Better prepared than synthesized: Adolf Butenandt, Schering Ag and the transformation of sex steroids into drugs (1930–1946)

This paper follows the trajectory of sex steroids in 1930s Germany as a way to investigate the system of research which characterized the development of these drugs. Analyzing the changing relationship between the pharmaceutical company Schering and the Kaiser Wilhelm Institute für Biochemie headed by Nobel Prize winner Adolf Butenandt, the paper highlights the circulation of materials, information and money as much as the role of patents in shaping the study of sex steroids. Semi-synthetic analogs and metabolic pathways thus emerged as shared bio-industrial assets. This collaborative work participated in a more general ‘internalization’ of biology, which took place in pharmaceutical firms during the 1920s and 1930s as a strategy to standardize and develop biologicals. The construction of the hormone market was also based on Schering’s collaboration with a selected group of clinicians who worked out the wide-range of indications associated with these ‘natural’ drugs. The paper finally shows how the wartime scientific and industrial mobilization in Nazi Germany marginalized the study of sex steroids and led to the dismantling of the KWIB–Schering network.     

The sex reform movement and eugenics in interwar Poland

This paper focuses on the relations between a liberal group of sex reformers, consisting of writers and literary critics, and physicians from the Polish Eugenics Society in interwar Poland. It illustrates the paradoxes of the mutual co-operation between these two groups during the 1930s and analyses the reason why compulsory sterilisation was rejected by politicians. From the early 1930s two movements began to forge an alliance in Poland: the sexual reform movement which advocated freedom of the individual, and eugenics, which called for limiting the freedom of the individual for the collective good. This paper draws attention to several issues which emerged as part of this collaboration: population politics, the relationship between reformers, eugenicists and state institutions, and the question of how both movements--eugenics and sexual reform--perceived the question of sexuality, birth control and abortion. It will also focus on those aspects of their thinking that led to mutual co-operation.     

Developmental profiles of TSH, sex steroids, and their receptors in the thyroid and their relevance to thyroid growth in immature rats.

Sex steroids are reported to influence thyroid pathogenesis in human and experimental animals. However, there is no report on this phenomenon during the early developmental period. The mitotic activity of thyrocytes in rats reaches its peak by day 10 postpartum. Thyrocytes actively proliferate in immature rats during the first three postnatal weeks, during which the pre-pubertal rise in serum titers of testosterone and estradiol has been recorded. The aim of the present study was to analyze whether there is a physiological relevance between thyroid growth and sex steroids during the postnatal period. Serum and thyroid tissue hormones (TSH, testosterone, and estradiol) were assayed by liquid phase RIA, and receptors for these hormones were also quantified. The peak rate of thyrocyte proliferation was observed during the second postnatal week in rats. Since the concentrations of sex steroids and their receptors also reached a peak around this period, it is suggested that elevated sex steroids and their receptors in the thyroid might enhance thyrocyte proliferation. A positive correlation between thyroid growth indices and sex steroids and their receptors further strengthens this suggestion. This is a preliminary study, and further experimental study may strengthen this proposal. This is the first report to show the availability of sex steroids and their receptors in the thyroid glands of immature rats under normal conditions.     

Making British Cortisone: Glaxo and the development of Corticosteroids in Britain in the 1950s–1960s

Following the announcement in 1949 in the USA that cortisone offered rheumatoid arthritis sufferers effective treatment for their crippling disease, the Ministry of Health came under considerable pressure from the medical profession and the public to make cortisone available in Britain. The Ministry, therefore, urged British companies to start manufacturing cortisone. Among the several pharmaceutical firms responding to the Ministry’s request, Glaxo’s expertise in the field of vitamins gave them a head start. This paper describes the varied and flexible strategy that enabled Glaxo to maintain this head start, and the scientific and technical capabilities which the company subsequently built up, enabling them to dominate the market for corticosteroids in Britain.Among the drugs to emerge out of the Glaxo project to manufacture cortisone, which began in 1950 and later became a wider R&D programme on steroids, was the topical steroid Betnovate, launched in 1963, which remains a best-seller today. However, although it led to successful new products, Glaxo’s programme had limitations. The paper identifies a missed opportunity, in the shape of the biosynthetic route to steroid drugs, often considered as a milestone in the development of the new biotechnology. Whether or not this missed opportunity proved costly to the company is uncertain. However, it illustrates the role of technological path-dependence, and the importance of the integration between different scientific disciplines, in this case chemistry and biology, in pharmaceutical innovation.     

