis.

      Chair at Oregon and Cleveland

      Leaving New Haven was difficult, but Leon had decided that he wanted to become a Chair; in the summer of 1976, he accepted a position as Professor and Chair of the Department of Obstetrics and Gynecology at the Oregon Health & Science University School of Medicine in Portland.
      Leon introduced daily morning obstetrical rounds. The department’s budget was derived from the Medical School, and faculty members negotiated their salaries with the Chair. In other words, faculty salaries were guaranteed, and the faculty did not have to see a certain number of patients or perform a certain number of procedures, which meant that they had time to teach, do research, and be clinicians. But all that gradually changed with a growing emphasis on finances.
      During a recession in 1983, the plans for a desperately needed new labor and delivery unit were canceled, so when the Chair at Leon’s alma mater became available, the temptation to move back to where Leon still had family proved too great. He left Oregon and took a position as Chair of the Department of Reproductive Biology at Case Western Reserve University in Cleveland and was charged with turning around the finances of the MacDonald Women’s Hospital, which was several million dollars in the red.
      Leon accomplished this feat in approximately four years, mainly from the income generated by the faculty he had recruited, to the point that the hospital was now $2-$3 million in the black. Subsequently, Leon called a meeting with the chief executive officer of the hospital, the dean, and the chief financial officer, presented the new financial situation, and requested that some of the funds be used to develop and support the academic enterprise and research of the department. The leadership was not favorable to this proposal, and Leon thus decided to return to Oregon.

      A new approach to contraception

      Executives of the Parke-Davis Pharmaceutical Company approached Leon in 1983 and asked for his advice on how to compete with the multiphasic oral contraceptives that were popular at the time. Leon conceived a new approach, using graduated doses of estrogen, with the aim being a beneficial impact on the lipid profile (a hope that did not work out) and better support of the endometrium, an effect that did yield reduced estrogen symptoms (including menstrual and breakthrough bleeding), with the eventual commercial product, Estrostep. The approach was called estrophasic dosing and was published in the Journal in 1999 (Figure 4).
      • Rowan J.P.
      “Estrophasic” dosing: a new concept in oral contraceptive therapy.
      Figure thumbnail gr5
      Figure 4The basis for a new formulation of birth control pills
      Romero. Profile of Leon Speroff, MD. Am J Obstet Gynecol 2017.
      In addition, Estrostep, with its low androgenicity, proved to be effective for the treatment of acne and was approved for that purpose by the Food and Drug Administration.
      • Jensen J.T.
      • Speroff L.
      Health benefits of oral contraceptives.
      Around the same time, Leon convinced Parke-Davis that the components of its oral contraceptives, ethynyl estradiol and norethindrone acetate, if used in significantly reduced doses, would provide effective postmenopausal hormone therapy. He organized the pilot studies that yielded the commercial product FemHRT.
      • Williams S.R.
      • Frenchek B.
      • Speroff T.
      • Speroff L.
      A study of combined continuous ethinyl estradiol and norethindrone acetate for postmenopausal hormone replacement.
      • Simon J.A.
      • Liu J.H.
      • Speroff L.
      • Shumel B.S.
      • Symons J.P.
      Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy.
      • Speroff L.
      • Rowan J.
      • Symons J.
      • Genant H.
      • Wilborn W.
      The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized controlled trial.
      Leon neither filed patents on his designs nor requested financial compensation from Parke-Davis, but the company spontaneously and graciously volunteered to provide his department an annual grant for the rest of his professional career. In this arena, Leon made a major contribution in the evolution of oral contraception with the use of a low dose of estrogen; additionally, he was instrumental in eliminating the age of 35 years as an upper limit for the use of oral contraceptives.

      Hormone replacement therapy and the Women’s Health Initiative Study

      After the first publication of the Women’s Health Initiative that reported the clinical trial results with postmenopausal hormone therapy, Leon was one of an intrepid few who offered critical analyses that highlighted the flaws of the trials and the study and provided an accurate interpretation of the data that, over the following years, proved to be correct.
      • Speroff L.
      WHI trial: it's time to be critical!.

      Speroff L. What have we learned from the WHI? Contemporary OB/GYN. 2007. Available from http://www.modernmedicine.com/modemmedicine/Estrogen/Guest-Editorial-What-have-we-learned-from-the-WHI/ArticleStandard/Article/detail/426598. Accessed on May 18, 2017.

      • Speroff L.
      Postmenopausal hormone therapy and the risk of breast cancer: a contrary thought.
      Looking back over those years, Leon said, “I am proud that, in my lectures and publications, I provided support to clinicians and patients who desired to continue to benefit from the appropriate use of postmenopausal hormone therapy, with doses and durations of treatment adjusted according to their individual needs.”

