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R L Rosenfield

Publications and source records attributed to R L Rosenfield.

At least 19 recordsLinked to original sources
PubMed2000

The role of specific retinoid receptors in sebocyte growth and differentiation in culture.

Retinoic acid derivatives (retinoids) exert their pleiotropic effects on cell development through specific nuclear receptors, the retinoic acid receptors and retinoid X receptors. Despite recent progress in understanding the cellular and molecular mechanisms of retinoid activity, it is unknown which of the retinoid receptor pathways are involved in the specific processes of sebocyte growth and development. In this study, we investigated the roles of specific retinoid receptors in sebocyte growth and differentiation, by testing the effects of selective retinoic acid receptor and retinoid X receptor ligands at concentrations between 10-10 M and 10-6 M in a primary rat preputial cell monolayer culture system. Cell growth was determined by number of cells and colonies, and cell differentiation by analysis of lipid-forming colonies. All-trans retinoic acid and selective retinoic acid receptor agonists (CD271 = adapalene, an RAR-beta,gamma agonist; CD2043 = retinoic acid receptor pan-agonist; and CD336 = Am580, an RAR-alpha agonist) caused significant decreases in numbers of cells, colonies, and lipid-forming colonies, but with an exception at high doses of all-trans retinoic acid (10-6 M), with which only a small number of colonies grew but they became twice as differentiated as controls (42.2 +/- 4.0% vs 22.6 +/- 2.7%, mean +/- SEM, lipid-forming colonies, p < 0.01). Furthermore, the RAR-beta,gamma antagonist CD2665 antagonized the suppressive effects of all-trans retinoic acid, adapalene, and CD2043 on both cell growth and differentiation. In contrast, the retinoid X receptor agonist CD2809 increased cell growth slightly and lipid-forming colonies dramatically in a clear dose-related manner to a maximum of 73.7% +/- 6.7% at 10-6 M (p < 0. 001). Our data suggest that retinoic acid receptors and retinoid X receptors differ in their roles in sebocyte growth and differentiation: (i) retinoic acid receptors, especially the beta and/or gamma subtypes, mediate both the antiproliferative and antidifferentiative effects of retinoids; (ii) retinoid X receptors mediate prominent differentiative and weak proliferative effects; (iii) the antiproliferative and antidifferentiative effects of all-trans retinoic acid are probably mediated by retinoic acid receptors, whereas its differentiative effect at high dose may be mediated by retinoid X receptors via all-trans retinoic acid metabolism to 9-cis retinoic acid, the natural ligand of retinoid X receptors.

Adapalene↗
PubMed2000

Role of hormones in pilosebaceous unit development.

Androgens are required for sexual hair and sebaceous gland development. However, pilosebaceous unit (PSU) growth and differentiation require the interaction of androgen with numerous other biological factors. The pattern of PSU responsiveness to androgen is determined in the embryo. Hair follicle growth involves close reciprocal epithelial-stromal interactions that recapitulate ontogeny; these interactions are necessary for optimal hair growth in culture. Peroxisome proliferator-activated receptors (PPARs) and retinoids have recently been found to specifically affect sebaceous cell growth and differentiation. Many other hormones such as GH, insulin-like growth factors, insulin, glucocorticoids, estrogen, and thyroid hormone play important roles in PSU growth and development. The biological and endocrinological basis of PSU development and the hormonal treatment of the PSU disorders hirsutism, acne vulgaris, and pattern alopecia are reviewed. Improved understanding of the multiplicity of factors involved in normal PSU growth and differentiation will be necessary to provide optimal treatment approaches for these disorders.

Acne Vulgaris↗
PubMed2000

Diagnosis of the polycystic ovary syndrome in adolescence: comparison of adolescent and adult hyperandrogenism.

We performed gonadotropin releasing hormone agonist (GnRHag) tests on 23 consecutive hyperandrogenic girls 9.9-17.5 years of age who were referred to our pediatric endocrinology clinic with symptoms suggestive of PCOS. They were compared to contemporaneously studied groups of adult normal and hyperandrogenic women. We found that hyperandrogenic adolescents had clinical and endocrine features similar to those of hyperandrogenic adults. However, there were some noteworthy unique features of adolescent hyperandrogenism, such as presentation in mid-childhood with premature pubarche and the occasional diagnosis before the age of 10 years. Some differences between adolescents and adults were statistically significant, for example, pelvic ultrasonography was not as helpful in the diagnosis of FOH as it is in adults. Nevertheless, a number of questions about the development of the ovarian dysfunction remain to be answered. For example, we are unable to diagnose ovarian dysfunction before puberty or in early puberty, and the relationship of "physiologic adolescent anovulation" to PCOS remains to be defined.

