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Biomedical subjects

M L Vance

Publications and source records attributed to M L Vance.

At least 19 recordsLinked to original sources
PubMed1992

Growth hormone and nutrition.

The regulation of growth hormone (GH) secretion in humans is a complex process which comprises more than stimulation by GH-releasing hormone and suppression by somatostatin. Although these two hypothalamic hormones are the primary regulators of GH secretion, they most likely function as the final pathway through which numerous factors influence GH synthesis and secretion. Some of the modulators of GH secretion include neurotransmitters, circulating glucose, insulin-like growth factor I and gonadal steroid concentrations. Age, nutrition and body composition are also related to the amount and pattern of GH secretion in humans. The influence of nutritional status on GH secretion is becoming more clearly defined.

Adult↗
PubMed1991

Temporal structure of in vivo growth hormone secretory events in humans.

The time course of spontaneous growth hormone (GH) secretion was studied in 12 normal men by analyzing serum GH concentrations measured in blood collected at 5-min intervals over 24 h with a multiple-parameter deconvolution model to simultaneously resolve endogenous GH secretory and clearance rates. Twenty-four-hour profiles of serum GH concentrations were accounted for by an average of 12 +/- 1.2 (SE) discrete GH secretory bursts having a mean half-duration (duration at half-maximal amplitude) of 25 +/- 2.3 min, indicating that 95% of daily GH secretion occurred in 8.8 h. The majority (96%) of GH was secreted in volleys composed of multiple (4.0 +/- 0.4) discrete secretory bursts. Such volleys of GH secretion were separated by 171 +/- 19 min, whereas their constituent individual secretory events occurred every 36 +/- 1.7 min (P = 0.0001). Between secretory volleys, calculated GH secretory rates fell asymptotically to zero. Significant positive and negative autocorrelations were observed for the series consisting of successive GH secretory burst mass and interburst intervals, respectively. Linear regression analysis revealed significant negative correlations between the mass of GH secreted per burst and both the preceding and following interburst intervals. Estimates of the half-life of endogenous GH (17 +/- 1.7 min) and of the endogenous GH production rate (0.25 +/- 0.033 mg/m2 for an assumed distribution volume of 7.9% body wt) agreed well with earlier independent measurements. We conclude that the human pituitary gland secretes GH in volleys consisting of multiple secretory bursts, without measurable intervening tonic secretion. This pattern of in vivo GH release in normal humans is consistent with a model of high-frequency GH-releasing hormone secretory events superimposed on low-frequency episodes of somatostatin withdrawal.

Adult↗
PubMed1991

Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group.

BACKGROUND: We wanted to determine the clinical and biochemical effects of long-term therapy with the somatostatin analog octreotide in 189 acromegalic patients. METHODS: Patients were treated at 23 medical centers for 6 days to 231 weeks (median, 24.2 weeks) with varying octreotide dosages (100 to 1500 micrograms/d; median, 300 micrograms/d). Serum growth hormone and insulin-like growth factor I (IGF-I) concentrations before and at the end of the study were compared, and correlations between the response to treatment with total daily dosage and duration of treatment were sought. RESULTS: The clinical response rate was 88%, irrespective of dosage or treatment duration. Serum growth hormone levels decreased in 172 (94%) of 182 patients and IGF-I levels decreased in 91 (92%) of 99. The mean pretreatment growth hormone level was 39.4 +/- 4.4 micrograms/L and decreased to 12.2 +/- 1.5 micrograms/L. Growth hormone levels decreased to less than 5 micrograms/L in 82 (45%) of 182 patients. The pretreatment IGF-I level was 5.62 +/- 0.41 U/mL and decreased to 2.64 +/- 0.19 U/mL; suppression to 2 U/mL or lower occurred in 46 (46%) of 99 patients. The degree of growth hormone suppression was associated with longer treatment duration but not with the total octreotide dosage per day. In 34 patients studied prospectively, pituitary tumor size decreased by greater than 20% in 15 (44%). Side effects occurred in 37% of patients and were most commonly transient loose alcoholic stools, pain at the injection site, and abdominal discomfort; severity was mild to moderate. Glucose tolerance was unchanged or improved in 52% and declined in 48% of 25 patients evaluated. CONCLUSIONS: Octreotide is an effective treatment for acromegaly that may be used as primary therapy or after surgery and/or pituitary irradiation.

