Testosterone supplementation in older men restrains insulin-like growth factor's dose-dependent feedback inhibition of pulsatile growth hormone secretion.

BACKGROUND: Pulsatile GH secretion declines in older men. The causal mechanisms are unknown. Candidates include deficient feedforward (stimulation) by endogenous secretagogues and excessive feedback (inhibition) by GH or IGF-I due to age and/or relative hypoandrogenemia. HYPOTHESIS: Testosterone (T) supplementation in healthy older men will restrain negative feedback by systemic concentrations of IGF-I. SUBJECTS: Twenty-four healthy men (ages, 50 to 75 yr; body mass index, 24 to 30 kg/m(2)) participated in the study. METHODS: We performed a prospectively randomized, double-blind, placebo-controlled assessment of the impact of pharmacological T supplementation on GH responses to randomly ordered separate-day injections of recombinant human IGF-I doses of 0, 1.0, 1.5, and 2.0 mg/m(2). ANALYSIS: Deconvolution and approximate entropy analyses of pulsatile, basal, and entropic (pattern-sensitive) modes of GH secretion were conducted. RESULTS: Recombinant human IGF-I injections 1) elevated mean and peak serum IGF-I concentrations dose-dependently (both P < 0.001); 2) suppressed pulsatile GH secretion (P = 0.003), burst mass (P = 0.025), burst number (P = 0.005), interpulse variability (P = 0.032), and basal GH secretion (P = 0.009); and 3) increased secretory pattern regularity (P = 0.020). T administration did not alter experimentally controlled IGF-I concentrations, but it elevated mean GH concentrations (P = 0.015) and stimulated pulsatile GH secretion (frequency P = 0.037, mass per burst P = 0.038). Compared with placebo, T attenuated exogenous IGF-I's inhibition of GH secretory-burst mass (P < 0.038) without restoring pulse number, basal secretion, or pattern regularity. CONCLUSION: The capability of systemic T to mute IGF-I feedback on pulsatile GH secretion suggests a novel mechanism for augmenting GH production.

Aromatase and 5alpha-reductase inhibition during an exogenous testosterone clamp unveils selective sex steroid modulation of somatostatin and growth hormone secretagogue actions in healthy older men.

BACKGROUND: How endogenous testosterone (Te), 5alpha-dihydrotestosterone (DHT), and estradiol (E(2)) regulate pulsatile GH secretion is not understood. HYPOTHESIS: Conversion of Te to androgenic (Te-->DHT) or estrogenic (Te-->E(2)) products directs GH secretion. SUBJECTS AND LOCATION: Healthy older men (N = 42, ages 50-79 yr) participated at an academic medical center. METHODS: We inhibited 5alpha-reduction with dutasteride and aromatization with anastrozole during a pharmacological Te clamp and infused somatostatin (SS), GHRH, GH-releasing peptide-2 (GHRP-2), and L-arginine/GHRH/GHRP-2 (triple stimulus) to modulate GH secretion. ENDPOINTS: Deconvolution-estimated basal and pulsatile GH secretion was assessed. RESULTS: Administration of Te/placebo elevated Te by 2.8-fold, DHT by 2.6-fold, and E(2) concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E(2) by 89 and 86%, respectively. Stepwise forward-selection regression analysis revealed that 1) Te positively determines mean (P = 0.017) and peak (P < 0.001) GH concentrations, basal GH secretion (P = 0.015), and pulsatile GH secretion stimulated by GHRP-2 (P < 0.001); 2) Te and E(2) jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E(2), P = 0.031); and 3) DHT correlates positively with pulsatile GH secretion during SS infusion (P = 0.011). These effects persisted when abdominal visceral fat was included in the regression. CONCLUSION: The present outcomes suggest a tetrapartite model of GH regulation in men, in which systemic concentrations of Te, DHT, and E(2) along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.

Estradiol supplementation in postmenopausal women attenuates suppression of pulsatile growth hormone secretion by recombinant human insulin-like growth factor type I.