      Leon, an author, outside medicine

      Leon indulged his passion and great gift as a storyteller and has written several nonmedical books. He published his first book, Carlos Montezuma,
      • Speroff L.
      Carlos Montezuma, M.D.: a Yavapai American hero—the life and times of an American Indian, 1866–1923.
      three years before he retired from medicine. It is about the Yavapai Native American doctor and activist, Wassaja, who was given the name Carlos Montezuma by the Italian photographer, Carlo Gentile, who purchased Wassaja for 30 silver dollars from the Pima raiders who had captured him and other children to sell or barter them.
      Leon was delighted to discover that the skills needed to write a nonmedical book were the same as those required to write a medical book, including the ability to distill a substantial amount of information into a story.
      His second book, The Deschutes River Railroad War,
      • Speroff L.
      The Deschutes River railroad war.
      explores the history of railroads in the Pacific Northwest, specifically about the contest between two railroad magnates, James J. Hill of the Great Northern and Edward H. Harriman of the Union Pacific, to extend railroad services from the Columbia River to Bend, Oregon, up the Deschutes River.
      Leon’s next book was closer to home: a biography of Gregory Pincus,
      • Speroff L.
      A good man, Gregory Goodwin Pincus: the man, his story, the birth control pill.
      the man who coinvented the combined birth control pill. Pincus had died a year before Leon arrived at the Worcester Foundation, the institution Pincus had founded, and so Leon interviewed his relatives and many others who knew Pincus personally for the book. Leon’s story recounts not only how the pill affected the lives of women around the world but also the emotional reactions to it, especially from the Catholic Church.
      Then came two books about senior softball: the first, A Slow-pitch Summer: My Rookie Senior Softball Season,
      • Speroff L.
      A slow-pitch summer: my rookie senior softball season.
      described Leon’s new passion; the second, Slow-Pitch Therapy: Playing Senior Softball Through Aches, Pains, and Illness,

      Speroff L. Slow-pitch therapy: playing senior softball through aches, pains, and illness. Seattle: Amazon Digital Services; 2014.

      is the very personal story of how softball got Leon through the ordeal of chemotherapy for lymphoma.

      Leon at leisure: softball world champion

      Along with fly fishing, reading is one of Leon’s great passions, and he reads a great deal, both fiction and nonfiction. It is difficult for him to pick out favorites, so he focused on books he had read in the last few years. In the nonfiction category, he especially likes two books that he believes to explain so much about human behavior: Sapiens, a Brief History of Humankind
      • Harrari Y.N.
      Sapiens: a brief history of humankind.
      by Yuval Noah Harari, and The Meaning of Human Existence
      • Wilson E.O.
      The meaning of human existence.
      by Edward O. Wilson. Among fiction, his recent favorites include A Gentleman in Moscow by Amor Towles
      • Towles A.
      A gentleman in Moscow.
      and Birds Without Wings
      • De Bernières L.
      Birds without wings. 1st American ed..
      by Louis de Bernieres.
      The metaphorical fork in the road for Leon came at the point in his life when it was time to consider retirement. He was 75 years old and still enjoying medicine, especially traveling and lecturing to clinicians; people with Leon’s energy, inquisitiveness, and zest for life never retire (well, not completely).
      Fortunately, Leon had found a new passion when he started playing softball at the age of 71 years, so he became Professor Emeritus in 2009, and for the last seven years, he has played in three leagues every summer (which means three double-headers every week); in the winter, he has batting practice twice a week. His new passion helped him face a battle in 2012 when he was diagnosed with a lymphoma and had to undergo three months of chemotherapy. On the day his oncologist told Leon that he was in complete remission, his wife asked him, “Do you think you could have done this without softball?”
      “I can’t answer that question with certainty,” Leon reflected. “But this much I do know: each time I came to the ballpark throughout that difficult summer, I gained strength from my interactions with the other ballplayers. My teammates’ cheers after a good hit, or their encouragement after a weak grounder, lifted my spirits.”
      In October 2016, Leon played in the World Senior Games in St George, Utah. There were more than 11,000 athletes aged 50 years or older from 34 different countries. The softball tournament is the largest in the world—nearly 4000 ball players. There were nine teams in Leon’s division of players 80 years old or older, and his team won the gold medal.

      Advice: passion is the key to a meaningful life

      Leon has no regrets. “Not one! I mean, I am so grateful I went to Yale; it opened up the rest of my life to me. Every person, every place, everything I’ve done: I’ve loved it. No regrets. I have been fortunate enough, after I retired, to find a new passion in playing senior softball, so that principle of having a passion continues to be a part of my life.”
      And that has always been Leon’s advice to students and residents: “You have to have a passion.” Leon even loved his internship and residency when he worked every day and every other night for five years. “I loved it. I loved every minute of it. If you don’t have that passion, then you need to make a change.”
      The current state of clinical academic medicine concerns Leon. One reflection, he pointed out, is that 60–70% of the articles in American clinical journals come from abroad: “There needs to be a fundamental change in the way academic medicine is funded because full-time faculty spend their entire day seeing patients, so they do not have time to teach or do research. I do not see that change coming, but I do see it in other countries. The reason we have such good research from Denmark, Sweden, and other countries is that academic medicine is independently funded and not dependent on clinical earnings. I have also read articles raising concern that our residents are not adequately trained, surgically, for example. Our young people need to become proactive and bring about much-needed change.”
      Leon has five children and three grandchildren, including a one-year-old granddaughter. Leon choked up as he told me, “Her middle name is Leonova, which is Macedonian and means daughter of Leon.” Despite being charismatic, insightful, generous, talented, and world renowned, Leon is humble and has both a great sense of humor and a memorable laugh. His passion for life is contagious, and he has inspired so many of us to be better physicians, scientists, and human beings.

      Appendix

      Figure thumbnail fx1
      Supplemental Figure 1Leon enjoys the sport of fly fishing
      Romero. Profile of Leon Speroff, MD. Am J Obstet Gynecol 2017.
      Figure thumbnail fx2
      Supplemental Figure 2Leon's passion for playing softball
      Romero. Profile of Leon Speroff, MD. Am J Obstet Gynecol 2017.

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