Adolescent↗
PubMed1999

Ovarian and adrenal function in polycystic ovary syndrome.

Androgens are secreted by both the ovaries and adrenal glands in response to their respective trophic hormones LH and ACTH. Androgens in women are not specifically under negative feedback control by these pituitary hormones because they are by-products of estradiol and cortisol secretion. Rather, androgen secretion seems to be regulated mostly by intraglandular mechanisms. Functional ovarian hyperandrogenism is found in about 70% of patients with PCOS. It is characterized by excessive secretion of 17-hydroxyprogesterone in response to GnRH agonist or hCG stimulation. Failure of dexamethasone to suppress plasma free testosterone normally in the presence of normal adrenocortical suppression is also typical. Functional adrenal hyperandrogenism is found in about half of patients with PCOS. It is most often characterized by moderately increased secretion of the 17-ketosteroid DHEA in response to ACTH. The most likely cause of the excessive androgen secretion by both glands seems to be abnormal regulation (dysregulation) of the 17-hydroxylase and 17,20-lyase activities of P-450c17, the rate-limiting step in androgen biosynthesis. There are also subtle generalized disturbances of steroid metabolism, including tendencies toward excessive estrogen and cortisol secretion. The cause of dysregulation of steroidogenesis is unknown. The hyperinsulinemia that is compensatory for resistance to the glucose-metabolic effect of insulin seems to have a role in many cases. In most cases, intrinsic intraovarian or intra-adrenal autocrine or paracrine regulatory mechanisms are most likely malfunctioning.

Adrenal Glands↗
PubMed1999

Rat preputial sebocyte differentiation involves peroxisome proliferator-activated receptors.

The hallmark of sebaceous epithelial cell (sebocyte) differentiation is the accumulation of fused neutral fat droplets. Very little sebocyte differentiation occurs, however, in primary or organ culture, even upon incubating with androgens, which are required for maturation in vivo. We hypothesized that sebocyte cell culture systems lack activators of the peroxisome proliferator-activated receptors that are involved in adipocyte differentiation. We here report that activation of peroxisome proliferator-activated receptor gamma and alpha by their respective specific ligands, a thiazolidinedione and a fibrate, induced lipid droplet formation in sebocytes but not epidermal cells. Linoleic acid and carbaprostacyclin, both peroxisome proliferator-activated receptor delta and alpha ligand-activators, were more effective but less specific, stimulating lipid formation in both types of cells. Either was more effective than the combination of peroxisome proliferator-activated receptor gamma and alpha activation, suggesting that peroxisome proliferator-activated receptor delta is involved in this lipid formation. Linoleic acid 0.1 mM stimulated significantly more advanced sebocyte maturation than any other treatment, including carbaprostacyclin, which suggests a distinct role of long chain fatty acids in sebocyte differentiation. Peroxisome proliferator-activated receptor gammal mRNA was demonstrated in sebocytes, but not in epidermal cells; it was more strongly expressed in freshly dispersed than in cultured sebocytes. In contrast, peroxisome proliferator-activated receptor delta mRNA was expressed to a similarly high extent before and after culture in both sebocytes and epidermal cells. These findings are compatible with the concepts that peroxisome proliferator-activated receptor gamma1 gene expression plays a unique role in the differentiation of sebocytes, while peroxisome proliferator-activated receptor delta activation and long chain fatty acids finalize sebocyte maturation and are capable of stimulating epidermal lipid formation. These findings have implications for the development of new modalities of treatment for acne vulgaris.

Animals↗
PubMed1999

Intrauterine growth retardation associated with maternal uniparental disomy for chromosome 6 unmasked by congenital adrenal hyperplasia.

