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Biomedical subjects

R B Barnes

Publications and source records attributed to R B Barnes.

At least 37 records · Page 2Linked to original sources
PubMed1993

Gonadotropin-releasing hormone agonist as a probe for the pathogenesis and diagnosis of ovarian hyperandrogenism.

We have found that women with typical polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to a 100-micrograms test dose of the gonadotropin-releasing hormone agonist nafarelin without evidence of hindered estrogen secretion. To understand the basis of this response, we computed the apparent efficiency of the steps in steroid biosynthesis from the pattern of plasma steroids in response to nafarelin. The proximate cause appears to be excessive 17 alpha-hydroxylase activity and high, yet partially down-regulated, 17,20-lyase activity in the delta 4-pathway. These results suggest that this pattern of steroid secretion results from abnormal regulation (dysregulation) of these activities, possibly involving the enzyme cytochrome P450c17. To determine the usefulness of nafarelin testing for the diagnosis of ovarian hyperandrogenism, we then prospectively studied 40 hyperandrogenic women. The plasma 17-PROG response to nafarelin was supranormal in 58% of the women. The responses of 17-PROG to nafarelin and free testosterone to dexamethasone correlated well and were concordant in approximately 85% of cases. Baseline serum luteinizing hormone concentration was elevated in only 48% of cases. To understand ovarian structure-function relationships, we studied another 20 consecutive hyperandrogenic women. Among seven women with polycystic ovaries, five had an elevated LH level, and four of these five (80%) had an elevated 17-PROG response to nafarelin. Conversely, about half of patients with the PCOS-like disorder of ovarian function did not have polycystic ovaries. Ovarian stromal area, but not LH levels, correlated significantly (r = 0.45) with the 17-PROG response to nafarelin. Thus, both stromal hyperplasia and dysregulation of steroidogenesis seem to be manifestations of abnormal intraovarian regulation of cell growth and function. We conclude that a PCOS-like disorder of ovarian function in response to nafarelin testing is found in approximately half of hyperandrogenic women. The pathogenetic implication of our results is that abnormal intraovarian modulation of LH action seems to be a major factor in ovarian hyperandrogenism. The diagnostic implication of our data is that ovarian androgen excess will often be missed by use of common diagnostic criteria for PCOS.

Androgens↗
PubMed1993

Ovarian steroidogenic responses to gonadotropin-releasing hormone agonist testing with nafarelin in hirsute women with adrenal responses to adrenocorticotropin suggestive of 3 beta-hydroxy-delta 5-steroid dehydrogenase deficiency.

Nonclassical 3 beta-hydroxy-delta 5-steroid dehydrogenase (3 beta-HSD) deficiency type of congenital adrenal hyperplasia has been hypothesized to occur in as many as 10-40% of hirsute women, based on the adrenal steroidogenic responses to ACTH. However, diagnostic criteria for this "late-onset" 3 beta-HSD deficiency are not clearly established. Among 40 successive hyperandrogenic women undergoing evaluation of adrenal steroidogenic responses to ACTH, 8 had responses suggestive of 3 beta-HSD deficiency. Since 3 beta-HSD is present in both the ovary and adrenal, we attempted to document the defect in the ovary by stimulating their ovarian function with a gonadotropin-releasing hormone agonist test using nafarelin (6-D-[2-naphthyl]alanine-gonadotropin-releasing hormone). The eight hirsute women had steroid responses to ACTH suggestive of 3 beta-HSD deficiency, namely, the values of the delta 5-steroids, 17-hydroxypregnenolone and dehydroepiandrosterone, 30 and 60 min after ACTH in each hirsute woman were greater than 2 SD above the normal mean. Seven of the eight hirsute women had at least one elevated delta 5/delta 4-steroid ratio; however, only three of the hirsute women had two abnormal ratios. Furthermore, the response of the delta 4-steroid androstenedione and the ratio of androstenedione to cortisol after ACTH were significantly increased in the hirsute women, findings not consistent with 3 beta-HSD deficiency. After nafarelin, five and six hirsute patients had elevated values of the delta 4-steroids androstenedione and 17-hydroxyprogesterone, respectively. No patient had an elevated delta 5/delta 4-steroid ratio after nafarelin. Thus, ovarian steroidogenic responses to nafarelin did not support the diagnosis of 3 beta-HSD deficiency. Rather, they are consistent in most cases with polycystic ovary syndrome due to dysregulation of 17-hydroxylase and 17,20-lyase activities. We propose that increased activity of the enzyme P450c17 alpha in the adrenal cortex is responsible for most of what is often termed late-onset 3 beta-HSD deficiency.

