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Biomedical subjects

Robert L Rosenfield

Publications and source records attributed to Robert L Rosenfield.

At least 19 recordsLinked to original sources
PubMed2007

KAL1 mutations are not a common cause of idiopathic hypogonadotrophic hypogonadism in humans.

Hypogonadotrophic hypogonadism results in the absence of puberty and if left untreated leads to infertility. Mutations in KAL1 are known to account for some of the cases of Kallmann syndrome. The aim of this study was to determine the prevalence of KAL1 mutations in a large number of patients with idiopathic hypogonadotrophic hypogonadism (IHH). One hundred and thirty eight patients (109 males and 29 females) with IHH were studied for mutations in KAL1. DNA from these patients was subjected to denaturing gradient gel electrophoresis or single strand conformation polymorphism to identify mutations. Sequencing was performed to confirm mutations detected. Four mutations were found in 109 males (3.7%). All four mutations were in anosmic/hyposmic men making the prevalence 4/63 (6.3%) in this group of patients. No mutations were found in the 29 female patients. KAL1 mutations are an uncommon cause of Kallmann syndrome.

Adult↗
PubMed2006

Clinical review: Identifying children at risk for polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) appears to arise as a complex trait with contributions from both heritable and nonheritable factors. Polygenic influences appear to account for about 70% of the variance in pathogenesis. In view of this evidence for congenital contributions to the syndrome, childhood manifestations may be expected. OBJECTIVE: The objective has been to review the evidence that risk factors for PCOS can be recognized in childhood. DESIGN: This study consisted of screening of the PCOS literature for articles pertaining to potential childhood and adolescent antecedents. RESULTS: Congenital virilizing disorders; above average or low birth weight for gestational age; premature adrenarche, particularly exaggerated adrenarche; atypical sexual precocity; or intractable obesity with acanthosis nigricans, metabolic syndrome, and pseudo-Cushing syndrome or pseudo-acromegaly in early childhood have been identified as independent prepubertal risk factors for the development of PCOS. During adolescence, PCOS may masquerade as physiological adolescent anovulation. Asymptomatic adolescents with a polycystic ovary occasionally (8%) have subclinical PCOS but often (42%) have a subclinical PCOS type of ovarian dysfunction, the prognosis for which is unclear. CONCLUSION: Identifying children at risk for PCOS offers the prospect of eventually preventing some of the long-term complications associated with this syndrome once our understanding of the basis of the disorder improves.

Adolescent↗
PubMed2006

Functional significance of polycystic-size ovaries in healthy adolescents.

CONTEXT: The relevance of adult polycystic ovary criteria to adolescence is unclear. OBJECTIVE: The objective was to determine the functional significance of polycystic-size ovaries (PSO) in healthy adolescents. DESIGN/SETTING/PARTICIPANTS/INTERVENTIONS: Healthy 11- to 18-yr-old postmenarcheal volunteers (n = 22) were recruited and divided into groups with normal size ovaries (VNSO; n = 10) or a polycystic-size ovary (VPSO; n = 12). They were secondarily compared with adolescents with polycystic ovary syndrome (PCOS; n = 8) matched for gynecological age and a PSO. All underwent GnRH agonist (GnRHag), oral glucose tolerance, and ACTH1-24 testing in our General Clinical Research Center. RESULTS: VPSO had a higher peak 17-hydroxyprogesterone (17PROG) response to GnRHag than VNSO (146 +/- 14 ng/dl, mean +/- sem, vs. 85 +/- 11; P = 0.008), as well as larger ovaries (13.3 +/- 0.7 cc vs. 8.5 +/- 0.8 cc). VPSO peak 17PROG was elevated (>137 ng/dl) in 42% (5 of 12). However, VPSO and VNSO androgen levels were similar, with the exception of one VPSO subject who had hyperandrogenemia and thus met criteria for PCOS. VPSO were similar to VNSO in LH, FSH, estradiol, and adrenal androgenic function. Although the VPSO group resembled the PCOS group in their 17PROG response to the GnRHag test, they differed in having significantly smaller ovaries and lower body mass index and in lacking evidence of peripheral androgen excess and of insulin resistance. CONCLUSION: A PSO in asymptomatic adolescents seems typically to be a normal variant. However, about half have a subclinical PCOS type of ovarian dysfunction; it is unknown whether this indicates a genetic carrier state or a risk for anovulation.

