Barry B. Bercu

Reduced pulsatile growth hormone secretion in children after therapy for acute lymphoblastic leukemia.

Basal growth hormone levels were measured every 20 minutes over 24 hours in eight long-term survivors of acute lymphoblastic leukemia and in 13 age- and pubertal stage-matched normal children. Among the patients, the median total basal growth hormone output (AUC) was 43 units, compared with 341 units in the normal control group (P less than 0.001). In the patients, mean pulse amplitude (6.9 ng/ml) and frequency (4.6) over 24 hours also were reduced, compared with the control values (32 ng/ml and 8.5, P less than 0.001 and P less than 0.05, respectively). In addition, normal children secreted more GH at night (median AUC 280) than during the day (113, P less than 0.001). However, this diurnal pattern was absent in three of the patients studied. These data suggest that perturbations of spontaneous pulsatile GH secretion are common after standard therapy for ALL and may be a sensitive means of detecting therapy-related neuroendocrine damage. Blunting of spontaneous pulsatile GH secretion may contribute to the abnormalities in growth seen in children with ALL.

6 Growth hormone neurosecretory dysfunction

Summary The basis for understanding clinical disorders in the neuroregulation of GH secretion is derived from the complexity of the CNS—hypothalamic-pituitary axis. Studies in animals and humans demonstrate an anatomic, physiological and pharmacological evidence for neurosecretory control over GH secretion including neurohormones (GRH, somatostatin), neurotransmitters (dopaminergic, adrenergic, cholinergic, serotonergic, histaminergic, GABAergic), and neuropeptides (gut hormones, opioids, CRH, TRH, etc). The observation of a defect in the neuroregulatory control of GH secretion in CNS-irradiated humans and animals led to the hypothesis of a disorder in neurosecretion, GHND, as a cause for short stature. We speculate that in this heterogeneous group of children a disruption in the neurotransmitter-neurohormonal functional pathway could modify secretion ultimately expressed as poor growth velocity and short stature.

Fatigue, weight gain, lethargy and amenorrhea in breast cancer patients on chemotherapy: is subclinical hypothyroidism the culprit?

AbstractBackground. The purpose of this study was to prospectively observe the relative contribution of each viable mechanism such as hyperphagia, physical activity, body composition, steroid hormonal and thyroid function, fatigue scores on changes in body weight in breast cancer patients, receiving adjuvant chemotherapy. Methods. This was a prospective observational research design where 198 consecutive breast cancer patients receiving adjuvant chemotherapy were monitored from start to end and 6 months post-therapy on changes in anthropometics, fatigue, nutritional intake, physical activity, thyroid and steroid hormones. Results. We observed a weight gain over >5 lb in 22.2% of this patient population with a significant and progressive gain of 6.7 lb (P < 0.0001) at 6 months. Ninety four percent of all patients reported fatigue and 56% of patients reported lowered physical activity. A significant reduction in serum free and total estradiol (P < 0.0001) was observed indicative of reduction in ovarian function with 86% amenorrehic at the end of treatment. A significant reduction in mean serum triiodothyronine uptake levels (P < 0.05), in addition to a significant increase in TBG (P < 0.0001) from baseline to end of chemotherapy, was observed. In addition 20–25% of this patient group was already diagnosed with clinical hypothyroidism at diagnosis and treated. Changes in fatigue frequency and serum sex-hormone-binding globulin (SHBG) were variables significantly predictive of weight gain (P < 0.0001). Conclusions. Cytotoxic agents may influence thyroid function in breast cancer patients contributing to and progressively worsening symptoms such as weight gain, amenorrhea, fatigue and lowered physical activity in this population. The present study indicates the value of screening breast cancer patients for thyroid function at diagnosis or pre-treatment.

