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Biomedical subjects

D L Loriaux

Publications and source records attributed to D L Loriaux.

At least 127 records · Page 7Linked to original sources
PubMed1987

Dissociation of adrenarche and gonadarche in precocious puberty and in isolated hypogonadotropic hypogonadism.

Adrenarche is a developmental change of the adrenal gland that results in increased secretion of adrenal androgens. This maturational process generally begins several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche). To study further the relationship between adrenarche and gonadarche, we examined adrenarche in patients with precocious puberty and in patients with isolated hypogonadotropic hypogonadism. Plasma dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and cortisol were measured basally and during an infusion of ACTH in 50 children with precocious puberty, 5 patients with isolated hypogonadotropic hypogonadism, 7 preadrenarchal children with constitutional short stature, 44 normal pubertal children, and 40 normal adults. Children with precocious puberty did not have a corresponding advance in the timing of adrenarche. Their basal and ACTH-stimulated adrenal androgen levels were markedly lower than those of normal children matched for pubertal stage (P less than 0.05) and were only slightly greater than those reported for normal children of the same age. Similarly, patients with isolated hypogonadotropic hypogonadism and delayed puberty had no corresponding delay of adrenarche. Their adrenal androgen levels were appropriate for chronological age. Thus, these data provide further support for the hypothesis that adrenarche and gonadarche are independent maturational events controlled by separate mechanisms.

Adolescent↗
PubMed1987

Evidence for Leydig cell dysfunction in infertile men with a selective increase in plasma follicle-stimulating hormone.

Recent studies in acutely castrated males of several species have demonstrated that testosterone (T) alone, given in doses that produce normal plasma T levels, can maintain normal plasma FSH and LH levels. This suggests that a nonsteroidal factor from the seminiferous tubule is not required to regulate FSH release, and raises the possibility that Leydig cell function may not be fully normal in oligo- or azoospermic men with increased plasma FSH levels. To clarify this, we studied T production rates in 11 sexually mature, infertile, but otherwise healthy men who had increased plasma FSH and normal plasma LH, T, and estradiol levels and in 9 normal men. Although individual plasma T and LH levels in the infertile men were within the normal ranges, the mean plasma T level of the infertile men was significantly lower (P less than 0.002), and the mean plasma LH level was significantly higher (P less than 0.002) than values in the normal men. The infertile men also had significantly lower plasma free T concentrations (P less than 0.005), while sex hormone-binding globulin and estradiol levels were similar to those of the normal men. The production rate of T in the infertile men was half that in the normal men (P less than 0.001). We conclude that T production is significantly reduced in infertile men who have a selective increase in plasma FSH. Because of the known role of Leydig cell sex steroids in the negative feedback control of FSH, this finding may explain the elevated plasma FSH concentrations characteristic of men with germ cell loss without the need to postulate a deficiency of a separate seminiferous tubule factor.

Adolescent↗
PubMed1987

The effects of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide, a 5 alpha-reductase inhibitor and antiandrogen, on the development of baldness in the stumptail macaque.

We used a primate model of male-pattern baldness to test the efficacy of a topically applied 5 alpha-reductase inhibitor and antiandrogen (4-MA) in the prevention of baldness. Six periadolescent stumptail macaques were given daily topical applications of either 4-MA in dimethylsulfoxide or dimethylsulfoxide alone for 27 months. The three control monkeys developed varying degrees of baldness, while the three 4-MA-treated monkeys retained their juvenile pattern of hair growth. The percentage of actively growing hair follicles in the frontal scalp did not change in the 4-MA-treated group [46 +/- 6 (+/- SE) vs. 48 +/- 4], while a significant decrease occurred in the control group (63 +/- 6 vs. 25 +/- 12; P less than 0.025). Skin 5 alpha-reductase activity was reduced in the scalp of the 4-MA-treated monkeys. We conclude that topical 4-MA can prevent the development of baldness in the stumptail macaque, a primate model of androgen-dependent baldness.

