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G D Case

Publications and source records attributed to G D Case.

17 recordsLinked to original sources
PubMed1988

Effects of changing gonadotrophin-releasing hormone pulse frequency on gonadotrophin secretion in men.

To investigate the effects of alterations in GnRH pulse frequency on gonadotrophin secretion, we administered low dose GnRH pulses (25 ng/kg) at hourly or 2-hourly frequencies to eight normal men. All subjects received GnRH pulses i.v. every 2 h for 88 h. Following this, exogenous GnRH was discontinued in four normal men (Group A, GnRH withdrawal), and the frequency of GnRH injections was increased to one pulse every hour for 24 h in the other four normal men (Group B, hourly GnRH). Blood samples were obtained every 20 min for LH and FSH and every 12 h for testosterone (T) and oestradiol (E2). Plasma LH increased in all subjects during injection of GnRH pulses every 2h. Withdrawal of GnRH pulses in Group A men was accompanied by a fall in mean LH, reductions in LH pulse amplitude (means +/- SEM: control 6.5 +/- 1.0; GnRH withdrawal 4.0 +/- 0.5 mIU/ml) and pulse frequency (control 5.5 +/- 0.2; GnRH withdrawal 3.5 +/- 0.7 pulses/12 h), and an increase in plasma E2 (control 122 +/- 15; GnRH withdrawal 340 +/- 37 pmol/l). Gonadotrophin responses to GnRH (25 ng/kg) were normal when tested 32 h after GnRH withdrawal. Injection of hourly GnRH pulses in Group B men was accompanied by a time-dependent change in mean LH, which transiently rose, then fell, and subsequently rose to a plateau during the second 12 h period of hourly GnRH. The final rise in LH was accompanied by an increase in LH frequency to 11.8 +/- 0.3 pulses/12 h. These data suggest that: (1) increases in gonadal steroids decrease LH secretion by reducing the amplitude and frequency of endogenous GnRH pulses; and (2) the normal adult male pituitary requires approximately 12 h to initiate a sustained increase in LH secretion in response to a doubling in GnRH pulse frequency.

Adult↗
PubMed1985

Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulation.

Hypothalamic amenorrhea (HA) is a clinical disorder of unknown etiology. The diagnosis is made by exclusion of known abnormalities of pituitary and ovarian function. To determine if abnormalities of GnRH secretion could account for the anovulation and amenorrhea, we measured plasma gonadotropins every 20 min for 10- to 24-h periods in 19 women with HA. Ovarian steroids and gonadotropin responses to an iv bolus dose of GnRH (25 ng/kg) were also measured. The results were compared to those obtained during the early follicular (EF) and late luteal (LL) phases of ovulatory cycles in normal women. Plasma estradiol was lower (mean +/- SE, 52 +/- 5 pg/ml) than either cycle stage in normal women. Mean plasma LH was lower than EF values and FSH was higher than LL values. The amplitude of LH pulses in HA was similar to that in normal women. LH pulse frequency was the same as that present during the LL, but lower than that during the EF (HA, 4.7 pulses/12 h; EF, 7.7 pulses/12 h; P less than 0.05). In addition to the similar frequency, the patterns of LH secretion in HA resembled that of LL in that the amplitude of LH pulses was highly variable and pulses occurred at irregular intervals. Consistent changes in diurnal gonadotropin secretion were not found, and LH secretion was greater at night in 9 studies and during the day in 5 studies. Repeat studies in three patients (5-13 months later) revealed that LH pulse frequency was variable, being unchanged in 1, increased in 1, and decreased in the third patient. Thus, LH pulse frequency and, by inference, GnRH pulse frequency are similar in HA to those in the normal luteal phase despite a different steroid milieu. GnRH pulse frequency increases from the luteal to the follicular phases of normal cycles and may be important in the initiation of ovarian follicular maturation. These data suggest that the absence of cyclical gonadotropin secretion and anovulation in HA result from a decreased frequency and irregular amplitude of GnRH secretion and consequent absence of ovarian follicular maturation.

Adolescent↗
PubMed1984

The effects of opiate antagonism on gonadotropin secretion in children and in women with hypothalamic amenorrhea.

