Following extensive examination of published and unpublished materials, we provide a history of the use of dexamethasone in pregnant women at risk of carrying a female fetus affected by congenital adrenal hyperplasia (CAH). This intervention has been aimed at preventing development of ambiguous genitalia, the urogenital sinus, tomboyism, and lesbianism. We map out ethical problems in this history, including: misleading promotion to physicians and CAH-affected families; de facto experimentation without the necessary protections of approved research; troubling parallels to the (...) history of prenatal use of diethylstilbestrol (DES); and the use of medicine and public monies to attempt prevention of benign behavioral sex variations. Critical attention is directed at recent investigations by the U.S. Food and Drug Administration (FDA) and Office of Human Research Protections (OHRP); we argue that the weak and unsupported conclusions of these investigations indicate major gaps in the systems meant to protect subjects of high-risk medical research. (shrink)

Oncogenic hyperplasia is the first and inevitable stage of formation of a (solid) tumor. This stage is also the core of many other proliferative diseases. The present work proposes the first minimal model that combines homeorhesis with oncogenic hyperplasia where the latter is regarded as a genotoxically activated homeorhetic dysfunction. This dysfunction is specified as the transitions of the fluid of cells from a fluid, homeorhetic state to a solid, hyperplastic-tumor state, and back. The key part of the (...) model is a nonlinear reaction-diffusion equation (RDE) where the biochemical-reaction rate is generalized to the one in the well-known Schlögl physical theory of the non-equilibrium phase transitions. A rigorous analysis of the stability and qualitative aspects of the model, where possible, are presented in detail. This is related to the spatially homogeneous case, i.e. when the above RDE is reduced to a nonlinear ordinary differential equation. The mentioned genotoxic activation is treated as a prevention of the quiescent G0-stage of the cell cycle implemented with the threshold mechanism that employs the critical concentration of the cellular fluid and the nonquiescent-cell-duplication time. The continuous tumor morphogeny is described by a time-space-dependent cellular-fluid concentration. There are no sharp boundaries (i.e. no concentration jumps exist) between the domains of the homeorhesis- and tumor-cell populations. No presumption on the shape of a tumor is used. To estimate a tumor in specific quantities, the model provides the time-dependent tumor locus, volume, and boundary that also points out the tumor shape and size. The above features are indispensable in the quantitative development of antiproliferative drugs or therapies and strategies to prevent oncogenic hyperplasia in cancer and other proliferative diseases. The work proposes an analytical-numerical method for solving the aforementioned RDE. A few topics for future research are suggested. (shrink)

Hyperplasia and hypertrophy are elements of phenotypic plasticity adjusting organ size and function. Because they are costly, we assume that they are beneficial. In this review, the authors discuss examples of tissue and organ systems that respond with plastic changes to osmotic stress to raise awareness that we do not always have sufficient experimental evidence to conclude that such processes provide fitness advantages. Changes in hydranth architecture in the hydroid Cordylophora caspia or variations in size in the anal papillae (...) of insect larvae upon changes in medium salinity may be adaptive or not. The restructuring of salt glands in ducklings upon salt‐loading is an example of phenotypic plasticity which indeed seems beneficial. As the genomes of model species are recently sequenced and the animals are easy to rear, these species are suitable study objects to investigate the biological significance of phenotypic plasticity and to study potential epigenetic and other mechanisms underlying phenotypic changes. (shrink)

Disorders of sexual development are a heterogeneous group of disorders in which chromosomal, gonadal or anatomical sex development is atypical. The majority of these children are recognized at birth by ambiguous genitalia. Legal and societal pressures require the physician and parents to assign sex rapidly. Though sex assignment is undebated in several disorders of sexual development, many others need an individualized approach to gender-related concerns. Gender dysphoria is prevalent in disorders of sexual development, and early gender-defining surgeries have potentially lifelong (...) consequences. We use two cases, one of partial androgen insensitivity and another of simple virilizing congenital adrenal hyperplasia to illustrate that in disorders of sexual development, the ethical management principles remain the same at their core despite the vast differences in phenotypes. Sex assignment should maximize functional, psychological and sexual needs. Sex assigned should coincide with gender identity. We propose that we manage such children with the mutual participation of the physician, parents and the child. Though the parents and the physician have the child's best interests when making a decision, the child's developing autonomy should be protected. The communication of the health provider to the parent must be honest if early sex assignment is difficult. (shrink)

This article discusses the ethics of the use of preimplantation genetic diagnosis to prevent the birth of children with intersex conditions/disorders of sex development , such as congenital adrenal hyperplasia and androgen insensitivity syndrome . While pediatric surgeries performed on children with ambiguous genitalia have been the topic of intense bioethical controversy, there has been almost no discussion to date of the ethics of the use of PGD to reduce the prevalence of these conditions. I suggest that PGD for (...) those conditions that involve serious medical risks for those born with them is morally permissible and that PGD for other “cosmetic” variations in sexual anatomy is more defensible than might first appear. However, importantly, the arguments that establish the latter claim have radical and disturbing implications for our attitude toward diversity more generally. (shrink)