Alopecia↗
PubMed1987

Dissociation between cortisol and adrenal androgen secretion in patients receiving alternate day prednisone therapy.

To evaluate the hypothesis that chronic, low dose, alternate day prednisone treatment may suppress adrenal androgen secretion without causing long term suppression of the hypothalamic-pituitary-adrenal axis we studied seven patients with systemic lupus erythematosus who had been taking low dose (5-20 mg), alternate day prednisone therapy for at least 1 yr. Basal and ovine CRH (oCRH)-stimulated plasma ACTH, cortisol, and adrenal androgen levels were measured 12 h (day on) and 36 h (day off) after the most recent dose of prednisone, and the results were compared to those in seven age- and sex-matched normal subjects. The patients' basal ACTH and cortisol levels did not differ significantly from those in the normal subjects on either the day on or the day off prednisone treatment. By contrast, their basal adrenal androgen levels were significantly decreased compared to those in normal subjects on both the day on and the day off prednisone (P less than 0.05). The patients' oCRH-stimulated ACTH and cortisol levels on the day off prednisone did not differ from normal levels, but were significantly blunted during the day on prednisone (P less than 0.05). In contrast, the patient's oCRH-stimulated adrenal androgen levels were significantly decreased during both the day off and the day on prednisone (P less than 0.05). These findings are consistent with the hypothesis that chronic alternate day prednisone therapy, at doses close to or below replacement, suppresses adrenal androgen levels without long term suppression of the hypothalamic-pituitary-adrenal axis. Based upon these findings, we postulate that an alternate day regimen of prednisone might maintain the benefits while reducing the risks of glucocorticoid therapy of adrenal hyperandrogenism.

Adrenal Glands↗
PubMed1987

The corticotropin-releasing hormone test in the postoperative evaluation of patients with cushing's syndrome.

After surgical cure of Cushing's syndrome most patients develop transient secondary adrenal insufficiency that lasts for approximately 1 yr. Since ACTH-secreting pituitary adenomas generally respond to ovine CRH (oCRH), we tested the hypothesis that an early postoperative response to oCRH may indicate the presence of residual pituitary tumor and, therefore, predict recurrence. We also assessed the usefulness of oCRH for monitoring the recovery of the hypothalamic-pituitary-adrenal axis and for clarifying the pathophysiology of this condition. Thirty-four patients cured of Cushing's syndrome (29 with Cushing's disease, 3 with adrenal adenomas, and 2 with the ectopic ACTH syndrome) had an evening oCRH test 1-2 weeks after surgery. Nine patients (6 with Cushing's disease, 2 with adrenal adenomas, and 1 with the ectopic ACTH syndrome) participated in a longitudinal evaluation and had repeated oCRH and 1-h ACTH tests at 2-month intervals for a year after surgery. Patients were considered to be cured on the basis of at least 3 subnormal urinary [less than 20 micrograms/24 h (less than 55 nmol/day)] or morning plasma cortisol levels [0600-0900 h; less than 6 micrograms/dL (less than 170 nmol/L)] in the first 2 weeks after surgery. The plasma ACTH and cortisol responses to oCRH in the early postoperative period were subnormal in 23 and normal in 6 patients with Cushing's disease. Three patients developed recurrent Cushing's disease (3, 3, and 23 months after transphenoidal surgery). All 3 were among the 6 who had a normal early postoperative response to oCRH. All of the 23 patients who had a subnormal response to oCRH in the early postoperative period have remained in remission for an average follow-up period of 14 months (6-42 months). Thus, the recurrence rate was significantly greater in patients with normal oCRH tests in the early postoperative period (P less than 0.001, by chi 2 analysis). Surgically cured patients with adrenal adenomas or ectopic ACTH secretion also had subnormal plasma ACTH and cortisol responses to oCRH during the early postoperative period. During longitudinal evaluation for 12 months after surgery, the ACTH and cortisol responses to oCRH increased progressively (regardless of the cause of Cushing's syndrome). Cortisol responses to oCRH correlated significantly with the cortisol responses to exogenous ACTH (r = 0.89; P less than 0.00001). We conclude that most patients with Cushing's syndrome have suppressed responses to oCRH during the early postoperative period.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1987

CT of cerebral abnormalities in precocious puberty.