The effects of opiate antagonism [naloxone infusion, 1 mg/(m2 X h)] on gonadotropin secretion were examined in four children (one female and three males: two late prepubertal and two pubertal; chronologic age, range 11.8-15.9 yr; bone age, range 8.5-13.5 yr) and in four women with hypothalamic amenorrhea (two at normal body weight and two at low body weight). Naloxone had no effect on daytime gonadotropin secretion in three children who were biologically the youngest in the group, two late prepubertal and one early pubertal [plasma luteinizing hormone (LH) means +/- SE: control day, 1.2 +/- 0.1; control night, 4.5 +/- 0.4; and naloxone day, 1.3 +/- 0.1 mIU/ml]. In contrast, opiate blockade produced a slight but discernible increase in plasma LH in the child whose hypothalamic-pituitary-gonadal axis was the most mature, a boy at mid-puberty. Naloxone produced a striking increase in plasma LH in the amenorrheic women at normal body weight (LH, means +/- SE: control day, 3.4 +/- 0.3; control night, 7.0 +/- 1.0; and naloxone day, 7.4 +/- 0.7 mIU/ml) as well as in those at low body weight (LH, means +/- SE: control day, 3.5 +/- 0.3; control night, 2.8 +/- 0.2; naloxone day, 4.9 +/- 0.4; and naloxone night, 6.7 +/- 0.5 mIU/ml). Antagonism of endogenous opiate activity increased LH pulse frequency in all four women.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Abnormal patterns of pulsatile luteinizing hormone secretion in women with hyperprolactinemia and amenorrhea: responses to bromocriptine.

Pulsatile gonadotropin secretion was examined in seven women with hyperprolactinemia and amenorrhea by obtaining blood samples every 20 min for 24 h. When plasma PRL had returned to normal and menses had resumed during bromocriptine treatment, five women were restudied in an identical manner during the early to midfollicular stage of their cycles. Gonadotropin responses to a small dose of synthetic GnRH (25 ng/kg, iv) were measured after the initial 24-h study in each patient. In addition, low dose pulses of GnRH (25 ng/kg) were administered iv every 2 h for 88 h to three hyperprolactinemic women, and LH and FSH responses were determined. Before treatment with bromocriptine, mean +/- SE plasma gonadotropin concentrations (LH, 5.8 +/- 0.2 mIU/ml; FSH, 4.4 +/- 0.1 mIU/ml) were comparable to values during the follicular phase of normal menstrual cycles. LH pulse frequency during the pretreatment study in the hyperprolactinemic women (mean +/- SE, 7.6 +/- 1.2 pulses/24 h) was significantly less than that found during the early follicular stage of normal cycles (days 3-5; mean, 15.4 +/- 1.1 pulses/24 h). Mean +/- SE LH pulse amplitude before bromocriptine was 5.2 +/- 0.6 mIU/ml. The pattern of pulsatile LH secretion was highly variable before treatment and was characterized by prolonged periods (6-11 h) of low plasma LH concentrations. LH responses to GnRH were normal or increased (mean maximum increment in LH, 38.5 +/- 15.9; range, 4.3-125.2 mIU/ml), and no evidence of intermittent pituitary refractoriness was found during prolonged (88-h) administration of GnRH pulses. Treatment with bromocriptine was associated with the resumption of menses, and no significant change in mean gonadotropin concentrations. LH pulse frequency was increased (mean +/- SE = 10.2 +/- 1.0 pulses/24 h) and LH pulse amplitude was decreased (mean, 3.9 +/- 0.2 mIU/ml) in four of five patients receiving bromocriptine. Moreover, the pattern of pulsatile LH secretion was more uniform during treatment. We conclude that pituitary responsiveness to GnRH is not impaired in women with hyperprolactinemia and amenorrhea, and that periods of low LH secretion in these women are due to intermittent reductions in GnRH secretion. These observations suggest that the abnormal patterns of pulsatile gonadotropin secretion, and by inference GnRH secretion, are important factors in the etiology of amenorrhea associated with hyperprolactinemia.

Adult↗
PubMed1983

Selective inhibition of follicle-stimulating hormone secretion by estradiol. Mechanism for modulation of gonadotropin responses to low dose pulses of gonadotropin-releasing hormone.

Prepubertal girls and gonadotropin-releasing hormone (GnRH)-deficient females secrete follicle-stimulating hormone (FSH) preferentially in response to intravenous GnRH. With continued pulsatile GnRH stimulation, FSH secretion is reduced when plasma estradiol (E2) is increasing. To delineate the mechanisms involved in these changing gonadotropin responses, e studied the effect of low dose (0.025 micrograms/kg) pulsatile injections of GnRH in females with varying degrees and/or duration of endogenous GnRH deficiency (idiopathic panhypopituitarism, PHP; isolated growth hormone deficiency, IGHD; isolated gonadotropin deficiency, IGD; and anorexia nervosa, AN; both at low body weight and after weight regain). In patients presumed to have the most severe GnRH deficiency (PHP), responses of both FSH and luteinizing hormone (LH) were small and delayed, and no increase in plasma estradiol occurred during the 5 d of GnRH injections. In patients previously exposed to prepubertal or adult levels of endogenous GnRH secretion (IGHD, IGD, AN at low body weight), a rapid initial FSH response occurred that subsequently declined when plasma estradiol rose to concentrations greater than 40-50 pg/ml. Prior therapy with estrogen (micronized estradiol, Estrace) abolished FSH responses but LH responses were only slightly impaired. The degree of FSH response was dependent upon the time of initiation of estrogen relative to the onset of GnRH injections. Administration of estrogen after the first GnRH injection inhibited gonadotropin responses, whereas later estrogen therapy (after 1 d of GnRH pulses) blunted the GnRH induced FSH secretion without significantly impairing the LH response. In weight-regained anorexic patients who had spontaneous pulsatile LH secretion and a mean basal plasma estradiol concentration of 53 +/- 15 pg/ml, administration of GnRH pulses did not change plasma LH and a minimal FSH response was seen. The data indicate that the pattern of gonadotropin responses to low dose GnRH injections depends upon the degree of previous exposure of the pituitary to endogenous GnRH. Furthermore, estradiol selectively inhibits FSH secretion by a direct action on the pituitary gland. This action of estradiol provides an explanation for the selective reduction in FSH responses to GnRH seen during pubertal maturation in girls and during the mid-follicular stage of the menstrual cycle.