In this critical, feminist account of the management of intersex conditions under 2006's controversial “Disorders of Sex Development” (DSD) treatment model, I argue that like the “Optimal Gender of Rearing” (OGR) treatment model it replaced, DSD aims at securing a cisgendered future for the intersex patient, referring to a normalized trajectory of development across the lifespan in which multiple sexed, gendered, and sexual characteristics remain in “coherent” alignment. I argue this by critically analyzing two ways that intersex management has changed (...) between OGR and DSD: 1) regarding sex‐assignment recommendations for three patient populations and, 2) with the prenatal treatment of pregnant individuals at risk of conceiving a fetus with congenital adrenal hyperplasia with the steroid hormone dexamethasone. I conclude that like OGR before it, DSD also unjustifiably presumes that typical genitalia are necessary for cisgendered development. However, unlike OGR, it appeals to the empirically inadequate, theoretically suspect, and biologically determinist model of gender development known as brain‐organization theory. Given this, I conclude that the treatment of intersex people under DSD continues to be driven by problematically heterosexist and transphobic assumptions regarding the value and normalcy of cisgendered life, while practically and discursively constituting it as such. (shrink)

In a series of essays and letters published in 2010, commentators in bioethics debated the ethics of two interventions that aim to prevent or treat a symptom of a genetic condition called congenital adrenal hyperplasia, which can cause “virilization” in affected baby girls—the development of atypical, sometimes masculine‐appearing, genitals. Surgeries are often performed to try to “normalize” both the appearance and the function of affected girls’ genitals, and a drug thought to prevent virilization is sometimes prescribed to pregnant women (...) who are likeliest to be carrying an affected fetus. The CAH debates suggest that there is profound disagreement in the field about whether preventing or treating virilization is an appropriate goal of medicine—or, indeed, parenting. Of course, that disagreement has its roots in ongoing debates about how to understand and react to a range of anatomical and behavioral differences, from short stature to deafness to hyperactivity, as well as ongoing debates about the limits of autonomy—in this case, parental autonomy, which is all the more complex. These issues are at the heart of bioethics. Yet it can be very difficult for us to talk and write respectfully and clearly about them. Here, I recount the debates, show how they lost focus, and attempt to explain why the question about how parents and physicians should respond to atypical genitalia in children is so important and difficult. I argue that it is not a question that should be answered based on a single principle or philosophical commitment. No one principle can do all of the work. For each individual or family that faces it, the question is shaped by details about particular interventions aimed at altering a particular difference and offered in a particular social and family context. Scholars in bioethics who hold an especially strong commitment to any one principle should advocate for their views, but they must also make room for and respect the kind of pragmatic, particularized decision‐making that parents sometimes engage in. (shrink)