True precocious puberty occurs as a result of the premature release of luteinizing hormone-releasing hormone from the hypothalamus, which stimulates the secretion of the pituitary gonadotropins, which in turn stimulate the gonadal sex steroids. The differential diagnosis of true precocious puberty includes cerebral and idiopathic categories. This differentiation, which cannot be made endocrinologically due to similarities in pituitary gonadotropin and sex steroid levels, may be facilitated by high-resolution CT. A CT study of 90 children (73 girls and 17 boys) with true precocious puberty was performed at the NIH to detect cerebral causes of their precocious puberty. Thirty-four cerebral abnormalities were demonstrated in 32 children, 16 boys and 16 girls. These included hypothalamic hamartomas (17), hypothalamic astrocytoma (one), optic chiasm lesions (six), ventricular abnormalities (eight), arachnoid cyst (one), and teratoma (one). The CT appearance of these cerebral abnormalities is discussed and related to the endocrinologic findings and natural history of true precocious puberty. A practical neuroradiologic approach to the evaluation of children with precocious puberty is presented.

Astrocytoma↗
PubMed1987

Hirsutism.

Excess body hair, or hirsutism, is usually only a problem in women and can cause considerable psychological distress. The disorder is usually androgen mediated. Because androgens come only from the adrenal glands or gonads or by conversion in peripheral tissues of precursor steroids from these organs, the causes of hirsutism are found in these two organs. Adrenal causes include Cushing's disease, adrenal tumors, and congenital adrenal hyperplasia. Ovarian causes include tumors, polycystic ovarian syndrome, and most cases of idiopathic hirsutism. The clinical evaluation is designed to differentiate between these diagnostic possibilities. When an underlying abnormality can be identified, such as an ovarian tumor, the treatment course is clear. When the diagnosis is idiopathic hirsutism, however, the best treatment is uncertain and several available regimens are possible.

Androgens↗
PubMed1987

Pharmacology of ovine and human CRH.

In primates, ovine and human CRH cause ACTH- and cortisol secretion in a dose-dependent fashion. Ovine CRH has a half-life, which is about three times longer than that of human CRH and results in long lasting ACTH- and cortisol responses. Plasma ACTH- and cortisol rises after administration of human CRH mimic the spontaneously occurring secretory episodes of these hormones in man. Pulsatile administration of human CRH restores the diurnal secretory pattern of ACTH and cortisol to normal in patients with apparent CRH deficiency. Facial and upper body flush occur in about 20% of patients receiving intravenously a 1 microgram/kg dose of CRH. Higher doses result in hypotension due to a decrease in peripheral vascular resistance. The latter is primarily due to dilatation of the superior mesenteric vessels. In in vitro models desensitization of the pituitary corticotroph by continuous, high-dose CRH administration occurs. No down-regulation of ACTH- and cortisol secretion has been shown in vivo, however. Pituitary-adrenal responsiveness to CRH can be modulated by many factors. These factors are involved in the basal regulation of the hypothalamic-pituitary-adrenal axis and in its activation during the stress response. Such factors include AVP, morphine, DAMME, and drugs modulating the endogenous serotoninergic and GABA/benzodiazepine system. Glucocorticoid feedback inhibition of the pituitary is one of the most important factors modulating ACTH- and cortisol responses to CRH. A negative correlation exists between the net ACTH- and cortisol response to exogenous CRH and the basal cortisol plasma concentration. Replacement doses of glucocorticoid result in a drastic decrease of basal plasma concentrations of cortisol and adrenal androgens.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1987

Corticotropin releasing hormone: relevance to normal physiology and to the pathophysiology and differential diagnosis of hypercortisolism and adrenal insufficiency.