We report the first case of maternal uniparental disomy for chromosome 6 (UPD6mat) ascertained through congenital adrenal hyperplasia (CAH), which arose because of reduction to homozygosity of an autosomal recessive mutation. This case suggests that UPD6mat is associated with intrauterine growth retardation (IUGR). A case of paternal UPD (involving only the short arm of chromosome 6) ascertained as CAH has previously been reported, but was not stated to have IUGR. Our patient was born with IUGR followed by extraordinarily good catch-up growth. She had a history of a marked lag in motor development. She presented at 2.65 y of age with pubarche of 3 mo duration, clitoral enlargement, and an advanced bone age. Simple virilizing CAH was diagnosed by elevations of plasma 17-hydroxyprogesterone and testosterone. Mutation analysis showed that the CAH was due to homozygosity for the 1172N exon 4 mutation. When parental DNA was examined, the mother was found to be heterozygous for the uncommon exon 4 mutation, while the father had no detectable mutations. DNA microsatellite analysis was subsequently performed on the patient and parents using polymorphic markers spanning the entire chromosome 6. Seven markers were informative for inheritance of a single maternal allele and absence of paternal alleles in the proband. Analysis of microsatellite markers from other chromosomes confirmed biparental inheritance at these loci. This combination of findings is diagnostic of UPD6mat. The only other reported case of UPD6mat was discovered serendipitously when genotyped for renal transplantation; this patient had a history of IUGR. Since both cases of UPD6mat had IUGR, the phenotype appears to include IUGR as well as the potential to unmask an autosomal recessive trait.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Growth hormone and insulin-like growth factors have different effects on sebaceous cell growth and differentiation.

Several observations suggest that GH stimulates sebaceous gland growth and development. Therefore, we studied the effects of GH and insulin-like growth factors (IGFs), alone and with androgen, on sebaceous epithelial cell (sebocyte) growth and differentiation in vitro. The rat preputial cell culture model system was used to judge differentiation (induction of lipid-forming colonies, LFCs) and DNA synthesis. GH increased sebocyte differentiation. At a dose of 10(-8) M in the presence of micromolar insulin, GH was 3.8 times more potent than IGF-I (38.1+/-4.2%, SEM, vs. 10+/-1.5% LFCs) and 6 times more potent than IGF-II (6+/-0.5% LFCs). IGF-I 10(-8) M alone stimulated a similar amount of differentiation as insulin 10(-6) M, although it was less effective than insulin in augmenting the effect of GH on differentiation. GH had no effect on sebocyte uptake of 3H-thymidine at doses up to 10(-6) M. On the other hand, IGF-I was the most potent stimulus of DNA synthesis (168% of control; P < 0.001 vs. all others). IGF-II 10(-8) M stimulated 3H-thymidine incorporation similarly to insulin 10(-6) M. In the presence of insulin, dihydrotestosterone (DHT) 10(-6) M induced 31.4+/-1.7% LFCs, and there was a tendency of DHT and GH to interact in promoting differentiation. When insulin was omitted from the system, differentiation was decreased overall, but GH +/- DHT slightly improved differentiation. The IGFs had no effect on the response to DHT. DHT decreased DNA synthesis by 40%, an effect unaltered by GH or IGFs. These results suggest that GH and IGFs have different functions in sebaceous cell growth and differentiation: GH stimulated differentiation beyond that found with IGFs or insulin, yet had no effect on DNA synthesis, a parameter stimulated most potently by IGF-I. While GH augmented the effect of DHT on differentiation, the IGFs had no effect on the response of DHT. These data indicate that GH may in part act directly on sebocytes rather than indirectly through IGF production. These data are consistent with the concept that increases in GH and IGF production contribute in complementary ways to the increase in sebum production during puberty and in acromegaly.

Animals↗
PubMed1999

Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.