Long-Term Surveillance of Growth Hormone Therapy

Oregon Health & Science University (R.G.R.), Portland, Oregon 97239; University of California-Los Angeles (P.Co.), Los Angeles, California 90095; St. Jude Children’s Research Hospital (L.L.R.), Memphis, Tennessee 38105; University of South Florida College of Medicine (B.B.B.), Tampa, Florida 33612; The University of Manchester (P.Cl.), Manchester M13 9PL, United Kingdom; Stanford University (A.R.H.), Stanford, California 94305; Johns Hopkins Medical Institutions (S.R.), Baltimore, Maryland 21287; Montefiore Medical Center (P.S.), Bronx, New York 10467; Saint Bartholomew’s and the Royal London School of Medicine and Dentistry (M.O.S.), London E1 2AD, United Kingdom; and Leiden University Medical Center (J.M.W.), 2333 ZA Leiden, The Netherlands

Robust Growth Hormone (GH) secretion in aged female rats co-administered GH-releasing hexapeptide (GHRP-6) and GH-releasing hormone (GHRH)

Aging is associated with a blunted growth hormone (GH) secretory response to GH-releasing hormone (GHRH), in vivo. The objective of the present study was to assess the effects of aging on the GH secretory response to GH-releasing hexapeptide (GHRP-6), a synthetic GH secretagogue. GHRP-6 (30 micrograms/kg) was administered alone or in combination with GHRH (2 micrograms/kg) to anesthetized female Fischer 344 rats, 3 or 19 months of age. The peptides were co-administered to determine the effect of aging upon the potentiating effect of GHRP-6 on GHRH activity. The increase in plasma GH as a function of time following administration of GHRP-6 was lower (p less than 0.001) in old rats than in young rats; whereas the increase in plasma GH secretion as a function of time following co-administration of GHRP-6 and GHRH was higher (p less than 0.001) in old rats than in young rats (mean Cmax = 8539 +/- 790.6 micrograms/l vs. 2970 +/- 866 micrograms/l, respectively; p less than 0.01). Since pituitary GH concentrations in old rats were lower than in young rats (257.0 +/- 59.8 micrograms/mg wet wt. vs. 639.7 +/- 149.2 micrograms/mg wet wt., respectively; p less than 0.03), the results suggested that GH functional reserve in old female rats was not linked to pituitary GH concentration. The differential responses of old rats to individually administered and co-administered GHRP-6 are important because they demonstrate that robust and immediate GH secretion can occur in old rats that are appropriately stimulated. The data further suggest that the cellular processes subserving GH secretion are intact in old rats, and that age-related decrements in GH secretion result from inadequate stimulation, rather than to maladaptive changes in the mechanism of GH release.

Inhibition of Müllerian Inhibiting Substance Secretion by FSH

Summary: To evaluate the role of gonadotropins in the control of Müllerian Inhibiting Substance (MIS) secretion, pregnant rats were injected with rabbit antiserum against luteinizing hormone releasing hormone (LHRH), and their pups replaced with follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG). The LHRH antiserum (LHRH-AS) was given at 13 and 20 days of gestation. Control dams were injected with an equal volume of normal rabbit serum. The male pups from mothers treated with LHRH antiserum were given 5 daily s.c. injections of the FSH, hCG, or vehicle. The male pups from mothers treated with normal rabbit serum were given vehicle s.c. Testicular fragments of 6 day old pups born to mothers treated with LHRH antiserum during pregnancy showed an increase relative to controls in MIS activity in a graded organ culture bioassay system (grade 3.4 ± 0.3 vs. 2.3 ± 0.2) (P < 0.01). FSH given to pups from mothers treated with LHRH antiserum reduced testicular MIS secretion compared to vehicle treated pups from the same mothers (grade 2.3 ± 0.2 vs. 3.4 ± 0.3) (P < 0.01). Thus, postnatal injections of FSH after immunologic blockade of gonadotropins in utero reduced MIS activity of the testes to the same level found in testes of 6 day control pups (grade 2.3 ± 0.2 vs. 2.3 ± 0.2). In contrast, MIS activity remained high despite postnatal hCG injection in pups born to mothers given LHRH-AS (grade 3.4 ± 0.4 vs. 3.4 ± 0.3). These studies suggest that secretion of MIS is dependent on normal hypothalamic secretion of LHRH and may be inhibited by FSH.Speculation: FSH inhibits MIS secretion.