Nongenital malformations following exposure to progestational drugs: the last chapter of an erroneous allegation

In the late 1960s and 1970s, a number of epidemiological studies were published indicating that pregnant women who were exposed to an array of sex steroids delivered infants with an increased incidence of nongenital congenital malformations. Because of these publications, the Food and Drug Administration (FDA), in conjunction with various pharmaceutical companies, labeled the therapeutic exposure of progestational drugs and contraceptives in pregnant women as a risk factor for limb‐reduction defects (LRDs) and congenital heart defects (CHDs). Subsequently there was a rapid decrease in the exposure of pregnant women to these drugs and the initiation of numerous lawsuits alleging that a particular progestational drug was responsible for a child's nongenital congenital malformation. Wilson and Brent ( 1981 ) published an article indicating that epidemiological and animal studies of these drugs, and basic science did not support the package insert's warnings. Many new and previous animal and epidemiological studies did not support the FDA box warning. In 1987 the FDA held a hearing in which the FDA, the Teratology Society, the Centers for Disease Control and Prevention, the American College of Obstetrics and Gynecology, and other organizations supported the position that progestational agents did not result in nongenital malformations. An editorial appeared in Teratology congratulating the FDA for removing the warning label on oral contraceptives regarding nongenital malformations. In 1999 the FDA published new wording for package inserts that removed warnings for nongenital malformations for all progestational agents. In spite of the recent changes in the package inserts, lawsuits have alleged that progestational drugs cause nongenital malformations. It took 22 years from the time a box warning was required by the FDA until the warnings were removed in 1999. The 1999 FDA publication, which is a scholarly and objective document, should put an end to 2 decades of concern and anxiety for pregnant women or women of reproductive age. Could scientists, the pharmaceutical companies, or the FDA have prevented the mislabeling of progestational drugs with regard to their teratogenic risks? Was the epidemiological or teratology community at fault because they did not critique and respond to the early publications? Did the FDA act too slowly? The epidemiologic analyses, animal studies, and basic science principles have been reviewed, and it is obvious that clinically utilized progestational drugs do not cause nongenital malformations (i.e., LRDs and CHDs). Birth Defects Research (Part A) 2005. © 2005 Wiley‐Liss, Inc.     

Sex determination: a hypothesis based on steroid ratios

This paper presents a hypothesis for sex determination based on the ratio of androgen to estrogen in the gonad during sexual differentiation. In vertebrates the ratio of these steroids, and therefore, the sex of an individual is controlled by the quantity of the enzyme aromatase. For animals with a ZZ, ZW sex determining mechanism, such as birds, in which the heterogametic sex is female, an inducer for the aromatase gene is postulated to be on the W chromosome. In animals with an XX, XY system in which the heterogametic sex is male, such as mammals, the Y chromosome is postulated to code for a repressor of the aromatase gene. This hypothesis can account for naturally occurring sex reversal such as seen in some fish and amphibians, experimentally induced sex reversal by administration of steroids in birds, reptiles, fish and amphibians, and temperature-dependent sex determination as in reptiles. For invertebrates the same hypothetical model applies though the specific androgenic and estrogenic steroids differ. Both the X-to-autosome ratio method of sex determination typified by fruit flies and the haplodiploid method of bees as well as hormonal control of sexual differentiation in crustaceans are accounted for by this hypothesis.     