OBJECTIVE: NIDDM occurs commonly among women with polycystic ovary syndrome (PCOS). The prevalence and natural history of its precursor, impaired glucose tolerance (IGT), is less well known. The objective of this study was to characterize the prevalence and incidence of glucose intolerance in a large cohort of women with well-characterized PCOS. RESEARCH DESIGN AND METHODS: A total of 122 women with clinical and hormonal evidence of PCOS were recruited from the Medicine, Endocrinology, Gynecology, and Pediatrics Clinics at the University of Chicago. All women had a standard oral glucose tolerance test (OGTT) with measurement of glucose and insulin levels. A subset of 25 women were subsequently restudied with the aim of characterizing the natural history of glucose tolerance in PCOS. RESULTS: Glucose tolerance was abnormal in 55 (45%) of the 122 women: 43 (35%) had IGT and 12 (10%) had NIDDM at the time of initial study. The women with NIDDM differed from those with normal glucose tolerance in that they had a 2.6-fold higher prevalence of first-degree relatives with NIDDM (83 vs. 31%, P < 0.01 by chi 2) and were significantly more obese (BMI 41.0 +/- 2.4 vs. 33.4 +/- 1.1 kg/m2, P < 0.01). For the entire cohort of 122 women, there was a significant correlation between fasting and 2-h glucose concentrations (r = 0.76, P < 0.0001); among the subset with IGT, the fasting glucose concentration was poorly predictive of the 2-h level (r = 0.25, NS). After a mean follow-up of 2.4 +/- 0.3 years (range 0.5-6.3), 25 women had a second OGTT. The glucose concentration at 2 h during the second glucose tolerance test was significantly higher than the 2-h concentration during the first study (161 +/- 9 vs. 139 +/- 6 mg/dl, P < 0.02). CONCLUSIONS: The prevalence of IGT and NIDDM in women with PCOS is substantially higher than expected when compared with age- and weight-matched populations of women without PCOS. The conversion from IGT to NIDDM is accelerated in PCOS. The fasting glucose concentration does not reliably predict the glucose concentration at 2 h after an oral glucose challenge, particularly among those with IGT, the subgroup at highest risk for subsequent development of NIDDM. We conclude that women with PCOS should periodically have an OGTT and must be closely monitored for deterioration in glucose tolerance.

Adult↗
PubMed1998

Role of cytochrome P450c17 in polycystic ovary syndrome.

The hyperandrogenism of polycystic ovary syndrome (PCOS) appears to be due to dysregulation of steroidogenesis within the ovaries and adrenal glands. P450c17 is the key enzyme that regulates androgen synthesis. It is the only enzyme known to have the capacity to convert C21-precursors to the androgen pre-hormones, the 17-ketosteroids. It is a single enzyme with two activities, 17-hydroxylase and 17,20-lyase. Thus, its regulation is a significant factor in the expression of hyperandrogenism. Androgen secretion is LH-dependent in the ovary and ACTH-dependent in the adrenal glands. The androgenic response to each of these tropic hormones seems to be modulated by intra-ovarian or intra-adrenal autocrine and paracrine mechanisms. This modulation serves to regulate steroid hormone secretion in tissue-specific ways. Insulin, IGFs and inhibin are among the many growth factors capable of augmenting the response to LH and ACTH. The insulin/IGF system stimulates P450c17 mRNA expression and activities in the ovaries and adrenal glands. An integrating link between insulin resistance and hyperandrogenemia may be serine phosphorylation, which inhibits activity of the insulin receptor and promotes the 17,20-lyase activity of P450c17. However, it must be kept in mind that there is some evidence for the existence of P450c17-independent pathways of androgen biosynthesis.

Female↗
PubMed1998

Mechanisms of androgen induction of sebocyte differentiation.

It has been difficult to induce the expected sebocyte differentiation in vitro with dihydrotestosterone (DHT). We reasoned that our culture system lacks differentiating factors, and peroxisome proliferator-activated receptors (PPARs) were the prime candidates. We tested PPAR activators informative about diverse PPAR subtypes, with and without DHT (10(-6) M): BRL-49653 (10(-6) M, PPAR-gamma), WY-14643 (10(-6) M, PPAR-alpha), and linoleic acid (LIN, 10(-4) M, PPAR-delta). Treatments were added in serum-free medium to cultures of rat preputial sebocytes. Control, DHT, BRL and BRL + DHT treatments caused 11, 25, 66 and 80%, respectively, of preputial cell colonies to differentiate into lipid-forming colonies (LFCs) (p < 0.001). WY induced 20% and LIN over 95% LFC formation. PPAR-gamma mRNA was identified in preputial sebocytes by the RNase protection assay. These data suggest that differentiation of sebocytes is transduced by PPARs and have implications for the development of new treatments for acne.

Androgens↗
PubMed1998

Optimizing estrogen replacement treatment in Turner syndrome.

