Advice on the management of ambiguous genitalia to a young endocrinologist from experienced clinicians.

The birth of a child with ambiguous genitalia is a challenging and distressing event for the family and physician and one with life-long consequences. Most disorders of sexual differentiation (DSD) associated with ambiguous genitalia are the result either of inappropriate virilization of girls or incomplete virilization of boys. It is important to establish a diagnosis as soon as possible, for psychological, social, and medical reasons, particularly for recognizing accompanying life-threatening disorders such as the salt-losing form of congenital adrenal hyperplasia. In most instances, there is sufficient follow-up data so that making the diagnosis also establishes the appropriate gender assignment (infants with congenital adrenal hyperplasia, those with androgen resistance syndromes), but some causes of DSD such as steroid 5α-reductase 2 deficiency and 17ß-hydroxysteroid dehydrogenase deficiency are associated with frequent change in social sex later in life. In these instances, guidelines for sex assignment are less well established.

Reflections on future research in adolescent reproductive health.

A group of basic scientists, clinicians, clinical investigators, psychologists, patient advocacy groups, and representatives from professional societies and governmental agencies met at the National Institutes of Health in October, 2007 with the long-term goal of having the menstrual cycle accepted and understood as a marker of general health in adolescent girls. An equally important goal was to develop a research agenda for this area of investigation. This chapter comprises the highlights of discussions throughout that meeting, with an emphasis on ideas generated during a final session led by an internationally renowned physician-scientist, in which reports from four breakout groups were presented. The specific goal assigned to each group was to develop an agenda that would set the stage for how research should be conducted over the next 100 years, and to identify the pressing research questions that should be addressed related to the menstrual cycle and adolescent health. The four research areas represented in discussion groups included: emotional health; genetics; metabolism and reproduction; and the promotion of conduct of clinical research. Insights are also provided by five clinical investigators, including two outside experts, on topics of priority for a research agenda in the area of adolescent reproductive health, as well as how the research itself should be conducted.

A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant.

A common cause of micropenis is congenital hypogonadotropic hypogonadism, whether isolated or associated with multiple pituitary hormone deficiencies. The postnatal surge in FSH, LH, and testosterone in the male infant as a consequence of the continued function of the fetal GnRH pulse generator provides a 6-month window of opportunity to establish the diagnosis of hypogonadotropic hypogonadism and alert the clinician to the possibility of its association with multiple pituitary hormone deficiencies. When ACTH or GH deficiency or both deficiencies are present, hypoglycemia and cortisol deficiency can lead to neonatal and infantile death or increased morbidity. Establishing the diagnosis of hypogonadotropic hypogonadism in infancy preempts the uncertainties and delays in distinguishing constitutional delay in puberty from hypogonadotropic hypogonadism. Accordingly, hormone replacement therapy can be initiated at the normal age of pubertal onset. The ontogenesis of infantile testicular function, including the possible significance of the infantile surge in gonadotropins and testosterone, is reviewed. The molecular basis for certain developmental disorders associated with hypogonadotropic hypogonadism and micropenis is considered and the management and treatment of congenital hypopituitarism discussed.

Mutations in the synthesis and action of estrogen: the critical role in the male of estrogen on pubertal growth, skeletal maturation, and bone mass.

The discovery of males with mutations in CYP19, the gene that encodes aromatase, the enzyme catalyzing the final step in the conversion of androgen to estrogen, and of a man with a mutation in the estrogen receptor alpha gene has led to increasing recognition of the critical role of estrogen in the male. The diverse roles of estrogen in the male, both circulating and locally synthesized, is supported by extensive studies in male mice generated with disruption of the aromatase gene or the genes encoding the alpha- and beta-estrogen receptor. This presentation focuses on the crucial role of estradiol in the human male on the pubertal growth spurt, skeletal maturation and the cessation of linear growth, and the accrual of bone mass.

Management of the clinically inapparent adrenal mass ("incidentaloma").