Behavior and physiological effects of supplemental episodes of testosterone, its precursors and metabolite in rats

Androgen-sensitive behavior and physiology were examined in gonadally intact male rats receiving daily injections of steroids (0.4 mg/kg) in two pharmaceutical forms for one month. When steroids were injected as aqueous solutions of hydroxypropyl-beta-cyclodextrin complexes, a form which insures a rapid distribution through the organism, testerosterone strongly increased behavioral parameters, while testosterone precursors (dehydroepiandrosterone and 4-androstene-3, 17-dione) and metabolite (5-alpha-dihydrotestosterone) decreased them. These results suggest that it is not possible to produce an effective testosterone pulse by metabolic conversion through supplemental pulses of precursors. The treatments did not affect sperm counts in epididymis. The size of ventral prostate was increased only after the administration of 4-androstene-3,17-dione or 5-alpha-dihydrotestosterone, not after testosterone or dehydroepiandrosterone. When steroids were injected in oil, a pharmaceutical form which distributes steroids slowly and in a protracted manner, testosterone led to an enlargement of the prostate in addition to the increase in behavioral parameters seen with the complexed form. The suppression in behavior and prostate enlargement by other steroids were more pronounced than when these were administered in complexed forms. Obviously, some of the adverse effects of the presently used depot steroid preparations are of pharmacokinetic origin.     

The Forgotten Promise of Thiamin: Merck, Caltech Biologists, and Plant Hormones in a 1930s Biotechnology Project

The physiology of plant hormones was one of the most dynamic fields in experimental biology in the 1930s, and an important part of T. H. Morgan's influential life science division at the California Institute of Technology. I describe one episode of plant physiology research at the institution in which faculty member James Bonner discovered that the B vitamin thiamin is a plant growth regulator, and then worked in close collaboration with the Merck pharmaceutical firm to develop it as a growth-boosting agrichemical. This episode allows one to draw continuities between certain fields of life science in the United States circa 1940 and the biotechnology industry today, and also foregrounds a number of similarities between plant physiology of the late 1930s and the molecular biology of the period. This revised version was published online in July 2006 with corrections to the Cover Date.     

Commercializing medical technology

As medicine moves into the 21st century, life saving therapies will move from inception into medical products faster if there is a better synergy between science and business. Medicine appears to have 50-year innovative cycles of education and scientific discoveries. In the 1880’s, the chemical industry in Germany was faced with the dilemma of modernization to exploit the new scientific discoveries. The solution was the spawning of novel technical colleges for training in these new chemical industries. The impact of those new employees and their groundbreaking compounds had a profound influence on medicine and medical education in Germany between 1880 and 1930. Germany dominated international science during this period and was a training center for scientists worldwide. This model of synergy between education and business was envied and admired in Europe, Asia and America. British science soon after evolved to dominate the field of science during the prewar and post World War (1930’s–1970’s) because the German scientists fled Hitler’s government. These expatriated scientists had a profound influence on the teaching and training of British scientists, which lead to advances in medicine such as antibiotics. After the Second World War, the US government wisely funded the development of the medical infrastructure that we see today. British and German scientists in medicine moved to America because of this bountiful funding for their research. These expatriated scientists helped drive these medical advances into commercialized products by the 1980’s. America has been the center of medical education and advances of biotechnology but will it continue? International scientists trained in America have started to return to Europe and Asia. These American-trained scientists and their governments are very aware of the commercial potential of biotechnology. Those governments are now more prepared to play an active role this new science. Germany, Ireland, Britain, Singapore, Taiwan and Israel are such examples of this government support for biotechnology in the 21st century. Will the US continue to maintain its domination of biotechnology in this century? Will the US education system adjust to the new dynamic of synergistic relationships between the education system, industry and government? This article will try to address these questions but also will help the reader understand who will emerge by 2015 as the leader in science and education.     