Estrogen has a biphasic effect on growth, stimulatory at low doses but inhibitory at higher doses. Therefore, designing optimal sex hormone replacement treatment in girls with Turner syndrome (TS) who are being treated with growth hormone (GH) involves considering the dose and form of the estrogen as well as the route and timing of its administration. We report here a preliminary analysis of a study to test the concept that an optimal estrogen replacement regimen should consist of estradiol administered in a low dose by a systemic route. The study population consisted of 9 girls with TS who had been treated with GH for 6 or more months. When the girls were 12 to 15 years old, we added depot estradiol at a monthly intramuscular dose of 0.2 mg and increased the dose at 6-month intervals to 0.4, 0.6, and, in 7 of the girls, 0.8 mg. We compared the results in these subjects with those in a matched group of 37 patients with TS in whom routine estrogen treatment had been started at similar ages and who were treated with a similar course of GH therapy. The gain in height at 2 years was 2.6 cm greater in those who were treated with depot estradiol than in those who were treated with routine estrogen. The bone age in the patients who were treated with depot estradiol increased in proportion to their chronologic age, suggesting that this difference indicates an increase in their predicted adult height. We conclude that using very low doses of systemic estradiol to induce puberty before the age of 15 years in girls with TS who are treated with GH, instead of using routine estrogen therapy, can result in increased final heights.

Adolescent↗
PubMed1997

Current concepts of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) may be loosely defined as unexplained hyperandrogenism, with variable degrees of cutaneous symptoms, anovulatory symptoms, and obesity. The vast majority of patients with the full-blown Stein-Leventhal syndrome have functional ovarian hyperandrogenism (FOH). However, FOH often occurs without the LH excess or polycystic ovaries of classic PCOS. Functional adrenal hyperandrogenism (FAH) is often found in the syndrome, but it is less closely associated with anovulatory symptoms than is FOH. The vast majority of FOH seems to arise from abnormal regulation (dysregulation) of ovarian androgen secretion. This typically is due to escape from desensitization to luteinizing hormone (LH); this appears to occur because of a breakdown in the processes that normally coordinate ovarian androgen and oestrogen secretion so as to prevent hyperoestrogenism. Similar dysregulation of adrenal androgen secretion in response to ACTH seems to account for most FAH. Dysregulation of androgen secretion may affect the ovary alone (isolated FOH), the adrenal alone (isolated FAH), or both together. Modest insulin resistance is common in PCOS/FOH, and the resultant hyperinsulinaemia is a major candidate as the cause of the dysregulation. The hyperinsulinaemia may arise from either 'nature' (genetic defects) or 'nurture' (exogenous obesity). Although hyperinsulinaemia alone does not have an obvious effect on steroidogenesis, it may act in genetically predisposed women as a 'second hit' to unmask latent abnormalities in steroidogenesis. The ovary, the adrenal cortex, and several other organs paradoxically function as if responding to the hyperinsulinaemic state in spite of resistance to the effects of insulin on glucose metabolism. PCOS should be viewed as an early manifestation of a hyperinsulinaemic condition that will predispose to cardiovascular and metabolic complications later in life. A subset of PCOS patients appear to have not only insulin resistance but also beta-cell secretory dysfunction, which may indicate a relationship of the disorder to NIDDM. The fundamental genetic defects remain to be elucidated.

Acne Vulgaris↗
PubMed1997

A pilot study of the human chorionic gonadotrophin test for ovarian hyperandrogenism.

A controlled clinical study was designed to investigate the value of human chorionic gonadotrophin (HCG) challenge as a test for functional ovarian hyperandrogenism. Dexamethasone administration was followed by 5000 IU HCG and blood samples for steroid hormone assay were obtained 0, 8, 16, and 24 h thereafter. Study subjects were normal women (n = 13); women with functional ovarian hyperandrogenism, defined by androgen excess, amenorrhoea and an increased 17-hydroxyprogesterone response to nafarelin (n = 6); and normal men (n = 4). The responses of 17-hydroxyprogesterone, androstenedione and testosterone to HCG in women with functional ovarian hyperandrogenism were significantly greater than in normal women. However, the 17-hydroxyprogesterone response to HCG in functional ovarian hyperandrogenism was significantly lower after HCG than after nafarelin. The oestradiol response was also significantly lower after HCG than nafarelin, although oestradiol concentration more than doubled in normal women as well as in women with functional ovarian hyperandrogenism. The responses to HCG confirm that functional ovarian hyperandrogenism abnormalities are luteinizing hormone (LH)-dependent. Therefore, the 17-hydroxyprogesterone response to HCG could represent a useful test for the diagnosis of ovarian hyperandrogenism. The lower 17-hydroxyprogesterone response to HCG than to nafarelin in functional ovarian hyperandrogenism suggests that a follicle-stimulating hormone (FSH)-responsive factor modulates thecal 17-hydroxyprogesterone secretion. The oestradiol response to HCG is consistent with HCG directly stimulating the oestradiol secretion by thecal cells.

17-alpha-Hydroxyprogesterone↗