17-alpha-Hydroxyprogesterone↗
PubMed2006

Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome.

CONTEXT: We determined the relationship of metabolic syndrome (MBS) to polycystic ovary syndrome (PCOS). OBJECTIVE: We tested the hypothesis that parental MBS is related to the PCOS phenotype in their offspring. DESIGN/SETTING: We phenotyped for MBS and PCOS in our General Clinical Research Center. PATIENTS: Girls with PCOS, 12-19 yr old (n = 36, including one pair of siblings), and their parents (35 mothers, 19 fathers) were recruited from the Pediatric Endocrinology Clinic. Healthy girls, 12-19 yr old (n = 21), were recruited as a reference population. INTERVENTIONS: We measured anthropometrics, blood pressure, fasting lipids and androgens, oral glucose tolerance, and ultrasonographically determined polycystic ovary status. MAIN OUTCOME MEASURES: MBS in parents, and PCOS features in mothers, were related to the presence of PCOS features in probands. RESULTS: Fathers had strikingly high prevalence of excess adiposity (94% were obese or overweight) and MBS (79%). Premenopausal mothers more commonly had MBS (36%) than features of PCOS (< or =22%). Polycystic ovaries in proband offspring of premenopausal mothers were associated with maternal polycystic ovaries only in a minority of cases. Proband polycystic ovary status was completely concordant to fathers' MBS status (P = 0.008), but not their own or their mothers' MBS status, in families whose premenopausal mothers lacked polycystic ovaries. Proband prevalence of MBS was 27.8%, 3-fold greater than expected for obesity status. CONCLUSION: Familial factors related to paternal MBS seem to be fundamental to the pathogenesis of PCOS.

Adolescent↗
PubMed2006

A workshop on pubertal hormone replacement options in the United States.

BACKGROUND: The optimal pubertal hormone replacement therapy in females and males is unclear. OBJECTIVE: To review hormone replacement options for hypogonadal teenagers and to determine the relevant attitudes and practices of pediatric endocrinologists in the United States. DESIGN/METHODS: A workshop on pubertal hormone replacement options was held during the Lawson Wilkins Pediatric Endocrine Society meeting in 2004. A questionnaire was distributed to investigate the audience's attitudes and practices in inducing puberty. RESULTS: The majority of respondents used conjugated estrogens to treat hypogonadal girls with the primary aim of treatment being attainment of maximal adult height. The majority of respondents used depot testosterone to treat hypogonadal boys with the primary aim of treatment being pubertal development and virilization. CONCLUSIONS: The use of physiological sex hormone replacement to optimize the induction of puberty in hypogonadal adolescents was recommended. The workshop revealed striking differences between US and European pediatric endocrinologists regarding their practices and attitudes regarding the induction of puberty in hypogonadal females. Detailed studies are necessary to develop more uniform guidelines.