BACKGROUND: Why pulsatile GH secretion declines in estrogen-deficient postmenopausal individuals remains unknown. One possibility is that estrogen not only enhances stimulation by secretagogues but also attenuates negative feedback by systemic IGF-I. SITE: The study took place at an academic medical center. SUBJECTS: Subjects were healthy postmenopausal women (n=25). METHODS: The study included randomized assignment to estradiol (n=13) or placebo (n=12) administration for 16 d and randomly ordered administration of 0, 1.0, 1.5, and 2.0 mg/m2 recombinant human IGF-I sc on separate days fasting. ANALYSIS: Deconvolution analysis of pulsatile and basal GH secretion and approximate entropy (pattern-regularity) analysis were done to quantify feedback effects of IGF-I. OUTCOMES: Recombinant human IGF-I injections increased mean and peak serum IGF-I concentrations dose dependently (P<0.001) and suppressed mean GH concentrations (P<0.001), pulsatile GH secretion (P=0.001), and approximate entropy (P<0.001). Decreased GH secretion was due to reduced secretory-burst mass (P=0.005) and frequency (P<0.001) but not basal GH release (P=0.52). Estradiol supplementation lowered endogenous, but did not alter infused, IGF-I concentrations while elevating mean GH concentrations (P=0.012) and stimulating pulsatile (P=0.008) and basal (P<0.001) GH secretion. Estrogen attenuated IGF-I's inhibition of pulsatile GH secretion (P=0.042) but was unable to restore physiological GH pulse frequency or normalize approximate entropy. CONCLUSION: Short-term estrogen replacement in postmenopausal women selectively mutes IGF-I-mediated feedback on pulsatile GH secretion. Disinhibition of negative feedback thus confers a novel mechanism by which estrogen may obviate hyposomatotropism.

Gonadal status and body mass index jointly determine growth hormone (GH)-releasing hormone/GH-releasing peptide synergy in healthy men.

CONTEXT: Sex steroid hormones potentiate whereas increased body mass index (BMI) represses GH secretion. Whether sex steroids modify the negative effect of BMI on secretagogue-induced GH secretion in men is not known. The issue is important in designing GH-stimulation regimens that are relatively insensitive to both gonadal status and adiposity. OBJECTIVE: Our objective was to compare the relationships between BMI and peptide-stimulated GH secretion in men with normal and reduced testosterone and estradiol availability. SETTING: The study was performed at an academic medical center. SUBJECTS: Healthy young men were included in the study. INTERVENTIONS: Randomized separate-day iv infusion of saline and/or maximally effective doses of L-arginine/GHRH, L-arginine/GH-releasing peptide (GHRP)-2, and GHRH/GHRP-2 in eugonadal (n=12) and experimentally hypogonadal (n=10) men was performed. OUTCOMES: Regression of paired secretagogue-induced GH responses on BMI was determined. RESULTS: In eugonadal men, peak GH concentrations correlated negatively with BMI. In particular, BMI accounted for only 38% of the response variability after L-arginine/GHRH (P=0.0165), but 62% after GHRH/GHRP-2 (P=0.0012) and 65% after L-arginine/GHRP-2 (P=0.00075). In contrast, in hypogonadal men, GH responses were uncorrelated with BMI. The negative effects of BMI on peak GH responses in eugonadal and hypogonadal states differed most markedly after stimulation with GHRH/GHRP-2 (P=0.0019). This contrast was corroborated using integrated GH responses (P=0.0007). CONCLUSIONS: Short-term experimental gonadal sex hormone depletion attenuates dual secretagogue-stimulated GH secretion in lean young men. The inhibitory effect of relative adiposity on GH secretion appears to predominate over that of acute sex steroid withdrawal.

Short-term testosterone supplementation does not activate GH and IGF-I production in postmenopausal women.

BACKGROUND: Testosterone (Te), oestradiol, GH and IGF-I concentrations fall in postmenopausal women. OBJECTIVE: To test the effect of increased Te availability on impoverished GH/IGF-I secretion in this context. DESIGN/PATIENTS: Placebo (Pl) and a low vs. high dose of Te were administered transdermally for 7 days to each of 15 healthy older women (ages 48-81 years) in a randomized, double-blind crossover design. MEASUREMENTS: Frequent blood sampling, GHRP-2 (Growth hormone releasing peptide-2) infusion, and deconvolution analysis were used to assess GH secretion. RESULTS: Graded Te supplementation increased serum Te concentrations (nmol/l) from 0.87 +/- 0.06 [Pl] to 5 +/- 1 [low] and 7.3 +/- 1.6 [high] (P < 0.001), but did not affect: (i) pulsatile GH secretion (microg/l/12 h; conversion factor: 1 microg/l = 0.33 mU/l), 29 +/- 7.2, 32 +/- 5.6 and 27 +/- 4.9; (ii) GH regularity (approximate entropy), 0.52 +/- 0.05, 0.57 +/- 0.05 and 0.56 +/- 0.05; (iii) IGF-I concentrations (microg/l; conversion factor: 1 microg/l = 0.131 nmol/l), 126 +/- 13, 135 +/- 15 and 141 +/- 13; (iv) IGFBP-3 (mg/l), 3.7 +/- 0.2, 3.6 +/- 0.1 and 3.7 +/- 0.2; (v) IGFBP-1 (microg/l), 41 +/- 2.3, 44 +/- 3.8 and 44 +/- 3.2; and (vi) the mass of GH secreted (microg/l/3 h) after GHRP-2 injection, 123 +/- 27, 146 +/- 32 and 147 +/- 38. CONCLUSION: Up to 8-fold elevation of Te concentrations for 1 week in postmenopausal women does not detectably amplify GH secretion or action, thus indicating that low androgen availability is not a proximate acute mediator of hyposomatotropism in postmenopausal individuals.