CRH is a 41 amino acid peptide first isolated from ovine and subsequently from rat and human hypothalami. We have conducted a series of clinical studies with oCRH and hCRH in volunteers and patients with various disorders of hypothalamic-pituitary-adrenal function. In volunteers, it was demonstrated that hCRH administration produced ACTH and cortisol responses which closely mimic naturalistically occurring secretory episodes. This data, as well as the demonstration that pulsatile hCRH can reestablish normal ACTH and cortisol secretion in patients with hypothalamic CRH deficiency, strongly argue that CRH is of physiological relevance to the human pituitary-adrenal axis. However, since the ACTH response to an insulin tolerance test is greater than the maximal ACTH response to CRH, other factors such as vasopressin may be relevant to stress-induced ACTH secretion in man. Following the demonstration that CRH seems to be of physiological relevance to human subjects, a CRH stimulation test was developed based on pharmacokinetic and dose response studies with oCRH and hCRH. Based on these data, which revealed that oCRH functions as a long-acting analogue of hCRH, and the demonstration that hormonal responses to CRH are greatest in the evening, patient groups with abnormalities of the hypothalamic-pituitary-adrenal axis were tested with intravenous oCRH with a dose of 1 micrograms/kg given at 2000 hours. This CRH stimulation test has proved helpful in clarifying the pathophysiology of hypercortisolism in a variety of psychiatric disorders characterized by this endocrine abnormality. Thus, blunted ACTH responses in hypercortisolemic patients with depression, anorexia nervosa, and panic anxiety disorder indicate normality of the pituitary corticotroph in these patient subgroups. These data, along with the finding that a continuous infusion of CRH to normal volunteers, reproduces the pattern and magnitude of hypercortisolism in depression and anorexia nervosa, suggest that the hypercortisolism in these disorders represents a defect at or above the hypothalamus resulting in the hypersecretion of CRH. This hypothesis is particularly intriguing in light of the demonstration that CRH administration to experimental animals produces many of the physiological and behavioral responses classically associated with depression and anorexia nervosa, including hypercortisolism, hypothalamic hypogonadism, and decreases in libido and appetite. The CRH stimulation test has also helped to resolve one of the oldest endocrinological dilemmas, namely whether the hypercortisolism of depression and Cushing's disease share a common or dissimilar pathophysiological basis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Insufficiency↗
PubMed1987

Growth hormone-releasing hormone: therapeutic perspectives.

Growth hormone-releasing hormone (GHRH), the hypothalamic peptide which stimulates the release of growth hormone (GH) from the pituitary, has been the center of intense study since its structure was described in 1982. It is in the area of growth hormone deficiency (GHD) that GHRH has its greatest clinical potential. Several studies have addressed the efficacy of GHRH as an alternative therapy in GHD. It appears that GHRH can be equally effective, whether given in a pulsatile manner or as discrete injections several times a day; i.e. the total dose may be more crucial than how it is given. While there are several issues that must be addressed before an optimal GHRH regimen can be devised, the available data would suggest that GHRH may become a safe, effective alternative to GH therapy in some patients with GHD.

Child↗
PubMed1987

Recurrent anaphylaxis in menstruating women: treatment with a luteinizing hormone-releasing hormone agonist--a preliminary report.

Recurrent idiopathic anaphylaxis is an illness consisting of recurring anaphylactic or anaphylactoid attacks of unknown cause. A patient has been described whose attacks appeared to be associated with endogenous progesterone secretion and who was treated successfully with an analog of luteinizing hormone-releasing hormone (LHRH). This report summarizes the treatment of four additional women with recurrent anaphylaxis in a randomized, double-blind trial of an LHRH agonist and placebo. Two out of the four women experienced remission of their symptoms with the LHRH analog. The patients who responded to therapy had experienced systemic anaphylactoid reactions after provocation with an LHRH infusion and the intradermal injection of medroxyprogesterone; the nonresponders had no adverse reactions to either challenge. Ovarian suppression with LHRH agonist may benefit a subset of women with recurrent idiopathic anaphylaxis.