Acromegaly↗
PubMed1990

Treatment of prolactin-secreting pituitary macroadenomas with the long-acting non-ergot dopamine agonist CV 205-502.

STUDY OBJECTIVE: Evaluation of the effects of an experimental long-acting non-ergot dopamine agonist, CV 205-502, on serum prolactin, tumor size, gonadal function, visual abnormalities, and tolerability in patients with macroprolactinomas. DESIGN: Prospective, unblinded, dose escalation as needed. SETTING: Four university medical centers; patients referred for treatment. PATIENTS: Twenty-six hyperprolactinemic patients (prolactin greater than 150 micrograms/L) with a pituitary macroadenoma were treated for 24 weeks with CV 205-502 given once daily. MEASUREMENTS AND MAIN RESULTS: Serum prolactin was measured at regular intervals. Prolactin levels decreased in all patients during treatment (mean pretreatment level, 2051.7 +/- 1077 micrograms/L [+/- SE]; 24 weeks, 39.0 +/- 11.3 micrograms/L; P = 0.0001); normal prolactin levels were achieved in 15 (58%). Tumor size decreased in 21 of 26 patients and ranged from 6% to 67% (mean, 19.2% +/- 3.4%). Onset or return of regular menses occurred in 11 of 15 premenopausal women, accompanied by an increase in estradiol concentrations (pretreatment, 186.5 +/- 25.0 pmol/L; on treatment, 690.9 +/- 104.3 pmol/L; P = 0.0003). Serum testosterone increased in 6 of 8 men; sexual function improved in 5 of 7 with pretreatment abnormalities. Two patients with reversible visual abnormalities improved within 2 weeks of starting treatment. Side effects occurred in 11 patients and abated over 1 to 2 weeks or after the dose was reduced. There was no evidence of toxicity as indicated by serial serum chemistries, liver function tests, hematologic profiles, thyroxine levels, and electrocardiogram studies. CONCLUSIONS: CV 205-502 reverses hyperprolactinemia and promotes reduction in tumor size with reversal of visual abnormalities and restoration of gonadal function in most patients. This compound will probably be useful in treating prolactinomas.

Adenoma↗
PubMed1990

Physiological role of somatostatin on growth hormone regulation in humans.

Growth hormone (GH) secretion in man is pulsatile and this pattern is regulated by both GH-releasing hormone (GHRH) and somatostatin. A large body of experimental evidence in both man and animals supports the model that bursts of GH secretion are mediated by a reduction of tonic hypothalamic somatostatin secretion. Our studies have been performed in normal subjects with frequent blood sampling for GH measurements (from 20-minute to 30-second intervals); the data have been analyzed by computer algorithms to objectively determine pulse characteristics and, in some studies, to estimate both pituitary secretion and clearance rates using deconvolution analysis. The studies include profiles of GH secretion in normal men and women in fed and fasted states; analysis of GH secretion during sleep; and administration of GHRH during different stages of sleep and after sleep deprivation. The variable GH response to exogenous GHRH and the attenuated response after 6 hours of GHRH infusion to GHRH, while not to hypoglycemia, as well as the pulsatile profile of GH secretion in response to continuous GHRH infusions (24 hours to 14 days), all support the thesis that it is hypothalamic somatostatin that determines the timing of bursts of GH secretion. This is further confirmed by the profile of GH secretion in a patient with ectopic GHRH secretion. Recently, we have initiated studies with the novel synthetic GH releasing hexapeptide, HisDTrpAlaTrpDPheLysNH2 (GHRP). Our studies show that it acts synergistically with GHRH. Several lines of evidence suggest that GHRP stimulates GH secretion independently of GHRH receptors and acts at both the hypothalamic and pituitary levels. It may act to functionally antagonize somatostatin.