17-alpha-Hydroxypregnenolone↗
PubMed1993

Defects in beta-cell function in functional ovarian hyperandrogenism.

Previous studies have shown that hyperinsulinism is associated with hyperandrogenism in patients with the polycystic ovary syndrome, a form of functional ovarian hyperandrogenism (FOH). Although many studies have documented insulin resistance and hyperinsulinemia in polycystic ovary syndrome, the relative roles of insulin secretion and clearance in the pathogenesis of the hyperinsulinism remain uncertain. In this study, using individually derived C-peptide kinetic parameters, insulin secretion rates were calculated directly from plasma C-peptide concentrations in 10 patients with FOH and 7 weight-matched control subjects. All subjects were studied during a 24-h period when they ate a standardized diet consisting of 3 mixed meals. On a separate occasion, insulin sensitivity was calculated during a hyperinsulinemic euglycemic clamp. Although glucose concentrations in both groups were within the normal range, the FOH group had higher basal (P < 0.01) and 24-h insulin (P < 0.04) concentrations. The increased insulin concentrations reflected both a reduced clearance (P < 0.02) and an increased secretion of insulin. Basal insulin secretion rates were significantly increased (P < 0.04) in the FOH patients. By contrast, their incremental insulin secretory response to meals was markedly reduced. This reduction in the postprandial responses resulted from a reduction in the relative amplitude of meal-related (P < 0.007) secretory pulses, rather than from a reduction in the number of pulses present. Insulin sensitivity was also lower in those with FOH. Thus, women with FOH have significantly higher basal insulin secretory rates and attenuated secretory responses to meals. These secretory patterns resemble those of noninsulin-dependent diabetes mellitus more than they do those of simple obesity.

Adult↗
PubMed1993

Menstrual disorders in adolescence.

Current concepts of normal and pathologic puberty have been reviewed because menstrual abnormalities are usually due to abnormal maturation of the reproductive endocrine system. Schema are presented for the initial evaluation of patients with amenorrhea or oligomenorrhea based upon whether they are hypoestrogenic or estrogenized. The role of the bone age in the differential diagnosis of delayed puberty is emphasized. The differential diagnosis and management of excessive genital bleeding and dysmenorrhea in adolescence are given.

Adolescent↗
PubMed1992

Detection of functional ovarian hyperandrogenism in women with androgen excess.

BACKGROUND: Distinguishing between ovarian and adrenal causes of androgen excess may be difficult. We have found that women with the polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to the gonadotropin-releasing hormone agonist nafarelin. We determined the usefulness of testing with nafarelin to distinguish ovarian causes of hyperandrogenism in women. METHODS: We studied 40 consecutive women with hyperandrogenism who had oligomenorrhea, hirsutism, or acne. All 40 underwent testing with nafarelin, dexamethasone, and corticotropin with measurement of circulating concentrations of gonadotropins and steroid hormones, and 19 underwent ovarian ultrasonography. RESULTS: The plasma 17-hydroxyprogesterone response to nafarelin was supranormal in 23 of the 40 women (58 percent), and the plasma androgen response to corticotropin was elevated in 23; 13 women had both abnormalities. Only one woman had conclusive evidence of a steroidogenic block; she had nonclassic adrenal 21-hydroxylase deficiency. Of the 23 women with abnormal responses to nafarelin, only 11 (48 percent) had elevated base-line serum luteinizing hormone concentrations. Of the 13 women with abnormal responses to nafarelin who underwent ultrasonography, 7 (54 percent) had polycystic ovaries. Peak plasma 17-hydroxyprogesterone concentrations after nafarelin administration correlated closely with plasma free testosterone concentrations after dexamethasone administration (r = 0.75, P less than 0.001). CONCLUSIONS: Approximately half of women with oligomenorrhea, hirsutism, or acne have an abnormal response to the gonadotropin-releasing hormone agonist nafarelin, suggesting an ovarian cause of their androgen excess.