Adult↗
PubMed1987

Pharmacokinetic properties of the antiglucocorticoid and antiprogesterone steroid RU 486 in man.

RU 486 (17 beta-hydroxy-11 beta-[4-dimethylamino phenyl]-17 alpha-[1-propynyl]estra-4,9-dien-3-one) is a clinically useful glucocorticoid and progesterone antagonist. The authors studied the pharmacokinetic properties of this drug in normal volunteers and patients with Cushing's syndrome using a rat progesterone radioreceptor assay. This assay gave values similar to those obtained with a rat glucocorticoid radioreceptor assay. After a single oral dose of 25 mg/kg (n = 11) or 10 mg/kg (n = 11) to normal volunteers, plasma concentrations of progesterone receptor-reactive material reached maximal levels of 754 +/- 288 (mean +/- S.D.) and 517 +/- 183 micrograms/dl. This occurred at 3.1 +/- 1.9 and 2.5 +/- 1.0 h, respectively. The respective apparent plasma half-lives were 19.2 +/- 7.0 and 20.6 +/- 7.7 h. Four patients with Cushing's syndrome treated chronically (10-20 mg/kg/day) had relatively constant plasma levels of receptor reactivity ranging from 506 to 1184 micrograms/dl. Chromatographic characterization of circulating receptor reactivity showed that the active fraction corresponded to RU 486 and its hydrophilic N-mono- and N-didemethylated metabolites. Less than 0.5% of the daily dose was excreted in the urine of two of these patients as receptor reactivity. The drug bound extensively to circulating albumin, which competed with the glucocorticoid receptor of intact human mononuclear leukocytes for [3H]RU 486 in a concentration-dependent manner.

Adult↗
PubMed1987

Hormones, emotional dispositions, and aggressive attributes in young adolescents.

Relations among hormone levels, emotional dispositions, and aggressive attributes were examined in 56 boys and 52 girls, age 9 to 14 years. The adolescents represented all 5 stages of pubertal development. Serum levels of gonadotropins, gonadal steroids, adrenal androgens, and testosterone-estradiol binding globulin were assessed. Levels of these hormones were related to stage of pubertal development and were assumed to represent relatively stable biological characteristics. The emotional dispositions assessed were adolescent self-reported anger, nervousness, sadness, and impulse control. The aggressive attributes assessed were mother-reported acting out and aggressive behavior problems and rebellious and nasty characteristics. Hormone levels were related to emotional dispositions and aggressive attributes for boys but not for girls. For example, higher levels of androstenedione in boys were related to higher levels of acting-out behavior problems. Level of testosterone-estradiol binding globulin was negatively related to sad affect and acting out behavior.

Adolescent↗
PubMed1987

Differentiation of adrenal masses by magnetic resonance imaging.

Eighty-one adrenal masses in 68 patients were examined with magnetic resonance imaging (MRI). Masses included nonfunctioning adenomas (17), metastases (25), adrenocortical carcinomas (10), and pheochromocytomas (23). T1-weighted pulse sequences depicted the anatomy with a resolution comparable to that of computed tomography (CT). T2-weighted pulse sequences provided some histologic specificity separating nonfunctioning adenomas with low signal-intensity from metastases with intermediate signal-intensity and pheochromocytomas with high signal-intensity. Pheochromocytomas could always be distinguished from other adrenal masses. In 20% of the cases, metastases with low signal-intensity could not be distinguished from nonfunctioning adenomas.