Amino Acid Sequence↗
PubMed1990

Somatotropin pulse frequency and basal concentrations are increased in acromegaly and are reduced by successful therapy.

Alterations in pulsatile GH release in 13 acromegalic patients (7 men and 6 women) were studied by measuring serum GH concentrations in blood sampled every 5 min over 24 h. Specific properties of pulsatile GH release were quantitated by Cluster analysis, and Fourier expansion time series analysis was used to resolve fixed periodicities underlying GH secretion. Compared with sex-matched controls, 24-h integrated GH concentrations (IGHC; min.mg/L) were elevated 15-fold in the acromegalic men (40 +/- 27 vs. 2.6 +/- 0.35; P = 0.02) and 10-fold in the acromegalic women (43 +/- 19 vs. 4.1 +/- 0.35; P = 0.01). The increase in integrated GH concentrations was accounted for by an increase in the nonpulsatile fraction [men, 31 +/- 20 vs. 0.65 +/- 0.10 (P = 0.001); women, 35 +/- 14 vs. 1.2 +/- 0.10 (P = 0.0008)]; the pulsatile component was not different from that in normal subjects. Acromegalics had an increased number of pulses per 24 h [men, 17 +/- 1.5 vs. 6.7 +/- 1.4 (P = 0.0001); women, 19 +/- 1.6 vs. 11 +/- 1.0 (P = 0.002)] and increased basal GH concentrations [men, interpulse valley mean, 22 +/- 14 vs. 1.4 +/- 0.30 micrograms/L (P = 0.0006); women, 27 +/- 12 vs. 1.3 +/- 0.20 micrograms/L (P = 0.0001)]. The proportion of the mean GH concentration attributable to 24-h rhythmicity was decreased in the acromegalic patients. Five patients studied during biochemical remission (4 after transsphenoidal surgery and 1 during bromocriptine therapy) had GH profiles that resembled those of normal subjects. Pulsatile GH secretion in acromegaly is characterized by augmented basal GH concentrations, increased GH pulse frequency, and an attenuation of the underlying 24-h rhythm. Such a pattern may be secondary to the intrinsic pathology of adenomatous somatotrophs and/or the effects of altered hypothalamic regulation.

Acromegaly↗
PubMed1990

Plasma transport of human growth hormone in vivo.

We have previously shown that a substantial part of human GH is complexed with GH-binding proteins (BPs) when GH is incubated with plasma in vitro. The proportion of GH bound in vivo, however, is unknown and may differ because of factors that cannot be assessed in vitro, such as binding to tissue receptors, distribution of GH outside the vascular compartment, and fluctuating GH and possibly BP levels. Accordingly, we studied the plasma transport characteristics of GH in vivo in six normal men. Monomeric, natural sequence human GH (Humatrope, Eli Lilly Co.) was injected iv in a dose designed to yield physiological plasma levels. Endogenous GH was suppressed before injection with oral glucose administration. Fifteen minutes after injection, plasma was obtained and immediately analyzed by zonal and frontal analysis in gel chromatography, followed by GH measurement in the fractions by RIA. The results obtained were very similar to those derived from in vitro studies, regardless of which analytical method was used. Frontal analysis at 37 C, which most directly reflects the true bound fraction, showed that 38.8 +/- 4.7% (mean +/- SD) of GH was bound to BPs at plasma GH levels ranging from 32-59 micrograms/L, indistinguishable from in vitro results. [When allowance was made for partial BP saturation, the fraction bound at low GH levels (greater than 7 micrograms/L) was calculated as 45.5 +/- 7.5%.] There was evidence for binding to both high and low affinity BPs in the expected proportions. In contrast to complex formation between GH and BPs, no evidence was obtained for conversion of the monomeric GH to oligomeric forms. We conclude that in vitro predictions about binding of GH to BPs in human plasma are representative of in vivo conditions. Shortly after a GH pulse, almost half of plasma GH circulates in complexed form, primarily bound to the high affinity (receptor-related) BP. Aggregation of GH in plasma does not occur (at least within a 15-min period), suggesting that the pituitary is the predominant, if not sole, source of circulating GH oligomers.