17-alpha-Hydroxyprogesterone↗
PubMed1990

Dysregulation of cytochrome P450c 17 alpha as the cause of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) appears to be due to a previously unrecognized type of steroidogenic abnormality, one in which hyperandrogenism arises from a regulatory abnormality (dysregulation) rather than from enzyme deficiency. It appears that PCOS typically arises from masculinized regulation of the androgen-forming enzyme (cytochrome P450c17 alpha) within ovarian thecal cells. This may arise by either excessive stimulation by luteinizing hormone (LH) or by escape from desensitization to LH. We review evidence which is compatible with the concept that the latter situation may result from an intrinsic intraovarian flaw in the paracrine feedback mechanism by which thecal androgen biosynthesis is inhibited and that coexistent adrenal 17-ketosteroid hyper-responsiveness to corticotropin (ACTH) may be due to a similar type of dysregulation of adrenocortical P450c17 alpha.

Adrenal Cortex↗
PubMed1990

Quantitative and qualitative tests for urinary luteinizing hormone. Comparison in spontaneous and clomiphene-citrate-treated cycles.

A study was performed to evaluate conditions in which false-positive and -negative predictions of ovulation occur with qualitative urinary luteinizing hormone (LH) tests. Three urine specimens and a serum sample were collected daily for LH determination from five anovulatory women treated with clomiphene citrate and from six spontaneously cycling women. The urinary LH was determined with one quantitative and three qualitative tests, and the serum LH was determined with a quantitative assay. Ovulation was determined with transvaginal ultrasound and a serum progesterone level on day 22 of the menstrual cycle. There were six ovulatory and five anovulatory cycles. In those 11 cycles the qualitative urinary LH tests were falsely positive twice and falsely negative thrice. All the false-positive and -negative tests except for one occurred when the quantitative urinary LH was 24-28 mIU/mL. Two false-positive tests occurred one to two days after clomiphene administration. Two false-negative tests occurred in a cycle in which follicular development appeared suboptimal, and one occurred in a cycle with a brief urinary LH surge.

Clomiphene↗
PubMed1989

Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome.

To investigate the basis of polycystic ovary syndrome, we examined the responses of patients to nafarelin, a specific gonadotropin-releasing-hormone agonist, given to stimulate pituitary and gonadal secretion. We compared 16 normal women in the follicular phase, 5 normal men, 8 women with polycystic ovary syndrome, and 1 woman with polycystic ovary syndrome caused by a 3 beta-hydroxysteroid dehydrogenase deficiency. After 100 micrograms of nafarelin was given subcutaneously, serum follicle-stimulating hormone and luteinizing hormone increased rapidly to peak levels within four hours. The women with polycystic ovary syndrome had a pattern similar to that of the men, with greater early luteinizing-hormone responses (30 minutes to 1 hour) and lower peak follicle-stimulating-hormone responses than normal women (P less than 0.05). Patients with polycystic ovary syndrome responded to gonadotropin stimulation with normal to increased production of plasma estrogens and increased levels of androstenedione at 16 to 24 hours (P less than 0.05). Elevated production of 17 alpha-hydroxyprogesterone was found in all the women with polycystic ovary syndrome and in the men. These abnormal responses were unchanged by pretreatment with dexamethasone to suppress adrenal function. In the patient with the 3 beta-hydroxysteroid dehydrogenase deficiency, both basal and stimulated plasma levels of delta 5-3 beta-hydroxysteroids before the enzymatic block were elevated, whereas plasma levels of 17 alpha-hydroxyprogesterone and androstenedione--the steroids immediately beyond the block--were low. We conclude that women with polycystic ovary syndrome have masculinized pituitary and ovarian responses to stimulation by nafarelin. Our findings suggest that the regulation of the ovarian 17-hydroxylase and C-17,20-lyase activities is abnormal in such women.