Adenoma↗
PubMed1986

Production of monoclonal antibodies against human growth hormone releasing hormone and their use in an enzyme-linked immunosorbent assay (ELISA)

Two murine monoclonal antibodies (mAbs) specific for human growth hormone releasing hormone (GHRH-44-NH2) were produced from a fusion of spleen cells from a BALB/c mouse immunized with GHRH-conjugated BSA with SP 2/0 myeloma cells. The antibodies were of the IgG1 kappa, and IgG2b-kappa isotypes. The binding of both antibodies to GHRH-coated plates was inhibited by a 30-44 amino acid fragment but not by a 1-26 fragment. Thus, both antibodies are directed against the carboxy terminus of the peptide. Furthermore, both antibodies bind to the same epitope on the 30-44 amino acid portion since they cross-inhibit each other's binding to intact GHRH. Using these mAbs, a direct binding GHRH enzyme-linked immunosorbent assay (ELISA) was developed which had a least detectable dose of 30 pg. The availability of these antibodies and their use in ELISA methodology permits consistent and specific detection of GHRH in a non-isotope assay. They should prove of value in screening acromegalic patients for ectopic sources of GHRH secretion and in studies of ontogenic analysis of GHRH production.

Animals↗
PubMed1986

Treatment of precocious puberty in the McCune-Albright syndrome with the aromatase inhibitor testolactone.

The McCune-Albright syndrome is characterized by café au lait spots, fibrous dysplasia of bones, and sexual precocity. Girls with precocious puberty due to this syndrome have episodic increases in serum estrogen levels together with the formation of large ovarian cysts. The serum gonadotropin levels are typically suppressed, and the precocious puberty has not responded to treatment with long-acting analogues of luteinizing hormone-releasing hormone (LHRH). Encouraged by our initial success in a pilot study of one patient, we have now treated five girls with the McCune-Albright syndrome with the aromatase inhibitor testolactone, which blocks the synthesis of estrogens. Testolactone decreased the levels of circulating estradiol (P less than 0.05) and the ovarian volume (P less than 0.05), and there was a return to pretreatment levels after testolactone was stopped. During treatment, the peak responses of luteinizing hormone and follicle-stimulating hormone to stimulation by LHRH rose above suppressed pretreatment levels--significantly above pretreatment levels for follicle-stimulating hormone (P less than 0.02)--and then returned to pretreatment levels after testolactone was discontinued. Growth rates fell in three patients during treatment but could not be assessed in the other two because of bone deformities. The mean rate of bone maturation decreased and menses stopped in three of the four girls who were menstruating regularly. We conclude that testolactone is an effective treatment of precocious puberty in the McCune-Albright syndrome.

Aromatase Inhibitors↗
PubMed1986

Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications.

Primary depression can be associated with substantial hypercortisolism, thus prompting some researchers to suggest that depression shares pathophysiologic features with Cushing's disease. Clinically, depression can be difficult or impossible to distinguish from mild or early Cushing's disease that is associated with depressive features. The purpose of this study was to evaluate whether the pituitary-adrenal responses to ovine corticotropin-releasing hormone could help to clarify the mechanism of hypercortisolism in depression and in Cushing's disease and to assist in the differential diagnosis of these disorders. As compared with controls (n = 34), depressed patients (n = 30) had basal hypercortisolism (P less than 0.001) that was associated with attenuated plasma ACTH responses to ovine corticotropin-releasing hormone (P less than 0.001). This indicates that in patients with depression, the corticotroph cell in the pituitary responds appropriately to the negative feedback of high cortisol levels. In contrast, patients with Cushing's disease (n = 29) had plasma ACTH hyperresponsiveness to ovine corticotropin-releasing hormone (P less than 0.001), despite basal hypercortisolism (P less than 0.001), which indicates a gross impairment of the mechanism by which cortisol exerts negative feedback on the pituitary. Less than 25 percent of the patients with depression or Cushing's disease had peak ACTH responses that overlapped. We conclude that the pathophysiologic features of hypercortisolism in depression and Cushing's disease are distinct in each of the disorders and that the ovine corticotropin-releasing hormone stimulation test can be helpful in their differential diagnosis.

Adrenocorticotropic Hormone↗