Carrier Proteins↗
PubMed1990

Growth-hormone-releasing hormone.

Growth-hormone-releasing hormone (GHRH, somatoliberin) is the hypothalamic peptide hormone that specifically stimulates synthesis and release of growth hormone (GH, somatotropin) by somatotrope cells of the anterior pituitary gland. GHRH is the last of the classically postulated hypothalamic hormones to be characterized, synthesized, and used in clinical medicine. In this review of GHRH, I discuss the discovery and characterization of the peptide, its role in the regulation of GH secretion, and its clinical use in pathological states of GH excess and GH deficiency. The two most clinically useful aspects of GHRH are to establish the etiology of GH deficiency, most commonly the result of a hypothalamic GHRH deficiency, and to treat GH-deficient children. Use of GHRH as therapy for GH deficiency currently is experimental and, to date, results encourage the idea of a therapeutic role for this peptide in promoting endogenous GH secretion with resulting acceleration of linear growth.

Child↗
PubMed1989

Lack of in vivo somatotroph desensitization or depletion after 14 days of continuous growth hormone (GH)-releasing hormone administration in normal men and a GH-deficient boy.

In vitro and in vivo studies of somatotroph responsivity to GHRH stimulation indicate that partial loss of GH responsiveness occurs during constant GHRH stimulation. To determine if these observations reflect either a short term effect of GHRH or if the absence of somatostatin effects somatotroph desensitization (as occurred in in vitro studies), we administered GHRH-40 (10 ng/kg.min) by continuous iv infusion for 14 days to five normal men and one GH-deficient boy. Serum insulin-like growth factor I (IGF-I) concentrations were measured at frequent intervals to assess the biological effect of GHRH on GH secretion. The GH secretory profiles were assessed by measuring serum GH levels every 20 min for 24 h before (day 0), on the 14th GHRH infusion day, and 14 days after discontinuation of the GHRH infusion in the normal men. The GH-deficient boy was studied before and during the 14th GHRH infusion day. A supramaximal iv GHRH dose was administered at the end of the 24-h sampling period, and the GH responses were compared. Serum IGF-I concentrations increased on the 14th day of GHRH infusion in the normal men [day 0 mean, 0.84 +/- 0.14 (+/- SE) X 10(3); day 14, 1.74 +/- 0.20 X 10(3) U/L; P less than 0.05] and from 0.20 X 10(3) on day 0 to a maximum of 0.67 X 10(3) U/L on day 3 in the GH-deficient boy; they declined to pretreatment levels after discontinuation of GDRH. The mean integrated serum GH concentrations in the normal men were 1.44 +/- 0.10 micrograms/L.h on day 0 and 3.11 +/- 0.95 on day 14 of GHRH infusion. The integrated GH concentration in the GH-deficient boy was 1.53 micrograms/L.h on day 0 and 4.23 on day 14 of GHRH infusion. Pulsatile GH secretion, assessed by cluster analysis, was preserved in the normal men and occurred de novo in the GH-deficient boy on the 14th GHRH infusion day. The GH response to bolus GHRH administration was also preserved; no attenuation of the response occurred in the normal men or the GH-deficient boy after 14 days of GHRH infusion. The increase in IGF-I concentrations during 14 days of continuous GHRH administration, the persistence of pulsatile GH release in normal men, the de novo appearance of GH pulses in the GH-deficient boy, and the preservation of the response to a supramaximal GHRH dose indicates that the somatotrophs remain responsive to prolonged constant stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1989

CV 205-502 treatment of hyperprolactinemia.