3-Hydroxysteroid Dehydrogenases↗
PubMed1989

Early differentiation of retinal ganglion cells: an axonal protein expressed by premigratory and migrating retinal ganglion cells.

A monoclonal antibody, RA4, was developed that recognizes retinal ganglion cell axons in the mature retina. Between embryonic days 3 and 9, the RA4 antigen was associated with cell bodies in certain regions of the retina in addition to the ganglion cell axons. The RA4-positive cells were of 3 types: an apolar cell adjacent to the ventricular surface, a bipolar cell that spanned the thickness of the retina, and a monopolar cell in the ganglion cell layer. Evidence suggests that these cells are premigratory and migrating retinal ganglion cells. The expression of the RA4 antigen is the earliest indicator of ganglion cell differentiation yet reported. The existence of RA4-positive apolar cells along the outer surface of the retina suggests that the ganglion cell phenotype is expressed as soon as the cell becomes postmitotic. Approximately 20% of the migrating ganglion cells were in pairs. The paired cells most likely arose from the terminal division of a germinal cell. One possibility suggested by these data is that a ganglion cell-specific germinal cell arises from a pluripotent germinal cell. Immunoblots and other analyses revealed the RA4 antigen to be a 140 kDa cytoplasmic protein in the retina. RA4 also recognized many long tract axons in the brain. In the brain, the RA4 epitope was observed on proteins with at least 7 different molecular weights. Evidence suggests that different cell types may express the RA4 antigen with slightly different molecular weights.

Animals↗
PubMed1988

Secretory dynamics of bioactive and immunoreactive prolactin in polycystic ovary syndrome.

To further investigate prolactin (PRL) secretion in polycystic ovary syndrome (PCO), the authors evaluated immunoreactive (immuno) and bioactive (bio) PRL levels in the basal state and in response to provocative testing with intravenous dopamine (DA), metoclopramide (MCP), and gonadotropin-releasing hormone (GnRH), before and after disulfiram. Basal measurements of immuno-PRL, bio-PRL, and the ratio of bio/immuno-PRL were similar in PCO and controls. The immuno-PRL decrement after DA was greater than that of bio-PRL in both groups (P less than 0.05). After MCP, immuno-PRL increased more than bio-PRL in PCO (P less than 0.01), and this immuno-PRL increment was greater than that of controls (P less than 0.05). Bio-PRL and immuno-PRL increased after GnRH in PCO, but not controls, and these responses were inhibited by disulfiram. These data confirm PRL hypersecretion in some women with PCO, which is better expressed by immunoreactivity than bioactivity. Given the assay systems and patients studied, bioactivity

Adult↗
PubMed1987

Correlation of transabdominal and transvaginal ultrasound measurements of follicle size and number with laparoscopic findings for in vitro fertilization.

This paper compared the use of a transvaginal scanning approach with the conventional transabdominal scanning method. In study I, 15 patients with previous suboptimal abdominal ultrasounds were evaluated in subsequent cycles with both the transabdominal and the transvaginal techniques. With the transvaginal method, improvement was observed in 13 patients (87%). Study II compared both the transabdominal and transvaginal ultrasound measurements of follicle number and size with surgical findings. A high correlation (r = 0.914, P less than 0.001) was demonstrated between the number of follicles visualized by transvaginal sonogram and the number of follicles aspirated. A significant correlation (r = 0.639, P less than 0.001) was also observed between follicular fluid volume and the mean ultrasound follicle diameter determined transvaginally.

Female↗
PubMed1987

Peripheral dopamine metabolism in polycystic ovary syndrome.