Adolescent↗
PubMed2005

Identification of a functional polymorphism of the human type 5 17beta-hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is characterized by chronic hyperandrogenic anovulation and is associated with insulin resistance. Its pathogenesis is believed to be multifactorial, and abnormal gene regulation could be one contributing factor. Type 5 17beta-hydroxysteroid dehydrogenase (17beta-HSD5) appears to be the major testosterone-forming 17beta-HSD isoenzyme in females. OBJECTIVE: Our objective was to investigate the role of a potentially activating 17beta-HSD5 gene (HSD17B5) variant in hyperandrogenism. DESIGN AND SETTING: We conducted a case study and case-control cohort study in our General Clinical Research Center. STUDY SUBJECTS: Subjects included a case of PCOS who had hyperthecosis associated with profound type B insulin resistance and an unusual, frankly male testosterone response to a GnRH agonist test, as well as 121 PCOS patients and 128 population controls. INTERVENTIONS: Interventions were diagnostic. MAIN OUTCOME MEASURES: Main outcome measures included sequencing of HSD17B5 5'-flanking region and nine exons, genotype/phenotype studies, and in vitro functional studies. RESULTS: Our case had a previously undescribed homozygous HSD17B5 variant (G-to-A substitution) -71 bp in the promoter region. Genotyping controls showed this to be a single-nucleotide polymorphism (SNP)-71G. Luciferase activity of a SNP-71G promoter construct was significantly higher than that of the wild type, and EMSAs revealed that SNP-71G possessed significantly increased affinity to nuclear transcription factors. SNP-71G allele frequency (32.2 vs. 22.3%) and SNP-71G allele presence (53.7% vs. 38.3%) were significantly increased in PCOS (P = 0.01) [corrected] SNP-71G homozygosity tended to contribute about 20% to the plasma testosterone level. CONCLUSIONS: SNP-71G is a functional polymorphism that may contribute to testosterone excess in a subset of PCOS patients.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

Salutary effects of combining early very low-dose systemic estradiol with growth hormone therapy in girls with Turner syndrome.

CONTEXT: Optimizing pubertal estrogen replacement in girls with Turner syndrome is important. OBJECTIVE: The study objective was to test the hypotheses that physiological estradiol replacement administered early with GH will preserve height potential as much as if administered late and that it will bring about a greater height gain than standard oral estrogen therapy combined with GH. DESIGN: The study was randomized to early or late estrogen treatment; follow-up was at 3.5 yr or later. SETTING: This was a multicenter outpatient study. PATIENTS: Turner syndrome girls 12.0-12.9 yr (n = 7) or 14.0-14.9 yr (n = 7) of age who began GH before age 12.0 yr were the patients. The girls were matched to National Cooperative Growth Study registry patients who began GH and oral conjugated estrogen at similar ages and were similarly followed to adult or near-adult height. INTERVENTIONS: Depot estradiol, 0.2 mg/month i.m., was given initially and gradually increased; GH was 0.05 mg/kg daily. MAIN OUTCOME VARIABLE: Adult or near-adult height was the main outcome variable. RESULTS: Depot estradiol treatment resulted in height significantly taller than predicted at 12 yr of age (P < 0.02). All height potential was gained in the first 2 yr of the study, during which the early group grew 3.5 cm more than the late group, which was receiving GH alone (P < 0.01). The early depot estradiol group also gained 5.9 cm more height after starting estrogen than did the early National Cooperative Growth Study group (P < 0.05). Although feminization proceeded slowly on the lowest dose of estradiol, it advanced normally thereafter. CONCLUSIONS: These results suggest that very low-dose parenteral estradiol permits relatively age-appropriate feminization without interfering with the effect of GH on the enhancement of height potential.

Body Height↗
PubMed2005

Characterization of the basal promoter element of the human type 5 17beta-hydroxysteroid dehydrogenase gene.

Testosterone biosynthesis from androstenedione is carried out by androgenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activity. Of the androgenic 17beta-HSD isoenzymes, only type 5 (17beta-HSD5) is expressed ubiquitously, including the human adrenal gland and ovary. To characterize this gene promoter, luciferase constructs of the human 5'-flanking region were transiently transfected into the H295R human adrenal carcinoma cell line. A series of fragment deletion constructs and electrophoretic mobility shift assays suggested that a sequence of CCTCCTCCT at -65 to -58 bp is the core sequence and demonstrated Sp1/Sp3 binding to this CCT repeat. Forskolin stimulated the promoter activity of the HSD17B5 gene through this Sp1/Sp3 binding site. Mutation of this site resulted in a significant reduction of HSD17B5 promoter basal and forskolin-induced activity. Mithramycin A, which inhibits the binding of Sp1 and Sp3 to DNA, also remarkably decreased HSD17B5 mRNA expression in the H295R cell line. These results indicate that members of the Sp family of transcription factors play an important role in regulating constitutive and stimulated expression of the HSD17B5 gene in H295R cells.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

Polycystic ovary syndrome in adolescence.