Making British cortisone: Glaxo and the development of corticosteroids in Britain in the 1950s-1960s

Following the announcement in 1949 in the USA that cortisone offered rheumatoid arthritis sufferers effective treatment for their crippling disease, the Ministry of Health came under considerable pressure from the medical profession and the public to make cortisone available in Britain. The Ministry, therefore, urged British companies to start manufacturing cortisone. Among the several pharmaceutical firms responding to the Ministry's request, Glaxo's expertise in the field of vitamins gave them a head start. This paper describes the varied and flexible strategy that enabled Glaxo to maintain this head start, and the scientific and technical capabilities which the company subsequently built up, enabling them to dominate the market for corticosteroids in Britain. Among the drugs to emerge out of the Glaxo project to manufacture cortisone, which began in 1950 and later became a wider R&D programme on steroids, was the topical steroid Betnovate, launched in 1963, which remains a best-seller today. However, although it led to successful new products, Glaxo's programme had limitations. The paper identifies a missed opportunity, in the shape of the biosynthetic route to steroid drugs, often considered as a milestone in the development of the new biotechnology. Whether or not this missed opportunity proved costly to the company is uncertain. However, it illustrates the role of technological path-dependence, and the importance of the integration between different scientific disciplines, in this case chemistry and biology, in pharmaceutical innovation.     

Do Sex Differences in the Brain Explain Sex Differences in the Hormonal Induction of Reproductive Behavior? What 25 Years of Research on the Japanese Quail Tells Us

Early workers interested in the mechanisms mediating sex differences in morphology and behavior assumed that differences in behavior that are commonly observed between males and females result from the sex specificity of androgens and estrogens. Androgens were thought to facilitate male-typical traits, and estrogens were thought to facilitate female-typical traits. By the mid-20th century, however, it was apparent that administering androgens to females or estrogens to males was not always effective in sex-reversing behavior and that in some cases a “female” hormone such as an estrogen could produce male-typical behavior and an androgen could induce female-typical behavior. These conceptual difficulties were resolved to a large extent by the seminal paper of C. H. Phoenix, R. W. Goy, A. A. Gerall, and W. C. Young in (1959,Endocrinology65, 369–382) that illustrated that several aspects of sexual behavior are different between males and females because the sexes have been exposed during their perinatal life to a different endocrine milieu that has irreversibly modified their response to steroids in adulthood. Phoenixet al.(1959) therefore formalized a clear dichotomy between the organizational and activational effects of sex steroid hormones. Since this paper, a substantial amount of research has been carried out in an attempt to identify the aspects of brain morphology or neurochemistry that differentiate under the embryonic/neonatal effects of steroids and are responsible for the different behavioral response of males and females to the activation by steroids in adulthood. During the past 25 years, research in behavioral neuroendocrinology has identified many sex differences in brain morphology or neurochemistry; however many of these sex differences disappear when male and female subjects are placed in similar endocrine conditions (e.g., are gonadectomized and treated with the same amount of steroids) so that these differences appear to be of an activational nature and cannot therefore explain sex differences in behavior that are still present in gonadectomized steroid-treated adults. This research has also revealed many aspects of brain morphology and chemistry that are markedly affected by steroids in adulthood and are thought to mediate the activation of behavior at the central level. It has been explicitly, or in some cases, implicitly assumed that the sexual differentiation of brain and behavior driven by early exposure to steroids concerns primarily those neuroanatomical/neurochemical characteristics that are altered by steroids in adulthood and presumably mediate the activation of behavior. Extensive efforts to identify these sexually differentiated brain characteristics over the past 20 years has only met with limited success, however. As regards reproductive behavior, in all model species that have been studied it is still impossible to identify satisfactorily brain characteristics that differentiate under early steroid action and explain the sex differences in behavioral activating effects of steroids. This problem is illustrated by research conducted on Japanese quail (Coturnix japonica), an avian model system that displays prominent sex differences in the sexual behavioral response to testosterone, and in which the endocrine mechanisms that control sexual differentiation of behavior have been clearly identified so that subjects with a fully sex-reversed behavioral phenotype can be easily produced. In this species, studies of sex differences in the neural substrate mediating the action of steroids in the brain, including the activity of the enzymes that metabolize steroids such as aromatase and the distribution of steroid hormone receptors as well as related neurotransmitter systems, did not result in a satisfactory explanation of sex differences in the behavioral effectiveness of testosterone. Possible explanations for the relative failure to identify the organized brain characteristics responsible for behavioral sex differences in the responsiveness to steroids are presented. It is argued that novel research strategies may have to be employed to successfully attack the fundamental question of the hormonal mechanisms regulating sex differences in behavior.     