The extent of neurogenesis in Drosophila is under the control of the so‐called neurogenic genes, named for their mutant phenotype of causing neural hyperplasia. Their wild‐type products appear to be responsible for a signal chain that decides the fate of ectodermal cells in the embryo. Various kinds of data, from cell transplantation experiments as well as from genetic and molecular analyses, suggest that the proteins encoded by the genes Notch and Delta may act at the membrane of the signal‐transmitting (...) cells to provide a ligand to a still unknown receptor molecule; in contrast, the locus of Enhancer of split codes for several functions related to the transduction and further processing of the signal. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Finding My Compass*Laura Inter+I was born in the 1980s, and much to my parents surprise, the doctors could not say whether I was a boy or a girl because my body had ambiguous genitalia. They then conducted a chromosome test and the result was XX chromosomes. I was assigned female and only later was diagnosed with congenital adrenal hyperplasia (CAH). Fortunately for me the endocrinologist who treated me (...) did not mention the option of surgery, so my medical treatment consisted only of taking cortisol. Apart from this, from the time I turned one, I was subjected to genital examinations twice a year, during which the endocrinologist would touch my genitals and look to see how they were developing.These unnecessary and intrusive examinations had a profound effect on me. As a young child, I did not understand why I had to lower my pants in front of a stranger—the endocrinologist—and let him touch me. The fact that my mother was present, and approved of this was something that made me feel completely helpless. All this seemed very strange to me; I found it confusing, and terribly uncomfortable, and I just felt it wasn’t right.I remember the doctor always spoke as if I wasn’t right there, and I did not always understand everything the doctor said when I was young, because of all the medical terms he used. I grew up with a feeling of being “inadequate,” of having a sense that something was wrong with me, though I didn’t know exactly what. These exams lasted until I was about 12 years old. Years later, as I began my adult, sexual life, I realized how much those displays had affected me emotionally.I discovered what was “wrong” with me during sex education classes in the first year of high school. There was a class session in which two images were shown: one displaying the external female sex organs, and the other the male sex organs. I noticed that my body was not like either of them. I was very distressed, thinking “I have deformed genitals!” I feared I could not perform sexually as either a man or a woman. I became very depressed. I was sure nobody would want me, that I would never have a relationship. I was unacceptable, “abnormal,” or at least that is what the doctors had said. And in any case my parents never spoke of it, and I didn’t know that I had CAH.Skip forward a few years: I was still looking for answers, I found my medical file and read in the documents “pseudo–hermaphrodite,” and [End Page 95] “congenital adrenal hyperplasia.” I searched the internet, but only found medical opinions that said that in the case of genital ambiguity, the best option was surgery. I wondered to myself: “Why didn’t they operate on me?”I put the question to my parents, and, at fifteen, I found myself being examined once more in the doctor’s office, this time to consider the possibility of a genital surgery which might once and for all, I believed, make me a “normal” person.I have never told anyone outside my family before, but one of those exams was the most humiliating experiences of my life. One doctor wanted to speak with me alone, so she made my mother wait outside the exam room. My mother agreed, thinking that after the doctor talked with me, my mother would be able to be present during the rest of the exam. The doctor asked me questions, some of which made me very uncomfortable: “Do you feel good about being a woman”? Did you ever feel like a man? Why don’t you dress up more, use more makeup? Are you a lesbian? Have you ever had sex? She then said she wanted to see my genitals. I felt awful and wanted my mother present, but I also wanted it to be over quickly, and said nothing. Examining my genitals, the doctor told me they “would not be adequate for sex,” and that she needed to “perform surgery.” Something else that made me uncomfortable was the presence of another doctor in... (shrink)

The two provocative essays in this issue of the Hastings Center Report should stimulate debate not only about female genital cutting, fetal dexamethasone, and clitoral reduction surgery, but also about our fierce commitment to particular cultural norms about the body. Under what conditions may adults irreversibly modify a child's body because they think the change is in her best interest? Certainly, parents who opt for female genital cutting or for surgical reduction of an enlarged clitoris in a girl with congenital (...) adrenal hyperplasia want to make choices that will contribute to their child's potential happiness. If cutting in Africa—or mitigating CAH symptoms here—upholds a girl's gender identity, which will translate into a fulfilled life as an adult, some argue that a parent's refusal to abide by social prescriptions does the child a serious disservice. (shrink)

Growth and morphogenesis in the mammary gland depend on locally derived growth factors such as those in the epidermal growth factor (EGF) superfamily. Cripto-1 (CR-1, human; Cr-1, mouse)—also known as teratocarcinoma-derived growth factor-1—is a novel EGF-related protein that induces branching morphogenesis in mammary epithelial cells both in vitro and in vivo and inhibits the expression of various milk proteins. In the mouse, Cr-1 is expressed in the growing terminal end buds in the virgin mouse mammary gland and expression increases during (...) pregnancy and lactation. Cr-1/CR-1 is overexpressed in mouse and human mammary tumors and inappropriate overexpression of Cr-1 in mouse mammary epithelial cells can lead to the clonal expansion of ductal hyperplasias. Taken together, this evidence suggests that Cr-1/CR-1 performs a role in normal mammary gland development and that it might contribute to the early stages of mouse mammary tumorigenesis and the pathobiology of human breast cancer. BioEssays 1999;21:61–70. Published 1999 John Wiley & Sons, Inc. (shrink)

There is some very limited evidence for a role of estrogens in human psychosexual masculinization; its interpretation is uncertain. Fitch & Denenberg's demonstration of a role for estrogens in the behavioral feminization of nonhuman mammals implicitly suggests an answer to a riddle posed by the syndrome of congenital adrenal hyperplasia in women.

Most basic research on cancer concerns genetic changes in benign and malignant tumors. Yet evidence indicates that the majority of the mutations in tumors occur in the preneoplastic field stage of their development. That early stage is represented by grossly invisible, broad regions of “field cancerization” which have not, heretofore, been operationally analyzed in cell culture. Conditions are described for quantitating preneoplasia by increased saturation density followed by progression to transformation. These parameters are driven by Darwinian selection of spontaneously occurring, (...) cumulative mutations, in accordance with recent genomic analyses of human cancer, just as it is in the evolution of species. The cell culture model will allow correlation of the preneoplastic increases in saturation density with genetic changes, and development of methods for demarcating fields during surgery so that they can be excised along with the tumor, thereby reducing the possibility of recurrence at the site. (shrink)