Adolescent↗
PubMed1976

Intramitochondrial positions of cytochrome haem groups determined by dipolar interactions with paramagnetic cations.

E.p.r.(electron-paramagnetic-resonance) spectra of the ferricytochromes were studied in normal and 'nickel-plated' pigeon heart mitochondria and pigeon heart submitochondrial particles. NiCL2 added to either mitochondria or particles was bound completely to the membranes, but none was transported across the vesicles. Hence, any perturbations of the haem e.p.r. spectra by Ni(II) should occur only for those cytochromes in close proximity to the exterior surface. Whenever Ni(II) can approach to within 1 nm of cytochrome haem. the consequent acceleration of the haem e.p.r. relaxation kinetics should elicit dipolar line broadening. Relaxation acceleration should also increase the incident power level required to saturate the haem e.p.r. signal. In pigeon heart mitochondria, at least three e.p.r. resonances, attributable in part to cytochromes c1, bK and br, are observed at gz=3.3 resonance. In these submitochondrial particles, the peak at gz=3.5 is missing, and the resonance at gz=3.6 resolves into two components, neither of which is sensitive to added Ni(ii). Addition of free haemin (ferric, a paramagnetic anion) to intact mitochondria elicits the same e.p.r. signal changes as does a preparation of submitochondrial particles. Saturation curves for cytochrome oxidase obtained for e.p.r. spectra of the high-spin form (g = 6) and the low-spin form (gz=3.1) also reveal no effect of Ni(II) on the haem e.p.r. relaxation in either mitochondria or inverted submitochondrial particles. Further, Ni(II) fails to alter the spectra or saturation properties of cytochrome c in either mitochondria or submitochondrial particles therefrom. Only with a 50-fold molar excess of Ni(II) can one accelerate the e.p.r. relaxation of cytochrome c in aqueous solution, although other more subtle types of magnetic interactions may occur between the cytochrome and either Ni(II) or ferricyanide. Addition of haemin to mitochondria likewise failed to alter the e.p.r. characteristics of either cytochrome c or cytochrome oxidase. The present observations strongly suggest that cytochromes bK, br and c1 reside on the exterior surface of the inner mitochondrial membrane. On the other hand, we find no positive evidence for the location of cytochrome c or cytochrome oxidase haem groups within 1 nm of either membrane surface. Because of possible shielding effects from the protein moieties, however, we cannot unequivocally assign the location of the haem groups to the membrane interior. The present results are not inconsistent with the observations of other investigators who used different techniques. However, it is clear that any model of energy coupling in mitochondrial oxidative phosphorylation must account for the positioning of all the b-c cytochrome haem groups on the outside.

Animals↗
PubMed1976

Intramitochondrial positions of ubiquinone and iron-sulphur centres determined by dipolar interactions with paramagnetic ions.