Inhibition of angiotensin-induced contractions of guinea-pig isolated ileum by high concentrations of non-steroidal antiinflammatory drugs and various steroids and its reversal by prostaglandin E1

Nine non-steroidal antiinflammatory drugs, five steroidal antiinflammatory drugs and four sex steroids were found to potently and reversibly inhibit angiotensin-induced contractions of guinea-pig isolated ileum. The effects of these drugs were reversed by small amounts of PGE₁ but the mechanism of their action was probably non selective for angiotensin.     

Watching the ‘Eugenic Experiment’ Unfold: The Mixed Views of British Eugenicists Toward Nazi Germany in the Early 1930s

Historians of the eugenics movement have long been ambivalent in their examination of the links between British hereditary researchers and Nazi Germany. While there is now a clear consensus that American eugenics provided significant material and ideological support for the Germans, the evidence remains less clear in the British case where comparatively few figures openly supported the Nazi regime and the left-wing critique of eugenics remained particularly strong. After the Second World War British eugenicists had to push back against the accusation that their science was intrinsically dictatorial or totalitarian and, as a result, many of their early perceptions of the Nazis were ignored or rationalised away. Further, historians in recent years have focused more directly on the social reformist elements of eugenics, discussing the links between hereditary science and the birth control and feminist movements in addition to others. While undoubtedly making valuable contributions to the scholarly understanding of the eugenic milieu in the interwar years, these studies have neglected to recontextualize the sentiments of British eugenicists who did indeed view the Nazi government positively in the early years of the 1930s. This article argues that there was a significant, though not numerically sizable, faction in the British eugenics movement, though mostly outside the Eugenics Society itself, in the early 1930s that viewed the Nazi Germany as an admirable state for its implementation of eugenic principles. One of these figures was later interned by his own government for being too closely aligned with the German regime, though he argued that this affinity was driven by the quest for scientific truth rather than politics. Eugenics in Britain thus contained a greater diversity of views toward Germany than scholars have previously assumed, warranting more research into the individuals and organizations harbouring these views.     

Identification of a Single Nucleotide Polymorphism in Porcine Testis Cytochrome P450-c17 (CYP17) and Its Effect on Steroidogenesis

Raising uncastrated male pigs could have significant economic benefits for pig production. Uncastrated male pigs can accumulate high levels of 16-androstene steroids, however, resulting in boar taint, which is highly objectionable to consumers. Cytochrome P450-c17 (CYP17) interacts with cytochrome b5 in the biosynthesis of the 16-androstene steroids and the sex steroids from pregnenolone. Amino acid substitutions in CYP17 could therefore affect the ability of this enzyme to catalyze the reactions leading to the production of androstenone and the sex steroids. In this study, we established a sensitive and flexible single-stranded conformational polymorphism technique capable of detecting a single nucleotide polymorphism. We then used this method to identify a substitution from T to A at nucleotide 1317 of CYP17, which caused a change in the amino acid sequence from Leu(439) to His(439). This mutation, however, did not alter the enzyme activity of CYP17 in the biosynthesis of androstenone or sex steroids. Other polymorphisms previously suggested for CYP17, which are vital for the functional interaction of CYP17 with CYB5 in human, were not observed. This study suggests that the synthesis of androstenone in pig testis is not directly affected by any polymorphisms in the coding region of the porcine CYP17 gene.     

Towards a genetic theory for the evolution of the sex ratio

A genetical model is formulated in which the sex ratio in broods and the relative size of broods are determined by the genotype at an autosomal locus. The results also apply to the case in which the sex-ratio locus is sex linked and expressed in the homogametic sex and to the case in which the locus is expressed in the diploid sex of a haplodiploid organism. Fisher (1930) argued that the sex ratio evolves under natural selection to a value such that parental expenditure is equalized between the sexes. Shaw and Mohler (1953) and MacArthur (1965) proposed that the sex ratio evolves to increase a certain expression for fitness. The sex ratio suggested by Fisher (1930) is in fact identical to the sex ratio specified by these maximization principles. Further, in our model, the Fisherian sex ratio corresponds exactly to the sex ratio at certain equilibria that are approached whenever they exist.     