CV 205-502 is a nonergot oral dopamine agonist with specific D2 activity, which has a prolonged suppressive effect on serum PRL and may have fewer side-effects than other dopamine agonists. We treated 26 hyperprolactinemic women with this compound given as a single bedtime (hs) dose for up to 12 weeks. All had gonadal dysfunction, either amenorrhea or oligomenorrhea, and 15 had galactorrhea. The initial and subsequent doses were administered in a randomized fashion; the initial dose ranged from 0.01-0.05 mg, and the dose at 12 weeks ranged from 0.03-0.09 mg. The women were evaluated every 2 weeks, and the dose was increased by 0.02 mg every 4 weeks if the serum PRL level was greater than 20 micrograms/L. Of the 26 women initially enrolled, 24 completed 12 weeks of therapy, and 2 discontinued therapy because of side-effects. Thirteen women (54%) had return of menses, and 12 (80%) had either a decrease in or disappearance of galactorrhea. Serum PRL concentrations decreased to a variable degree in all patients; 13 (54%) achieved a normal serum PRL level (less than or equal to 20 micrograms/L). The mean (+/- SE) pretreatment serum PRL concentration was 129 +/- 34, and it was 29.9 +/- 5.9 micrograms/L after 12 weeks of treatment (P = 0.005). The mean (+/- SE) percent reduction in serum PRL was 66.5 +/- 5.0% (median, 78.0%). A dose response was not demonstrated (r = -0.08; P = 0.70) among the 6 dose groups during the last 4 weeks of therapy. In 5 women, serum PRL levels, measured frequently for 24 h after treatment remained low. Side-effects after the initiation of therapy included nausea, headache, and morning fatigue in 10 women. These symptoms caused 2 women to discontinue therapy; they subsided in the other women. An optimal dose was not determined and will probably need to be determined by titration in each patient. CV 205-502, given once daily, appears to be a safe and effective alternative to other dopamine agonists in the treatment of hyperprolactinemia.

Amenorrhea↗
PubMed1989

Octreotide suppresses both growth hormone (GH) and GH-releasing hormone (GHRH) in acromegaly due to ectopic GHRH secretion.

Two patients with acromegaly secondary to ectopic GHRH secretion by metastatic carcinoid tumors were studied before and during therapy with the somatostatin analog octreotide (SMS 201-995). GH and GHRH secretory patterns were assessed during intermittent sc administration, continuous sc infusion (CSI), and continuous iv infusion of octreotide. Octreotide reduced serum GH and plasma GHRH levels in the two patients, although there was differential sensitivity of GH and GHRH. Intermittent sc therapy transiently lowered serum GH in both patients. A higher iv dose was required to reduce plasma GHRH by 50% than to reduce serum GH by 50% (2.0 vs. 0.05 micrograms/kg.h, respectively; patient 1). A similar pattern was found during CSI octreotide administration in the same patient. Chronic therapy with intermittent sc and CSI octreotide was assessed by serial 24-h profiles of GH and GHRH secretion in patient 2. Mean hourly serum GH levels decreased from a pretreatment level of 31.5 +/- 3.5 (+/- SE) to 9.5 +/- 1.5 micrograms/L during CSI therapy (1000 micrograms/day or 0.40 micrograms/kg.h). In contrast, plasma GHRH levels were less effectively suppressed. The mean serum GH levels and the variation in hourly GH values were reduced to a greater extent with CSI than with intermittent sc therapy. Serum insulin-like growth factor I also declined from 5.9 x 10(3) to 2.5 x 10(3) U/L during chronic CSI therapy (patient 2). CSI therapy with octreotide can be more effective than intermittent sc therapy in controlling GH excess in the rare syndrome of ectopic GHRH secretion, although serum GH may not decline to normal.

Acromegaly↗
PubMed1989

Half-time of endogenous growth hormone (GH) disappearance in normal man after stimulation of GH secretion by GH-releasing hormone and suppression with somatostatin.

The half-life (t1/2) of disappearance of endogenous GH from serum was studied using physiological effectors to stimulate and then suppress GH release. GH secretion was stimulated by a single iv injection of GHRH, followed 45 min later by an iv bolus dose and then a 2.5-h infusion of somatostatin (SRIH) to suppress further release. The in vivo t1/2 of GH in seven men was calculated from serum GH concentrations measured at frequent intervals after beginning the SRIH infusion. The mean t1/2 of endogenous GH was 18.9 +/- 0.8 (+/- SE) min by monoexponential analysis and 3.5 +/- 0.7 and 20.7 +/- 0.7 min by biexponential fitting. In these normal men, the decline in GH concentrations after GHRH and SRIH administration was similar to that after the administration of GHRH alone, which yielded a t1/2 of 20.3 +/- 1.9 min. We conclude that the physiological kinetics of endogenous GH removal/disappearance can be estimated in vivo in man using GHRH with or without SRIH infusion.