Complementary secretagogue pairs unmask prominent gender-related contrasts in mechanisms of growth hormone pulse renewal in young adults.

The present study examines the thesis that pulsatile GH secretion is controlled simultaneously by three principal signals; viz., GHRH, GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS). According to this ensemble notion, no single regulatory peptide acts alone or can be interpreted in isolation. Therefore, to investigate gender-specific control of pulsatile GH secretion, we designed dual-effector stimulation paradigms in eight young men and six women as follows: 1) L-arginine/GHRH (to clamp low SS and high GHRH input); 2) L-arginine/GHRP-2 (to clamp low SS and high GHRP drive); 3) GHRH/GHRP-2 (to clamp high GHRH and high GHRP feedforward); vs. 4) saline (unclamped). Statistical comparisons revealed that: 1) fasting pulsatile GH secretion was 7.6-fold higher in women than men (P < 0.001); 2) L-arginine/GHRH and L-arginine/GHRP-2 evoked, respectively, 4.6- and 2.2-fold greater burst-like GH release in women than men (P < 0.001 and P = 0.015); and 3) GHRH/GHRP-2 elicited comparable GH secretion by gender. In the combined cohorts, estradiol concentrations positively predicted responses to L-arginine/GHRP-2 (r2= 0.49, P = 0.005), whereas testosterone negatively predicted those to L-arginine/GHRH (r2= 0.56, P = 0.002). Based upon a simplified biomathematical model of three-peptide control, the current outcomes suggest that women maintain greater GHRH potency, GHRP efficacy, and opposing SS outflow than men. This inference upholds recent clinical precedence and yields valid predictions of sex differences in self-renewable GH pulsatility.

Optic neuropathy of Graves disease: results of transantral orbital decompression and long-term follow-up in 215 patients.

PURPOSE: To review demographic characteristics, clinical features, and long-term outcomes of patients with optic neuropathy of Graves disease after transantral orbital decompression. DESIGN: Retrospective analysis of noncomparative interventional case series; long-term follow-up by questionnaire. METHODS: Medical record data (preoperative and postoperative assessments) were collected from patients who had transantral orbital decompression to treat Graves optic neuropathy. Responses to two follow-up questionnaires concerning patient satisfaction were evaluated. Statistical analysis (reflected as P values) compared preoperative and early postoperative (< or =182 days) data. RESULTS: Between November 1969 and May 1989, 215 patients underwent transantral orbital decompression for Graves optic neuropathy. In 205 eyes with visual acuity of 20/40 or worse before decompression, visual acuity improved by 3 Snellen lines or more in 110 (54%) (P <.001). Of 291 eyes with visual field defects preoperatively, 120 (41%) had resolution, and 126 (43%) had improvement postoperatively (P <.001). Proptosis was reduced in 350 eyes by 4.4 +/- 2.3 mm (mean +/- SD) (P <.001). In 104 eyes, disk edema resolved in 72 (69%) and improved in 28 (27%). Responses to questionnaires mailed in 1990 and 2000 showed that 76% and 88% of respondents, respectively, were subjectively satisfied with the results of orbital decompression. CONCLUSIONS: Transantral orbital decompression appeared to be effective in treating optic neuropathy of Graves disease. Patient satisfaction was high at 10-year and 20-year follow-up.

Learning the thyroid examination--a multimodality intervention for internal medicine residents.

BACKGROUND: Many physicians have inadequate physical diagnosis skills and cannot detect thyroid abnormalities on physical examination. PURPOSE: To evaluate a multimodality intervention to improve thyroid examination skills using a prospective controlled trial in first-year residents enrolled in an academic internal medicine program. METHODS: The intervention group received a 60-minute educational session during which an endocrinologist described anatomical landmarks, thyroid abnormalities, and examination techniques using a slide show, computerized animation, videotape, and live demonstration on a volunteer with goiter. Residents examined a normal and a goitrous thyroid under the observation of a preceptor and received an evidence-based handout on the thyroid examination. The control group received no specific intervention. Examination technique and identification of thyroid abnormalities were blindly assessed in 2 stations of an objective structured clinical examination (OSCE). RESULTS: Of the 19 residents in the intervention group and the 20 in the control group, 6 (32%) and 3 (15%), respectively, observed the neck for thyroid abnormalities (P = 0.3), 17 (90%) and 16 (80%) used proper hand position (P = 0.7), and 13 (68%) and 15 (75%) had the patient swallow while the neck was palpated (P = 0.7). There was a significant difference in the mean scores based on thyroid physical findings during the OSCE between the intervention and control groups (100 vs. 52.5 [maximal possible score = 200], P = 0.047). CONCLUSION: A 1-hour multimodality learning session furthered the ability of first-year internal medicine residents to detect thyroid abnormalities.