Neuroendocrine-immune (NEI) circuitry from neuron-glial interactions to function: Focus on gender and HPA-HPG interactions on early programming of the NEI system

Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life. Signals generated by the hypothalamic-pituitary-gonadal axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids), and by the hypothalamic-pituitary-adrenocortical axis (glucocorticoids (GC)), are major players coordinating the development of immune system function. Conversely, products generated by immune system activation exert a powerful and long-lasting regulation on neuroendocrine axes activity. The neuroendocrine-immune system is very sensitive to preperinatal experiences, including hormonal manipulations and immune challenges, which may influence the future predisposition to several disease entities. We review our work on the ongoing mutual regulation of neuroendocrine and immune cell activities, both at a cellular and molecular level. In the central nervous system, one chief compartment is represented by the astroglial cell and its mediators. Hence, neuron-glial signalling cascades dictate major changes in response to hormonal manipulations and pro-inflammatory triggers. The interplay between LHRH, sex steroids, GC and pro-inflammatory mediators in some physiological and pathological states, together with the potential clinical implications of these findings, are summarized. The overall study highlights the plasticity of this intersystem cross-talk for pharmacological targeting with drugs acting at the neuroendocrine-immune interface.     

Ascertainment and treatment of delayed puberty

The majority of patients with pubertal delay, can be classified as having primary pubertal delay (constitutional delay of growth and puberty, CDGP), although any child with a chronic disease could present with delayed puberty. In contrast, children with hypogonadism, either hyper- or hypogonadotropic, exhibit a total absence of pubertal development. Hence, early evaluation of these patients should be performed. Delay of puberty leads to psychological problems, secondary to short stature and/or delay in the acquisition of secondary sex characteristics and the reduction of bone mass. Although the final height in patients with CDGP is usually normal, some of these patients do not reach the third percentile or remain in the lowest part of the growth chart according to familial height. The most common reason for treating CDGP patients, usually with sex steroids, is for psychological difficulties and for loss of bone mineralization. Treatment must be individualized. Therapeutic options and new drugs will be discussed. Appropriate treatment and adequate nutritional intake are indicated in patients with delayed puberty due to chronic illness. In patients with hypo- or hypergonadotropic hypogonadism, puberty must be induced or completed. Different treatments (GnRH analogues, gonadotropins and sex steroids), and the main objectives are discussed.     

Production of methylparaben in Escherichia coli

Journal of Industrial Microbiology & Biotechnology - Since the 1930s, parabens have been employed widely as preservatives in food, pharmaceutical, and personal care products. These alkyl esters...     

Freud’s Lamarckism’ and the Politics of Racial Science

This article re-contextualizes Sigmund Freud’s interest in the idea of the inheritance of acquired characteristics in terms of the socio-political connotations of Lamarckism and Darwinism in the 1930s and 1950s. Many scholars have speculated as to why Freud continued to insist on a supposedly outmoded theory of evolution in the 1930s even as he was aware that it was no longer tenable. While Freud’s initial interest in the inheritance of phylogenetic memory was not necessarily politically motivated, his refusal to abandon this theory in the 1930s must be understood in terms of wider debates, especially regarding the position of the Jewish people in Germany and Austria. Freud became uneasy about the inheritance of memory not because it was scientifically disproven, but because it had become politically charged and suspiciously regarded by the Nazis as Bolshevik and Jewish. Where Freud seemed to use the idea of inherited memory as a way of universalizing his theory beyond the individual cultural milieu of his mostly Jewish patients, such a notion of universal science itself became politically charged and identified as particularly Jewish. The vexed and speculative interpretations of Freud’s Lamarckism are situated as part of a larger post-War cultural reaction against Communism on the one hand (particularly in the 1950s when Lamarckism was associated with the failures of Lysenko), and on the other hand, against any scientific concepts of race in the wake of World War II.