It has been proposed that a relative dopamine deficiency or an increased sensitivity of the gonadotrope to dopamine may explain the elevated luteinizing hormone (LH) levels characteristic of polycystic ovary syndrome. To study one aspect of this issue, that of peripheral dopamine metabolism in polycystic ovary syndrome, we measured the conversion of dopamine to norepinephrine after intravenous dopamine infusions in women with polycystic ovary syndrome and in matched controls. In addition, we measured urinary metabolites of dopamine and norepinephrine, which reflect in part central catecholamine turnover, after daily ingestion of L-dopa with carbidopa, which increases brain dopamine levels. After dopamine infusion in women with polycystic ovary syndrome and in matched controls, steady state levels of plasma dopamine, norepinephrine, and the ratio of dopamine/norepinephrine were similar in the two groups. Similarly, urinary metabolites of dopamine, norepinephrine, and their ratios were not different in patients and controls after L-dopa with carbidopa. We suggest that no major alterations in dopamine metabolism exist in these patients with polycystic ovary syndrome.

Adult↗
PubMed1986

Modulation of luteinizing hormone immunoreactivity and bioactivity by dopamine but not norepinephrine in women.

It has been suggested that changes in bioactive luteinizing hormone in women occur toward midcycle and may result in increased bioactive/immunoreactive luteinizing hormone ratios. To determine whether dopamine or norepinephrine modulate immunoreactive and bioactive luteinizing hormone secretion, 15 ovulatory women were studied in the mid to late follicular phase. Dopamine in two doses (0.5 micrograms/kg/min and 4 micrograms/kg/min) and norepinephrine, 0.1 microgram/kg/min, were infused for 4 hours, and metoclopramide, 10 mg intravenously, was also given to determine whether dopamine receptor antagonism results in changes. Bioactive luteinizing hormone and the bioactive/immunoreactive luteinizing hormone ratio increased in women from the early to late follicular phase (p less than 0.05). Both intravenous doses of dopamine resulted in significant decrements in immunoreactive luteinizing hormone (20 +/- 2 and 20 +/- 3%, p less than 0.02) and bioactive luteinizing hormone (36.7% and 43.2%, p less than 0.05). With dopamine there was also a significant decrease in the bioactive/immunoreactive luteinizing hormone ratio (p less than 0.02). Intravenous norepinephrine, however, resulted in no changes in either immunoreactive or bioactive luteinizing hormone levels. Metoclopramide also did not change immunoreactive or bioactive luteinizing hormone levels. These data suggest that although endogenous dopaminergic blockade may not play a significant role in determining basal levels of luteinizing hormone, decreases in dopamine at the pituitary level may increase the bioactive/immunoreactive luteinizing hormone ratio. Norepinephrine does not appear to exert major changes in immunoreactive or bioactive luteinizing hormone.

Adult↗
PubMed1986

Correlation of the bioactivity of luteinizing hormone in follicular fluid with oocyte maturity in the spontaneous cycle.

This study was done to measure the bioactivity of luteinizing hormone (LH) in follicular fluid (FF) and to correlate this and other hormonal values with oocyte maturity in the spontaneous cycle. Twenty follicles (greater than 18 mm) from 18 ovulatory patients were obtained, and FF, according to oocyte maturity, was divided into three groups (I to III) of increasing maturity. FF progesterone correlated with maturity and was highest (P less than 0.01) in group III; estradiol, prolactin, and follicle-stimulating hormone were similar in the three groups. Immunoreactive LH was similar in groups I and II but was highest (30.5 +/- 7 mIU/ml) in group III (P less than 0.02). Bioactive (bio) LH was much higher in group III follicles (1307 +/- 387 mIU/ml); the bio:immunoreactive LH ratio also increased significantly (P less than 0.05). FF progesterone correlated positively with bio LH (r = 0.89, P less than 0.005) and the bio:immunoreactive LH ratio (r = 0.9, P less than 0.001); immunoreactive LH did not correlate. These data suggest that bioactivity of LH is an important correlate of oocyte maturity and that local ovarian factors may modulate these concentrations in FF.

Adult↗