Polycystic ovary syndrome (PCOS) is a syndrome of variable combinations of menstrual irregularity, hirsutism or acne, and obesity. It can be diagnosed in adolescence and has early childhood antecedents. PCOS is the single most common endocrine cause of an ovulatory infertility and a major risk factor for the metabolic syndrome and, in turn, development of type 2 diabetes mellitus in women. Thus, it appears that PCOS increases a woman's risk of developing cardiovascular disease. Therefore, identifying girls at risk for PCOS and implementing treatment early in the development of PCOS may be an effective means of preventing some of the long-term complications associated with this syndrome. This article reviews the definition, clinical features, diagnosis, and treatment of PCOS.

Adolescent↗
PubMed2005

Hirsutism and the variable response of the pilosebaceous unit to androgen.

The pilosebaceous unit (PSU) response to androgen is variable. Certain population of PSU respond to androgen in a distinctive pattern that results in sexual hair development in some, sebaceous gland development in others. Furthermore, androgen excess is variably manifest in women as hirsutism, acne vulgaris, seborrhea, or pattern alopecia. Although sebaceous cells act as intracrine cells, activating pro-hormones to potent androgens that act within the sebocyte, hair follicle metabolism predominantly inactivates testosterone. Androgen action in the sexual hair follicle appears to be mediated by the dermal papilla and possibly, by inducing expression of a specific keratin, hHa7, in the hair medulla. The data do not clearly support a relationship between idiopathic hirsutism, the hirsutism that occurs in the absence of androgen excess, and variations in androgen mechanism of action. Androgens are prominent among the hormones that modulate the biological mechanism regulating the hair cycle. However, the basis for the variable pattern of PSU response to androgen is unclear, as is the basis for the variable development of hirsutism in response to androgen excess and the incomplete reversal of hirsutism by anti-androgen treatment. Improved treatment of hirsutism awaits improved understanding of the nature of the interaction between androgens and other determinants of hair follicle biology.

Androgens↗
PubMed2004

GnRH agonist stimulation of the pituitary-gonadal axis in children: age and sex differences in circulating inhibin-B and activin-A.

BACKGROUND: Inhibin-B decreases and activin increases FSH secretion in adults. We investigated whether an FSH-inhibin/activin feedback loop exists before or during puberty. METHODS: FSH secretion was stimulated with 10 microg/kg leuprolide acetate (GnRH agonist) in 18 girls, ages 1.0-13.2 years, and 11 boys, ages 8.9-15.2 years, with variations in pubertal development, and in five normal 9- to 10-year-old girls. Blood, obtained at 0, 0.5, 1, 2, 4, 8, 12, 16, 20 and 24 h after GnRH agonist, was analysed for LH, FSH, activin-A, inhibin-A, inhibin-B, follistatin 288 and estradiol/testosterone. RESULTS: FSH increased within 30 min of GnRH agonist administration with a peak greater in girls than boys (P=0.0006). Baseline inhibin-B was greater in boys than girls (P=0.01), while baseline activin-A concentrations were greater in girls. GnRH agonist-stimulated FSH increased inhibin-B in girls by 8 h and in boys by 20 h (P<0.05), but did not affect activin-A. Inhibin-B increases were seen only in girls older than 5 years. CONCLUSIONS: An inhibin-B-FSH feedback loop exists prior to the onset of puberty in girls older than 5 years. Sex differences in activin-A and inhibin-B concentrations may be responsible for sex differences in serum FSH concentrations.

Activins↗
PubMed2003

Bartter syndrome complicated by immune complex nephropathy. Case report and literature review.