The National Institutes of Health Consensus Development Program convened surgeons, endocrinologists, pathologists, biostatisticians, radiologists, oncologists, and other health care professionals, as well as members of the general public, to address the causes, prevalence, and natural history of clinically inapparent adrenal masses, or "incidentalomas"; the appropriate evaluation and treatment of such masses; and directions for future research. Improvements in abdominal imaging techniques have increased detection of adrenal incidentalomas, and because the prevalence of these masses increases with age, appropriate management of adrenal tumors will be a growing challenge in our aging society. To address six predetermined questions, the 12-member nonfederal, nonadvocate state-of-the-science panel heard presentations from 21 experts in adrenal incidentalomas and consulted a systematic review of medical literature on the topic provided by the Agency for Healthcare Research and Quality and an extensive bibliography developed by the National Library of Medicine. The panel recommended a 1-mg dexamethasone suppression test and measurement of plasma-free metanephrines for all patients with an adrenal incidentaloma; additional measurement of serum potassium and plasma aldosterone concentration-plasma renin activity ratio for patients with hypertension; and surgery for patients with biochemical evidence of pheochromocytoma, patients with tumors greater than 6 cm, and patients with tumors greater than 4 cm who also meet other criteria. The panel also advocated a multidisciplinary approach to managing adrenal incidentalomas. The statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the federal government.

The neuroendocrinology of human puberty revisited.

The fundamental aspects of the hypothalamic luteinizing hormone-releasing hormone (LHRH)(1) [1]pulse generator-pituitary gonadotrophin-gonadal apparatus in mammals have striking commonalities. There are, however, critical, substantive differences in the neuroendocrinology of puberty among species. The onset of puberty in the human is marked by an increase in the amplitude of LH pulses, an indirect indicator of the increase in amplitude of LHRH pulses. The hypothalamic LHRH-pituitary gonadotrophin complex is functional by at least 0.3 gestation in the human foetus; the sex difference in the fetal and neonatal pattern of LH and FSH secretion is an apparent consequence of imprinting of the fetal hypothalamus-pituitary-gonadotropin apparatus by fetal testosterone. Until about 6 months of age in boys and 12-24 months in girls, the testes and ovaries respond to the increased LH in boys and follicle-stimulating hormone (FSH) in girls by secreting testosterone and oestradiol, respectively, reaching levels that are not again achieved before the onset of puberty. Striking features of the ontogeny of the human hypothalamic pulse generator are: (1) its development and function in the foetus; (2) the continued function of the hypothalamic LHRH pulse generator-pituitary gonadotrophin-gonadal axis in infancy; (3) the gradual damping of hypothalamic LHRH oscillator activity during late infancy; (4) its quiescence during childhood - the so-called juvenile pause; (5) during late childhood the gradual disinhibition and reactivation of the LHRH pulse generator, mainly at night; (6) the increasing amplitude of the LHRH pulses, which are reflected in the progressively increased and changing pattern of circulating LH pulses, with the approach of and during puberty. The intrinsic central nervous system (CNS) mechanisms responsible for the inhibition of the LHRH pulse generator during childhood (the juvenile phase) involve the major role of an inhibitory neuronal system - the CNS inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and GABAergic neurons, as revealed by studies in the rhesus monkey by Terasawa and her associates. With the onset of puberty, the disinhibition and reactivation of the LHRH pulse generator is associated with a fall in GABAergic neurotransmission and a concomitant increase in the input of excitatory amino acid neurotransmitters (including glutamate) and possibly astroglial-derived growth factors. Despite remarkable progress over the past three decades, large gaps remain in our understanding of the neurobiological, genetic and environmental mechanisms involved in the control of the onset of puberty. The role of leptin in the control of the onset of puberty is reviewed. Severe leptin deficiency is associated with hypogonadotrophic hypogonadism; it appears that a critical level of leptin and a leptin signal is required to achieve puberty. The weight of evidence supports the hypothesis that leptin acts as one of several permissive factors and not a trigger in the onset of human puberty. The application of these advances provides a framework for the described classification of sexual precocity and delayed puberty.1 GnRH is synonymous with LHRH.