E.p.r. (electron-paramagnetic-resonance) spectra of ubisemiquinone (QH) organic radicals and all of the known iron-sulphur centres were studied in normal and 'nickle-plated' pigeon heart mitochondria, submitochondrial particles and submitochondrial particles from which succinate dehydrogenase had been removed. Incubation of pigeon heart mitochondria, submitochondrial particles or succinate dehydrogenase-depleted submitochondrial particles with substrate in the presence of pure O2 results in the accumulation of Q-H. In mitochondria, the e.p.r. spectrum of Q-H is characterized by in-homogeneous line broadening. A heterogeneous population of semiquinones appears to be partly responsible for these effects in mitochondria. Additon of Ni(II) to mitochondria renders saturation of the Q-H resonance more difficult. On the other hand, the resonance in either submitochondrial particles or succinate dehydrogenase-depleted particles is narrower than the same spectrum in mitochondria, and saturates like a homogeneous line. The presence of Ni(II) in either of these preparations, further, has no effect on either the A-H spectrum or the saturation curve. Therefore QH appears to be situated on the exterior surface of the mitochondrion. Likewise, the e.p.r. spectra and saturation curves of iron-sulphur centre N-2 exhibit characteristics of inhomogeneous line broadening, not only in intact mitochondria but also in both submitochondrial particles and succinate dehydrogenase-depleted particles. Because of the small pool size of centre N-2, this effect is likely to arise from a spin interaction with some other component in the membrane. Ni(II) has no effect on the saturation in centre N-2 in mitochondria or submitochondrial particles, and only a marginal effect in the succinate dehydrogenase-depleted preparation. These results are indeterminate with respect to the position of centre N-2 in the membrane; but suggest that its distance from the succinate dehydrogenase binding site is on the order of 1 nm. All of the other ferredoxin-type iron-sulphur centres in both preparations were not affected by paramagnetic ions. Homogeneous e.p.r. spectra and saturation curves are observed for both of the HiPIP-type (high-potential iron-sulphur protein-type) iron-sulphur centres in mitochondrial centres S-3 and bc-3. Addition of No(II) to intact mitochondria results in a dipolar interaction with centre bc-3. No effect was observed on centre S-3 in either preparation. A comprehensive model is presented for the structure of the respiratory electron-transport system in mitochondria, based on e.p.r. relaxation studies in the present and the preceding paper. There is no direct evidence for transmembrane electron flow through any of the known energy-coupling sites in mitochondria, so that direct hydrogen atom transfer across the membrane (as a combination of H+ translocation coupled to electron flow) does not occur...

Animals↗
PubMed1976

Comparison of absorbable sutures in urinary bladder.

Experimental cystotomy wounds in dogs were closed with sutures of polyglactin-910, polyglycolic acid, and chromic catgut. Animals were sacrificed at intervals of five to thirty days, and wounds were examined grossly and microscopically. This study reconfirms the benignity of early tissue reaction to catgut and points out the similarity of tissue reaction to polyglycolic acid and polyglactin-910 suture in the urinary bladder, the reaction characterized by early separation and invasion of suture fibers by cellular infiltration.

Animals↗
PubMed1975

Magnetic resonance studies on the mitochondrial divalent cation carrier.

Measurements of water proton spin relaxation enhancements (epsilon) can be used to discriminate high-affinity binding of Mn-2+ or Gd-3+ to biological membranes, from low-affinity binding. In rat liver mitochondria, epsilon b values of approx. 11 are observed upon binding of Mn-2+ to the inner membrane, while internal or low-affinity binding remains invisible to this technique. Energy-driven Mn-2+ uptake by liver mitochondria results in the subsequent decay of epsilon. Comparison of epsilon with the initial velocity of Mn-2+ uptake in rat liver mitochondria reveals a linear correlation, which holds at all temperatures between 0 degrees C and 40 degrees C, regardless of the mitochondrial protein concentration. Consequently, enhancement appears to reflect the binding of Mn-2+ to the divalent cation pump. Binding of Mn-2+ to blowfly flight muscle also results in substantial epsilon, which is associated with the glycerol-1-phosphate dehydrogenase instead of divalent cation transport. Consequently, no decay in epsilon due to uptake occurs after Mn-2+ is bound. Lanthanide ions are also bound and transported by mitochondria. Addition of Gd-3+ to pigeon heart or rat liver mitochondria results in epsilon b approximately equal to 5-6, which decays with similar kinetics in both systems. The uptake velocity of Gd-3+ in rat liver mitochondria is about 1/6 the rate with which Mn-2+ is transported. Lanthanides also diminish epsilon due to the addition of Mn-2+, and greatly retard the Mn-2+ uptake kinetics. The presence of carbonylcyanide-p-trifluoromethoxyphenylhydrazone depresses epsilon upon addition of Mn-2+ or Gd-3+ and also uncouples energy-driven uptake. On the other hand, prolonged anaerobic incubation in the presence of antimycin and rotenone exhausts the mitochondria of their energy stores, blocks the uptake of Mn-2+, but does not affect epsilon significantly. Evidently, the uncoupler-induced disappearance of divalent cation binding sites is not the result of "de-energization". Measurements of epsilon at several NMR frequencies indicate a correlation time (tau b) for carrier-bound Mn-2+ in rat liver mitochondria between 20 ns and 4 ns as one varies the temperature between 10 degrees C and 30 degrees C. The 13 Kcal/mole activation energy for tau b suggests that the 11 ns time constant at room temperature represents the movement of the Mn-11-carrier comples. On the other hand, tau b is probably approx. 100 times too short to represent the rotational motion of a carrier protein. Apparently, Mn-2+ binds to a small arm of the carrier which moves independent

Animals↗