The unusual coincidence of Bartter syndrome and C1q nephropathy is described and the literature reviewed. An African-American girl presented at 4 years of age with acute hyponatremic dehydration and failure to thrive. Persistent hypokalemic alkalosis and secondary hyperaldosteronism were found. The case was atypical for Bartter syndrome in that proteinuria (0.19 g/day) was present. Renal biopsy showed juxtaglomerular hyperplasia and C1q nephropathy. Molecular analysis showed deletion of the renal chloride channel gene (CLCNKB) typical of autosomal recessive childhood Bartter syndrome. Chronic sodium and potassium chloride replacement therapy together with indomethacin normalized her metabolic status, and she experienced catch-up growth. Proteinuria persisted, however. This is the first documentation of C1q nephropathy, in mild form, complicating autosomal recessive Bartter syndrome. This case shows the importance of the renal biopsy and of molecular analysis in delineating the cause of atypical nephropathy associated with Bartter syndrome. These findings add to the evidence of a possible association between the congenital syndrome and acquired immune complex nephropathy.

Anion Transport Proteins↗
PubMed2003

Molecular genetic and endocrine mechanisms of hair growth.

The prenatal morphogenesis of hair follicles depends upon a precisely regulated series of molecular genetic processes. Hormones and their receptors play prominent roles in modulating postnatal hair cycling, which recapitulates some aspects of morphogenesis. The responses to androgen are the most obvious of these. The postnatal androgen sensitivity of pilosebaceous units in different skin areas is programmed during prenatal development to permit clinical outcomes such as hirsutism and pattern baldness. Thyroid hormone, glucocorticoids, insulin-like growth factor-I, and prolactin have clinically significant effects on specific aspects of hair growth. The nuclear receptors vitamin D receptor and retinoid X receptor are essential for postnatal hair cycling. Other hormones have less clear effects on hair growth. Advances in research on the interaction of hormone target genes with the biological processes involved in hair morphogenesis and cycling can be expected to improve management of hirsutism and alopecia.

Alopecia↗
PubMed2002

Oestrogens and puberty.

Oestrogens induce the development of female reproductive tissues. Endogenous human oestrogens include oestradiol, oestrone and oestriol. Oestrogen signalling in target tissues is dependent on the tissue concentration of oestrogen and the interaction of oestrogen receptors with an array of cell-specific co-regulator proteins. The diverse mechanisms of oestrogen signalling are complex and incompletely understood. In puberty, oestrogen is derived from both gonadal and peripheral sources. Originally, oestrogen was only thought to drive feminization in females; now, oestrogen is known to be important for pubertal development of males as well. Oestrogen is required for normal maturation of the neuroendocrine-gonadal axis and bone in both sexes, and a variety of other tissues are also responsive to oestrogen. Abnormal puberty can be associated with either excessive or inadequate oestrogen production. Girls deficient in oestrogen should receive replacement in physiological doses. Aromatase inhibitors and anti-oestrogens may prove to be useful therapeutic tools in some types of abnormal puberty.

Estradiol Congeners↗
PubMed2002

The role of LH and FSH in ovarian androgen secretion and ovarian follicular development: clinical studies in a patient with isolated FSH deficiency and multicystic ovaries.

Inactivating mutations have proven to be instructive in elucidating the role of FSH in human ovarian function. We performed a detailed reproductive endocrine evaluation of a patient with inactivating mutations in the FSH beta-subunit gene who was hypo-estrogenic and had LH excess. The patient underwent a pelvic ultrasound and overnight frequent blood sampling followed by a human chorionic gonadotrophin (HCG) stimulation test. One month later she received human recombinant FSH, followed 24 h later by a second HCG stimulation test. Despite a mean LH serum concentration and LH pulse characteristics typical for polycystic ovaries (PCOS), baseline and dexamethasone-suppressed free testosterone were low-normal. The administration of HCG led to minimal stimulation of 17-hydroxyprogesterone and androgens. The patient had multicystic ovaries containing follicles 3-5 mm in diameter and responded to FSH with prompt increases in estradiol and inhibin B. There were no clinical or laboratory consequences of LH excess in this FSH-deficient woman. These findings support the hypothesis that excessive LH stimulation alone does not cause ovarian hyperandrogenism. We also found that follicular development was present in the absence of FSH. These antral follicles had apparently developed normally, since estradiol and inhibin B increased promptly after FSH administration.

17-alpha-Hydroxyprogesterone↗