Lymphocyte Recovery After Breast Cancer Treatment and Mindfulness-Based Stress Reduction (MBSR) Therapy

Objectives: This randomized controlled trial was conducted to examine immune recovery following breast cancer (BC) therapy and evaluate the effect of mindfulness-based stress reduction therapy (MBSR) on immune recovery with emphasis on lymphocyte subsets, T cell activation, and production of T-helper 1 (Th1; interferon [IFN]-γ) and T-helper 2 (Th2; interleukin-4 [IL-4]) cytokines. Method: Participants who completed the study consisted of 82 patients diagnosed with Stage 0–III BC, who received lumpectomy and adjuvant radiation ± chemotherapy. Patients were randomized into an MBSR(BC) intervention program or a control (usual care) group. Immune cell measures were assessed at baseline and within 2 weeks after the 6-week intervention. The numbers and percentages of lymphocyte subsets, activated T cells, and Th1 and Th2 cells in peripheral blood samples were determined by immunostaining and flow cytometry. Results: Immune subset recovery after cancer treatment showed positive associations with time since treatment completion. The B and natural killer (NK) cells were more susceptible than T cells in being suppressed by cancer treatment. Women who received MBSR(BC) had T cells more readily activated by the mitogen phytohemagglutinin (PHA) and an increase in the Th1/Th2 ratio. Activation was also higher for the MBSR(BC) group if <12 weeks from the end of treatment and women in MBSR(BC) <12 weeks had higher T cell count for CD4+. Conclusion: MBSR(BC) promotes a more rapid recovery of functional T cells capable of being activated by a mitogen with the Th1 phenotype, whereas substantial recovery of B and NK cells after completion of cancer treatment appears to occur independent of stress-reducing interventions.

The effects of high altitude on hypothalamic‐pituitary secretory dynamics in men

OBJECTIVE Individuals adapted to high altitude (HA) have abnormalities In endocrine function and specifically In the pituitary‐thyroid axis and aldosterone regulation. In this study we assessed hypothalamic‐pituitary function In men adapted to high altitude living using exogenous administration of synthetic hypothalamic hormones

Sexual Precocity: Etiology, Diagnosis and Management

In this volume, international experts assess the worldwide experience in treating precocious puberty and highlight major advances in research on the etiology of different forms of precocious puberty. The book features extensive reviews of the clinical data on treatment of gonadotropin-dependent precocious puberty with agonists of gonadotropin-releasing hormone. Other contributors describe effective therapies for two forms of precocious puberty that result from gonadotropin-independent mechanisms: McCune-Albright syndrome and familial male precocious puberty. Several investigators present new basic science research on the etiology of familial male precocious puberty, the molecular basis of the McCune-Albright syndrome, and the intragonadal signalling pathways that play a role in gonadotropin-independent forms of precocious puberty. The book also includes a commentary on psychosocial and ethical issues in the treatment of sexual precocity.

Hypothalamic-pituitary dysfunction in primary empty sella syndrome in childhood

In a series of 37 consecutive CT scans performed in children referred to our pediatric endocrine unit, an empty (eight) or partially empty (one) sella turcica was found in nine (24%) patients with short stature or delay in sexual maturation, precocious puberty, or hypoparathyroidism. The size and contour of the sella were abnormal in only three patients. Five of the nine children had evidence of decreased growth hormone secretion as determined by subnormal GH secretory responses to provocative tests (peak GH concentration less than 7 ng/ml) or assessment of endogenous 24-hour GH secretion (mean 24-hour GH concentration less than 3 ng/ml). Two children had multiple pituitary hormone deficiencies. Although primary empty sella syndrome was often associated with hypothalamic-pituitary dysfunction in this series, the prevalence of an empty sella in normal children is unknown. Further identification and evaluation of children with empty sella may provide new information regarding the cause of pituitary dysfunction in childhood.