Adult↗
PubMed1989

Fasting alters pulsatile and rhythmic cortisol release in normal man.

The effect of a 5-day fast on integrated, pulsatile, and periodic cortisol release was studied in 10 normal men by measuring serum cortisol concentrations every 20 min for 24 h before (day 0) and during the fifth day of fasting (day 5). Serum concentration profiles were analyzed for integrated cortisol release (area under the curve), pulsatile hormone release by an objective, statistically based pulse detection algorithm (cluster analysis), and periodic hormone release (circadian and ultradian rhythms) by Fourier expansion time series analysis. Urinary cortisol excretion per 24 h was measured in 5 men. The mean 24-h integrated serum cortisol concentration increased 1.7-fold during fasting (P = 0.0006). This increase resulted from a 2-fold increase in the serum cortisol concentrations between pulses (valley mean; P = 0.0004), an increase in the pulse height (P = 0.001), and an increase in pulse increment above baseline (P = 0.01). There were no changes in the number of pulses per 24 h, the interval between pulses, the width of the pulses, or the area of the pulses during fasting. Twenty-four-hour urinary cortisol excretion increased in all men, and the mean urinary cortisol (nanomoles per L)/creatinine clearance (milliliters per s) ratio increased from 119 on day 0 to 187 on day 5 (n = 5; P = 0.05). The pattern of periodic hormone release also changed during fasting; the mean (+/- SE) circadian rhythm (24-h) amplitude decreased from 160 +/- 14 nmol/L on day 0 to 102 +/- 105 nmol/L on day 5 (P = 0.06), and the amplitude of the 12-h rhythm increased from 68 +/- 11 to 99 +/- 11 nmol/L. There also were significant increases in the amplitudes of rhythms with periodicities of 8.1, 4.1, 2.4, 1.6, and 1.3 h (P = 0.02-0.008). Fasting in normal men results in distinct changes in the amount and pattern of pulsatile, circadian, and ultradian cortisol release.

Adult↗
PubMed1989

Recurrent diabetes insipidus associated with pregnancy: pathophysiology and therapy.

Diabetes insipidus during pregnancy is an uncommon medical problem. We present a woman who developed transient central diabetes insipidus during two successive pregnancies. A water deprivation study with plasma arginine vasopressin concentrations confirmed the diagnosis and established the efficacy of 1-desamino-8-d-arginine-vasopressin (dDAVP). The patient was then successfully and safely treated through the second pregnancy with dDAVP.

Adult↗
PubMed1988

Transdermal testosterone treatment of hypogonadal men.

Hypogonadism, either primary or secondary, results in diminished libido and/or impotence. Conventional treatment consists of periodic intramuscular injections (usually bimonthly) of a depot testosterone preparation or daily oral ingestion of methyl testosterone. These conventional treatments may be associated with side effects, such as gynecomastia, liver function abnormalities and edema. A new method of administering testosterone is by daily application of a transdermal therapeutic system. We studied the efficacy and safety of the transdermal therapeutic system in 4 hypogonadal men. Three patients were treated for 12 weeks and 1 for 7 weeks, and they were evaluated weekly. Of 4 patients 3 had improvement in erectile and/or sexual function. Mean plasma testosterone levels increased significantly compared to pre-treatment values during 7 of 12 treatment weeks. There were no adverse effects of the transdermal therapeutic system as indicated by serial physical examinations, daily reports, blood chemistry studies, liver function tests, urinalysis and hematological profiles. This preliminary report of transdermal testosterone delivery indicates that it may provide an effective alternative method of gonadal steroid replacement.

Administration, Cutaneous↗